Darrow DH. Diagnosis and Management of Infantile Hemangioma .En - Id

LAPORAN KLINIK Pedoman untuk Clinician di Rendering Pediatric Perawatan
Diagnosis dan Penatalaksanaan infantil

Hemangioma
David H. Darrow, MD, DDS, Arin K. Greene, MD, Anthony J. Mancini, MD, Amy J. Nopper, MD, BAGIAN dermatologi, BAGIAN ON THT - KEPALA
DAN LEHER BEDAH, dan BAGIAN ON BEDAH PLASTIK
abstrak hemangioma infantil (IHS) adalah tumor yang paling umum dari masa kanak-kanak. Tidak seperti tumor
lainnya, mereka memiliki kemampuan unik untuk rumit setelah proliferasi, yang sering menimbulkan
penyedia perawatan primer untuk menganggap mereka akan menyelesaikan tanpa intervensi atau
konsekuensi. Sayangnya, bagian dari IHS cepat mengembangkan komplikasi, mengakibatkan rasa sakit,
gangguan fungsional, atau dis permanen fi gurement. Akibatnya, dokter primer memiliki tugas menentukan
lesi memerlukan konsultasi awal dengan dokter spesialis. Meskipun beberapa ulasan baru-baru ini telah
diterbitkan, laporan klinis ini adalah fi pertama berdasarkan masukan dari individu yang mewakili banyak
spesialisasi yang terlibat dalam pengobatan IH. Tujuannya adalah untuk memperbarui masyarakat pediatrik
mengenai penemuan terbaru di IH patogenesis, pengobatan, dan asosiasi klinis dan untuk memberikan
dasar untuk pengambilan keputusan klinis dalam pengelolaan IH.
Dokumen ini merupakan hak cipta dan milik dari American Academy of Pediatrics dan
Dewan Direksi. Semua penulis memiliki fi dipimpin con fl ik laporan kepentingan dengan
American Academy of Pediatrics. setiap con fl ik telah diselesaikan melalui proses yang
disetujui oleh Dewan Direksi. The American Academy of Pediatrics telah tidak diminta
atau diterima keterlibatan komersial apapun dalam pengembangan isi dari publikasi ini.
TATA NAMA
laporan klinis dari American Academy of Pediatrics bene fi t dari keahlian dan sumber Nomenklatur dan klasifikasi fi kation tumor pembuluh darah dan malformasi telah berevolusi
daya penghubung internal dan (American Academy of Pediatrics) dan peninjau
dari deskripsi klinis ( “ strawberry tanda lahir, ”“ salmon Patch, ”“ hemangioma kavernosum, ” dan “ Port
eksternal. Namun, laporan klinis dari American Academy of Pediatrics mungkin tidak
kembali fl dll pandangan penghubung atau organisasi atau instansi pemerintah yang wine stain “) terminologi berdasarkan fitur selular mereka, sejarah alam, dan perilaku klinis.
mereka wakili.
Awalnya digambarkan oleh Mulliken dan Glowacki pada tahun 1982, yang diklasifikasikan
terbaru dan diterima secara luas fi kation anomali vaskular yang diadopsi oleh Masyarakat
Bimbingan dalam laporan ini tidak menunjukkan kursus eksklusif pengobatan atau
berfungsi sebagai standar perawatan medis. Variasi, dengan keadaan individu akun,
Internasional untuk Studi Vascular Anomali (Tabel 1). 1 Sistem ini mencakup hemangioma
mungkin tepat. infantil (IH) antara neoplasma vaskuler, yang lesi ditandai dengan proliferasi abnormal dari
Semua laporan klinis dari American Academy of Pediatrics secara otomatis berakhir 5
sel-sel endotel dan arsitektur pembuluh darah yang menyimpang. Sebaliknya, malformasi
tahun setelah publikasi kecuali reaf fi rmed, direvisi, atau pensiun pada atau sebelum vaskular adalah anomali struktural dan kesalahan bawaan morfogenesis pembuluh darah.
waktu itu.
www.pediatrics.org/cgi/doi/10.1542/peds.2015-2485
DOI: 10,1542 / peds.2015-2485
Pediatrics (Nomor ISSN: Print, 0031-4005; Online, 1098-4275). Meskipun IH adalah neoplasma yang paling umum, kelompok ini juga termasuk tumor seperti
Hak cipta © 2015 oleh American Academy of Pediatrics hemangioma bawaan, granuloma piogenik, angioma berumbai (TA), dan beberapa jenis
hemangioendothelioma. hemangioma bawaan secara biologis dan perilaku berbeda dari IH.
PENGUNGKAPAN KEUANGAN: Para penulis telah mengindikasikan bahwa mereka tidak memiliki fi hubungan
keuangan yang relevan untuk artikel ini untuk mengungkapkan. sebagai re fl tercermin dalam nama, hemangioma bawaan hadir dan sepenuhnya terbentuk
saat lahir; mereka tidak menunjukkan fase proliferasi postnatal
POTENSI KONFLIK KEPENTINGAN: Para penulis telah mengindikasikan bahwa mereka tidak memiliki potensi
con fl ik kepentingan untuk mengungkapkan.
download dari www.aappublications.org/news oleh tamu di April 9, 2019

DARI American Academy of Pediatrics Pediatri Volume 136, nomor 4, Oktober 2015
karakteristik IH. 2 varian adalah noninvoluting Ini adalah reaktif berkembang biak lesi vaskular dan dapat tumbuh perlahan-lahan selama bulan
bawaan hemangioma (nich), yang tetap stabil yang diklasi fi ed sebagai neoplasma vaskuler ke tahun, tumbuh dengan cepat, spontan mundur,
tanpa pertumbuhan atau involusi, 2,3 dan (Tabel 1). Lesi ini umum diperoleh pembuluh atau tetap aktif selama bertahun-tahun. 14 - 16 Tidak
berinvolusi dengan cepat hemangioma kongenital darah pada kulit dan selaput lendir terutama seperti KHE dan TA, IHS tidak berhubungan
(RICH), yang mengalami fase involusi cepat mempengaruhi bayi dan anak-anak dan sering dengan trombositopenia atau koagulopati.
dimulai pada fi tahun pertama kehidupan (Gambar salah didiagnosis sebagai IH. Sekitar 12% terjadi malformasi vaskular adalah lesi kongenital, tetapi
1). 4 RICHs, dalam beberapa kasus, telah dikaitkan pada masa bayi, dan 42% hadir selama fi rst 5 beberapa mungkin menjadi jelas secara klinis
dengan trombositopenia tetapi dengan lebih tahun hidup. 10 granuloma piogenik yang paling hanya di kemudian hari, mungkin karena ectasia
ringan dan lebih transient koagulopati daripada sering terletak di kepala dan leher, cepat progresif lambat yang dihasilkan dari intraluminal fl ow.
yang terlihat di fenomena Kasabach-Merritt (KMP; membesar ke ukuran rata-rata 6,5 mm, sering Mereka menunjukkan tingkat normal pergantian
lihat diskusi yang berikut); jarang, mereka dapat mengembangkan basis pedunkulata, dan, sel endotel sepanjang sejarah alam mereka, tetapi
dengan erosi, rentan terhadap pendarahan yang
dikaitkan dengan gagal jantung kongestif. 5,6 Beberapa berkembang sebagai pasien tumbuh. malformasi
dif fi kultus untuk mengontrol (Gambar 2). 10
RICHs menunjukkan involusi lengkap, dan adalah vaskular tidak rumit, dan pertumbuhan mereka
mungkin bahwa KAYA dan nich kebohongan di mungkin dalam fl dipengaruhi oleh trauma, infeksi,
ujung-ujung spektrum klinis yang sama. 7,8 Kedua dan perubahan hormonal. klasifikasi fi kation
subtipe dari hemangioma bawaan awalnya didasarkan pada jenis kapal dominan: kapiler atau
diyakini varian IH yang menunjukkan granuloma piogenik terlihat dengan frekuensi yang venulocapillary, vena, limfatik, arteri, atau
pertumbuhan prenatal sampai Utara et al 9 menunjukkanlebih tinggi dalam kulit yang mengandung campuran. 17 Seperti neoplasma vaskuler,
bahwa, tidak seperti IH, lesi tidak mengungkapkan malformasi kapiler. Dua neoplasma yang berbeda nomenklatur malformasi vaskular telah
transporter glukosa protein isoform 1 (GLUT1). lainnya jinak pembuluh darah, kaposiform menyebabkan kebingungan besar. Kapiler atau
granuloma piogenik, juga dikenal sebagai hemangioendothelioma (KHE) dan TA, telah venulocapillary malformasi telah memiliki banyak
hemangioma kapiler lobular, bukanlah piogenik bingung dengan IH. KHE menyajikan terutama sebutan alternatif, yang paling umum
atau granulomatosa. pada masa bayi tetapi dengan rentang usia jauh
lebih luas daripada IH, yang biasanya tampak
dalam fi bulan pertama kehidupan. KHE dianggap
sebagai neoplasma lokal agresif yang biasanya
muncul sebagai massa jaringan dalam, lembut.
Lesi ini telah dikaitkan dengan KMP, 11 sebuah
koagulopati konsumtif berpotensi mengancam
nyawa yang ditandai dengan perangkap platelet “ Port wine stain ” dan “ nevus
parah. Sebelum KHE digambarkan di awal fl ammeus. ” malformasi vena sering keliru
1990-an, KMP keliru diduga terjadi dalam untuk IH,
TABEL 1 klasifikasi fi kasi Cutaneous hubungan dengan IH. Histopatologi, KHE
Vascular Anomali 2014 menunjukkan di fi lembar infiltratif ramping, sel-sel
malformasi vaskular endotel yang melapisi GLUT1negative slitlike

malformasi vena limfatik malformasi kapiler kapiler. 12 TA adalah tumor pembuluh darah jinak
malformasi arteriovenosa malformasi dan fi stulae yang terjadi pada bayi, anak-anak, atau orang
Campuran (gabungan) malformasi
dewasa muda dan biasanya terletak pada leher
atau bagian atas dada. 13 Penampilan klinis mereka
tumor pembuluh darah adalah variabel dan termasuk eritematosa untuk
Jinak lembayung patch, plak, dan nodul. Histopatologi,
Infantil hemangioma (IH)
TA menunjukkan wellde fi jumbai ned kapiler pada
hemangioma kongenital (cepat berinvolusi
dermis yang kekurangan atypia selular atau
[KAYA]; non-berinvolusi [nich]) lobulated
hemangioma kapiler (LCH)
GLUT1 positif dan, seperti KHE, dikaitkan dengan
(Piogenik granuloma) * peningkatan pembuluh limfatik dan kecenderungan
berumbai angioma (TA) Lainnya untuk KMP. Kedua tumor berperilaku tak terduga
lokal agresif
Kaposiform hemangioendothelioma (KHE) Kaposi
sarcoma Lainnya
Ganas
angiosarcoma
Lainnya GAMBAR 1
Diadaptasi dari Masyarakat Internasional untuk Studi Vascular Anomali KAYA sepenuhnya terbentuk saat lahir (A) dan kemudian involutes,
2014, ref 1 (issva.org/classi fi kation). sebagian besar selama fi tahun pertama kehidupan. B, Lesi yang sama
* Reaktif berkembang biak vaskular lesi terlihat pada usia 8 bulan.

Pediatri Volume 136, nomor 4, Oktober 2015 e1061
diistilahkan “ hemangioma kavernosum ” tahun, terutama mendahului perbedaan antara bayi perempuan; Namun, data yang meskipun
dan “ hemangioma vena ” dalam literatur antara IH dan hemangioma bawaan. lebih tua menyarankan femaleto-laki rasio mulai dari
(Gambar 3A). malformasi limfatik, yang dibagi 3: 1 sampai 5: 1, penelitian yang lebih baru
lagi menjadi varietas microcystic dan “ hemangioma ” juga telah tidak tepat digunakan menunjukkan berbagai 1,4: 1 sampai 3: 1. 23,24 Perbedaan
macrocystic atas dasar ukuran kekosongan untuk menggambarkan, secara umum, varietas jenis kelamin tampaknya meningkat di antara
dominan, mungkin juga keliru untuk IH bila ada lainnya noninfantile hemangioma dan pembuluh anak-anak dengan sindrom PHACE ( P osterior cacat
perdarahan ke dalam vesikel pada permukaan darah malformasi. fossa,
kulit atau mukosa (Gambar 3B). Lesi ini secara
tradisional telah disebut sebagai H emangiomas, serebrovaskular
SEBUAH anomali rterial, C anomali ardiovascular
termasuk coarctation aorta, dan E anomali kamu),
“ higroma kistik ” atau Highlights dari Bagian ini di mana penelitian telah menemukan 9: 1 rasio
“ lymphangiomas, ” sebutan yang tidak akurat perempuan-ke-laki-laki. 25 Tidak ada de fi penjelasan
• Infantil hemangioma (IH) adalah
menganggap potensi proliferasi, sehingga definitif untuk perbedaan gender ini. Kebanyakan
terminologi yang diterima saat ini
semakin kebingungan diagnostik. penelitian melaporkan signi fi cantly insiden yang
untuk lesi yang menjadi fokus dari
laporan klinis ini. lebih tinggi pada bayi putih. 23,24,26 Atas dasar
Penggunaan berbagai nama untuk IH telah keberhasilan pengobatan IH menggunakan
• hemangioma bawaan secara
mengakibatkan kebingungan diagnostik besar.
biologis dan perilaku berbeda dari
Misalnya, istilah
IH.
“ hemangioma kapiler ” dan
• granuloma piogenik adalah reaktif
“ angioma kapiler ” telah digunakan untuk b- Terapi blocker, telah diusulkan bahwa bayi
berkembang biak lesi vaskular yang
merujuk ke sebuah IH yang terletak terutama di hitam mungkin menunjukkan beberapa bentuk “ endogen
diklasi fi ed sebagai neoplasma vaskuler
dermis dan cerah berwarna merah. Sebaliknya, beta blokade, ” dan ada data biologis molekuler
dan kadang-kadang dapat salah
sebutan untuk mendukung gagasan ini. 27
didiagnosis sebagai IH.
“ cekung ” atau “ vena ” telah tidak tepat
digunakan untuk de fi ne sebuah IH itu, karena
kedalaman di bawah dermis, bisa menanamkan • Lesi didiagnosis sebagai “ hemangioma
semburat biru pada permukaan kulit. Selain itu, kavernosum ” biasanya, pada Insiden IH meningkat pada bayi prematur, yang
malformasi vena dan limfatik dalam serta kenyataannya, dalam IHS atau mempengaruhi 22% sampai 30% dari bayi dengan
arteriovenous malformasi vena. berat kurang dari 1 kg. 24,28 Analisis multivariat telah
mengungkapkan bahwa berat badan lahir rendah
• Fenomena Kasabach-Merritt atau
malformasi telah salah didiagnosis sebagai IH KMP (a koagulopati konsumtif) tidak (BBLR) adalah penyumbang utama risiko ini; ada
mendalam. Akhirnya, berdasarkan prevalensi terkait dengan IH melainkan dengan peningkatan 25% dalam risiko mengembangkan IH
belaka, istilah “ hemangioma, ” tanpa deskripsi kata 2 neoplasma vaskuler lainnya, dengan setiap pengurangan 500-g berat lahir. 29 faktor
sifat “ kekanak-kanakan ” atau dengan deskriptor “ remaja, kaposiform hemangioendothelioma prenatal juga telah diteliti untuk peran mereka
” telah digunakan dalam referensi untuk IH bagi (KHE) dan angioma berumbai (TA). dalam IH. Studi berbeda mengenai peningkatan
banyak risiko yang dihasilkan dari chorionic villus sampling
ibu 24,30 atau amniosentesis, 30,31
EPIDEMIOLOGI dan setiap peningkatan risiko yang timbul

chorionic villus sampling tampaknya terbatas
Studi dari kejadian IH, termasuk studi prospektif
pada prosedur yang dilakukan transcervically. 31 Faktor-faktor
dan review menggabungkan 1 penelitian
prenatal lain yang mungkin termasuk usia yang
retrospektif dan 2 kohort cross sectional,
menunjukkan bahwa 4% sampai 5% dari bayi lebih tua ibu, kehamilan ganda kehamilan,
yang terpengaruh. 18,19 Studi lain menunjukkan plasenta previa, dan preeklampsia. 24 anomali
bahwa IH diamati dalam 1% hingga 3% bayi baru plasenta, seperti hematoma retroplasenta,
lahir 20,21 infark, dan komunikasi vaskular melebar, juga
telah dikaitkan dengan perkembangan IH. 32 Hal
GAMBAR 2 dan 2,6% menjadi 9,9% dari anak-anak, 22,23 tapi ini berteori bahwa benang merah
granuloma piogenik memiliki beberapa fitur klinis dan
kekurangan metodelogi mungkin memiliki di fl dipengaruhi
histologis mirip dengan IHS, tetapi mereka umumnya lebih
kecil, bertangkai, dan lebih mungkin untuk berdarah. ini fi Temuan. IHS lebih umum

e1062 DARI American Academy of Pediatrics
dalam asosiasi ini adalah hipoksia
plasenta. 32,33
Meskipun sering disarankan sebagai faktor

risiko, riwayat keluarga IH dilaporkan hanya
12% dari kasus 24;
Namun, keluarga pengelompokan telah
dilaporkan. 34,35 Asosiasi juga dilaporkan dengan
penggunaan ibu dari obat kesuburan, 36 penggunaan
eritropoietin, 37 tingkat pendidikan ibu, 36 presentasi
sungsang, 23 dan menjadi fi pertama lahir. 23
GAMBAR 3
A, The darah vena yang terkandung dalam malformasi vena menanamkan rona kebiruan yang dapat menyebabkan misdiagnosis sebagai IH yang
Highlights dari Bagian ini mendalam. B, Perdarahan ke dalam vesikel permukaan malformasi limfatik dapat menyebabkan misdiagnosis sebagai IH.
• Insiden pada populasi umum adalah

sekitar 5%.
vasculogenesis, atau pembentukan de novo Konsep ini dikembangkan dari penelitian yang
• Faktor risiko untuk IH termasuk menjadi pembuluh darah baru. 39,40 menunjukkan bahwa penanda molekuler
putih, menjadi perempuan, dan memiliki Teori ini didukung oleh penelitian yang karakteristik jaringan plasenta, termasuk GLUT1,
berat lahir rendah. menunjukkan angka peningkatan yang beredar antigen Lewis Y, merosin, Fc- g reseptor-IIb,
EPC dalam sampel darah dari anak-anak dengan indoleamin 2,3-deoxygenase, dan tipe III
IH. 41 bukti tambahan berasal dari studi di mana iodothyronine deiodinase, juga hadir di IHS. 3,9 bukti
• Asosiasi juga dilaporkan dengan usia
sel-sel induk multipoten berasal dari spesimen IH klinis untuk teori ini disarankan oleh mereka
yang lebih tua ibu, kehamilan ganda
(HemSCs) telah menunjukkan kemampuan untuk penelitian yang menunjukkan peningkatan
kehamilan, plasenta previa,
rekapitulasi IH manusia di immunode fi tikus efisien. 42 insiden IH dalam hubungan dengan chorionic
preeklamsia, penggunaan obat
villus sampling, plasenta previa, dan
kesuburan atau erythropoietin,
preeklampsia. 24,30,31
presentasi bokong, dan menjadi fi pertama
lahir. Ini HemSCs dan EPC darah tali berperilaku
serupa satu sama lain dalam beberapa uji in
vitro, menunjukkan bahwa beredar EPC bisa
menjadi asal dari sel endotel IH. 42 Konsep yang
Sebuah teori pemersatu menunjukkan bahwa IH
IHS berasal dari sirkulasi sel progenitor
hasil dari proliferasi menyimpang dan
multipoten bisa menjelaskan beberapa fitur diferensiasi dari endotelium hemogenic dengan
PATOGENESIS DAN HISTOPATOLOGI yang mereka berbagi dengan pembuluh darah fenotipe saraf puncak dan kapasitas untuk
plasenta, karena disregulasi EPC beredar juga endotel, hematopoetic, mesenchymal, dan
Patogenesis
telah terlibat dalam banyak ibu terkait dan diferensiasi neuronal. Ini adalah hipotesis
Patogenesis IH, meskipun studi intensif, belum kondisi komorbiditas janin (preeklampsia, bahwa sel-sel inti plasenta chorionic villus
sepenuhnya dijelaskan. Baris bukti mendukung retinopati prematuritas, dll) . HemSCs juga telah mesenchymal embolisasi bagi perkembangan
asal selular baik dari sel intrinsik endotel terbukti memiliki potensi adipogenic, 43 yang janin dan bahwa waktu embolisasi ini dalam
progenitor (EPC) atau angioblasts asal dapat menjelaskan kehadiran adiposit dicatat kaitannya dengan migrasi sel pial neural
plasenta, namun faktor intrinsik dan ekstrinsik
selama involusi. Stimulus untuk divisi dari EPC sepanjang rute somitic mereka menentukan
juga memberikan kontribusi pemikiran untuk
tidak diketahui, tetapi mungkin mutasi somatik morfologi IH (segmental vs lokal [focal], lihat
perkembangan mereka. 38
atau sinyal yang abnormal dari jaringan lokal. bagian berjudul “ Penampilan klinis “). 44
Teori asal plasenta menunjukkan bahwa sel-sel
progenitor janin timbul dari gangguan plasenta
Faktor intrinsik meliputi di fl pengaruh faktor selama kehamilan atau kelahiran.
angiogenik dan vaskulogenik dalam IH. Faktor
eksternal meliputi hipoksia jaringan dan Sitokin niche dalam IH, termasuk faktor
perkembangan fi gangguan lapangan. Teori EPC pertumbuhan endotel vaskular (VEGFs),
menyatakan bahwa IHS berkembang dari insulin-seperti faktor pertumbuhan, tumor
ekspansi klonal dari EPC yang beredar, sehingga necrosis factor - terkait apoptosis-inducing
ligand-osteoprotegerin (TRAIL-OPG)

jalur, dan sistem renin-angiotensin, kemudian adalah sensor penting hipoksia. 9 histopatologi
mengatur pertumbuhan IH dan responnya GLUT1 telah terbukti diregulasi di zona hipoksia
Terlalu proliferatif dan awal IHS involutif yang
terhadap terapi farmakologis. 44 penulis lain juga tumor mesenkim dan di tali pusat - berasal sel
baik terbatas, massa unencapsulated dengan
telah memeluk induk mesenchymal manusia dalam kondisi
merah-Totan permukaan potong. Kemudian lesi
hipoksia. 49,50 faktor Hypoxiainduced diproduksi
involutif yang fi brofatty dalam konsistensi dan
“ ceruk ” konsep, menunjukkan bahwa EPC beredar fi nd oleh sel endotel tampaknya memainkan peran
kurang de fi ned. Fitur histologis IH berubah
penting dalam lalu lintas fi cking sel progenitor
perjalanan mereka ke lokasi tertentu yang secara dramatis karena mereka melanjutkan
untuk jaringan iskemik. Faktor-faktor ini telah
memberikan kondisi yang menguntungkan untuk mengikuti pelatihan alami mereka presentasi
terbukti diregulasi dalam darah (VEGF-A,
pertumbuhan ke dalam jaringan placentalike. 44 Dalam neonatal, pertumbuhan yang cepat, dan involusi
MMP-9) dan di jaringan IH (sel stroma - berasal
jaringan seperti kulit dan hati, sel-sel progenitor berikutnya, membutuhkan interpretasi dalam
faktor 1 Sebuah, MMP-9, VEGF-A, dan
mungkin mengalami sinyal selular dan faktor jaringan konteks klinis yang tepat. 52 - 54 Tidak ada garis
hipoksia-inducible factor 1 Sebuah)
lokal diperlukan untuk merangsang perkembangan pemisah yang tajam antara proliferasi dan
mereka. Atas dasar proliferasi cepat dari sel endotel,

involusi, dan fitur involusi biasanya hidup
berdampingan dengan fitur proliferasi selama
sebelumnya
banyak proses. Awal IHS fase proliferasi terdiri
dari wellde fi ned, massa unencapsulated kapiler
dari anak-anak dengan berkembang biak IH. 41
dilapisi oleh sel endotel gemuk dikelilingi oleh
penyelidikan asal IH difokuskan pada Selain itu, telah ditunjukkan bahwa penggunaan
pericytes gemuk tertanam dalam membran
angiogenesis, yang tumbuhnya sel-sel endotel erythropoietin pada bayi prematur meningkatkan
basement multilaminated tanpa sel-sel otot
dari pembuluh darah yang ada. Studi semacam risiko mengembangkan IH. 37 Dengan demikian,
polos terkait (Gambar 4). Lesi pada tahap ini
telah menunjukkan peningkatan konsentrasi faktor iskemia jaringan mengakibatkan
mungkin setidaknya focally menyerupai
angiogenik di IH, seperti dasar fi faktor neovaskularisasi dari beredar EPC telah
diusulkan sebagai stimulus mengarah ke proliferations vaskular lainnya berkembang
pertumbuhan broblast (bFGF), VEGF-A, faktor
pengembangan dari IH. 41 Secara klinis, daerah pesat seperti granuloma piogenik awal. Kapiler
pertumbuhan seperti insulin, dan matriks
pucat atau darah menurun fl ow di kulit telah berkembang biak disusun dalam lobulus, yang
metaloprotease (MMP) 9 dalam lesi selama
dicatat mendahului perkembangan IH, lanjut dipisahkan oleh halus fi septae brous atau oleh
proliferasi. 45 Juga dalam fase ini, peneliti telah
mendukung hipotesis ini. 51 jaringan intervensi normal. Ini kapiler lesi,
mengidentifikasikan fi ed indoleamin
tergantung pada lokasi jaringan, berbaur
nondestructively dengan super fi otot rangka
2,3-deoxygenase, protein berpikir untuk

resmi fi bers, saraf perifer, kelenjar ludah, dan
memperlambat involusi IH dengan menghambat adiposit. sel endotel dan pericytes menunjukkan
sitotoksik respon T-limfosit. 46 inti bervariasi membesar dan sitoplasma jelas
Selama involusi, apoptosis sel endotel disertai berlimpah. biasanya con fi mitosis gured fi gures
dengan downregulation faktor angiogenik, relatif banyak (Gambar 1B); dan ekspresi luas
sedangkan inhibitor angiogenesis seperti penanda proliferasi sel, seperti Ki-67, con fi rm
Highlights dari Bagian ini
interferon b dan spidol pematangan sel seperti yang baik pericytes dan sel endotel secara aktif
adhesi antar molekul 1 diregulasi. 47 Ini juga • dapat berkembang baik dari sel membagi. Karena IHS fase proliferasi yang
telah menunjukkan bahwa berinvolusi IHS progenitor endotel intrinsik (EPC) tinggi fl lesi ow, meskipun biasanya tanpa signi fi tidak
pameran penurunan produksi oksida nitrat, atau dari angioblasts asal plasenta. bisa arteriovenous shunting, mereka sering
berisi diperbesar menguras urat dengan tebal,
• Pertumbuhan IH dipengaruhi oleh dinding asimetris.
intrinsik di fl uences, seperti faktor
sebuah potentiator dari jalur VEGF, yang diukur angiogenik dan vaskulogenik dalam IH,
dengan penurunan kadar oksida nitrat sintase dan oleh faktor-faktor eksternal seperti
endotel. 48 hipoksia jaringan dan perkembangan fi gangguan
lapangan.
Telah dihipotesiskan bahwa hipoksia memicu
respon vaskular pada bayi. Seperti dibahas di atas,
BBLR adalah signi fi faktor risiko tidak bisa untuk IH,
dan dalam rahim hipoksia merupakan penyebab • Sebuah teori pemersatu mengusulkan
umum dari BBLR. Tidak mengherankan, ada bukti bahwa beredar EPC bermigrasi ke lokasi di
pemasangan peran hipoksia dalam pengembangan mana kondisi yang menguntungkan untuk
IH. GLUT1, transporter glukosa fasilitatif digunakan pertumbuhan ke dalam jaringan
sebagai penanda untuk IH, placentalike. Berinvolusi IHS hadir tantangan diagnostik yang
berbeda. mitosis fi gures berkurang, dan badan-badan
apoptosis dan tiang

lapisan seluler. Epidermal atrofi dan mendasari fi jaringan
Highlights dari Bagian ini
parut fibrosa dapat hadir jika lesi ulserasi pada fase
proliferasi. arteri besar dan vena dimodelkan • Berkembang biak IHS baik
selama tinggi yang fl ow fase proliferasi tidak dibatasi dan kekurangan kapsul.
sepenuhnya mundur ketika tidur kapiler tetes
keluar dan dengan demikian sering hadir dalam • Berinvolusi IHS adalah fi brofatty dan
berinvolusi IH. Fenomena ini, dipasangkan dengan kurang de fi ned.
hilangnya aktivitas mitosis endotel, dapat
• GLUT1 adalah penanda immunochemical
menyebabkan diagnosis histologis keliru sebagai
umum digunakan untuk IH.
malformasi vaskular. Misdiagnosis biasanya dapat
dihindari dengan mempertimbangkan penampilan
GAMBAR 4
IH fase proliferasi. lobulus baik terbatas dari kapiler histologis secara keseluruhan dan riwayat klinis.
erat dikemas terdiri dari sel endotel gemuk dan Pada akhirnya, seperti dibahas di bawah, masalah
pericytes dipisahkan oleh elemen dermal stroma KLINIS, KOMPLIKASI, DAN ASOSIASI Fase
tersebut dapat diatasi dengan GLUT1
normal-muncul (hematoxylin dan eosin; Magni asli fi kation
immunoreaction, karena berinvolusi infantil IHS, Pertumbuhan
3 100; foto courtesy of Paula Utara, MD.)
tetapi tidak malformasi, akan menunjukkan GLUT1
immunopositivity di lesi-jenis kapiler residual. 9,56
IHS pameran siklus hidup yang khas.
pengamatan klinis telah menyarankan bahwa
setidaknya ada 2 tahap evolusi dinamis, yaitu,
sel peningkatan jumlah selama involusi awal. 48,55
proliferasi dan involusi. Proliferasi terjadi
kapiler lesi mulai menghilang. Tidak ada bukti
selama masa bayi awal; bertahap spontan
dari trombosis, dan di fl Radang tidak menonjol.
involusi atau regresi dimulai dengan usia 1
Sebagai hasil involusi, membran dasar lesi Pemeriksaan histologis, disertai dengan studi tahun. 58 - 65 Periode menengah antara proliferasi
kapiler menjadi tebal dan hyalinized dan imunohistokimia rutin, menunjukkan bahwa fase dan involusi selama pertengahan-ke-akhir masa
mengandung bintik puing-puing apoptosis proliferasi IHS infantil adalah campuran seluler bayi, sering disebut sebagai “ dataran ”
(Gambar 5). Akhirnya yang tersisa dalam kompleks dengan melengkapi besar sel endotel,
stadium akhir lesi longgar fi brous atau fi brofatty pericytes, sel mast, dan sel dendritik interstitial.
stroma, yang berisi beberapa sisa “ hantu ” mikroskop elektron mengungkapkan sel-sel
endotel yang melapisi gemuk lumina kecil dan fase, lebih mungkin merupakan periode
bertumpu pada membran basement keseimbangan temporer antara sel-sel
multilaminated yang menyelubungi manset dari individual yang berkembang biak dan mereka
pembuluh terdiri dari sisa, kerupuk rambak pericytes. Sel-sel endotel IH telah dilaporkan yang menjalani involusi dan apoptosis. 59 - 66 Proses
menebal dari bahan membran basement yang immunoreact positif untuk “ normal ” penanda involusi memakan waktu beberapa tahun dan
berisi puing-puing apoptosis dan tanpa utuh endotel pembuluh darah darah, seperti CD31, bervariasi dalam durasi.
CD34, faktor VIII - antigen terkait (von Willebrand
factor), dan lain-lain. 57 Saat ini, penanda
imunohistokimia yang paling berguna dan
Proliferatif Tahap (Hingga 12 Bulan Usia)
banyak digunakan untuk diagnosis IH adalah
GLUT1. 9,57 GLUT1 Sangat diekspresikan oleh
Yg memberi pertanda fi Temuan di kulit selama masa
sel endotel dari IHS pada semua tahap evolusi
bayi awal mungkin termasuk blanching lokal atau
mereka dan tidak diungkapkan oleh anomali
makula lokal telangiektasis eritema. Sebagai
vaskular jinak lainnya dan proliferasi reaktif.
proliferasi sel endotel terus, IH membesar, menjadi
GLUT1 imunohistokimia sering digunakan untuk
membedakan IHS dari neoplasma vaskuler lain lebih tinggi, dan mengembangkan konsistensi karet.
dan memberikan bukti yang meyakinkan bahwa Selama periode ini, IHS sering menunjukkan pucat
IHS memang sebagai biologis yang khas dan dilatasi pembuluh darah sekitarnya sekitarnya.
karena mereka khas klinis. Selama periode pertumbuhan yang cepat, ulserasi
mungkin timbul, menyebabkan rasa sakit dan
GAMBAR 5 jaringan parut akhirnya. IHS biasanya memiliki onset
IH fase involutif. kapiler lesi ditetapkan dalam longgar fi
klinis mereka sebelum 4 minggu usia. 66,67 Mereka
bro-jaringan adiposa dan kurang padat daripada di
fase proliferasi. Perhatikan menebal dan membran berkembang biak untuk periode variabel
dasar hyalinized bertabur dengan puing-puing
apoptosis, re fl efektif dari proses involutif. sel-sel
lapisan endotel sisa yang mitotically tidak aktif. (Foto
milik Paula Utara, MD)

waktu, tergantung sebagian pada morfologi dan
con mereka fi gurasi. Namun, sebagian besar
pertumbuhan IH tampaknya terjadi antara 1 dan 2
bulan. 68 Sebuah studi prospektif besar telah
menunjukkan bahwa 80% dari ukuran IH umumnya
dicapai dengan 3 bulan, dan paling pertumbuhan
selesai sekitar 5 bulan. 66 Mendalam IHS muncul
agak kemudian dan tumbuh agak lebih lama
daripada mereka super fi rekan-rekan resmi. 66
involusi Tahap
Untuk sebagian besar bayi dengan IH, involusi GAMBAR 6

dimulai antara 6 dan 12 bulan. Meskipun Cutaneous IHS mungkin diklasi fi ed atas dasar kedalaman mereka. A, Super fi resmi IHS hanya terlihat di permukaan kulit dan mungkin focal (seperti
yang ditunjukkan) atau segmental. B, Deep IHS tidak memiliki keterlibatan permukaan. C, Campuran, atau senyawa, IHS memiliki keduanya yang super fi
proses berlanjut selama bertahun-tahun,
resmi dan komponen yang mendalam.
mayoritas regresi tumor terjadi sebelum usia 4. 48,69,70
Sebagai IHS rumit, kebanyakan lesi fl atten dan

kedalaman jaringan lunak. 61,62,72 Super fi resmi super fi resmi dan dalam IHS. Pengamatan ini
menyusut dari pusat ke luar. Bagi mereka
IHS (Gambar 6A) adalah mereka di mana menunjukkan bahwa IHS mendalam memerlukan
dengan super fi komponen resmi, ini disertai
permukaan tumor tampak merah dan ada sedikit waktu yang lebih lama dari pemantauan
dengan “ sentral kliring ” atau beruban
atau tidak ada komponen subkutan dilihat; dibandingkan mereka dengan super fi morfologi resmi.
permukaan. Meskipun IHS umumnya menjalani
historis, IHS ini telah digambarkan sebagai satu Sebuah spesifik fi c subtipe super fi resmi IH telah
regresi spontan, pengamatan “ involusi maksimal ”
bervariasi disebut sebagai gagal, nonproliferative,
tidak selalu berarti resolusi lengkap. Memang,
arrestedgrowth, minimal-pertumbuhan, baru lahir,
sekitar 50% sampai 70% dari IHS tekad,
“ stroberi ” mengetik. Dalam IHS (Gambar 6B) retikuler, atau telangiektasis IH. 73 - 76
meninggalkan perubahan kulit residual,
adalah mereka yang tumor berada dalam ke
termasuk telangiectasia, fi brofatty jaringan,
permukaan kulit, dan subkutan hasil lokasi
berlebihan kulit, anetoderma, dyspigmentation,
mereka di rona permukaan kebiruan atau tidak
atau bekas luka. 71 Jenis IH menyajikan sebagai makula, patch yang
ada perubahan permukaan jelas; historis, ini
telangiektasis yang mungkin disertai dengan
telah disebut sebagai “ gua, ”
blanching dari yang terlibat kulit (Gambar 7). Tidak
seperti kebanyakan IHS, IHS gagal kurang memiliki
istilah yang kurang tepat yang tidak lagi umum
signi jelas fi cant fase proliferasi. Sekitar dua-pertiga
digunakan. Dikombinasikan, campuran, atau
dari lesi ini terletak pada ekstremitas bawah.
senyawa IHS (Gambar 6C) adalah mereka di mana Banyak yang disertai dengan lokal, daerah papular
Highlights dari Bagian ini kedua yang super fi resmi dan komponen dalam kecil pertumbuhan jaringan pembuluh darah, sering
hidup berdampingan. Super fi resmi IHS cenderung sekitar pinggiran. 77 Gagal share IHS dengan IHS
• IHS biasanya membuat penampilan awal
muncul lebih awal dan mulai rumit lebih cepat penanda permukaan karakteristik yang lebih khas
mereka sebelum 4 minggu usia dan
daripada rekan-rekan mereka yang mendalam, (misalnya, GLUT1), con fi rming bahwa mereka
menyelesaikan sebagian besar pertumbuhan
yang, sebaliknya, cenderung muncul kemudian dan benar IHS; Namun, fase pertumbuhan mereka
mereka dengan 5 bulan usia.
tumbuh selama waktu yang cukup lama sebelum mungkin akan ditangkap. Banyak dari IHS
berinvolusi (rata-rata, sekitar 1 bulan lebih). 62,64,66 Penyelidikan
telangiektasis juga rumit lebih cepat,
• Involusi IHS dimulai sebagai anak
perbedaan ini con fi rm yang jadwal ini mewakili pola kadang-kadang sebelum usia 1 tahun. 78
mendekati usia 12 bulan. Dalam
pertumbuhan karakteristik untuk IHS ini daripada
kebanyakan kasus, mayoritas
timbul bias observasional. 66 Seperti bisa diduga,
involusi selesai pada usia 4.
mereka IHS dengan morfologi campuran memiliki
pola pertumbuhan yang penengah antara
orang-orang yang terkait dengan Namun demikian, komplikasi seperti ulserasi
dapat terjadi. IHS ini mungkin juga segmental
dan kadang-kadang memiliki asosiasi sindrom
Penampilan klinis (lihat bagian yang berjudul “ IH Syndromes dan
Selama fase proliferasi, IHS dapat Asosiasi “). 79
diklasifikasikan fi ed atas dasar mereka

de fi nitively focal or segmental are considered Multifocal cutaneous IHs are frequently isolated
indeterminate. Multifocal lesions are focal to the skin but may also serve as markers for
lesions occurring at more than 1 anatomic site. underlying hepatic involvement (Fig 9). 88 – 91 Previous
One large study found that most IHs (67.5%) are retrospective reports 26,81 suggested that the
localized, whereas the remainder were presence of a large or segmental (.5 cm)
segmental (13%), indeterminate (16.5%), or cutaneous IH might prove a useful marker for
multifocal (3.6%). 83 hepatic IHs. However, results from a large
prospective study suggest that it is the number
of cutaneous IHs rather than their size that is
The presence of a large, facial segmental IH is
FIGURE 7 the more predictive factor. 92 When 5 or more
a hallmark sign of PHACE syndrome, 25 whereas
Abortive IHs are macular, telangiectatic patches that have IHs are present on cutaneous examination,
failed to fully proliferate.
large segmental IHs of the anogenital and
ultrasonography may be helpful in assessing
lumbosacral areas may be associated with
potential hepatic involvement. 84,93
genitourinary system and spinal cord anomalies
IHS juga mungkin diklasi fi ed atas dasar con as part of other syndromes 84 – 86 ( see section
anatomi mereka fi gurasi baik sebagai lokal entitled “ IH Syndromes and Associations ”). More
(focal), segmental, tak tentu, atau multifokal. 26,80,81 recently, it has been recognized that
extracutaneous manifestations may also arise in
Localized (focal) IHs are discrete lesions that association with segmental IHs involving other
Hepatomegaly and congestive heart failure
seem to arise from a single focal point, whereas anatomic sites, as part of the so-called
also suggest the presence of liver IH.
segmental lesions cover a territory that is PHACE-withoutface phenomenon. 87 These
presumed to be determined by embryonic patients may have segmental IHs of the upper
neuroectodermal placodes. 82 Segmental IHs chest, shoulder, or arm in the absence of facial
tend to involve a larger surface area of skin. IH involvement and in conjunction with structural
Segmental IHs of the face have been observed heart disease, aortic or other major vessel Highlights of This Section
to conform to unique developmental units, which anomalies, central nervous system and sternal • IHs are characterized as super fi cial,
have been mapped into 4 distinct patterns: defects, or eye anomalies. deep, or mixed and as focal,
frontotemporal, maxillary, mandibular, and multifocal, or segmental.
frontonasal (Fig 8). 82 Lesions that are not
• Super fi cial IHs appear earlier and

begin involution sooner than their
deeper counterparts.
• Segmental IHs are more

commonly involved in PHACE (see
text for de fi nition) and other IH
syndromes and associations.
• The presence of more than 5 focal

IHs suggests a higher risk of hepatic
involvement.
FIGURE 8
(A) Patterns of segmental IH of the face extracted from image analysisde fi ned. Seg1 (frontotemporal), Seg2 (maxillary), FIGURE 9
Seg3 (mandibular), and Seg4 (frontonasal). (B) An ulcerated segmental IH in the maxillary distribution. Multifocal cutaneous IHs in a child with IH of the liver.
Downloaded from www.aappublications.org/news by guest on April 9, 2019

PEDIATRICS Volume 136, number 4, October 2015 e1067
Complications to develop complications and 8 times more usually results in scarring, with the risk of
likely to receive treatment. 84 permanent dis fi gurement. As a result, prompt
Although most IHs do not require urgent
Segmental lesions tend to have longer initiation of therapy is essential in the
treatment, a minority may develop
proliferative phases, some with signi fi cantly management of ulcerating IHs. The speci fi c
function-threatening or lifethreatening
prolonged duration of growth as long as 10 to mechanisms resulting in IH ulceration are poorly
complications, necessitating therapeutic
44 months, and may therefore require signi fi cantly understood. It has been hypothesized that
longer treatment durations. 94
intervention. One study determined that ulceration may develop secondary to increased
approximately 24% of patients with IH who were tissue hypoxia, which leads to the development
referred to a group of tertiary care dermatology of dermal fi brosis and then progresses to
practices experienced some complication The size of the IH was also an important surface breakdown. 98 In such cases, early white
related to their IH. 84 It is therefore prudent for predictor of the need for treatment in the discoloration of an IH, possibly representing
pediatric providers to remain vigilant of possible aforementioned cohort study, although this super fi cial dermal
analysis did not appear to control for anatomic
subtype. 84 The mean size of complicated IHs
complications and of risk factors that may herald was 37.3 cm 2,
future complications. Ulceration accounts for the fi brosis, may be a premonitory sign of
majority of IH complications; others include compared with 19.1 cm 2 for uncomplicated IHs. impending ulceration. 99 Other proposed
bleeding, visual impairment, auditory In addition, IHs that received treatment of any mechanisms include outgrowing of the blood
impairment, congestive heart failure, and airway type had a mean size of 30.4 cm 2, which was supply or rapid expansion exceeding the elastic
obstruction. 84 Gastrointestinal bleeding has 11.1 cm 2 larger than those that did not receive capabilities of the skin. 99,100
been reported as a complication of segmental treatment. However, the mean size of

intestinal hemangiomatosis, in which the IH is segmental IHs is approximately 10 times that of
Several studies have shown that certain subsets
typically situated in the distribution of the localized IHs, 66 suggesting that morphology may
of patients with IHs are at higher risk of
mesenteric arterial system. 94 indeed be a more important indicator of
ulceration. As discussed previously, super fi cial
potential complications. Anatomic location was
and segmental IHs have been found to be at
also a predictor of complications due to IH. 84 Facial
higher risk of ulcerating. 96 – 98,101 In addition, speci fi
IHs were complicated 1.7 times more frequently
c locations at higher risk of ulceration include
than nonfacial IHs; they were also 3.3 times
the head, neck, perioral, and perineal/perianal
more likely than their nonfacial counterparts to regions and intertriginous sites (Fig 10). 96 – 98,102 The
The single best predictor of complications and receive some form of therapy, likely because of neck and anogenital regions sustain maceration
the need for therapeutic intervention for IH is concerns for cosmesis. Periocular IHs and and friction, which may contribute to the
morphologic subtype. 84 Focal IHs have the those in the “ beard ” distribution are also more development of ulceration. Ulceration has also
potential to cause complications primarily by likely to require intervention, as described been noted to occur more frequently in infants
virtue of their location on or near vital structures, below. In 1 study, perineal IHs were the most younger than 4 months, a period of time during
such as the eye (amblyopia, astigmatism), nose likely to ulcerate. 95 which the IH
(anatomic distortion and cartilaginous
destruction), ears (anatomic distortion and
cartilaginous destruction), lips (anatomic
distortion and ulceration), airway (obstruction),
or anogenital region (ulceration). On the face,
focal lesions are 3 times more common than
segmental IHs. 81 Segmental IHs are more
frequently complicated by ulceration. 84 A
prospective cohort study in 1058 patients
undertaken to identify clinical characteristics Ulceration
predicting complications and need for treatment Ulceration, or breakdown of the IH skin surface,
found, after controlling for size, that segmental occurs with an estimated incidence of 5% to
IHs were 11 times more likely than localized IHs 21%. 96
Ulceration was the most common complication

in a large prospective cohort of children with
IHs, occurring in 16% of the study population. 97
Ulceration can lead to signi fi cant pain,
bleeding, and secondary infection. Ulceration
FIGURE 10
also Ulcerated segmental IH of the perineal/perianal region.

e1068 FROM THE AMERICAN ACADEMY OF PEDIATRICS
is actively proliferating. 96 – 98 See the section IHs had feeding and oral sensory problems develop noisy breathing or a hoarse cry. 106
entitled “ Management of Ulcerated IH ” for a that resulted in failure to thrive. 105
discussion in greater detail.
The cutaneous fi ndings associated with
underlying airway involvement, when present,
Airway Involvement and Obstruction help to identify those patients at greatest risk of
Airway IHs can occur in the presence or airway IHs. Cutaneous IHs in a “ beard ”
Bleeding
absence of skin fi ndings. Symptomatic
Although concern for potential bleeding in IH is obstructive airway IHs, including supra- and distribution, de fi ned as involving the preauricular
common among caregivers and providers, it subglottic IHs, usually present with progressive regions, chin, anterior neck, or lower lip (Fig 11),
occurs rarely and almost exclusively in biphasic inspiratory and expiratory stridor during have been associated with airway involvement. 106,107
ulcerated lesions. The majority of bleeding that the fi rst 6 to 12 weeks of age as the lesion is Infants with IHs within this distribution bilaterally
occurs in nonulcerated IHs is minor and easily proliferating. 105 appear to be at an even higher risk of
controllable with pressure. The most common
such scenario is an IH that has sustained minor Affected infants may also rapidly
surface trauma (ie, from friction or a fi ngernail),
bled minimally, stopped bleeding spontaneously
or with minimal sustained pressure, and
subsequently presents with surface
hemorrhagic crusting.
In a large prospective study of ulcerated IHs,

bleeding occurred in 41% of lesions but was
clinically signi fi cant in only 2% of these cases. 96,98
Signi fi cant bleeding requiring blood transfusion
or other intervention is infrequently reported. 98 Rare
instances of lifethreatening bleeding have been
observed, including 1 report of ulceration of a
segmental neck IH into arterial vessels, the
bleeding from which necessitated transfusions,
systemic and topical treatment of the IH,
embolization, and surgical excision. 102
Feeding Impairment
Feeding impairment can occur in infants with

IHs involving either the perioral region or the
airway. Infants with ulcerated lip IHs may be
unable to latch onto a nipple secondary to
severe pain, which can lead to impaired feeding. 103
Obstructive airway IHs may complicate
breathing and swallowing, also leading to
impaired feeding. 104 In a small case series in
infants with complicated facial IHs, several with
ulcerated perioral lesions or airway FIGURE 11
A, The presence of multiple IHs in the “ beard ” distribution is associated with a higher likelihood of airway involvement
(reproduced with permission from J Pediatr. 1997;131(4):643 – 646 ©Elsevier). 106
B and C, Patient with airway involvement requiring tracheotomy is shown with “ beard ” involvement at the lip and chin (B)
as well as the parotid area and neck (C).

having associated airway involvement; in a compromise usually improves with treatment anomalies. The best-known such
recent series in 17 infants with airway IHs, of both the heart failure and the IH. association is PHACE (Online Mendelian
bilateral involvement of the lower facial segment Inheritance in Man
was present in 13 (76%). 106,108 Early referral to 606519). 114 The disorder is also referred
Diffuse lesions of the liver may also be
otolaryngology of infants with severe stridor and to as PHACES to include potential ventral
associated with severe consumptive
a cutaneous IH in the midline defects, speci fi cally S ternal cleft
hypothyroidism caused by excess production of
and/ or
type 3 iodothyronine deiodinase. Liver IHs are
S upraumbilical raphe. Originally described as a “
discussed in greater detail in the subsection
“ beard ” distribution is advisable, because syndrome, ” PHACE is more appropriately
entitled “ Liver ” of “ IHs With Special Anatomic
airway involvement can be life-threatening if termed an association, although there are
Concerns. ”
diagnosis and treatment are delayed. In less recent data suggesting that chromosomal region
symptomatic children, a high kilovoltage 7q33 may provide a genetic susceptibility to
radiograph of the airway may be useful in exhibit the PHACE phenotype. 115
identifying subglottic IH. Airway IHs are
Highlights of This Section
discussed in greater detail in the subsection
under “ IHs With Special Anatomic Concerns ” entitled • Segmental IHs are far more likely
The spectrum of anomalies in PHACE
than focal IHs to result in a
syndrome and the ipsilateral relationship
complication, usually ulceration.
between such anomalies and cutaneous IH
strongly suggest a “ developmental fi eld defect, ”
“ Airway. ” • Focal IHs cause complications
primarily by virtue of their location
whereby an insult at a critical time in
Visual Impairment and Other Ocular on or near vital structures.
embryogenesis gives rise to similar
Complications
developmental outcomes. 116 The precise timing
IHs occurring within the orbit have the potential • Facial IHs cause complications more of such an insult in PHACE syndrome is
to cause mechanical ptosis, strabismus, frequently than nonfacial IHs and are speculative, but both the anatomic IH patterns
anisometropia, or astigmatism, which can
several times more likely to receive and several of the associated structural
quickly lead to the development of amblyopia. 108
some form of therapy. abnormalities point to changes early during the fi
rst trimester, probably within the fi rst 3 to 12
Studies have identi fi ed speci fi c characteristics of
• Minor bleeding from an ulcerated IH weeks of gestation before or during early
periocular IHs, which place the child at higher
is common, but rarely of clinical signi fi vasculogenesis. 117 PHACE syndrome is now
risk of amblyopia. These include periocular IHs
cance; bleeding from a nonulcerated understood to be predominantly a congenital
that are larger than 1 cm in diameter, nasal
IH is rare. vasculopathy. In fact, many of its features can
location of the IH, associated ptosis, eyelid
be explained as downstream events of
margin change, or displacement of the globe. 109 – 111
arteriopathy with resultant ischemia, and it has
Orbital IHs are discussed in greater detail in the • Patients with an extensive IH in the “
been hypothesized that vascular dysplasia may
subsection entitled “ Eye and Orbit ” under “ IHs beard ” distribution are more likely to
be a key or even primary event in the
With Special Anatomic Concerns. ” have involvement of the airway.
pathogenesis of PHACE syndrome. 118
• High-risk periocular IHs are those

that are that are larger than 1 cm in
diameter, located near the nose,
Congestive Heart Failure and associated with ptosis or eyelid
Hypothyroidism margin change, or displacing the
Although rare, high-output congestive heart globe. Consensus criteria were recently developed for
failure can occur in infants with large IHs as a the diagnosis of PHACE syndrome (Tables 2
result of arteriovenous shunting of a large blood • Diffuse IH of the liver may be and 3). 25 Clinical examination of the skin and
volume through the lesion. This complication associated with severe eyes as well as detailed imaging of the head,
has been reported in infants with large consumptive hypothyroidism. neck, and chest are required to make the
cutaneous IHs and RICHs and in those with diagnosis. More than 90% of infants with
diffuse or multifocal hepatic IHs. 91,92,112,113 Symptomatic PHACE syndrome exhibit more than 1
infants may present with dif fi culty feeding, poor extracutaneous anomaly, although very few
growth, heart murmur, or hepatomegaly. The manifest the complete spectrum. 119 In contrast
IH Syndromes and Associations
cardiac to nonsyndromic IH, PHACE syndrome
A small subset of children with IH will exhibit
associated congenital

TABLE 2 Consensus Algorithm for the Diagnosis of PHACE Syndrome is more common in full-term singleton
PHACE Syndrome Possible PHACE Syndrome infants of normal birth weight, although
females are still more commonly affected. 120
Facial hemangioma Facial hemangioma Hemangioma of the No hemangioma plus
. 5 cm in diameter plus 1 . 5 cm in diameter plus neck or upper torso 2 major criteria
major criterion or 2 minor 1 minor criterion plus 1 major criterion or
The hallmark of PHACE syndrome is a large,
criteria 2 minor criteria
segmental, often super fi cial IH, characteristically
located on the face, scalp, and/or neck (Fig 12).
Adapted from ref 25.
PHACE syndrome – associated IHs most
commonly affect facial segments 1 and/or 3,
which also confers a particularly high risk of
associated central nervous system involvement. 84,119
TABLE 3 Consensus Diagnostic Criteria for PHACE Syndrome Organ System
Major Criteria Minor Criteria

PHACE syndrome is not exceedingly rare, and
Cerebrovascular Anomaly of major cerebral arteries Persistent embryonic artery other
probably even more common than
Dysplasia a of the large than trigeminal artery Proatlantal
Sturge-Weber syndrome. 121 The segmental IH
cerebral arteries b intersegmental
Arterial stenosis or occlusion artery (types 1 and 2) Primitive
associated with PHACE is sometimes confused
with or without moyamoya hypoglossal artery Primitive otic with the port wine stain associated with
collaterals artery SturgeWeber syndrome, especially in the
Absence or moderate-severe
newborn period before signi fi cant IH
hypoplasia of the large cerebral
proliferation or in cases of
arteries Aberrant origin or course
of
the large cerebral arteries b
Persistent trigeminal artery “ minimal growth ” IH in which there is an
Saccular aneurysms of any
absence of signi fi cant proliferation. The risk of
cerebral arteries
PHACE syndrome in an infant presenting with a
Structural brain Posterior fossa anomaly Enhancing extraaxial lesion with large, segmental IH ($22 cm 2)
Dandy-Walker complex or features consistent with
unilateral/bilateral cerebellar intracranial hemangioma Midline
anomaly c of the head or neck is approximately one-third. 120
hypoplasia/dysplasia
Neuronal migration disorder d
Cerebrovascular anomalies, present in more

Cardiovascular Aortic arch anomaly Ventricular septal defect
Coarctation of aorta Right aortic arch (double aortic arch) than 90% of patients, are the most common
Dysplasia a extracutaneous feature of PHACE syndrome,
Aneurysm followed by cardiac anomalies (67%) and
Aberrant origin of the subclavian structural brain anomalies (52%). 84
artery with or without a
vascular ring
The most common arterial abnormality in
Ocular Posterior segment abnormality Anterior segment abnormality
PHACE syndrome is dysgenesis of the anterior
Persistent hyperplastic Microphthalmia
circulation, particularly within the internal carotid
primary vitreous Sclerocornea
Persistent fetal vasculature Coloboma artery. 119 The neuroanatomic and
Retinal vascular anomalies Cataracts cerebrovascular anomalies observed in PHACE
Morning glory disc anomaly Optic may lead to a number of neurologic sequelae,
nerve hypoplasia Coloboma
including motor and speech delays, seizures,
migraine-like headaches, and rarely, arterial
Peripapillary staphyloma
ischemic stroke. 121 Hearing loss (conductive or
Ventral or midline Sternal defect Hypopituitarism
sensorineural) has also been reported in
Sternal cleft Ectopic thyroid
PHACE syndrome, particularly when the IH
Supraumbilical raphe
Sternal defects
involves the ear and periauricular scalp, which

can be related to the presence of ipsilateral
a Includes kinking, looping, tortuosity, and/or dolichoectasia.
b Internal carotid artery, middle cerebral artery, anterior cerebral artery, posterior cerebral artery, or vertebrobasilar system
c Callosal agenesis or dysgenesis, septum pellucidum agenesis, pituitary malformation, or pituitary ectopia.
d Polymicrogyria, cortical dysplasia, or gray matter heterotopia.

to be segmental and often “ minimal growth ” in
morphology. 85 Such IHs were often extensive (eg,
involving the entire leg) and showed additional
potential for ulceration and, rarely,
underdevelopment of the affected limb. Like
PHACE syndrome, the cutaneous IHs and
underlying anomalies showed regional
correlation. Myelopathies, particularly spinal
dysraphism, were the most common
extracutaneous anomaly. Interestingly, arterial
anomalies were noted in a minority of patients
who were speci fi cally studied for such anomalies,
although the true incidence and long-term risks
are unknown. Imaging is region-speci fi c; MRI is
FIGURE 12
A, Frontotemporal segmental IH typical of PHACE syndrome. B, Sternal clefting characteristic of PHACE syndrome (scar
useful in delineating the extent of lumbosacral
is congenital, not surgical). involvement and potential myelopathy, whereas
additional imaging with MRA may be warranted
intracranial IH involving auditory structures. It risk infants, progressive cerebrovascular changes
for infants with extensive lower limb involvement
has been suggested that children with PHACE may be identi fi ed early, and neurosurgical
to assess for arterial anomalies.
syndrome and periauricular IH be evaluated revascularization procedures can be performed to
with both MRI and audiometric testing. 122 potentially reduce arterial ischemic stroke – related
morbidity and mortality. 125 The presence of
Cardiovascular anomalies are the second most severe cerebrovascular and/or cardiovascular
common extracutaneous manifestation of PHACE arterial anomalies in patients with PHACE
syndrome. The aortic coarctation observed differs syndrome may preclude the use of propranolol
from classic coarctation in that it occurs in a more for treatment of IH in this population, or require
proximal location, often involves the arteries dose modi fi cation. (see section entitled
feeding the upper extremities, and affects longer
• PHACE syndrome includes features
segments, which may preclude detection based
of P osterior fossa defects, H emangiomas,
on a blood pressure gradient between the upper
cerebrovascular A rterial anomalies, C
and lower extremities. The aortic anomalies in “ Medical Therapy for IH ”).
PHACE syndrome are often noted to be
ardiovascular anomalies including
LUMBAR syndrome ( L ower body IH and other
particularly unusual and severe, often requiring coarctation of the aorta, and
cutaneous defects, U rogenital anomalies and
surgical repair; thus, detailed imaging of the arch
ulceration, M yelopathy,
is essential. 123
B ony deformities, A norectal malformations and E ye anomalies.
arterial anomalies, and R enal anomalies) may be
• The hallmark of PHACE syndrome
best considered the “ lower half of the body ”
is a large, segmental IH,
characteristically located on the
Even in asymptomatic infants, MRI or magnetic variant of PHACE syndrome. 85
face, scalp, and/or neck.
resonance angiography (MRA) of the head and LUMBAR has also been previously
neck is indicated, especially given the known described under the competing acronyms
potential for progressive vasculopathy and • The most common extracutaneous
SACRAL 87 ( S pinal dysraphism, A nogenital
resultant ischemic events in a small subset of features of PHACE syndrome are
anomalies,
severely affected patients. 124 cerebrovascular anomalies, followed
C utaneous anomalies, R enal and urologic
by cardiac anomalies and structural
anomalies, associated with
brain anomalies.
Arterial ischemic stroke, a rare but devastating A ngioma of L umbosacral localization) and
complication, appears to be more likely in PELVIS 86 ( P erineal hemangioma,
patients with PHACE who exhibit signi fi cant E xternal genitalia malformations, • LUMBAR syndrome may be best
narrowing or nonvisualization of large cerebral L ipomyelomeningocele, V esicorenal considered the “ lower half of the
arteries, especially when more than 1 vessel is abnormalities, I mperforate anus, S kin tag). The body ” variant of PHACE syndrome
involved and/or if there are associated IHs are usually segmental lumbosacral or and may be associated with
cardiovascular morbidities such as coarctation of anogenital lesions. In an analysis of 24 new urogenital, anal, skeletal, and spinal
the aorta. 125 patients and a review of 29 published cases, IHs cord anomalies.
in association with LUMBAR were noted
Through serial neuroimaging of high-

IMAGING OF IH high- fl ow feeding arteries and draining veins. CLINICAL APPROACH TO IH
The diagnosis of IH is generally made on the With administration of intravenous gadolinium, The traditional clinical approach to IH has been
basis of history and clinical appearance. lesion enhancement is usually early, with one of “ benign neglect. ” 60 The observation that,
Occasionally, imaging of the lesion may be intense and uniform enhancement on delayed as a neoplasm, IH has the unique ability to
required when the diagnosis is uncertain, when images; however, diffuse or multifocal hepatic undergo involution has led many practitioners to
evaluation of extent is necessary, or when lesions may show early enhancement believe that the best management is to
response to therapy needs to be monitored. peripherally and delayed fi lling centrally
IH-associated anomalies, such as spinal (centripetal enhancement). 91 Nonenhancing
dysraphism, anogenitourinary anomalies, and regions may represent thrombosis or necrosis. “ leave it alone and it will go away. ”
PHACE syndrome, are also best imaged with During the involution phase, as deposits of fat However, 1 study from a group of referral
MRI. However, the risk of early exposure to replace the lesion, foci of increased signal can pediatric dermatology practices suggests that
anesthesia is a consideration in determining the be seen on T1-weighted images, and more than one-third of patients with IH require
urgency and type of imaging for IH. some sort of intervention. 84 Hence, although this
postcontrast images reveal less avid
Ultrasonography is a reasonable initial imaging number may re fl ect referral bias, it is clear that
enhancement. Computed tomography (CT) is
modality for diagnosing IH, because it is some IHs are associated with a high risk of
mentioned only because it is occasionally
inexpensive and does not require sedation. The complications or permanent dis fi gurement. In
ordered when a diagnosis of IH is not expected.
sonogram generally reveals a well-de fi ned high- fl many such cases, early intervention may be
CT
ow parenchymal mass with possible shunting. justi fi ed to potentially arrest the growth of the
During the involution phase, areas of increased lesion, reduce associated complications, and
echogenicity (fat replacement) can be seen avoid years of psychosocial concerns. The fi rst
within the lesions. Gray scale and color Doppler consideration in the management of IH is
ultrasonography have also demonstrated utility fi ndings are similar to those on MRI, including
whether intervention is necessary. The
in monitoring the response of IH to medical well-de fi ned and avidly enhancing lesions
indications for intervention include the following:
therapy. 127 Ultrasonography is also a good fi rst-line during the proliferating phase and less (1) emergency treatment of potentially
modality to screen patients with multifocal IHs pronounced enhancement during the involution
lifethreatening complications; (2) urgent
for liver or visceral involvement, although MRI is phase. Although these studies are shorter in
treatment of existing or imminent functional
preferable to assess complicated or extensive duration than MRI (reducing the likelihood that
impairment, pain, or bleeding; (3) evaluation to
visceral lesions. 128 general anesthesia will be necessary), CT
identify structural anomalies potentially
carries the disadvantage of exposing young
associated with IH; and (4) elective treatment to
children to ionizing radiation and its attendant
reduce the likelihood of long-term or permanent
risks.
dis fi gurement. Lifethreatening lesions include
obstructing IHs of the airway as well as liver IHs
associated with high-output congestive heart
failure and severe hypothyroidism. Pain and
bleeding are examples of urgent sequelae that
occur as a result of ulceration; affected children
• Imaging of IH is not usually may have failure to thrive as well. Other
The extent of the lesion and the surrounding
necessary. examples of functional impairment include
anatomy are better shown on MRI. The most
useful sequences include T1-weighted images • When imaging of IH is performed, ocular impairment (loss of visual axis leading to
with and without fat saturation, T1-weighted ultrasound is generally the preferred deprivation amblyopia, astigmatism,
images with fat saturation post – gadolinium modality for diagnosis, whereas MRI
administration, T2-weighted images with fat is better to assess extent of the
saturation, and fl ow-sensitive sequences such lesion.
as gradient echo or MRA. 129 Proliferating IHs

typically appear as well-de fi ned masses with • Imaging may be required when the
features of high fl ow and intermediate signal diagnosis is uncertain, when
intensity on T1-weighted images and high signal evaluation of extent is necessary,
intensity on T2-weighted images. 130,131 Flow when the IH is a possible marker of
voids may be apparent on T2-weighted and PHACE or LUMBAR syndrome, or
when response to therapy needs to
be monitored.
fl ow-sensitive sequences, along with

FIGURE 13
Uncomplicated IHs. These lesions generally do not require medical or surgical intervention.
strabismus, visual fi eld cuts), impaired feeding ones in early infancy. 132 For less concerning complication and urgency of intervention;
because of involvement of the lips or mouth, IHs, providers may wish to counsel the family potential for adverse psychosocial
and reduced mobility because of complicated regarding changes of importance, such as rapid consequences; parental preference; and
involvement of the extremities. Structural growth or ulceration, and to establish with the clinician experience. A Cochrane review found a
anomalies of concern include spinal dysraphism family a means to see the child on short notice if dearth of well-designed clinical trials on which
associated with lumbosacral IHs as well as such changes are observed. appropriate interventions for IH could be
anomalies associated with PHACE and other IH determined. 133
“ syndromes. ”
Whether IH affects the psychosocial well-being of

Central to the decision of whether to intervene is affected patients, and the age at which it may do
Long-term and permanent dis fi gurement is a
a discussion of the risks, bene fi ts, and so, is uncertain. Some authors suggest that “ children
concern with IHs of certain anatomic sites
alternatives associated with each of these
(eyelid, nasal tip, lip, breast, genitalia) and with
choices and with each potential intervention. fi rst represent and re fl ect on themselves as
severe ulceration, because these will ultimately
Proper informed consent from the family is independent, objective entities ” in the latter half
leave a scar of similar size.
paramount in achieving a successful and of the second year of life 134 and that the
satisfying physician-patient relationship as well emotional responses of others may affect a child ’
s mood even earlier than 12 months of age. 135 Thus,
as a good therapeutic result. Once a decision
Most IHs are uncomplicated and are not there may be some effect on the child even
has been made to intervene, the second
likely to fall into any of these categories (Fig before entering preschool. In contrast, a review
consideration is which therapeutic modalities
13); the practice of initial observation or of the existing literature on psychosocial rami fi cations
are most appropriate. There is no formula or
of IH was less concerning. 136 Among the 7
algorithm that easily addresses all of the factors
“ watchful waiting ” is reasonable for such studies cited, questionnaires that were validated
in this decision; as a result, the treatment plan is
lesions. However, because the clinical but not speci fi c for IH revealed few or no signs
customized for each patient. Relevant factors
presentation of IH can change within days, it is of psychosocial impact in children with IHs. The
include age and medical condition of the patient;
prudent for pediatric providers to reexamine authors did note that the studies were
frequently, as often as weekly, those children growth phase, location, and size of the lesion or
conducted in small groups of parents, and all
with lesions at high risk of causing functional or lesions; degree of skin involvement; severity of were fl awed in one way or another. In a small
cosmetically critical changes, because many study, quality of life among children 5 to 8
uncomplicated lesions may become
complicated

years of age who had IHs of the head and neck patients who have undergone early surgery and
measuring 2 cm or greater was compared with in whom residual IH intentionally or inadvertently
that of normal controls. Although the remains postoperatively, there is potential for • The indications for intervention for IH
questionnaires were not disease-speci fi c, the additional growth of the lesion after the include the following:
authors found no differences in quality-of-life
procedure. In addition, because IHs are benign
indices or in self-perception scores. 137 1. emergency treatment of
lesions with the potential to involute, surgeons
potentially lifethreatening
do not always endeavor to obtain disease-free
Further complicating this subject is the fact that complications;
margins, instead allowing involution to assist in
quality-of-life investigations in young children
achieving the fi nal result. On occasion, in
require proxy reporting that often re fl ects quality 2. urgent treatment of existing or
surgery for wellinvoluted IHs, tissue may even
of life as perceived by the proxy rather than the imminent functional
be left behind intentionally, using the
child. Thus, no de fi nitive statement can be made impairment, pain, or
regarding psychosocial rami fi cations of IH; bleeding;
however, many clinicians who specialize in the fi eld
3. evaluation to identify structural
will consider treatment of those IHs projected to
anomalies potentially
be cosmetically signi fi cant beyond 4 years of fi brofatty remnant to serve as fi ller to preserve
associated with IH; and
age. 70 normal tissue contours. Lesion-related factors,
such as location, size, and degree of skin
4. elective treatment to reduce the
involvement or ulceration, often dictate the
likelihood of long-term or
feasibility of a given treatment modality. For
permanent dis fi gurement.
example, a pedunculated eyelid lesion causing
Details related to IH stage have been addressed
in a study examining growth characteristics of ptosis or ectropion or a small, ulcerated lesion
• There is no algorithm to determine
IHs. 66 The largest increase in IH size occurred at that is certain to scar may lend itself better to
the most appropriate intervention for
a mean age of 3 months, and by 5 months of early surgical excision rather than medical
IH. Factors affecting this choice
age both segmental and localized IHs had therapy. Conversely, an extensively ulcerated
include the following:
reached 80% of their fi nal size. As a result, segmental IH or a lesion of the genitalia is more
therapy initiated after the early proliferative appropriately addressed with medical therapy. 1. age of the patient,
phase is less likely to be effective in controlling Parental preference is another critical factor in
2. growth phase of the lesion,
the growth of the lesion or in prevention of treatment selection, more so in elective cases
complications. Age and stage are also factors in 3. location and size of the lesion,
than in those that are emergencies or urgent
the effectiveness of pharmacotherapy for IH. cases. Parents will often have strong feelings,
Early experience with systemic steroids for IH 4. degree of skin
particularly about surgical intervention or
suggested that younger children had a better involvement,
systemic medical therapy, that will have a major
response to therapy, 138,139 and most studies of 5. severity of complication and
effect on treatment planning for the child.
their mechanism of action suggest they inhibit urgency of intervention,
Similarly, the choice of treatment may be in fl uenced
components of the proliferative process. 140 Similar
by the experience of the treating provider and
data for propranolol therapy are not yet
his or her familiarity with the diversity of 6. potential for adverse
available, but proposed mechanisms of its
potential interventions. For these reasons, it psychosocial
action also suggest primary activity during
may be preferable for complicated IHs to be consequences,
proliferation. 139,141
managed by a practitioner or team who has 7. parental preference, and
experience with all of the available therapeutic 8. physician experience.
options.
MANAGEMENT OF ULCERATED IHS

Conversely, recent retrospective studies
indicate that b- blocker therapy for IH can The management of ulcerated IHs includes
be effective beyond the proliferative phase attention to wound care, pain, and IH growth. 96 Unfortunately,
as well. 142,143 there are no high-quality studies to guide care of
the ulcer, and therefore treatment preferences
Age and growth phase are also considerations are often based on case experience. 132
when surgery for IH is being considered. For

example, in

Approaches to ulcerated IHs are Pain control is a signi fi cant issue in infants with MEDICAL THERAPY FOR IH
summarized in Table 4. Some clinicians ulcerated IH. Pain can be severe and can
Background
disrupt sleep as well as interfere with daily
liken the
activities and/ or function. For example, Medical therapy for IH includes both topical and
management of ulceration to that of super fi cial
ulceration located on the lips or oral mucosa systemic administration of medications. Topical
burns and suggest culture and diligent wound
may affect oral intake or feeding, whereas agents may be a consideration for smaller, more
care. In 1 study, 16% of ulcerated IHs were
considered to be infected on clinical grounds, interference with urination or stooling may be super fi cial IHs or those for which systemic
and cultures revealed pathogens in half of these seen in the setting of perineal ulcerations. Oral therapy is contraindicated. Systemic therapy is
cases. 98 acetaminophen and cautious use of topical usually initiated for large IHs, those with a high
2.5% lidocaine ointment may be effective in risk of functional impairment or dis fi gurement,
managing the pain of ulceration. 96 With more and those refractory to other initial therapies.
Reepithelialization may be facilitated by
severe ulceration, the use of narcotics may be Beginning in the 1960s, systemic and
debriding crusts with the use of warm
indicated for inadequately controlled pain. intralesional steroids were the cornerstone of
compresses. The ulcer is then covered with a
Collaboration with experts in pain management medical therapy for IH. Shrinkage of IH with
barrier to prevent excessive drying, control pain,
may be useful in this high-risk group of infants. systemic corticosteroid therapy was fi rst
reduce the risk of trauma and potential bleeding,
and reduce the risk of bacterial colonization or observed serendipitously among patients with
infection. Such treatments may consist of topical hemangioendotheliomas (KMP) treated for
antibiotics or anesthetics, wound dressings, thrombocytopenia in the late 1950s and early
barrier creams, or all of the above. Most 1960s. 152 In
ulcerations improve with this conservative
approach to wound care. Because ulceration is
usually associated with proliferation of the IH,
therapies to curb its growth are often used.
Several case series have reported successful
treatment of IH ulceration with propranolol • Management of ulcerated IH
therapy. 144 – 146 Topical timolol has been reported consists primarily of the following: (1) 1967, Zarem and Edgerton 153 treated 7
to be successful for ulceration, 147 but its barrier dressings, (2) pain control, consecutive children with oral prednisolone for
absorption is unpredictable in this setting. enlarging IHs. All 7 experienced cessation of
and (3) control of IH growth.
Systemic steroids may also be a reasonable lesional growth and no rebound growth after
alternative. treatment. On the basis of this result, Fost and
Esterly 138 treated 6 children with oral prednisone
• Adjuvant therapies may include the for extensive IHs. All but 1 had dramatic
following: regression after only 2 weeks of therapy.
1. topical agents, including
Subsequent studies have continued to show ef fi cacy,
antibiotics, anesthetics, or
although physicians have raised concerns about
wound dressings, and
potential
2. pulsed dye laser.
In refractory cases, pulsed-dye laser (PDL)
therapy may also be effective in managing
ulcerated IHs. 96,148 – 150 In a prospective study in
78 children, 91% of the patients responded to TABLE 4 Treatment Options in the Management of Ulcerated IH
laser therapy with a mean number of Wound Care Adjuvant Therapies
Dressings Antimicrobials
2.0 treatments. 148 Thus, PDL therapy has been White petrolatum – impregnated gauze Metronidazole gel
used as both monotherapy and as adjunctive Nonadherent dressings (eg, Mepitel [Mölnlycke Mupirocin, gentamicin, bacitracin ointment Pain
Health Care; Gothenburg, Sweden], Telfa control
therapy in managing ulcerated IHs; however, it
[Covidien/Medtronic; Minneapolis, MN]) Topical
has been recommended that laser therapy be
Hydrocolloid dressings (eg, DuoDERM Anesthetics (eg, lidocaine, benzocaine) Oral
used with caution in patients with proliferating [ConvaTec; Luxembourg])
IHs because of the risks of atrophic scarring Topical agents Acetaminophen with or without narcotics
and/or ulceration. 151 Surgical excision may also White petrolatum, Aquaphor [Beiersdorf Inc.; Other
Hamburg, Germany], Silver sulfadiazine Becaplermin gel Topical timolol PDL
be a consideration for small ulcerations that are
(Silvadene; Monarch Pharmaceuticals; Early excision Oral propranolol or
poorly responsive to medical therapy.
Bristol, TN) steroids

adverse effects of steroids become the fi rst-line medical therapy; however, target hemangioma), compared with a 4% rate
administered in large doses for long periods of optimal dosing, treatment timing and duration, among those treated with placebo. 172 Another
time. and risk of complications have not yet been randomized trial in 40 patients found a marked
established in randomized trials, and improvement in IH volume, redness, and
In the late 1980s and early 1990s, interferon- a showed
recommendations for monitoring are still elevation among those taking propranolol
some promise in the treatment of
evolving. 161 An oral formulation free of alcohol, compared with those taking placebo. 173 In a
steroid-resistant IHs. This drug is a cytokine
sugar, and paraben developed for use in 2011 comprehensive review of the literature,
produced by leukocytes that play a role in the
children (Hemangeol; Pierre Fabre, Castres, response to propranolol therapy was evaluated
innate immune response against viruses. When
France) received approval from the US Food in 79 articles but quanti fi ed in only 6. 160 Positive
synthetic interferon- a 2a was used to treat
and Drug Administration in March 2014. There responses in all treated patients were reported
patients with HIV, an improvement in their
is a paucity of data regarding other b- adrenergic in 86% of publications; the remaining 14%
Kaposi sarcoma lesions was noted. 154
blockers. 162 discussed at least some treatment failures. In
total, 19 of 1175 patients in these publications
were reported as treatment failures, suggesting
a 1.6% treatment failure rate. 160
Because interferon-induced genes are
upregulated during involution of IH, there was a
theoretical basis for its mechanism of action in
Mode of Action in IH
IH, 152 and anecdotal reports as well as clinical
trials subsequently documented its ef fi cacy in The mode of action of propranolol in the
vascular lesions, including IHs refractory to treatment of IH is unknown. Proposed

mechanisms include vasoconstriction, inhibition Moreover, lightening of the color and softening
corticosteroid therapy. 156,157 However, it is now
of angiogenesis (via suppression of VEGF-A of the tumor was noted in most children within
clear that signi fi cant neurologic toxicities,
and downregulation of MMPs and interleukin hours to days of the initial dose of propranolol. 158,159,173,174
including impairment of higher cortical and
[IL] 6), regulation of the renin-angiotensin After initiation of propranolol therapy,
motor function, can occur and generally
system, and inhibition of nitric oxide production; progressive improvement has been noted for at
preclude its use as a fi rst-line therapy. In 2008,
propranolol ’ s ability to stimulate apoptosis is least 3 months in most patients. 158,159,173,174 Like
Léauté-Labrèze et al 158
equivocal. 44,49,140,141,159,161,163 – 167 systemic corticosteroids, propranolol appears to
stabilize IHs in their growth phase; however, it
may also be effective after proliferation has
ended. In 1 study that assigned visual analog
reported their serendipitous observation scores to IHs in children treated with propranolol
Investigators have shown the presence of b 2-adrenergic
that oral propranolol, a nonselective blocker at ages 7 to 120 months, more than half of the
receptors on capillary endothelial cells in
of patients achieved a greater rate of improvement
proliferating IH, and vascular endothelial cell
b- adrenergic receptors used for decades to in their scores after starting the medication. 143 Other
growth factors, which are elevated in rapidly
treat cardiac disorders in children, is effective authors have also reported similar observations. 142,175
growing IHs, are suppressed in the presence of
and well tolerated in the management of IH. A
year later, they reported their experience with
32 infants with severe IH who were treated with
b- adrenergic receptor blockade. 158 – 160,168 It has
propranolol at 2 to 3 mg/kg per day in 2 to 3
also been suggested that propranolol may
divided doses. 159 These infants responded well
prevent the differentiation of IH stem cells into
with a rapid, consistent, therapeutic effect and
endothelial cells or pericytes, 169 reduce
minimal adverse effects. Since that time, there
contractility of pericytes, 170 and/or promote
have been numerous additional reports of the adipogenesis. 140,165,171
safe and effective use of propranolol for the
treatment of medically complex as well as Pretreatment Assessment, Contraindications, and
cosmetically signi fi cant IHs. 160 Risks of Therapy
A complete history and physical examination,

Ef fi cacy with special attention to the cardiac and
In a randomized controlled trial of oral pulmonary systems, aid in assessing a child ’ s
propranolol in 460 infants aged 1 to 5 months candidacy for propranolol initiation.
with IH, patients administered a dose of 3.4 Electrocardiography is often ordered as well,
mg/kg per day exhibited a 60% rate of particularly in younger infants, those with a low
b- Adrenergic Blockers heart rate, and those with an examination or
successful treatment (complete or nearly
For most clinicians treating complicated complete resolution of the
IHs, propranolol has

TABLE 5 Contraindications and Potential generally asymptomatic and do not require each dosage increase of $0.5 mg/kg per day.
Complications Associated With intervention. 177 Less common complications Heart rates or blood pressure measurements
Propranolol Therapy Contraindications include bronchospasm and hypoglycemia, the lower than 2 SDs from the mean suggest the
Complications latter of which has the potential to induce need for cardiologic evaluation. It should be
Sinus bradycardia Sinus bradycardia seizures. 159,161,180,181 In a systematic review of noted that, where there was controversy, the
Hypotension Hypotension propranolol treatment of IH, there were 371 total group recommended the most conservative
Greater than Diarrhea
adverse effects reported in 1189 patients. 182 approach to propranolol initiation. The risk of
fi rst-degree Cool extremities Sleep
heart block disturbance Reactive hypoglycemia may be reduced by administering
Heart failure airways propranolol and feeding children at intervals not
Cardiogenic shock Hypoglycemia/seizures Those most commonly reported were sleep to exceed 8 hours (or 6 hours in younger
Reactive airways
disturbance (136 patients), acrocyanosis (61 infants). 161
Hypoglycemia
patients), hypotension (39 patients, including 5
Hypersensitivity
to propranolol considered “ symptomatic ”),
hydrochloride Adapted
from ref 161. bradycardia (8 patients, including 1 considered

symptomatic), and respiratory events including Children with any acute illness, especially one
infections, wheezing, and stridor (35 patients). interfering with normal oral intake or one
family history consistent with congenital associated with vomiting or diarrhea, will
heart disease. 161 Some clinicians also require close monitoring and often a
prefer to have a cardiology consultation temporary decrease in dosing or cessation of
before starting the medication. However, therapy.
Initiation of Therapy and Dosing
pretreatment cardiac screening appears to
be of limited value in patients with an Although the optimal setting for the initiation of
unremarkable cardiac history and propranolol has yet to be established, a
examination. 176 – 179 Relative consensus group has suggested that inpatient
Duration of Therapy
contraindications to the use of propranolol hospitalization be considered for infants 8
for IH include weeks of age or younger, preterm infants less The most dramatic improvement using
than 48 weeks ’ propranolol for IH occurs within 3 to 4 months of
initiation of therapy. However, many
cardiogenic shock, sinus bradycardia, postconceptional age, those with poor social investigators continue therapy until patients
hypotension, heart block greater than the fi rst support, and those with cardiac or pulmonary reach an age when IH would normally begin to
degree, heart failure, bronchial asthma, and risk factors. 161 The group recommended regress without treatment. Hence, treatment is
initiating therapy at a dose of 1 mg/kg per day,
known hypersensitivity to the drug (Table 5). 161 Special often continued until at least 8 to 12 months of
precautions have been suggested for children with escalation to a target dose of 1 to 3 mg/kg age, which, in most studies, equated to 3 to 12
diagnosed with PHACE syndrome and signi fi cant per day, although this recommendation was months of therapy. 160,172 For discontinuation of
intracranial vascular anomalies because of the made prior to the FDA approval of Hemangeol, therapy, most practitioners taper propranolol
theoretically increased risk of acute ischemic which is dosed maximally at 3.4 mg/kg per day. gradually over a period of 1 to 3 weeks,
stroke. 161 The optimal dose for maintenance has yet to be primarily in an effort to prevent rebound sinus
established. The group ’ s recommended dosing tachycardia. Rebound growth of IH has been
frequency was 3 times daily; however, the drug observed in 6% to 25% of children, often well
has also been dosed twice daily and showed after their fi rst birthday, leading some clinicians
both safety and ef fi cacy. 172,183,184 Because the to wean propranolol over weeks to months. 185 – 189
Experience in the management of hundreds peak effect of oral propranolol on heart rate and Rebound growth may be more likely in patients
of infants with IH has shown propranolol to blood pressure is 1 to 3 hours after whose IH exhibited a long proliferative stage
have an excellent safety pro fi le and high administration, the group suggested that these and a large subcutaneous component. 185 In
tolerability. The most commonly reported measurements be taken at baseline, 1 and 2 such cases, reinitiation of therapy for variable
adverse effects of propranolol are sleep hours after the periods of time may be necessary.
disturbance and coolness and mottling of
the distal extremities. The use of
b- blockers can be also be associated with

adverse cardiac effects, including bradycardia
and hypotension, both of which are
fi rst dose, and 1 and 2 hours after

Topical b- Adrenergic Blockers The diversity of these effects may account for
the variability in response, particularly with the
Several investigators have reported
• Propranolol, administered orally stage of the treated lesion. Steroids inhibit
success using topical
at a dose of 1 to neovessel growth in cultured human IH biopsies 197
b- blockers in the treatment of IH. Timolol
3.4 mg/kg per day, is ef fi cacious in and IL-6 – mediated neovascularization in a rat
maleate is a nonselective
reducing the size and color intensity corneal model. 198 Corticosteroids also inhibit the
b- adrenergic receptor inhibitor available in
of IH. expression of proangiogenic proteins, including
a concentration of
• The mechanism of propranolol ’ s VEGF-A, urokinase plasminogen activator
0.25% and 0.5%, which has been used by
effect on IH likely involves several receptor, monocyte chemoattractant protein-1,
pediatric
processes, including IL-6, and MMP-1, from human IH stem cells in a
ophthalmologists in the United States for more
vasoconstriction, inhibition of murine model. 40,197 In addition, glucocorticoids
than 30 years as a fi rst-line therapy in children
angiogenesis, and stimulation of inhibit the antiadipocytic differentiation effect of
with glaucoma. In recent years, an
apoptosis. preadipocyte factor 1 199,200 and promote
extended-release gel-forming solution has
adipogenesis by increasing the expression of
become available in concentrations of 0.25%
peroxisome proliferator activated receptor. 201,202
and 0.5%. Systemic absorption of the • Common side effects of propranolol
gelforming solution is signi fi cantly lower than include sleep disturbance and
that of the solution, and absorption through discoloration with cooling of the
intact skin is likely much less than that through hands and feet.
the conjunctivae and lacrimal duct. 190
• Contraindications to the use of

This activity is thought to explain the
propranolol for IH include
development of the fi brofatty residuum during
cardiogenic shock, sinus
involution of the vascular components of IH.
bradycardia, hypotension, heart
block greater than
Case reports and case series have shown a
fi rst-degree, heart failure,
good response of IH to twice-daily topical Systemic Corticosteroids
bronchial asthma, and known
application of timolol. 191 – 195 In a randomized
hypersensitivity to the drug. Systemic therapy with corticosteroids for large
controlled trial, timolol was more effective than
and complicated IHs has, in many centers, been
placebo in reducing the size and color intensity
supplanted by systemic b- blockers.
of small super fi cial IHs. 196 Laboratory studies • A consensus report suggests that
Nevertheless, steroids have played a signi fi cant
were not monitored in the majority of studies, heart rate and blood pressure be
role in IH management over the past few
and only 1 infant in 1 large series developed a determined at baseline, 1 and 2
decades, and properly dosed and monitored,
transient sleep disturbance. Responses were hours after the fi rst dose of
they remain an effective modality in the
best in patients who had super fi cial IHs, used propranolol, and 1 and 2 hours after
management of IH, especially in patients in
the each dosage increase of $0.5 mg/kg
whom
per day.
b- blocker therapy is risky or contraindicated. 203 One

• Administration of propranolol with report in 60 children with IHs treated with either
0.5% gel-forming solution, and applied the feedings, and holding doses if oral 3 or 5 mg/kg per day of oral prednisone found
medication for more than 3 months. 195 Many intake is compromised, reduces the an excellent response in 68% and a good
experts now consider topical timolol gel-forming likelihood of hypoglycemia. response in 25%; therapy failed in 7%. 204 A
solution a reasonable consideration for systematic literature review showed an 84%
uncomplicated, super fi cial IHs for which • Topical application of timolol has response rate at an average dose of 2.9 mg/kg
treatment is desired but the risk-to-bene fi t ratio shown ef fi cacy in the management of per day of oral prednisone. 205 Another recent
is too great to justify systemic b- blocker therapy. super fi cial IHs. article reported the response to systemic
However, there are valid concerns regarding the corticosteroids was signi fi cant in 30% to 53% of
bioavailability of the drug when used topically in cases, equivocal in 35% to 40%, and negligible
neonates and infants, especially in the in the remainder. 206 In a prospective,
treatment of larger or ulcerated lesions and Corticosteroid Therapy
randomized, investigator-blinded trial comparing
those on or near mucous membranes. 190 The precise mechanism of action of prednisolone and propranolol dosed at 2.0
glucocorticoids in the treatment of IHs remains mg/kg per day, the drugs
largely unknown. Evidence suggests that
corticosteroid therapy has several effects on IH,
involving both vasculogenesis and adipogenesis.

showed similar ef fi cacy for reducing the area of localized complications involving the overlying occurs in lesions of the upper eyelid, with 3
symptomatic IH; however, although skin or underlying tissues. However, in cases of retinal embolization having been
prednisolone showed a somewhat faster appropriately selected lesions, many authors reported after an injection of corticosteroids into
response rate, propranolol was better tolerated consider intralesional corticosteroid injection IHs in this region. 221 – 223 This complication likely
with signi fi cantly fewer severe adverse effects. 207 an effective intervention, given its results from a combination of high injection
Rebound growth occurs in 14% to 37% during effectiveness and the relatively low frequency pressures (causing retrograde fl ow of the drug
dose tapering, occasionally requiring the of reported systemic adverse effects at low from the eyelid toward the apex of the orbit) and
resumption of steroid therapy. 205 This wide doses (#2 – 3 mg/kg). 210 – 219 excessive injection volume. 224
range in rebound rates likely re fl ects the varied

duration of corticosteroid therapy reported in the
literature. Optimal dosing of systemic However, in several large series of intralesional
In most studies, patients were injected with
corticosteroids remains somewhat controversial. corticosteroids for periorbital lesions, this
either triamcinolone alone or a mixture of
However, although recommendations for complication was not reported. Avoidance of
triamcinolone and betamethasone, at total
prednisolone dosing have ranged from 2 to 5 this complication is discussed further in the
equivalent doses of triamcinolone doses of
mg/ kg per day, 132,203,204,208,209 optimal dosing subsection “ Eye and Orbit ” under
appears to be 2 to 3 mg/kg per day. The , 3 mg/kg, by using a 27- or 30-gauge needle. 218
duration of therapy depends on response rate The interval between injections varied from 1 to “ IHs With Special Anatomic
as well as the age of the patient and phase of IH 6 weeks. 208 Concerns. ”
growth but generally ranges from 4 to 12 weeks After corticosteroid injection, large studies have
at full dose, followed by tapering over several Topical Corticosteroids
reported accelerated regression in 77% to 100%
months and completion of treatment by 9 to 12 of patients with IH and cessation of growth in The use of high-potency topical corticosteroids
months of age. 132,205 16% to 23%. 210 – 219 The effects of the steroid last in IH is usually limited to thin, super fi cial lesions.
approximately 3 to 4 weeks 216 and thus patients In the initial reports in the 1990s, topical
may require additional treatments during the clobetasol propionate was used for periocular
proliferating phase for rebound growth. IHs with good ef fi cacy and no signi fi cant
adverse effects. 225,226 A subsequent
retrospective chart review of 34 infants with
proliferating IHs who had been treated with
high-potency topical steroids found that 35% of
Local complications of intralesional
the infants had good response, whereas 38%
Intralesional Corticosteroids corticosteroids include fat and/or dermal
had a partial response. 227 A more recent
atrophy and/or hypopigmentation (0% – 3%). 213 –
The effectiveness of intralesional corticosteroid comparison of topical mometasone furoate
215
therapy for problematic IHs was fi rst described versus intralesional triamcinolone acetonide in
in 1967 by Zarem and Edgerton, 153 in the same Systemic adverse effects, including cushingoid
features (0% – 3%) 213 – 217 super fi cial IHs less than 5 cm in diameter
article in which they reported their success showed that 86.5% (50% excellent,
treating IH with oral corticosteroids. and adrenal suppression, 220 can occur when
very large doses of intralesional steroids are
given ($5 mg/kg). A more serious complication
Subsequently, numerous studies have of intralesional corticosteroid therapy

suggested that intralesional corticosteroid 36.5% good) of patients in the topical group and
injection is a safe and effective treatment of IH. 210
95.7% (63.8% excellent,
– 219
TABLE 6 Potential Adverse Effects of 31.9% good) in the intralesional group
Systemic Corticosteroids HPA responded to the therapy. 228
In general, corticosteroid injection is reserved
axis suppression Cushingoid features Growth
for small, bulky, welllocalized IH lesions. Large
deceleration Weight gain/increased appetite
or diffuse IHs are more dif fi cult to manage with Adverse Effects of Corticosteroid Therapy
Hypertension Gastric irritation Irritability
intralesional corticosteroids because of the Insomnia Immune suppression Cardiomyopathy
following: (1) a large volume of injectable steroid Steroid myopathy Osteopenia Potential systemic adverse effects of
is more likely to cause systemic adverse effects 220 corticosteroids used in the treatment of IH are
and (2) it is dif fi cult to evenly distribute the presented in Table 6 and are the most common
corticosteroid throughout a large tumor. In reason cited for using propranolol as fi rst-line
lesions that are relatively fl at or super fi cial, therapy. It should be noted, however, that a few
intralesional steroid injection carries an physicians have favored the safety pro fi le of
increased risk of corticosteroids over that of propranolol. 229
Ocular adverse effects (glaucoma, cataracts) HPA,
hypothalamic-pituitary-adrenal.

Suppression of the experts. 238 – 240 Furthermore, it has been
hypothalamicpituitary-adrenal axis has been suggested that infants not receive live vaccines
observed during therapy with both intralesional 215 during long-term corticosteroid therapy and that • Despite their ef fi cacy, systemic
– 217,220,230,231 and systemic 132,232 – 236 steroids. clinicians consider checking vaccine titers on corticosteroids are no longer
However, incidence estimates for completion of corticosteroid therapy to assess considered by most clinicians to be fi
hypothalamic-pituitary-adrenal axis the adequacy of response. 237 rst-line therapy for IH due to the
suppression vary widely, from associated risk of adverse effects.
1.7% 222 to 87%. 234 Furthermore, although

Ocular adverse effects of long-term systemic
many patients experience abnormal morning • Corticosteroids, administered orally
corticosteroid therapy include cataracts 241,242 and
cortisol levels, nearly all appear to normalize at a dose of 2 to 3 mg/kg per day,
increased intraocular pressure, 242 – 245 although
in a few months. 220,231 are ef fi cacious in reducing size and
neither has been frequently reported among
discoloration of IH.
children in general or among those being
Temporary growth deceleration has also been treated for IH in particular. The most serious
reported with both intralesional 218,220,232 and ocular adverse effect is that of vision loss • The mechanism of IH growth
systemic 132,236,237 steroid therapy of IHs. caused by embolic occlusion of the central inhibition by corticosteroids likely
Almost all children experience retinal artery after intralesional injection. 221 – 223 involves reduced vasculogenesis
and enhanced adipogenesis.
“ catch up ” growth after completion of therapy. 236 Gastric
irritation is seen in 21% 236 to 32% 234 of patients • Corticosteroids administered
taking oral corticosteroids. This adverse effect intralesionally and topically also
However, the actual risk is thought to be quite
can be ameliorated by concomitant use of H 2- receptorlow and is primarily related to high injection appear to be effective in certain
antagonists. 132,215,218 Mild behavioral changes pressure. 224,246,247 subsets of patients with more
have been seen in up to 29% of infants localized IH, but their dosing and
This complication is discussed in greater detail
receiving systemic corticosteroid for IH therapy. 236 safety pro fi le are not well studied.
in the subsection “ Eye and Orbit ” under “ IHs
These include irritability, fussiness, insomnia,
With Special Anatomic Concerns. ”
and personality changes. 230,234,236,237
• Periodic reexamination of children

Cutaneous adverse effects of steroids are most
receiving corticosteroid therapy for
often associated with intralesional and topical
IH has been suggested for
Osteopenia is a known adverse effect of therapy. The most common risks are atrophy
monitoring of growth and blood
long-term systemic corticosteroid therapy but is and hypopigmentation, although the former is
pressure as well as changes in the
rarely observed in children with IH, which often attributable to the IH itself, whereas the
lesion(s) being treated.
presumably is related to the relatively short latter is usually transient. 227,233 Other potential
duration and nonrepetitive nature of therapy but unusual risks include acne, periori fi cial
typically used for the treatment of IHs. dermatitis, striae distensae, and hypertrichosis.
Hypertension is also a risk of systemic In treating bulky IHs with intralesional therapy,
corticosteroid therapy, but the percentage of cutaneous complications can be avoided by
affected individuals is unknown and is likely keeping the injection well below the dermis. Other Medical Therapies
dose dependent. Immunosuppressive effects of Given the many potential adverse effects of
Before the discovery of the therapeutic ef fi cacy
systemic corticosteroid therapy are well known. glucocorticoid therapy, many physicians will
of propranolol for IH, several other agents were
These include increased infection risk, reduced periodically reevaluate those infants receiving
used in an attempt to optimize ef fi cacy and
B- and T-lymphocyte counts, and poor response systemic corticosteroids (oral or intralesional),
safety. This section will focus on 3 agents that
to vaccines. 132,218,236,237 with speci fi c attention to growth variables and
have documented utility in the treatment of IH:
blood pressure. Some physicians will also
vincristine, interferon- a, and imiquimod.
reassess adrenal function at the end of therapy
Unfortunately, the adverse effect pro fi les of
and determine the need for stress doses of these agents limit their usefulness, and they are
steroids on cessation of therapy.
Rare cases of pneumonia attributable to Pneumocystis generally reserved as treatments only for
carinii infection have been reported in infants recalcitrant lesions. In addition, the potential
taking corticosteroids for IH, and prophylaxis of usefulness of newer angiogenesis inhibitors will
these patients with be discussed.
trimethoprim-sulfamethoxazole has been
advocated by some

Vincristine neutropenia, and spastic diplegia. Although The drug was used 3 times weekly in 10
some have reported response rates of up to patients and 5 times weekly in 8 patients, with a
Vincristine is a plant-derived vinca alkaloid that
90% in steroid-resistant lesions, the effect is mean duration of therapy of 17 weeks. All super fi
impairs mitosis via microtubule formation. It has
gradual in onset, and rebound can occur on cial IHs improved, but little or no change
traditionally been used as a chemotherapeutic
discontinuation. 254 occurred in mixed and deep IHs. Irritation and
agent and possesses multiple antiangiogenic
crusting were the most common adverse
qualities. It induces endothelial cell apoptosis
effects. This study was criticized because of the
and is also a potent inhibitor of endothelial cell Up to 20% of children treated with interferon- a appear
lack of a control group. 263
growth, migration, and in vitro capillary-like tube to develop spastic diplegia. 255 This complication
formation. 248 Given that endothelial cells also tends to occur later in the treatment course and
possess a high tubulin content, a biological may be irreversible. 256
rationale for IH sensitivity to vincristine exists. 249 A subsequent phase II, open-label study
followed 16 children with mixed results. 264
Most reports on the ef fi cacy of vincristine Some practitioners initially theorized that only
address the treatment of patients with vascular interferon- a 2a, or perhaps the preservative or
lesions that were not true IHs but rather KHE or vehicle, were the cause of these symptoms; Although some proponents of imiquimod
TAs associated with KMP. 250 however, similar toxicities have also been continue to use it for the treatment of super fi cial
reported with interferon- a 2b. 257 IH, irritation, crusting, and occasionally signi fi cant
ulceration noted with treatment seriously limit its
Given these concerns, interferon- a is generally utility. Imiquimod does not have a role in the
considered a “ last resort ” treatment of deep IHs.
treatment, and most physicians prefer to use
However, vincristine has also been used propranolol, systemic corticosteroids, or
successfully in the management of vincristine before treating with this agent.
Antiangiogenic Agents
function-threatening or lifethreatening IHs
(airway, orbital, or hepatic). 251,252 The drug is Although all of the above treatments have
administered weekly through a central catheter antiangiogenic effects, a few newer therapies
Imiquimod (Imidazoquinoline 5%)
because of its extreme vesicant and irritative have speci fi c antiangiogenic mechanisms of
This topical immune-response modi fi er
potential. Adverse effects include irritation, action that make them theoretically attractive
stimulates the innate immune system by
neurotoxicity, loss of deep tendon re fl exes, therapeutic options. Antagonists to vascular
augmenting the production of cytokines,
constipation, cranial nerve palsies, and bone growth factors or receptors, such as inhibitors of
including interferons ( a, b, and g); IL-10, IL-12,
pain. Alopecia, rash, and myelosuppression are VEGF or bFGF, have been successfully used to
and IL-18; and tumor necrosis factor. These
also possible. Reported adverse effects were blunt angiogenesis in tumor models and as
agents enhance cell-mediated immunity and
transient. 253 This drug appears to be particularly therapies for advanced neoplasms; however, the
induce apoptosis. However, it may well be that
useful in patients with corticosteroid-resistant simultaneous administration of cytotoxic agents
imiquimod ’ s therapeutic effect on IH results from
KMP, but it is not a fi rst-line therapy for IH. appears to be required to achieve signi fi cant
the inhibition of angiogenesis by these
response rates. 265 An incidental decrease in the
cytokines. In addition, imiquimod downregulates
size of a liver IH was noted in a patient treated
proangiogenic factors such as bFGF and
with bevacizumab, a VEGF inhibitor. 266 Most
MMP-9 and upregulates other endogenous
recently, the antivasculogenic effect of
angiogenesis inhibitors, including
rapamycin has been shown in a mouse
interferon-inducible protein
hemangioma model; the drug diminished the
Interferon- a
self-renewal capacity of the IH stem cells while
Interferon- a 2a and 2b have both been used simultaneously inducing other antiangiogenic
successfully for IH in children. 156,157 Interferon- a is effects on IH endothelial cells. 267 Rapamycin is a
10, tissue inhibitor of MMPs, and
given subcutaneously with an initial dose of 1 macrolide known to have both
thrombospondins. 258 Topical application of
million IU/m 2, increasing to 3 million U daily over immunosuppressant and antiangiogenic actions,
imiquimod has been shown to markedly inhibit
the fi rst month of therapy while monitoring and therefore the risk-bene fi t ratio of this agent
tumor cell – induced angiogenesis in a human
neurologic status, white blood cell count, and will need to be clearly established before it
keratinocyte model. 259,260
liver function status. 206 Most patients have
required between 2 and 12 months of therapy.
Adverse effects are signi fi cant and include fl ulike In 2002, the successful use of imiquimod
reactions, rash, gastrointestinal symptoms, was reported in the treatment of scalp
transaminitis, IHs. 261
Subsequently, a retrospective study reported

the ef fi cacy of topical imiquimod in 18 children
with IH. 262

can be considered a safe alternative to the for absorption by hemoglobin and of an treated and observation groups. 280
agents currently available for the treatment of appropriate exposure time to avoid the Although these fi ndings have been disputed, 281 another
IH. generation of excess thermal energy in article authored by leading laser authorities
adjacent tissues. As indicated in these reports, suggested that infants were particularly
PDL achieves these parameters and has susceptible to complications from PDL
Highlights of This Section become the “ workhorse ” laser in the treatment treatment. 151 The controversy over laser use
of super fi cial vascular lesions. was recently rekindled by a study that showed
• Medications other than
an advantage to early laser management. 282
b- blockers and corticosteroids may
have ef fi cacy in treating IH, but their
utility is limited by their safety pro fi le. PDL was developed primarily for the treatment
of port wine stains. IHs differ greatly in many Although small IHs may be treated without
• Vincristine is used for lesions respects. Although port wine stains are sedation, children with larger lesions often
associated with KMP; however, such malformations made up of low- fl ow, thin-walled require general anesthesia. Recent data
lesions are KHEs and TAs rather ectatic postcapillary venules, IHs are tumors suggest that early exposure to general
than IHs and are associated with made up of small capillaries lined with plump anesthesia may have a negative effect on
potential risks of irritation and endothelial cells and have a higher rate of blood learning and behavior. 283 As a result, repeated
neurotoxicity. fl ow. IHs are also of more varied thickness. As anesthetics required to treat such lesions may
a result, improvement in IH with the use of PDL be less desirable when the likelihood of
is somewhat less predictable than that for port improvement is low and other available
• Interferon- a and imiquimod, although
wine stains. The mechanism for laser treatment options are available. Proposed uses
effective in IH treatment, are
destruction of IHs has not been completely for PDL in IH management include the following:
associated with an undesirable rate
elucidated. (1) early super fi cial facial IHs, (2) treatment of
of complications.
compound IHs in which sacri fi ce of the overlying
skin is undesirable, (3) refractory ulceration, and
(4) signi fi cant residual telangiectasia or fl at IH
persisting after involution.
PDL has undergone multiple improvements
LASER THERAPY FOR IH since it was fi rst introduced. Current models use
Before the discovery of the ef fi cacy of a wavelength of 595 nm and larger spot sizes
propranolol in the treatment of IH, PDL therapy (up to 10 mm) with higher
was frequently a component of the treatment
strategy for IHs. 268 – 277 However, given their fl uences, allowing the laser to penetrate deeper. 279
limited depth of penetration of less than 2 mm, Longer pulse durations facilitate the treatment of Early Super fi cial IHs
these lasers proved useful primarily for super fi cial larger vessels. 279 In addition, the introduction of Although not all super fi cial lesions warrant
lesions and for deep and compound lesions in dynamic cooling delivered to the skin before the intervention, early treatment in cosmetically
which salvage of the super fi cial skin was laser pulse has made treatment safer and less critical areas can reduce or eradicate a super fi cial
desired. Although many such lesions are now painful. dermal IH, allowing the return of normal dermis
treated medically, laser therapy may still have a and preventing the atrophic scarring commonly
role in IH management, particularly when used observed after involution. 268 – 277 Although topical b-
as a part of multimodal therapy or in ulcerating In the 1990s, many laser proponents embraced blocker therapy is also an option in managing
lesions refractory to other therapies. In the the theory that early laser treatment could small super fi cial IHs, there may be greater
1980s, technological advances imparted to eradicate super fi cial proliferating lesions and, at bioavailability of the drug when treating infants,
lasers the capability of selective the very least, reduce the discoloration of the particularly those with IHs that have ulcerated or
photothermolysis, a process by which blood are located near mucous membranes. 189
super fi cial component of a mixed IH. As a
vessels are selectively destroyed while causing result, children often received multiple laser
minimal collateral damage to surrounding tissue. 278 treatments during their
For laser light to be optimized for this purpose, it
needed to be of an appropriate wavelength fi rst year of life. However, a 2002 study in 120
children randomly assigned to laser treatment PDL is a treatment option in such cases.
or observation found that the complete
clearance or presence of minimum residual IH
Treatment of Critical Skin
at 1 year was not signi fi cantly different in the
PDL- In certain anatomic locations, the sacri fi ce of
skin that is atrophic or

still contains IH tissue is undesirable. The face, During the involution phase of IH, children are
and the nasal tip in particular, are areas in which reevaluated periodically if it is likely they might
the removal of affected skin may leave • Laser treatment of IHs may be require excision of residual fi brofatty tissue,
undesirable scars or a poor color match with useful in early, nonproliferating, resection of scarred/excess skin, or
grafted skin. In such cases, early laser super fi cial lesions; management of reconstruction of damaged structures. A residual
treatment may preserve the overlying skin, critical skin; treatment of ulcerating scar will always be present after ulceration of an
allowing it to be later lifted as a fl ap to provide lesions; “ multimodal ” therapy; and IH and may therefore lower the threshold for
access for excision of the deeper IH management of persisting surgery in some cases. Similarly, those lesions
(demonstrated in Fig 17 later in report). postinvolution telangiectasia. likely to leave large fi brofatty residua may be
addressed early. Surgery is rarely an option for
extensive IHs fromwhich the resulting defect is
too large to close primarily or for those cases in
• Pulsed dye laser (PDL) is used most which surgery will result in signi fi cant functional
Treatment of Ulcerated IH
commonly because its light is impairment or an unacceptable scar.
The potential bene fi t of, and evidence for, laser preferentially absorbed by Conversely, resection of small, complicated IHs
treatment of ulcerated IH has previously been hemoglobin. in cosmetically favorable locations may
discussed (see the previous section entitled “ Management
• Use of laser on proliferating and occasionally be preferable to months of
of Ulcerated IHs ”). 96,148 – 150 In most cases, such super fi cial IHs may lead to observation and/or medical therapy. As
intervention is a consideration only after ulceration. discussed earlier, the timing of intervention is
medical management has failed. based on the age of the patient, the degree of
• Atrophic scarring and
deformity, and whether the tumor is still
hypopigmentation are also potential
regressing. If a child has a minor deformity,
complications of laser use in IH.
postponing intervention until maximal involution
has occurred may obviate the need for a
Persisting Telangiectasia or IH After Involution
procedure. Following the patient for as long as
possible may also be indicated for lesions in
After treatment or involution of IH, super fi cial SURGICAL THERAPY FOR IH problematic locations (eg, lip or nasal tip),
vascular ectasias frequently remain. These are because maximal involution may facilitate
effectively treated with PDL. 284 PDL may also be Timing of Intervention reconstruction and reduce the number of
used to treat fl at areas of residual IH tissue. Elective resection of an IH during the proliferative required interventions. Once it is obvious that a
phase is usually not necessary and occasionally child will require operative intervention, surgery
ill advised. Given their young age and the is usually preferable in early childhood (#4 years
vascularity of the tumor, affected patients are at of age), before the child has much awareness of
Complications of Laser Therapy greater risk of anesthetic morbidity, blood loss, the lesion. 287,288,290 – 292 However, by postponing
Complications of laser treatment include and iatrogenic injury. 287,288 In addition, in many intervention until at least 3 years of age, the
atrophic scarring and hypopigmentation, locations such as the lip and nasal tip, the fi nal tumor has had time to involute, often facilitating
particularly in individuals of darker complexion. 151 cosmetic result is superior when growth of the the procedure and improving the fi nal cosmetic
lesion has ceased and the number of surgical result. 287,288
Lasers are also capable of inducing ulceration, interventions can be kept to a minimum.
although this is rare and seen more commonly However, certain factors lower the threshold for
in rapidly proliferating IHs and segmental IHs, resection of a cosmetically or functionally
which, if left untreated, also have a higher risk of problematic lesion during early infancy, including
ulcerating spontaneously. 81,84,151 Scarring is the following: (1) contraindication to
seen when the dermis between the vessels is pharmacotherapy, (2) failure of pharmacotherapy
coagulated. 285 In IHs in which the dermis is to ameliorate the problem, (3) focal involvement
largely replaced by vessels, ef fi cient in an anatomically favorable area, and (4) a high
likelihood that resection will be necessary in the
future (due to bulk or ulceration) and the scar will
be the same. 287 – 289
photocoagulation of these vessels will lead to
scarring. Although the complication rate of PDL
use for IH has not been studied, it is less than Location Considerations
1% in the treatment of port wine stains. 286 For an IH that causes a deformity that cannot be
easily concealed (eg, on the face), surgical
intervention may be

considered in early childhood to prevent diameter of the original IH. 293 This technique IHS WITH SPECIAL ANATOMIC
psychosocial morbidity. If the tumor is hidden by can also be used to alter a vertical forehead
CONCERNS Eye and Orbit
clothing and is not bothersome to the child, scar to a horizontal orientation. In the scalp,
waiting for maximal involution to occur is lenticular excision and linear closure is
acceptable. When considering resection, it is preferred to circular excision/purse-string IHs of the orbit, eyelid, and conjunctiva, also
important to weigh the postoperative scar after closure because a long linear scar is camou fl aged known as periocular IHs, have the potential to
removal of the IH against the preoperative by hair, whereas a circular scar may leave an cause a unique set of vision-related
appearance of the lesion. Linear scars are area of visible alopecia. 288 complications because of their anatomic
ideally placed along the relaxed skin tension location. Compression of the globe, obstruction
lines in the anatomic area where the IH is of the visual axis, and extension into the
located to facilitate the best possible cosmetic Fibrofatty residuum from the deep component of retrobulbar space have the potential to cause
outcome. an IH can be removed by using suction-assisted refractive errors, strabismus, and amblyopia.
lipectomy; similar lesions on the cheek can Although evaluation and management follow
occasionally be approached intraorally to avoid principles common to all IHs, additional
a major cutaneous scar. considerations in these cases strongly in fl uence
Certain anatomic locations present speci fi c clinical decision-making. The importance of
challenges to the surgeon. IHs of the auricular early ophthalmologic assessment of patients
helix and nasal tip involve skin that does not with periocular IH cannot be overemphasized.
move well over the underlying cartilage and is Ophthalmologic consultation is often necessary
dif fi cult to replace. Lesions of the lip that to determine the urgency of intervention. In
extend outside the vermilion may require addition, the full depth of these lesions within
• Indications for surgery for IH during
reestablishment of the vermilioncutaneous the orbit is often underappreciated on routine
infancy are limited to the following:
border as well as the natural labial contours. physical examination, as are visual
Surgery involving the eyelids, oral
1. failure of, or contraindication to,
commissure, and genitalia also carries a risk of
pharmacotherapy;
functional impairment from the procedure itself.
2. focal involvement in an area

anatomically favorable for
resection; and
fi eld cuts and changes in refraction or
3. a high likelihood that resection will
extraocular motion. Amblyopia is the most
ultimately be necessary and the
Technical Considerations common and most serious ophthalmic
scar will be the same regardless
complication of periocular IHs. This disorder
Because an IH itself acts as a tissue expander, of timing.
results when, because of improper stimulation
there is usually adequate skin to allow primary,
linear closure of the wound; skin grafts and local of the involved eye, the portion of the brain
• During involution, surgery may be
fl aps are rarely needed. Because the tumor is serving that eye does not develop properly.
indicated for excision of residual fi brofatty
benign, the entire lesion does not need to be Amblyopia occurs in 43% to 60% of
tissue, resection of scarred/excess
removed; the goal is to improve the appearance
skin, and/or reconstruction of
of the child and subtotal excision is often
damaged structures.
performed. For circular lesions located in visible
areas, the length of the scar and distortion of
• Timing of surgery is based on the
surrounding structures can be minimized by
age of the patient, the location and
circular excision and purse-string closure. 293 Although
degree of deformity, and whether the
lenticular excision of such a lesion will result in a
tumor is still regressing.
scar 2 to 3 times the diameter of the lesion,
purse-string closure, followed by second-stage
lenticular excision several months later, will • Elective surgical intervention for IH is
leave a scar approximately the same length as reasonable after age 4 years
the because, by this age, self-esteem
and long-term memory begin to form
and the tumor has completed most of FIGURE 14
its involution. IH of the left eye causing visual fi eld cut and
astigmatism. Untreated, the lesion could proliferate,
potentially resulting in deprivation amblyopia.

children with untreated periocular IHs, involvement is common in typical superonasal the region all in fl uence the treatment method
usually as a result of visual deprivation or eyelid and orbit cases, but the strabismus is selected. As with most IHs, treatment with
refractive errors. 294 – 296 subtle and requires forced ductions or other propranolol has become the mainstay of
testing to diagnose. Permanent eyelid deformity systemic therapy for periocular lesions.
results from direct invasion, vascular steal, or Numerous case series suggest success not only
Deprivation amblyopia occurs when a bulky IH,
usually in the upper eyelid, completely obstructs prolonged pressure of adjacent structures, in controlling the growth and size of the lesion
visual input into the involved eye. The lack of including the levator palpebrae superioris, but also in improvement of astigmatism. 302 – 304 Unfortunately,
input causes a maldevelopment of visual tarsus, eyelash follicles, and lamina papyracea. perceived successes with propranolol therapy
pathways and may result in irreversible loss of The levator muscle can be salvaged with early may, in some cases, lead to delayed
vision. 297 treatment, but prolonged invasion produces a ophthalmologic referral for more subtle
fatty, atrophic muscle akin to true congenital sequelae, resulting in irreversible changes and
ptosis. Tarsus, lash follicles, and the bones of limiting treatment alternatives, underscoring the
Refractive errors are due to astigmatism or
need for early ophthalmologic evaluation. Before
anisometropia. Astigmatism is the production of the orbit also respond well to early intervention
the advent of propranolol, intralesional steroid
a blurred image on the retina due to altered because the ongoing anatomic destruction or
injection was a popular intervention for the
curvature of the cornea and occurs in 20% to deformity can be arrested at a very early stage.
management of bulky periocular IHs. 299 With the
46% of patients with periocular IHs. 298 IHs Preservation of the tarsus ensures eyelid
use of a combination of triamcinolone and
causing this disorder usually involve the upper margin stability, whereas maintenance of the
betamethasone, a response within 2 weeks
lid 294 ( Fig 14) but may occur in the lower lid as bony socket prevents enophthalmos and facial
could be anticipated in 60% to 80% of patients. 305
well. The astigmatism can be reversed with asymmetry.
However, intralesional steroids have been
early intervention, preferably before 9 months of
associated with a number of complications.
age. Beyond 13 months of age, astigmatism
typically persists despite involution of the IH; 295,296 Most feared is embolism of the central retinal
artery. 221 – 223 This complication is thought to
result from several factors, including high
injection pressures (causing retrograde fl ow of
the drug from the eyelid toward the apex of the
Proptosis is the forward displacement of the orbit), excessive injection volumes, and direct
however, some cases of improvement during
globe from an intraorbital IH. Occurring in intravascular injection. 224,246,247 Although it has
involution have also been reported. 299 – 301 Anisometropia
approximately one-third of children with orbital been argued that high pressures can be avoided
is a difference in refractive error between the
IHs, proptosis can result in impaired by using a large-capacity syringe and small bore
eyes that results in a relatively clear retinal
approximation of the eyelids and corneal cannula, 306
image in the eye with the smaller refractive error
exposure. Optic neuropathy may also result
and a relatively blurred retinal image in the eye
from compression or stretching of the optic
with the larger refractive error. Although children
nerve. 294
with refractive errors attributable to IH can be
treated with contralateral patching regimens,
many still develop permanent spectacle Patients with PHACE syndrome may present
dependence; in many cases, the brain may
with a unique set of ophthalmologic
ignore the blurry image in the involved eye,
abnormalities, including increased retinal
resulting in amblyopia.
vascularity, microphthalmia, optic nerve
hypoplasia, exophthalmos, choroidal
hemangiomas, strabismus, colobomas,
cataracts, and glaucoma. Twenty percent of
affected patients will have at least 1 of these fi ndings,studies suggest that even these precautions
Strabismus, or misalignment of the eyes, occurs often on the side contralateral to the IH. 118 may be insuf fi cient in preventing embolization. 224
in approximately onethird of children with Other reported complications include
untreated periocular IHs. 294 Strabismus may hypopigmentation, atrophy of subcutaneous fat,
result from deprivation amblyopia, mechanical and full-thickness eyelid necrosis. 307 – 310 With
obstruction of extraocular muscle movements, improvements in systemic medications and
or direct extraocular muscle invasion. Medial Alternatives available to treat periocular IHs surgical techniques, many now believe that
rectus involvement is most common and most mirror general treatment options, but special there are better options for the management of
obvious, producing esotropia. Superior oblique regional factors may in fl uence the periocular IHs.
fi nal treatment plan. Urgency, laser safety, and

the luxuriant vascularity of

Airway
IHs can involve any part of the airway. 314 The

exact incidence of airway IH is unknown;
however, over a 4-year period, 33 freestanding
US children ’ s hospitals discharged an average
of 2.5 patients with this diagnosis who had
undergone an airway procedure. 315
Symptoms of airway IH usually manifest during

the period of rapid growth during the fi rst few
months of life. A total of 80% to 90% of affected
infants will present within the fi rst 6 months of
life, with a mean age of 3.6 months at diagnosis. 316,317
Most develop biphasic stridor and barky cough
as the IH enlarges in the subglottis, the
narrowest portion of the pediatric airway (Fig
15). Voice and swallowing are generally normal.
Often, the symptoms are mistaken for those of
infectious or in fl ammatory croup or reactive
FIGURE 15 airway disease, especially when the symptoms
Airway IH extending from the vocal folds inferiorly into the subglottic space, the narrowest region of the pediatric airway. worsen in the presence of upper respiratory
(Photo courtesy of Jonathan Perkins, DO.)
illness. As a result, symptoms are often present
for several weeks before a de fi nitive diagnosis is
made. Approximately half of infants in whom an
Topical use of timolol has shown ef fi cacy in the eyelid, and orbit preservation. 312,313 airway IH is diagnosed also will have a
management of super fi cial periocular IHs, as For periocular IHs that are considered for cutaneous IH, but only 1% to 2% of children with
well as IHs involving the conjunctiva and iris. 194,311 surgical resection, preoperative imaging aids in cutaneous IHs also have airway IHs. 318,319 Symptomatic
This drug has replaced other topical therapies establishing the extent of the lesion. Those that airway IHs can be associated with lower facial
such as imiquimod, which causes signi fi cant are best suited for surgery are located outside cutaneous or oral/pharyngeal mucosal IHs in
irritation of the skin, conjunctiva, and cornea, the bony orbit and well circumscribed and nonin fi approximately 50% of cases. 106,107
ltrative on MRI. 313
and topical steroids, which carry the risk of
glaucoma and cataract formation. Laser
treatment (PDL) can also be very effective in
treating super fi cial periocular IHs but usually
requires corneal protection and general
anesthesia.
• IHs of the periocular area have the

potential to cause compression of the
globe, obstruction of the visual axis,
and extension into the retrobulbar
Periocular IHs are often diffuse and are Most infants suspected of having an airway IH
space, resulting in refractive errors,
therefore dif fi cult to excise. Surgery can also on the basis of historical and clinical presentation
strabismus, and amblyopia, leading to
cause hemorrhage that complicates the surgery undergo operative endoscopy. 320 Imaging of the
vision loss.
and can cause postsurgical changes, such as head and neck may be useful in some cases to
ptosis and ectropion, which may be dif fi cult to con fi rm the diagnosis of IH, to de fi ne the extent
correct. However, early surgical removal, in • The permanence of ophthalmic of the airway lesion, or to detect any associated
selected lesions, eliminates the risk of complications due to IH is often vascular, brain, or chest anomalies that could
amblyopia, decreases amblyopia treatment related to their severity and duration, affect treatment. 321,322 Because these airway
times, and dramatically improves the chances underscoring the need for early lesions have a characteristic clinical and
for extraocular muscle, ophthalmologic evaluation. endoscopic

appearance, biopsy of airway IH is not usually initial management of all airway IHs. 338 in patients with bilateral or circumferential
necessary, but when performed, the histologic lesions who may be at risk of postoperative
appearance and cellular markers are the same stenosis or require tracheotomy. However, open
Corticosteroids may be helpful in refractory
as those of cutaneous IH. 323,324 As in cutaneous surgical excision may be more dif fi cult in cases
cases. Initial doses of prednisolone at 2 to 4
IH, airway IH can be localized (focal) or involving signi fi cant extension outside the
mg/kg per day are generally necessary to
extensive (segmental), and many subglottic
control growth. Maintenance doses of larynx, and the procedure may potentially result
lesions show transglottic or paratracheal
approximately 1 to 2 mg/kg per day are often in some degree of dysphonia.
extension. 108,314 The more extensive the lesion,
considered before weaning the medication, and
the more signi fi cant the airway compromise, and
treatment duration is based on clinical
aggressive therapy is usually necessary to
response. Response rates reported in the
prevent airway obstruction. literature vary between 30% and 93%, although
there is little consistency among dosing Highlights of This Section
regimens. 339 • Most patients with IHs of the airway

have subglottic involvement causing
biphasic stridor and barky cough,
The need for and type of intervention for airway often mistaken as croup. Voice and
IH is determined by several factors, including swallowing are generally normal.
Intralesional steroids are a consideration for
the degree of airway obstruction, the extent of
patients whose IHs have necessitated
extralaryngeal IH, the location of the patient at
endoscopy or endoscopic resection. Although
the time of diagnosis, the experience of the • Diagnosis of airway IHs is usually
repeated injections are usually necessary as
treating physician, and the preferences of the single-modality therapy, 327 these medications made by endoscopy in the
parents/ caregivers. Because involution is the may be effective adjuvant therapy for patients operating room.
ultimate fate of virtually all IHs, whose lesions are being observed, treated • In most cases, IHs of the airway may
pharmacologically, or partially resected. be managed medically; in cases of
Successful management has been achieved in severe obstruction, surgical
“ watchful waiting ” is reasonable in cases 77% to 87% of cases with the use of reduction or excision may be
involving minimal intralesional steroids. 317,327 entertained.
symptomatology. In rare symptomatic cases for
which observation is still preferred or pediatric
airway expertise is not readily available,
tracheotomy is occasionally necessary. 325 However,
Airway IHs causing focal obstruction may be Nose
in most cases, some alternative intervention for
addressed surgically by a subtotal endoscopic
the IH is more desirable. Nasal IHs deserve special attention for several
approach by using a microscope or telescope or
reasons. First, the prominence and central
by total excision through an open approach.
location of the nose make it a critical facial
Subtotal approaches generally use a laser 317 or
feature. As a result, even a small IH of the nose
Before the advent of propranolol therapy, rotarypowered instrument. 340 However, subtotal
can have a greater effect on appearance than a
endoscopic laser ablation or surgical excision resection carries the risk of growth of the
lesion of the same size located elsewhere. In
was often recommended in the management of residual lesion during the proliferative phase,
addition, damaged nasal tip skin is exceedingly
airway IH, because the only medical therapy and laser treatment carries a 5% to 25% risk of
dif fi cult to excise or replace without considerable
was long-term corticosteroids. 317,326 – 330 However, subglottic stenosis that is greatest with deeper
cosmetic consequence. Functionally, a nasal IH
many clinicians have now reported success and resections and in cases of bilateral or
may also cause collapse of the nasal introitus
low complication rates using propranolol in the circumferential disease. 326,341,342
and intranasal obstruction. Focal nasal IHs
management of airway IHs. 326,331 – 336 Although
account for 15% to 20% of all focal IHs of the
the optimal dose and appropriate duration of
face; of these, approximately one-third involve
therapy remain uncertain, most clinicians are
the nasal tip. 81 These lesions appear to have
dosing the drug as they would for cutaneous IH. 337
their origin in the intercartilaginous ligament of
Open surgical excision of a focally obstructing the lower lateral nasal cartilages. 346 As the IH
airway IH became popular in the 1990s, after grows, it displaces the
complications of laser therapy became
increasingly apparent. 329,343 – 345 The procedure is
Some authors have suggested that useful in cases refractory to medical therapy and
treatment with propranolol should may be preferable to laser
become the standard for

playwright known as much for his prodigious
proboscis as for his dramatic works. 290,347 Segmental
IHs involving the nose typically affect more
nasal subunits than their focal counterparts, and
they are more likely to ulcerate, resulting in
destruction of critical areas such as the
columella and ala. Conservative management of
nasal IHs is associated with a poor outcome in
most cases. 129,209,348 As a result, early
management of nasal IHs has been advocated
to avoid complications and improve the
likelihood of a favorable outcome, 290,346,349,350 although
the assumed bene fi t is yet unproven. The
approach to nasal IHs is often multimodal,
varying with the location, the stage, and the
depth of the IH. 290,350,351
Medical therapy may commence once the

diagnosis has been made and it is clear that the
IH is growing. The duration of treatment will
depend on the type of lesion and its response.
Focal IHs that respond to propranolol are
generally treated until at least 9 to 10 months of
age, at which time growth of these lesions is
FIGURE 16
Open rhinoplasty approach to nasal tip IH. These lesions (H) originate within intercartilaginous ligament of the lower likely to cease. Rebound growth may be
lateral nasal cartilages (arrows), rotating them outward. addressed by restarting the medication for a
month at a time until there is no further growth.
cartilages outward, rotating them in an “ open involution of the IH, will remain dis fi gured. The
Because segmental IHs may proliferate for
book ” fashion (Fig 16). The net effect is a deformity has been referred to as the “ Cyrano ” nose,
longer periods of time, weaning is often delayed
bulbous, distorted nasal tip, which, even with after Cyrano de Bergerac, the French
until 18 months of age; rebound may be
complete
addressed with additional treatment in 3-month
intervals.
Propranolol-treated IHs of the nasal tip are less

likely than untreated lesions to undergo surgery
or laser therapy, but many lesions still require
such interventions. 352
Extensive skin involvement in focal lesions

may respond to topical
b- blockers or judicious use of laser (PDL)
during proliferation (Fig 17). This treatment will
salvage the skin by reducing the number of
intracutaneous vessels and will also diminish
FIGURE 17
A, Compound IH of the nasal tip with signi fi cant surface involvement. B, Nasal tip after treatment with PDL to salvage tip the risk of venous stasis in
skin before surgical resection.

the deep component after surgical resection. It
also helps to maintain more normal collagen
and skin after proliferation has ceased.
Similarly, for nasal lesions within segmental IHs
that have failed to respond to medical therapy, it
may be best to delay surgery until the overlying
skin has been adequately treated. 350 It is
generally preferable to delay surgical
intervention for such lesions until there is no
further proliferation. PDL may also be used to
treat residual involvement of the overlying skin
after surgery.
Nasal IHs that fail to respond to propranolol or FIGURE 18
leave signi fi cant residual tissue after treatment Ulcerated IH of the lower lip has resulted in distortion of the soft tissue and obliteration of the vermilion-cutaneous
border.
are usually addressed surgically. Although
some authors have advocated surgery for focal
IHs as early as 10 to 12 months of age, 346
occurs, some infants will have dif fi culty latching
on to a breast or bottle nipple without
• Early management of nasal tip IH discomfort, occasionally leading to failure to
most physicians will operate at 1 to 3 years of reduces the likelihood of poor thrive. Furthermore, the vermilion of the lip is a
age. 353 This approach allows for complete cosmesis resulting from skin unique tissue that cannot be replaced if
cessation of growth and adequate time for excision and/or replacement and permanently damaged by ulceration, 358 and
involution of small lesions that may ultimately effects on the underlying cartilage. reconstruction of the normal lip contours after
cause no signi fi cant distortion of the tip.
ulceration can be challenging. Proactive
• Goals of surgery for nasal tip IHs management of IH of the lip, often systemic, is
include complete IH excision, vital if ulceration is to be avoided. However, in
Several publications have dealt with the surgical reconstruction of the cartilaginous the lower lip, some 30% of IH lesions ultimately
approach to nasal IHs. 346,347,350,353 – 357 All of framework, and judicious skin ulcerate. 98 Once ulceration has occurred,
these publications predate the treatment of IH excision and redraping. occlusive dressings are impractical, and
with propranolol, which has clearly changed the therapies such as topical anesthetics and
management paradigm. The major issues in petroleumbased products carry the risk of
surgery for IHs of the nasal tip relate to accidental oral ingestion. Occasionally, children
adequate access and the ability to dispose of with IHs on the lip bene fi t from laser treatment
Lips
the excess skin once the lesion has been of the ulcer, but worsening of the ulceration is a
removed. In general, smaller lesions may be The lips deserve special consideration in the risk. 151 Early surgical resection is a
addressed in a single procedure through an management of IH due to their critical role in consideration, but only for small ulcers in
external rhinoplasty approach, leaving a scar cosmesis and function. Distortion of the lips cosmetically favorable areas. Otherwise,
only on the columella of the nose. 290,350,353,356 Larger from IH is common, and restoring normal lip attention is best directed to systemic therapies
IHs may require external incisions on the ala, contour is one of the greatest challenges in to reduce the likelihood of further ulceration and
also described as a “ modi fi ed subunit approach, ” reconstructive surgery. Furthermore, the lips of excessive lengthening of the lip.
which simpli fi es excision and redraping of the (and the lower lip, in particular) are at increased
skin. 346 Surgery is also useful in restoring the risk of ulceration, 96,98 resulting in pain and
normal position of the lower lateral cartilages bleeding in the short term and in increased
and other components of the cartilaginous scarring and dis fi gurement in the long term.
framework. During proliferation, the goals of managing IH of
the lips are to minimize distortion and to control
ulceration (Fig 18). Once ulceration
Reconstruction of a lip that is scarred and dis fi gured
because of IH is best performed only after
growth of the IH has de fi nitively ceased,
because

recurrence is certain to interfere with be fraught with complications, management failure, hepatomegaly, or abdominal distension. 84,91,92
recontouring. Furthermore, the mucosa of strategies generally focus on those topical and Hepatic IHs have been characterized as
the mandibular oral vestibule is most useful systemic medical remedies previously occurring in 3 patterns: focal, multifocal, and
for discussed (see “ Management of Acute IH diffuse. 362 Focal singular lesions are usually
reconstruction of the vermilion when it is free of Ulceration ”). In rare cases, colostomy has been detected on antenatal imaging or as an
the IH. performed to facilitate wound care. 361 abdominal mass in the newborn infant. It is now
clear that these lesions are not true IHs; rather,
Lesions located exclusively on the vermilion can
they are the hepatic manifestation of a RICH,
be removed by using a transverse mucosal
which explains why they are fully grown at birth. 362,363
incision to hide the scar at the junction of the
They spontaneously involute 90% volumetrically
vermilion and vestibular mucosa 358;
Highlights of This Section by 13 months of age, and involution is not likely
lesions traversing both tissues may require a to be hastened by pharmacologic agents. 362 Diagnosis
• IHs involving the lips and perineum
vertical incision. Bulkier lesions that cause may be made by ultrasonography on the basis
have a tendency to ulcerate, and
lengthening of the lip and those that cross the of the presence of arteriovenous shunting or on
these regions are dif fi cult to
vermilioncutaneous border are best addressed CT or MRI, which reveal hyperintense peripheral
reconstruct. Such lesions are
by using a wedge excision, 359 with some authors contrast enhancement and central sparing.
appropriately managed aggressively
advocating a 2-stage procedure to improve scar Some hepatic RICHs have associated
with medical therapy.
camou fl age. 358 In such cases, incisions may be macrovascular shunts (usually hepatic artery to
placed along the mucocutaneous junction or hepatic vein) that can cause high-output cardiac
philtral columns. Debulking lip IH while failure. If shunts are absent, a hepatic RICH can
preserving vermilion can be performed through be observed with serial ultrasonography to
a mucosal incision; however, it is often Liver determine whether its behavior is typical.
exceedingly dif fi cult to separate IH from Differential diagnosis can include
The liver is the most common location for
orbicularis oris muscle. 359 hepatoblastoma and mesenchymal hamartoma.
visceral IH. Research from the past decade has
If imaging and involution are not diagnostic,
contributed greatly to the classi fi cation of
hepatic tumors and to clarify their natural percutaneous biopsy may be indicated. If shunts
history. 91,362 are present and causing high-output failure,

selective embolization can ameliorate cardiac
Previously viewed homogenously, and often
Eversion of the lower lip can be corrected by failure, and the lesion can be allowed to
treated inappropriately, it is now becoming clear
excision of a mucosal strip, and correction of involute. There is a very small risk of rupture
which patients are at risk and what treatment
inversion may require a lyophilized dermal and hemorrhage with extremely large tumors.
options are sensible.
implant or dermal graft. 359 Setting the “ white roll ” Surgical resection or transplantation is rarely
( ridge at the vermilioncutaneous border) of the necessary. Multifocal and diffuse hepatic IHs
lower lip and restoring normal sublabial Patients at risk of hepatic and other exist on a spectrum. They are true IHs and often
concavity may be particularly challenging. 360 extracutaneous IHs are those with multiple or coexist with cutaneous lesions. In a prospective
multifocal cutaneous IHs. Because studies have study in 151 infants, 16% of infants with 5 or
documented that infants with multiple cutaneous more cutaneous IHs were found to have hepatic
IHs are at increased risk of having hepatic lesions on screening ultrasonography. 364 Multifocal
involvement, screening for hepatic lesions with lesions have ample normal hepatic parenchyma
abdominal ultrasonography has been suggested between them. 362 They
Perineum
for infants with 5 or more cutaneous IHs. 89,92,93 Other
Although perineal area IHs occur in a nonhepatic visceral organ involvement is
nonconspicuous area, they are highly prone to relatively rare in infants with multiple cutaneous
ulceration. In case series from tertiary care IHs; however, performing a thorough review of
dermatology practices, perineal IHs account for systems and physical examination on any infant
approximately one-third of all ulcerating lesions, with multiple cutaneous hemangiomas is
and approximately 50% of IHs occurring in this advisable.
area ultimately ulcerate. 96,98
Perineal ulceration can, at least transiently,

result in signi fi cant pain during defecation and
urination and during diaper changes. Because Infants with hepatic IHs may remain clinically
surgical intervention involving structures in this asymptomatic or can present with
area may life-threatening symptoms of congestive heart

are often asymptomatic; however, some patients with massive hepatomegaly and abdominal CONCLUSIONS
will have macrovascular shunting causing high- fl ow compartment syndrome occasionally has
The management of IHs has evolved
and possible high-output cardiac failure. These disease that cannot wait for drug-induced
considerably in the past decade. The
patients are best treated pharmacologically with involution; in rare cases, such a child may be a
serendipitous discovery of the response of IH to
propranolol or corticosteroids. Shunts will usually candidate for hepatic transplantation.
systemic b- blockers has expanded therapeutic
close with involution of the IH. Selective shunt options for these tumors. Timolol, a topical
embolization is a consideration in those rare
instances in which rapid cardiac failure does not b- blocker, has shown promise as a potential
allow suf fi cient time for response to therapy for super fi cial lesions. A greater
pharmacotherapy. understanding of the indications and limitations
Highlights of This Section of laser therapy also has emerged.
Concurrently, bench research has provided a
• Hepatic IHs have been
deeper understanding of the origins of IH and
characterized as occurring in 3
Diffuse lesions have little hepatic parenchyma patterns of IH growth. It is anticipated that
patterns: focal, multifocal, and
apparent between densely packed nodular IHs continued research will further clarify the
diffuse.
throughout the liver. 362 Patients present with etiology of IH, hopefully leading to
• Focal hepatic IHs are the hepatic
hepatomegaly, which can become massive. pathogenesis-directed therapeutic options.
manifestation of RICH; they are fully
They may develop abdominal compartment
grown at birth, and involution is
syndrome with compromised ventilation, renal
almost complete by 1 year of age.
failure attributable to renal vein compression, or
poor inferior vena caval blood return to the heart Although many IHs can be observed without
and may progress to death. 92 Virtually all diffuse treatment, others will clearly bene fi t from
hepatic IHs cause acquired hypothyroidism • Multifocal and diffuse hepatic IHs are
medical or surgical intervention. It is important
attributable to the inactivation of thyroid true IHs and often coexist with
for pediatricians to keep abreast of advances in
hormones by type 3 iodothyronine deiodinase cutaneous lesions.
IH management, because the types of
constituent in the lesions. 365 intervention and the threshold for their use are
• Multifocal hepatic IHs have normal likely to evolve. When complications are likely or
hepatic parenchyma between them. the threshold for intervention is uncertain,
Many patients are asymptomatic; referral to an experienced specialist or a
however, those with high- multidisciplinary vascular anomalies center may
Hypothyroidism can be very profound and can be advantageous.
require massive replacement hormone dosing. fl ow and/or high-output cardiac
Multifocal lesions also suggest the need for failure require pharmacologic
prompt thyroid screening, because they may therapy with propranolol or
collectively contain enough tumor mass to corticosteroids.
overwhelm endogenous thyroid production. 91,92,365 • Patients with diffuse hepatic IHs
present with hepatomegaly that can LEAD AUTHORS
lead to compromised ventilation, David H. Darrow, MD, DDS, FAAP Arin K.
renal failure attributable to renal vein Greene, MD, FAAP Anthony J. Mancini,
Infants with diffuse hepatic IH, particularly
compression, poor inferior vena MD, FAAP Amy J. Nopper, MD, FAAP
those with congestive heart failure, are at
caval blood return to the heart, and
greatest risk of mortality. 363 Aggressive
death.
CONTRIBUTING AUTHORS
pharmacologic therapy and thyroid hormone
Richard J. Antaya, MD, FAAP (Dermatology) Bernard
replacement are indicated for infants with such Cohen, MD, FAAP (Dermatology) Beth A. Drolet, MD
lesions. Effective IH treatment will result in a • Diffuse hepatic IHs may cause (Dermatology) Aaron Fay, MD (Ophthalmology) Steven
gradual reduction in the requirement for thyroid acquired hypothyroidism. J. Fishman, MD, FAAP (Pediatric Surgery)
replacement and eventual return to the

euthyroid state. 366,367 • Most hepatic IHs are managed Sheila F. Friedlander, MD, FAAP (Dermatology) Fred E.
medically; rarely, embolization, Ghali, MD, FAAP (Dermatology) Kimberly A. Horii, MD,
High- fl ow shunts are uncommon in diffuse surgical resection, and FAAP (Dermatology) Manish N. Patel, DO (Radiology,
transplantation have been Interventional Radiology) Denise W. Metry, MD

lesions. There is no role for embolization in the
(Dermatology) Paula E. North, MD (Pediatric Pathology)
absence of macrovascular shunts and a necessary.
Teresa M. O, MD (Otolaryngology)
highoutput state. An infant who presents

Jonathan A. Perkins, DO (Otolaryngology) Michael L. Smith, Noninvoluting congenital hemangioma: a rare
MD, FAAP (Dermatology) Patricia A. Treadwell, MD, FAAP ABBREVIATIONS
cutaneous vascular anomaly.
(Dermatology) Milton Waner, MD (Otolaryngology, Facial
bFGF: basic fi broblast growth Plast Reconstr Surg. 2001;107(7): 1647 – 1654
Plastic Surgery)
factor CT: computed
Albert C. Yan, MD, FAAP (Dermatology) tomography EPC: endothelial progenitor 3. North PE, Waner M, James CA, Mizeracki
cell GLUT1: glucose transporter A, Frieden IJ, Mihm MC Jr. Congenital
nonprogressive hemangioma: a distinct
SECTION ON DERMATOLOGY EXECUTIVE
protein isoform 1 HemSC: clinicopathologic entity unlike infantile
COMMITTEE, 2014 – 2015
multipotential stem cell hemangioma. Arch Dermatol. 2001; 137(12):1607 – 1620
Bernard A. Cohen, MD, FAAP, Chairperson Richard J.
derived from IH
Antaya, MD, FAAD, FAAP Anna L. Bruckner, MD, FAAP
Kim Horii, MD, FAAP
specimens IH: infantile 4. Boon LM, Enjolras O, Mulliken JB. Congenital
hemangioma IL: interleukin hemangioma: evidence of accelerated involution. J
Nanette B. Silverberg, MD, FAAP Teresa KHE: kaposiform Pediatr. 1996; 128(3):329 – 335
S. Wright, MD, FAAP
Albert C. Yan, MD, FAAD, FAAP, Chairperson-Elect Michael L.
hemangioendothelioma KMP: 5. Baselga E, Cordisco MR, Garzon M, Lee MT,
Smith, MD, FAAP, Ex Of fi cio
Kasabach-Merritt Alomar A, Blei F. Rapidly involuting congenital
phenomenon LBW: low birth haemangioma associated with transient

FORMER SECTION ON DERMATOLOGY weight LUMBAR: Lower body IH and thrombocytopenia and coagulopathy: a case
EXECUTIVE COMMITTEE MEMBER series. Br J Dermatol. 2008;158(6):1363 – 1370
Sheila F. Friedlander, MD, FAAP other cutaneous defects,

Urogenital anomalies and 6. Rangwala S, Wysong A, Tollefson MM, Khuu P,
STAFF ulceration, Myelopathy, Bony Benjamin LT, Bruckner AL. Rapidly involuting
Lynn Colegrove, MA deformities, Anorectal congenital hemangioma associated with profound,

transient thrombocytopenia. Pediatr Dermatol. 2014;31(3):402
malformations and arterial
– 404
anomalies and Renal anomalies
SECTION ON OTOLARYNGOLOGY – HEAD AND NECK
SURGERY EXECUTIVE COMMITTEE, 2014 – 2015

MMP: matrix metalloprotease PDL:
pulsed-dye laser PHACE: Posterior 7. Berenguer B, Mulliken JB, Enjolras O, et al.
fossa defects, Rapidly involuting congenital hemangioma:

Charles Bower, MD, FAAP, Chairperson Christina
clinical and histopathologic features. Pediatr Dev
Baldassari, MD, FAAP German Paul Digoy, MD,
Pathol. 2003;6(6):495 – 510
FAAP Andrew Hotaling, MD, FAAP Stacey Ishman,
MD, MPH, FAAP John McClay, MD, FAAP Diego Hemangiomas, cerebrovascular
Preciado, MD, PhD, FAAP Kristina Rosbe, MD, 8. Mulliken JB, Enjolras O. Congenital hemangiomas
Arterial anomalies, Cardiovascular
FAAP
anomalies including coarctation of and infantile hemangioma: missing links. J Am
Acad Dermatol. 2004;50(6):875 – 882
the aorta, and Eye anomalies MRA:
Scott Schoem, MD, FAAP, Past Chairperson Jeffrey magnetic resonance
Simons, MD, FAAP Steven Sobol, MD, FAAP David 9. North PE, Waner M, Mizeracki A, Mihm MC Jr.
Walner, MD, FAAP GLUT1: a newly discovered immunohistochemical
angiography NICH: marker for juvenile hemangiomas. Hum Pathol.
noninvoluting congenital
STAFF 2000;31(1):11 – 22
hemangioma RICH: rapidly
Vivian Thorne involuting congenital 10. Patrice SJ, Wiss K, Mulliken JB. Pyogenic
hemangioma TA: tufted angioma granuloma (lobular capillary hemangioma): a

clinicopathologic study of 178 cases. Pediatr
SECTION ON PLASTIC SURGERY EXECUTIVE VEGF: vascular endothelial growth
Dermatol. 1991; 8(4):267 – 276
COMMITTEE, 2014 – 2015
Peter J. Taub, MD, FAAP, Chairperson Stephen factor

B. Baker, MD, FAAP Arin K. Greene, MD, FAAP 11. Enjolras O, Wassef M, Mazoyer E, et al. Infants with
Timothy W. King, MD, MPH, FAAP Kasabach-Merritt syndrome do not have “ true ” hemangiomas.
Donald R. Mackay, MD, FAAP, Immediate Past REFERENCES

J Pediatr. 1997;130(4):631 – 640
Chairperson
1. International Society for the Study of Vascular
Delora L. Mount, MD, FAAP, Chairperson-Elect Jordon 12. Zukerberg LR, Nickoloff BJ, Weiss SW.
Anomalies. ISSVA classi fi cation of vascular
Philip Steinberg, MD, FAAP Mark M. Urata, MD, DDS, Kaposiform hemangioendothelioma of infancy
anomalies. 2014. Available at: issva.org/classi fi cation.
FAAP, Vice Chairperson and childhood: an aggressive neoplasm
Accessed April 2015
associated with KasabachMerritt syndrome and
lymphangiomatosis. Am J Surg Pathol.
STAFF
2. Enjolras O, Mulliken JB, Boon LM, Wassef M,
Kathleen Kuk Ozmeral Kozakewich HP, Burrows PE. 1993;17(4):321 – 328

13. Jones EW, Orkin M. Tufted angioma 34. Walter JW, Blei F, Anderson JL, Orlow SJ, Speer
the Dutch population. Paediatr Perinat Epidemiol. 2012;26(2):156
(angioblastoma): a benign progressive angioma, – 162 MC, Marchuk DA. Genetic mapping of a novel
not to be confused with Kaposi ’ s sarcoma or familial form of infantile hemangioma. Am J Med
24. Haggstrom AN, Drolet BA, Baselga E, et al;
low-grade angiosarcoma. J Am Acad Dermatol. Genet.
Hemangioma Investigator Group. Prospective
1999;82(1):77 – 83
study of infantile hemangiomas: demographic,
1989;20(2 pt 1):214 – 225
prenatal, and perinatal characteristics. J Pediatr. 35. Grimmer JF, Williams MS, Pimentel R, et al.
14. Osio A, Fraitag S, Hadj-Rabia S, Bodemer Familial clustering of hemangiomas. Arch
C, de Prost Y, Hamel-Teillac D. Clinical 2007;150(3):291 – 294 Otolaryngol Head Neck Surg. 2011;137(8):757 – 760
spectrum of tufted angiomas in childhood: a
25. Metry D, Heyer G, Hess C, et al; PHACE Syndrome
report of 13 cases and a review of the literature. Arch
Research Conference. Consensus statement on 36. Li J, Chen X, Zhao S, et al. Demographic and
Dermatol. 2010;146(7):758 – 763
diagnostic criteria for PHACE syndrome. clinical characteristics and risk factors for infantile
hemangioma: a Chinese case-control study. Arch
15. Lyons LL, North PE, Mac-Moune Lai F, Stoler MH, Pediatrics. 2009;124(5):1447 – 1456 Dermatol. 2011;147(9):1049 – 1056
Folpe AL, Weiss SW. Kaposiform
26. Chiller KG, Passaro D, Frieden IJ. Hemangiomas of
hemangioendothelioma: a study of 33 cases
infancy: clinical characteristics, morphologic 37. Doege C, Pritsch M, Frühwald MC, Bauer
emphasizing its pathologic, immunophenotypic,
subtypes, and their relationship to race, ethnicity, J. An association between infantile
and biologic uniqueness from juvenile
and sex. Arch Dermatol. 2002;138(12): 1567 – 1576 haemangiomas and erythropoietin treatment in
hemangioma. Am J Surg Pathol. 2004; 28(5):559 – 568
preterm infants. Arch Dis Child Fetal Neonatal Ed. 2012;97(1):
F45 – F49
27. Liggett SB, Cresci S, Kelly RJ, et al. A GRK5

16. Enjolras O, Mulliken JB, Wassef M, et al. Residual
polymorphism that inhibits betaadrenergic 38. Greenberger S, Adini I, Boscolo E, Mulliken JB,
lesions after Kasabach-Merritt phenomenon in 41
receptor signaling is protective in heart failure. Nat Bischoff J. Targeting NF- k B in infantile
patients. J Am Acad Dermatol. 2000;42(2 pt 1):225 – 235
Med. hemangioma-derived stem cells reduces VEGF-A
2008;14(5):510 – 517 expression.
17. Requena L, Sangueza OP. Cutaneous vascular Angiogenesis. 2010;13(4):327 – 335
28. Amir J, Metzker A, Krikler R, Reisner SH.
anomalies. Part I. Hamartomas, malformations,
Strawberry hemangioma in preterm infants. Pediatr 39. Yu Y, Flint AF, Mulliken JB, Wu JK, Bischoff J.
and dilation of preexisting vessels. J Am Acad
Dermatol. 1986;3(4): 331 – 332 Endothelial progenitor cells in infantile
Dermatol. 1997;37(4):523 – 549; quiz: 549 – 552
hemangioma. Blood. 2004; 103(4):1373 – 1375
29. Drolet BA, Swanson EA, Frieden IJ; Hemangioma

Investigator Group. Infantile hemangiomas: an
18. Kanada KN, Merin MR, Munden A, Friedlander SF. 40. Greenberger S, Boscolo E, Adini I, Mulliken JB,
emerging health issue linked to an increased rate
A prospective study of cutaneous fi ndings in Bischoff J. Corticosteroid suppression of VEGF-A in
of low birth weight infants. J Pediatr.
newborns in the United States: correlation with infantile hemangioma-derived stem cells. N Engl J
race, ethnicity, and gestational status using Med. 2010;362(11):1005 – 1013

2008;153(5):712 – 715; 715.e1
updated classi fi cation and nomenclature.
30. Bauland CG, Smit JM, Bartelink LR, Zondervan HA,
41. Kleinman ME, Blei F, Gurtner GC. Circulating
J Pediatr. 2012;161(2):240 – 245 Spauwen PH. Hemangioma in the newborn:
endothelial progenitor cells and vascular
increased incidence after chorionic villus sampling. Prenat
19. Kilcline C, Frieden IJ. Infantile hemangiomas: how anomalies. Lymphat Res Biol. 2005;3(4):234 – 239
Diagn. 2010;30(10): 913 – 917
common are they? A systematic review of the
medical literature. Pediatr Dermatol. 2008;25(2): 42. Khan ZA, Boscolo E, Picard A, et al.
168 – 173
Multipotential stem cells recapitulate human
31. Bauland CG, Smit JM, Scheffers SM, et al. Similar
infantile hemangioma in immunode fi cient mice. J
risk for hemangiomas after amniocentesis and
20. Pratt AG. Birthmarks in infants. AMA Clin Invest.
transabdominal chorionic villus sampling. J Obstet
Arch Derm Syphilol. 1953;67(3):302 – 305 2008;118(7):2592 – 2599
Gynaecol Res. 2012; 38(2):371 – 375
21. Jacobs AH, Walton RG. The incidence of 43. Yu Y, Fuhr J, Boye E, et al. Mesenchymal stem cells
birthmarks in the neonate. Pediatrics. and adipogenesis in hemangioma involution. Stem
1976;58(2):218 – 222 Cells.

32. Colonna V, Resta L, Napoli A, Bonifazi E. Placental
2006;24(6):1605 – 1612
22. Dickison P, Christou E, Wargon O. A hypoxia and neonatal haemangioma: clinical and
prospective study of infantile hemangiomas histological observations. Br J Dermatol. 2010; 44. Itinteang T, Withers AH, Davis PF, Tan ST. Biology of
with a focus on incidence and risk factors. Pediatr 162(1):208 – 209 infantile hemangioma. Front Surg. 2014;1(38):38
Dermatol. 2011;28(6):663 – 669
33. Drolet BA, Frieden IJ. Characteristics of infantile 45. Mihm MC Jr, Nelson JS. Hypothesis: the
23. Hoornweg MJ, Smeulders MJ, Ubbink DT, van der hemangiomas as clues to pathogenesis: does metastatic niche theory can elucidate infantile
Horst CM. The prevalence and risk factors of hypoxia connect the dots? Arch Dermatol. 2010;146(11): hemangioma development. J Cutan Pathol. 2010;37
infantile haemangiomas: a case-control study in 1295 – 1299 (suppl 1):83 – 87

46. Chang J, Most D, Bresnick S, et al. Proliferative human placenta. Arch Dermatol. 2001; 137(5):559 – 570 Pediatrics. 2012;130(2). Available at:
hemangiomas: analysis of cytokine gene www.pediatrics.org/cgi/content/full/ 130/2/e31
expression and angiogenesis. Plast Reconstr
58. Li Q, Yu Y, Bischoff J, Mulliken JB, Olsen BR.
Surg.
Differential expression of CD146 in tissues and 70. Couto RA, Maclellan RA, Zurakowski D, Greene
1999;103(1):1 – 9; discussion: 10
endothelial cells derived from infantile AK. Infantile hemangioma: clinical assessment of
47. Léauté-Labrèze C, Prey S, Ezzedine K. Infantile haemangioma and normal human skin. J Pathol. 2003; the involuting phase and implications for
haemangioma: part I. Pathophysiology, 201(2):296 – 302 management. Plast Reconstr Surg.
epidemiology, clinical features, life cycle and
associated structural abnormalities. J Eur Acad 2012;130(3):619 – 624
59. Lister WA. Natural history of strawberry nevi. Lancet. 1938;231(5991):1429
Dermatol Venereol. 2011;25(11): 1245 – 1253
– 1430 71. Bauland CG, Lüning TH, Smit JM, Zeebregts CJ,
Spauwen PH. Untreated hemangiomas: growth
60. Bivings L. Spontaneous regression of angiomas in
pattern and residual lesions. Plast Reconstr
children; twenty-two years ’
48. Razon MJ, Kräling BM, Mulliken JB, Bischoff J. Surg.
observation covering 236 cases.
Increased apoptosis coincides with onset of 2011;127(4):1643 – 1648
J Pediatr. 1954;45(6):643 – 647
involution in infantile hemangioma. Microcirculation.
72. Jackson R. The natural history of strawberry
61. Margileth AM, Museles M. Current concepts in
naevi. J Cutan Med Surg.
1998;5(2 – 3):189 – 195 diagnosis and management of congenital
1998;2(3):187 – 189
cutaneous hemangiomas.
49. Dai Y, Hou F, Buckmiller L, et al. Decreased eNOS
Pediatrics. 1965;36(3):410 – 416 73. Drolet BA, Esterly NB, Frieden IJ.
protein expression in involuting and
Hemangiomas in children. N Engl J Med. 1999;341(3):173
propranolol-treated hemangiomas. Arch 62. Moroz B. Long-term follow-up of hemangiomas in
– 181
Otolaryngol Head Neck Surg. 2012;138(2):177 – 182 children. In: Williams HB, ed. Symposium on
Vascular Malformations and Melanotic Lesions. 74. Martinez-Perez D, Fein NA, Boon LM, Mulliken JB.
Not all hemangiomas look like strawberries:
50. Ahrens WA, Ridenour RV III, Caron BL, Miller DV,
St Louis, MO: CV Mosby; 1982:27 – 35 uncommon presentations of the most common
Folpe AL. GLUT-1 expression in mesenchymal
tumor of infancy. Pediatr Dermatol.
tumors: an 63. Mulliken JB. Diagnosis and natural history of
immunohistochemical study of 247 soft tissue and hemangiomas. In: Mulliken JB, Young AE, eds. Vascular
1995;12(1):1 – 6
bone neoplasms. Hum Pathol. 2008;39(10):1519 – 1526 Birthmarks: Hemangiomas and Malformations.
75. Corella F, Garcia-Navarro X, Ribe A, Alomar A,
Philadelphia, PA: WB Saunders; 1988: 41 – 62 Baselga E. Abortive or minimal-growth
51. Lavrentieva A, Majore I, Kasper C, Hass
hemangiomas: immunohistochemical evidence
R. Effects of hypoxic culture conditions on
that they represent true infantile hemangiomas.
umbilical cord-derived human mesenchymal stem 64. Esterly NB. Cutaneous hemangiomas, vascular
J Am Acad Dermatol.
cells. Cell Commun Signal. 2010;8:18 stains and malformations, and associated
syndromes. Curr Probl Pediatr. 1996;26(1):3 – 39
2008;58(4):685 – 690
52. Chisti M, Banka N, Alfadley A. Pallor sign: an
76. Toledo-Alberola F, Betlloch-Mas I, Cuesta-Montero
indicator of hemangioma in evolution. J Cutan 65. Bowers RE, Graham EA, Tomlinson KM. The
L, et al. Abortive hemangiomas: description of
Med Surg. 2012; 16(6):451 – 452 natural history of the strawberry nevus. Arch
clinical and pathological fi ndings with special
Dermatol. 1960;82(5): 667 – 670
emphasis on dermoscopy. Eur J Dermatol. 2010;20(4):497
53. North PE, Mihm MC Jr. – 500
Histopathological diagnosis of infantile 66. Chang LC, Haggstrom AN, Drolet BA, et al;
hemangiomas and vascular malformations. Facial Hemangioma Investigator Group. Growth
77. Suh KY, Frieden IJ. Infantile hemangiomas with
Plast Surg Clin North Am. 2001;9(4):505 – 524 characteristics of infantile hemangiomas:
minimal or arrested growth: a retrospective case
implications for management. Pediatrics. 2008;122(2):
series. Arch Dermatol. 2010;146(9): 971 – 976
54. North PE, Waner M, Buckmiller L, James CA, Mihm 360 – 367
MC Jr. Vascular tumors of infancy and childhood:

beyond capillary hemangioma. Cardiovasc Pathol. 2006;
67. Jacobs AH. Strawberry hemangiomas; the natural
15(6):303 – 317 78. Przewratil P, Sitkiewicz A, Andrzejewska
history of the untreated lesion. Calif Med. 1957;86(1):8
E. Serum levels of basic fi broblastic growth
– 10
factor (bFGF) in children with vascular
55. North PE. Pediatric vascular tumors and
68. Takahashi K, Mulliken JB, Kozakewich HPW, anomalies: another insight into endothelial
malformations. Surg Pathol Clin.
Rogers RA, Folkman J, Ezekowitz RAB. Cellular growth. Clin Biochem.
2010;3(3):455 – 494
markers that distinguish the phases of 2010;43(10 – 11):863 – 867
56. Tan ST, Wallis RA, He Y, Davis PF. Mast cells and hemangioma during infancy and childhood. J Clin
79. Przewratil P, Sitkiewicz A, Andrzejewska
hemangioma. Plast Reconstr Surg. 2004;113(3):999 – Invest.
E. Local serum levels of vascular endothelial
1011 1994;93(6):2357 – 2364
growth factor in infantile hemangioma: intriguing
57. North PE, Waner M, Mizeracki A, et al. A unique 69. Tollefson MM, Frieden IJ. Early growth of infantile mechanism of endothelial growth. Cytokine. 2010;
microvascular phenotype shared by juvenile hemangiomas: what parents ’ photographs tell 49(2):141 – 147
hemangiomas and us.

80. Mulliken JB, Marler JJ, Burrows PE, Kozakewich 101. Waner M, Suen JY. The natural history of
associated hepatic haemangioma. Clin Radiol. 2004;59(3):273
HP. Reticular infantile hemangioma of the limb – 280 hemangiomas. In: Waner M, Suen JY, eds. Hemangiomas
can be associated with ventral-caudal and Vascular Malformations of the Head and Neck.
90. Metry DW, Hawrot A, Altman C, Frieden IJ.
anomalies, refractory ulceration, and cardiac
Association of solitary, segmental hemangiomas of
overload. Pediatr Dermatol. New York, NY: Wiley-Liss; 1999:13 – 45
the skin with visceral hemangiomatosis. Arch
Dermatol. 2004; 140(5):591 – 596 102. Hermans DJ, Boezeman JB, Van de Kerkhof PC,
2007;24(4):356 – 362
Rieu PN, Van der Vleuten CJ. Differences between
81. Waner M, North PE, Scherer KA, Frieden IJ, Waner ulcerated and nonulcerated hemangiomas: a
91. Christison-Lagay ER, Burrows PE, Alomari A, et al.
A, Mihm MC Jr. The nonrandom distribution of retrospective study of 465 cases. Eur J Dermatol. 2009;19(2):152
Hepatic hemangiomas: subtype classi fi cation and
facial hemangiomas. Arch Dermatol. 2003; – 156
development of a clinical practice algorithm and
139(7):869 – 875
registry. J Pediatr Surg. 2007;42(1): 62 – 67;
discussion: 67 – 68 103. Connelly EA, Viera M, Price C, Waner M. Segmental
82. Haggstrom AN, Lammer EJ, Schneider RA, hemangioma of infancy complicated by
Marcucio R, Frieden IJ. Patterns of infantile life-threatening arterial bleed. Pediatr Dermatol. 2009;26(4):
92. Dickie B, Dasgupta R, Nair R, et al. Spectrum of
hemangiomas: new clues to hemangioma 469 – 472
hepatic hemangiomas: management and
pathogenesis and embryonic facial development. outcome. J Pediatr Surg. 2009;44(1):125 – 133
104. Yan AC. Pain management for ulcerated
Pediatrics. 2006;117(3):698 – 703 hemangiomas. Pediatr Dermatol. 2008; 25(6):586 – 589
93. Horii KA, Drolet BA, Baselga E, et al; Hemangioma
83. Jinnin M, Medici D, Park L, et al. Suppressed Investigator Group. Risk of hepatic hemangiomas
NFAT-dependent VEGFR1 expression and in infants with large hemangiomas. Arch Dermatol. 105. Thomas MW, Burkhart CN, Vaghani SP, Morrell DS,
constitutive VEGFR2 signaling in infantile Wagner AM. Failure to thrive in infants with
hemangioma. Nat Med. 2008;14(11):1236 – 1246 2010;146(2):201 – 203 complicated facial hemangiomas. Pediatr Dermatol. 2012;
29(1):49 – 52
94. Drolet BA, Pope E, Juern AM, et al. Gastrointestinal
84. Haggstrom AN, Drolet BA, Baselga E, et al. bleeding in infantile hemangioma: a complication
Prospective study of infantile hemangiomas: of segmental, rather than multifocal, infantile 106. Orlow SJ, Isakoff MS, Blei F. Increased risk of
clinical characteristics predicting complications hemangiomas. J Pediatr. 2012; 160(6):1021 – 6.e3 symptomatic hemangiomas of the airway in
and treatment. Pediatrics. 2006;118(3): 882 – 887 association with cutaneous hemangiomas in a “ beard
”
distribution. J Pediatr. 1997;131(4): 643 – 646
95. Brandling-Bennett HA, Metry DW, Baselga E, et al.
85. Iacobas I, Burrows PE, Frieden IJ, et al. LUMBAR: Infantile hemangiomas with unusually prolonged
association between cutaneous infantile growth phase: a case series. Arch Dermatol. 107. Haggstrom AN, Skillman S, Garzon MC, et al.
hemangiomas of the lower body and regional Clinical spectrum and risk of PHACE syndrome in
congenital anomalies. J Pediatr. 2010;157(5): 795 – 801.e1, 2008;144(12):1632 – 1637 cutaneous and airway hemangiomas. Arch
7 Otolaryngol Head Neck Surg. 2011;137(7):680 – 687
96. Kim HJ, Colombo M, Frieden IJ. Ulcerated
hemangiomas: clinical characteristics and
86. Girard C, Bigorre M, Guillot B, Bessis D. PELVIS response to therapy. J Am Acad Dermatol. 2001; 108. O TM, Alexander RE, Lando T, et al. Segmental
syndrome. Arch Dermatol. 2006; 142(7):884 – 888 44(6):962 – 972 hemangiomas of the upper airway. Laryngoscope. 2009;119(11):
2242 – 2247
87. Stockman A, Boralevi F, Taïeb A, LéautéLabrèze C. 97. Shin HT, Orlow SJ, Chang MW. Ulcerated
SACRAL syndrome: spinal dysraphism, haemangioma of infancy: a retrospective review of 109. Jockin YM, Friedlander SF. Periocular infantile
anogenital, cutaneous, renal and urologic 47 patients. hemangioma. Int Ophthalmol Clin. 2010;50(4):15 – 25
anomalies, associated with an angioma of Br J Dermatol. 2007;156(5):1050 – 1052
lumbosacral localization. Dermatology. 98. Chamlin SL, Haggstrom AN, Drolet BA, et al. 110. Schwartz SR, Blei F, Ceisler E, Steele M, Furlan L,
Multicenter prospective study of ulcerated Kodsi S. Risk factors for amblyopia in children
2007;214(1):40 – 45 hemangiomas. J Pediatr. with capillary hemangiomas of the eyelids and
2007;151(6):684 – 689; 689.e1 orbit.
88. Nabatian AS, Milgraum SS, Hess CP, Mancini AJ,
J AAPOS. 2006;10(3):262 – 268
Krol A, Frieden IJ. PHACE without face? Infantile 99. Maguiness SM, Hoffman WY, McCalmont TH,
hemangiomas of the upper body region with Frieden IJ. Early white discoloraton of infantile 111. Dubois J, Milot J, Jaeger BI, McCuaig C, Rousseau
minimal or absent facial hemangiomas and hemangioma: a sign of impending ulceration. Arch E, Powell J. Orbit and eyelid hemangiomas: is
associated structural malformations. Dermatol. there a relationship between location and ocular
2010;146(11):1235 – 1239 problems?
Pediatr Dermatol. 2011;28(3):235 – 241 J Am Acad Dermatol. 2006;55(4): 614 – 619
100. Thomas RF, Hornung RL, Manning SC, Perkins JA.
89. Hughes JA, Hill V, Patel K, Syed S, Harper Hemangiomas of infancy: treatment of ulceration in
J, De Bruyn R. Cutaneous haemangioma: the head and neck. Arch Facial Plast Surg. 2005;7(5): 112. Frank RC, Cowan BJ, Harrop AR, Astle WF,
prevalence and sonographic characteristics 312 – 315 McPhalen DF. Visual development in infants:
of visual complications of

periocular haemangiomas. J Plast Reconstr 124. Rao RP, Drolet BA, Holland KE, Frommelt PC. awareness in toddlers. Child Dev. 2007; 78(5):1426 – 1440
Aesthet Surg. 2010;63(1): 1 – 8 PHACES association: a vasculocutaneous
syndrome. Pediatr Cardiol. 2008;29(4):793 – 799
135. Brogdon J. Psychosocial impact of congenital
113. Howell DM, Gumbiner CH, Martin GE. Congestive vascular lesions. In: Waner
heart failure due to giant cutaneous cavernous 125. Metry DW, Garzon MC, Drolet BA, et al. PHACE M, Suen JY, eds. Hemangiomas and Vascular
hemangioma. Clin Pediatr (Phila). 1984;23(9):504 – 506 syndrome: current knowledge, future directions. Pediatr Malformations of the Head and Neck. New York,
Dermatol. NY: Wiley-Liss; 1999:13 – 45
2009;26(4):381 – 398
114. Weber TR, West KW, Cohen M, Grosfeld JL.
Massive hemangioma in infants: therapeutic 126. Siegel DH, Tefft KA, Johnson C, et al. Stroke in 136. Zweegers J, van der Vleuten CJ. The
considerations. J Vasc Surg. 1984;1(3):423 – 428 children with posterior fossa brain malformations, psychosocial impact of an infantile
hemangiomas, arterial anomalies, coarctation of haemangioma on children and their parents. Arch
the aorta and cardiac defects, and eye Dis Child. 2012;97(10): 922 – 926
115. Frieden IJ, Reese V, Cohen D. PHACE syndrome:
abnormalities (PHACE) syndrome: a systematic
the association of posterior fossa brain
review of the literature.
malformations, hemangiomas, arterial anomalies, 137. Cohen-Barak E, Rozenman D, Shani Adir
coarctation of the aorta and cardiac defects, and A. Infantile haemangiomas and quality of life. Arch
Stroke. 2012;43(6):1672 – 1674
Dis Child. 2013;98(9): 676 – 679
eye abnormalities. Arch Dermatol. 1996;132(3):307 –
311 127. Bingham MM, Saltzman B, Vo NJ, Perkins JA.
Propranolol reduces infantile hemangioma
138. Fost NC, Esterly NB. Successful treatment of
volume and vessel density. Otolaryngol Head
juvenile hemangiomas with prednisone. J Pediatr. 1968;72(3):
116. Mitchell S, Siegel DH, Shieh JT, et al. Candidate
Neck Surg. 2012;147(2):338 – 344
351 – 357
locus analysis for PHACE syndrome. Am J Med
Genet A. 2012; 158A(6):1363 – 1367
128. Kassarjian A, Zurakowski D, Dubois J, Paltiel HJ, 139. Cohen SR, Wang CI. Steroid treatment of
Fishman SJ, Burrows PE. Infantile hepatic hemangioma of the head and neck in children. Ann
117. Opitz JM, Gilbert EF. CNS anomalies and the midline
hemangiomas: clinical and imaging fi ndings and Otol Rhinol Laryngol.
as a “ developmental fi eld ”.
their correlation with therapy. AJR Am J 1972;81(4):584 – 590
Am J Med Genet. 1982;12(4):443 – 455
Roentgenol. 2004;182(3):785 – 795
140. Greenberger S, Bischoff J. Infantile
118. Metry DW, Dowd CF, Barkovich AJ, Frieden IJ.
hemangioma-mechanism(s) of drug action on a
The many faces of PHACE syndrome. J Pediatr. 2001;139(1):
129. Frieden IJ, Haggstrom AN, Drolet BA, et al. Infantile vascular tumor. Cold Spring Harb Perspect Med. 2011;1(1):a006460
117 – 123
hemangiomas: current knowledge, future
directions. Proceedings of a research workshop on
141. Storch CH, Hoeger PH. Propranolol for infantile
119. Hess CP, Fullerton HJ, Metry DW, et al. Cervical infantile hemangiomas, April 7 – 9, 2005, Bethesda,
haemangiomas: insights into the molecular
and intracranial arterial anomalies in 70 patients Maryland. Pediatr Dermatol.
mechanisms of action. Br J Dermatol. 2010;163(2):269
with PHACE syndrome. AJNR Am J Neuroradiol.
– 274
2005;22(5):383 – 406
2010;31(10):1980 – 1986 142. Vivas-Colmenares GV, Bernabeu-Wittel J,

130. Meyer JS, Hoffer FA, Barnes PD, Mulliken JB.
Alonso-Arroyo V, Matute de Cardenas JA,
120. Haggstrom AN, Garzon MC, Baselga E, et al. Risk Biological classi fi cation of soft-tissue vascular
Fernandez-Pineda I. Effectiveness of propranolol in
for PHACE syndrome in infants with large facial anomalies: MR correlation. AJR Am J Roentgenol. 1991;
the treatment of infantile hemangioma beyond the
hemangiomas. 157(3):559 – 564
proliferation phase. Pediatr Dermatol. 2015;32(3):
Pediatrics. 2010;126(2). Available at:
348 – 352
www.pediatrics.org/cgi/content/full/ 131. Flors L, Leiva-Salinas C, Maged IM, et al. MR
126/2/e418 imaging of soft-tissue vascular malformations:
143. Zvulunov A, McCuaig C, Frieden IJ, et al. Oral
diagnosis, classi fi cation, and therapy follow-up.
121. Metry DW, Haggstrom AN, Drolet BA, et al. A propranolol therapy for infantile hemangiomas
prospective study of PHACE syndrome in infantile beyond the proliferation phase: a multicenter
Radiographics. 2011;31(5):1321 – 1340;
hemangiomas: demographic features, clinical fi ndings, retrospective study. Pediatr Dermatol. 2011;28(2):
discussion: 1340 – 1341
and complications. Am J Med Genet A. 94 – 98
132. Maguiness SM, Frieden IJ. Current management of
2006;140(9):975 – 986 infantile hemangiomas.
144. Hermans DJ, van Beynum IM, Schultze Kool LJ,
Semin Cutan Med Surg. 2010;29(2): 106 – 114
122. Tangtiphaiboontana J, Hess CP, Bayer M, et al. van de Kerkhof PC, Wijnen MH, van der Vleuten
Neurodevelopmental CJ. Propranolol, a very promising treatment for
abnormalities in children with PHACE syndrome. J 133. Leonardi-Bee J, Batta K, O ’ Brien C, Bath- ulceration in infantile hemangiomas: a study of 20
Child Neurol. 2013;28(5): 608 – 614 Hextall FJ. Interventions for infantile cases with matched historical controls.
haemangiomas (strawberry birthmarks) of the
skin. Cochrane Database Syst Rev. 2011;(5):CD006545 J Am Acad Dermatol. 2011;64(5): 833 – 838
123. Duffy KJ, Runge-Samuelson C, Bayer ML, et al.
Association of hearing loss with PHACE syndrome. Arch
Dermatol. 2010; 146(12):1391 – 1396 134. Brownell CA, Zerwas S, Ramani GB. “ So 145. Saint-Jean M, Léauté-Labrèze C,
big ”: the development of body self- Mazereeuw-Hautier J, et al; Groupe de

Recherche Clinique en Dermatologie 156. White CW, Sondheimer HM, Crouch EC, Wilson H, 166. Kum JJ, Khan ZA. Propranolol inhibits growth of
Pédiatrique. Propranolol for treatment of Fan LL. Treatment of pulmonary hemangiomatosis hemangioma-initiating cells but does not induce
ulcerated infantile hemangiomas. with recombinant interferon alfa-2a. N Engl J Med. 1989;320(18):1197
apoptosis. Pediatr Res. 2014;75(3):381 – 388
J Am Acad Dermatol. 2011;64(5):827 – 832 – 1200
146. Hong E, Fischer G. Propranolol for recalcitrant 167. Ji Y, Chen S, Xu C, Li L, Xiang B. The use of
ulcerated hemangioma of infancy. Pediatr 157. Ezekowitz RA, Mulliken JB, Folkman J. Interferon propranolol in the treatment of infantile
Dermatol. 2012;29(1): 64 – 67 alfa-2a therapy for lifethreatening hemangiomas haemangiomas: an update on potential
of infancy. mechanisms of action. Br J Dermatol. 2015;172(1):24
N Engl J Med. 1992;326(22): 1456 – 1463 – 32
147. Cante V, Pham-Ledard A, Imbert E, Ezzedine K,
Léauté-Labrèze C. First report of topical timolol 168. Lamy S, Lachambre MP, Lord-Dufour S, Béliveau
treatment in primarily ulcerated perineal 158. Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, R. Propranolol suppresses angiogenesis in vitro:
Boralevi F, Thambo JB, Taïeb
haemangioma. Arch Dis Child Fetal Neonatal Ed. 2012;97(2):F155 inhibition of proliferation, migration, and
– F156 A. Propranolol for severe hemangiomas of infancy. N differentiation of endothelial cells.
Engl J Med. 2008;358(24): 2649 – 2651
Vascul Pharmacol. 2010;53(5-6):200 – 208

148. David LR, Malek MM, Argenta LC. Ef fi cacy of
pulse dye laser therapy for the treatment of 159. Sans V, de la Roque ED, Berge J, et al. 169. Frieden IJ, Drolet BA. Propranolol for infantile
ulcerated Propranolol for severe infantile hemangiomas: hemangiomas: promise, peril, pathogenesis. Pediatr
haemangiomas: a review of 78 patients. follow-up report. Dermatol. 2009; 26(5):642 – 644
Br J Plast Surg. 2003;56(4):317 – 327 Pediatrics. 2009;124(3). Available at:
www.pediatrics.org/cgi/content/full/
149. Lacour M, Syed S, Linward J, Harper JI. Role of the 170. Lee D, Boscolo E, Durham JT, Mulliken JB,
124/3/e423
pulsed dye laser in the management of ulcerated Herman IM, Bischoff J. Propranolol targets the
capillary haemangiomas. Arch Dis Child. 1996; 160. Starkey E, Shahidullah H. Propranolol for contractility of infantile haemangioma-derived
74(2):161 – 163 infantile haemangiomas: a review. pericytes. Br J Dermatol. 2014;171(5):1129 – 1137
Arch Dis Child. 2011;96(9):890 – 893
150. Morelli JG, Tan OT, Weston WL. Treatment of 161. Drolet BA, Frommelt PC, Chamlin SL, et al. 171. England RW, Hardy KL, Kitajewski AM, et al.
ulcerated hemangiomas with the pulsed tunable dye Initiation and use of propranolol for infantile Propranolol promotes accelerated and
laser. Am J Dis Child. 1991;145(9):1062 – 1064 hemangioma: report of a consensus conference. Pediatrics. dysregulated adipogenesis in hemangioma stem
cells. Ann Plast Surg. 2014;73(suppl 1):S119 – S124
2013;131(1):128 – 140
151. Witman PM, Wagner AM, Scherer K, Waner M,
162. Pope E, Chakkittakandiyil A, LaraCorrales I, Maki
Frieden IJ. Complications following pulsed dye 172. Léauté-Labrèze C, Hoeger P, MazereeuwHautier J,
E, Weinstein M. Expanding the therapeutic
laser treatment of super fi cial hemangiomas. Lasers et al. A randomized, controlled trial of oral
repertoire of infantile haemangiomas:
Surg Med. 2006;38(2):116 – 123 propranolol in infantile hemangioma. N Engl J
cohort-blinded study of oral nadolol compared with
Med.
propranolol. Br J Dermatol. 2013; 168(1):222 – 224
2015;372(8):735 – 746
152. Katz HP, Askin J. Multiple hemangiomata with
thrombopenia: an unusual case with comments on 173. Hogeling M, Adams S, Wargon O. A randomized
steroid therapy. Am J Dis Child. 1968;115(3):351 – 357 controlled trial of propranolol for infantile
163. Pan WK, Li P, Guo ZT, Huang Q, Gao Y.
hemangiomas.
Propranolol induces regression of hemangioma
Pediatrics. 2011;128(2). Available at:
153. Zarem HA, Edgerton MT. Induced resolution of cells via the downregulation of the
www.pediatrics.org/cgi/content/full/
cavernous hemangiomas following prednisolone PI3K/Akt/eNOS/VEGF pathway. Pediatr Blood
128/2/e259
therapy. Plast Reconstr Surg. 1967;39(1):76 – 83 Cancer. 2015; 62(8):1414 – 1420
174. Schiestl C, Neuhaus K, Zoller S, et al. Ef fi cacy
and safety of propranolol as
154. Groopman JE, Gottlieb MS, Goodman J, et al. 164. Sharifpanah F, Saliu F, Bekhite MM, Wartenberg M,
fi rst-line treatment for infantile hemangiomas.
Recombinant alpha-2 interferon therapy for Kaposi ’ Sauer H. b- Adrenergic receptor antagonists inhibit
Eur J Pediatr. 2011; 170(4):493 – 501
s sarcoma associated with the acquired immunode fi vasculogenesis of embryonic stem cells by
ciency syndrome. Ann Intern Med. 1984;100(5):671 – downregulation of nitric oxide generation and
676 175. de Graaf M, Breur JM, Raphaël MF, Vos
interference with VEGF signalling. Cell Tissue Res. 2014;358(2):
443 – 452 M, Breugem CC, Pasmans SG. Adverse effects of
propranolol when used in the treatment of
155. Ritter MR, Dorrell MI, Edmonds J, Friedlander
hemangiomas: a case series of 28 infants. J Am
SF, Friedlander M. Insulinlike growth factor 2
Acad Dermatol. 2011;65(2):320 – 327
and potential regulators of hemangioma growth 165. Ma X, Zhao T, Ouyang T, Xin S, Ma Y, Chang M.
and involution identi fi ed by largescale Propranolol enhanced adipogenesis instead of
expression analysis. Proc Natl Acad Sci USA. 2002;99(11): induction of apoptosis of hemangiomas stem 176. Raphael MF, Breugem CC, Vlasveld FA, et al. Is
7455 – 7460 cells. cardiovascular evaluation necessary prior to
Int J Clin Exp Pathol. 2014;7(7): 3809 – 3817 and during betablocker therapy for infantile

hemangiomas? A cohort study. J Am Acad hemangiomas treated with propranolol. Pediatr multicenter, cohort study. Pediatr Dermatol. 2012;29(3):28
Dermatol. 2015;72(3):465 – 472 Dermatol. 2011; 28(6):658 – 662 – 31
177. Blei F, McElhinney DB, Guarini A, Presti 196. Chan H, McKay C, Adams S, Wargon O. RCT of
S. Cardiac screening in infants with infantile 186. Shehata N, Powell J, Dubois J, et al. Late rebound timolol maleate gel for super fi cial infantile
hemangiomas before propranolol treatment. Pediatr of infantile hemangioma after cessation of oral hemangiomas in 5to 24-week-olds. Pediatrics.
Dermatol. 2014;31(4):465 – 470 propranolol. Pediatr Dermatol. 2013;30(5):587 – 591 2013;131(6). Available at: www.pediatrics.org/cgi/
content/full/131/6/e1739
178. Puttgen KB, Summerer B, Schneider J, Cohen 187. Shah S, Frieden I, Baselga E, McCuaig C, Pope E.
BA, Boss EF, Bauman NM. Cardiovascular and Rebound after discontinuation of propranolol in the 197. Hasan Q, Tan ST, Xu B, Davis PF. Effects of fi ve
blood glucose parameters in infants during commonly used glucocorticoids on haemangioma in
therapy of infantile hemangiomas: a retrospective
propranolol initiation for treatment of vitro. Clin Exp Pharmacol Physiol. 2003;30(3):140 – 144
study. In: 20th Workshop of the International
symptomatic infantile hemangiomas.
Society for the Study of Vascular Anomalies; April
2-4, 2014; Melbourne, Australia. Abstract 198. Ebrahem Q, Minamoto A, Hoppe G, Anand-Apte B,
Ann Otol Rhinol Laryngol. 2013;122(9): 550 – 554
Sears JE. Triamcinolone acetonide inhibits IL-6-
and VEGFinduced angiogenesis downstream of
179. McSwiney E, Murray D, Murphy M. Propranolol the IL-6 and VEGF receptors. Invest Ophthalmol
188. Solman L, Murabit A, Gnarra M, Harper JI, Syed
therapy for cutaneous infantile haemangiomas Vis Sci. 2006;47(11): 4935 – 4941
SB, Glover M. Propranolol for infantile
initiated safely as a day-case procedure. Eur J
haemangiomas: single centre experience of 250
Pediatr.
cases and proposed therapeutic protocol. Arch
2014;173(1):63 – 68
Dis Child. 199. Itinteang T, Vishvanath A, Day DJ, Tan ST.
180. Holland KE, Frieden IJ, Frommelt PC, Mancini AJ, 2014;99(12):1132 – 1136 Mesenchymal stem cells in infantile haemangioma. J
Wyatt D, Drolet BA. Hypoglycemia in children Clin Pathol. 2011;64(3): 232 – 236
189. Giachetti A, Garcia-Monaco R, Sojo M, et al.
taking propranolol for the treatment of infantile
Long-term treatment with oral propranolol
hemangioma. Arch Dermatol.
reduces relapses of infantile hemangiomas. Pediatr 200. Pantoja C, Huff JT, Yamamoto KR. Glucocorticoid
Dermatol. 2014;31(1):14 – 20 signaling de fi nes a novel commitment state during
2010;146(7):775 – 778
adipogenesis in vitro. Mol Biol Cell. 2008;19(10):
181. Fusilli G, Merico G, Gurrado R, Rosa T,
4032 – 4041
Acquafredda A, Cavallo L. Propranolol for infantile 190. McMahon P, Oza V, Frieden IJ. Topical timolol for
haemangiomas and neuroglycopenic seizures. Acta infantile hemangiomas: putting a note of caution in “
Paediatr. 2010;99(12):1756 cautiously optimistic ”. Pediatr Dermatol. 2012; 201. Ameshima S, Golpon H, Cool CD, et al.
29(1):127 – 130 Peroxisome proliferator-activated receptor gamma

(PPARgamma) expression is decreased in
182. Marqueling AL, Oza V, Frieden IJ, Puttgen KB.
pulmonary hypertension and affects endothelial
Propranolol and infantile hemangiomas four years 191. Semkova K, Kazandjieva J. Topical timolol maleate
cell growth. Circ Res. 2003;92(10): 1162 – 1169
later: a systematic review. Pediatr Dermatol. for treatment of infantile haemangiomas:
preliminary results of a prospective study. Clin Exp
2013;30(2):182 – 191 Dermatol. 2013;38(2):143 – 146
202. Wu Z, Bucher NL, Farmer SR. Induction of
183. Léauté-Labrèze C, Frieden I, Vabres P, Prey S,
peroxisome proliferator-activated receptor gamma
Voisard J. Propranolol in infantile hemangiomas 192. Moehrle M, Léauté-Labrèze C, Schmidt
during the conversion of 3T3 fi broblasts into
(IH): results from an international randomized, V, Röcken M, Poets CF, Goelz R. Topical timolol
adipocytes is mediated by C/EBPbeta, C/EBPdelta,
placebo controlled, multidose, adaptive phase 2/3 for small hemangiomas of infancy. Pediatr
and glucocorticoids. Mol Cell Biol. 1996; 16(8):4128 –
study. In: 20th Workshop of the International Dermatol. 2013;30(2): 245 – 249
4136
Society for the Study of Vascular Anomalies; April
2 – 4, 2014; Melbourne, Australia. Abstract
193. Oranje AP, Janmohamed SR, Madern GC, de Laat 203. Greene AK, Couto RA. Oral prednisolone for
PC. Treatment of small super fi cial haemangioma infantile hemangioma: ef fi cacy and safety using a
with timolol standardized treatment protocol. Plast Reconstr
184. Prey S, Léauté-Labrèze C, Frieden I, Delarue A,
0.5% ophthalmic solution: a series of 20 cases. Dermatology. Surg. 2011; 128(3):743 – 752
Voisard J. Safety of oral propranolol for the
2011;223(4): 330 – 334
treatment of infantile hemangioma: 2-years
results of a phase II/III randomized, doubleblind, 204. Sadan N, Wolach B. Treatment of hemangiomas
placebo-controlled multicenter trial. In: 20th 194. Ni N, Langer P, Wagner R, Guo S. Topical timolol for of infants with high doses of prednisone. J
Workshop of the International Society for the periocular hemangioma: report of further study. Arch Pediatr. 1996; 128(1):141 – 146
Study of Vascular Anomalies; April 2 – 4, 2014; Ophthalmol. 2011;129(3):377 – 379
Melbourne, Australia. Abstract

205. Bennett ML, Fleischer AB Jr, Chamlin SL, Frieden IJ.
195. Chakkittakandiyii A, Phillips R, Frieden IJ, et al. Oral corticosteroid use is effective for cutaneous
Timolol maleate 0.5% or 0.1% gel-forming hemangiomas: an evidence-based evaluation. Arch
185. Braqazquoitia L, Hernandez-Martin A, Torrelo A. solution for infantile hemangiomas: a Dermatol. 2001;137(9):1208 – 1213
Recurrence of infantile retrospective,

206. Itinteang T, Withers AHJ, Leadbitter P, Day DJ, Tan proliferative parotid hemangiomas. Int J Pediatr 227. Garzon MC, Lucky AW, Hawrot A, Frieden IJ.
ST. Pharmacologic therapies for infantile Otorhinolaryngol. 2008;72(1): 81 – 87 Ultrapotent topical corticosteroid treatment of
hemangioma: is there a rational basis? Plast hemangiomas of infancy.
Reconstr Surg. 2011;128(2):499 – 507 J Am Acad Dermatol. 2005;52(2): 281 – 286
217. Chantharatanapiboon W. Intralesional corticosteroid
therapy in hemangiomas: clinical outcome in 160
207. Bauman NM, McCarter RJ, Guzzetta PC, et al. cases. J Med Assoc Thai. 2008;91(suppl 228. Pandey A, Gangopadhyay AN, Sharma SP, Kumar
Propranolol vs prednisolone for symptomatic V, Gupta DK, Gopal SC. Evaluation of topical
proliferating infantile hemangiomas: a randomized 3):S90 – S96 steroids in the treatment of super fi cial
clinical trial. JAMA Otolaryngol Head Neck Surg. hemangioma.
218. Prasetyono TOH, Djoenaedi I. Ef fi cacy of
2014;140(4):323 – 330 Skinmed. 2010;8(1):9 – 11
intralesional steroid injection in head and neck
hemangioma: a systematic review. Ann Plast 229. Greene AK. Current concepts of vascular
208. Grantzow R, Schmittenbecher P, Cremer Surg. 2011;66(1): 98 – 106 anomalies. J Craniofac Surg.
H, et al. Hemangiomas in infancy and childhood. S 2012;23(1):220 – 224
2k Guideline of the German Society of
219. Samimi DB, Alabiad CR, Tse DT. An 230. Tan BH, Leadbitter PH, Aburn NH, Tan ST. Steroid
Dermatology with the working group Pediatric
anatomically based approach to intralesional therapy for problematic proliferating haemangioma. N
Dermatology together with the German Society for
corticosteroid injection for eyelid capillary Z Med J.
Pediatric Surgery and the German Society for
hemangiomas. 2011;124(1329):57 – 65
Pediatric Medicine. J Dtsch Dermatol Ges. 2008;6(4):324
Ophthalmic Surg Lasers Imaging. 2012; 43(3):190 – 195
– 329 231. Morkane C, Gregory JW, Watts P, Warner JT.
Adrenal suppression following intralesional
220. Goyal R, Watts P, Lane CM, Beck L, Gregory JW. corticosteroids for periocular haemangiomas. Arch
209. Frieden IJ, Eichen fi eld LF, Esterly NB,
Adrenal suppression and failure to thrive after Dis Child. 2011;96(6):587 – 589
Geronemus R, Mallory SB; American Academy of
steroid injections for periocular hemangioma.
Dermatology Guidelines/ Outcomes Committee.
Guidelines of care for hemangiomas of infancy. J 232. Ranchod TM, Frieden IJ, Fredrick DR.
Ophthalmology. 2004;111(2):389 – 395
Am Acad Dermatol. 1997;37(4):631 – 637 Corticosteroid treatment of periorbital
221. Shorr N, Seiff SR. Central retinal artery occlusion haemangioma of infancy: a review of the
associated with periocular corticosteroid injection evidence. Br J Ophthalmol. 2005; 89(9):1134 – 1138
210. Azzolini A, Nouvenne R. Nuove prospettive nella
for juvenile hemangioma. Ophthalmic Surg. 1986;
terapia degli angiomi immaturi dell infanzia, 115
17(4):229 – 231
lesion; trattate can in fi ltraziona; intralesionali di 233. Pope E, Krafchik BR, Macarthur C, et al. Oral
triamcinolone acetonide. Acta Biol Med (Gdansk). 1970;41(suppl versus high-dose pulse corticosteroids for
1):41 – 51 222. Ruttum MS, Abrams GW, Harris GJ, Ellis MK. problematic infantile hemangiomas: a randomized,
Bilateral retinal embolization associated with controlled trial. Pediatrics. 2007;119(6). Available
intralesional corticosteroid injection for capillary at: www.pediatrics.org/cgi/
211. Mazzola RF. Treatment of haemangiomas in
hemangioma of infancy. J Pediatr Ophthalmol content/full/119/6/e1239
children by intralesional injection of steroids. Chir
Strabismus. 1993;30(1):4 – 7
Plast (Berl). 1978;4:161 – 171
234. George ME, Sharma V, Jacobson J, Simon S,
223. Egbert JE, Schwartz GS, Walsh AW. Diagnosis Nopper AJ. Adverse effects of systemic
212. Kushner BJ. The treatment of periorbital infantile
and treatment of an ophthalmic artery occlusion glucocorticosteroid therapy in infants with
hemangioma with intralesional corticosteroid. Plast
during an intralesional injection of corticosteroid hemangiomas. Arch Dermatol. 2004;140(8):963 – 969
Reconstr Surg. 1985;76(4):517 – 526
into an eyelid capillary hemangioma.
235. Lomenick JP, Reifschneider KL, Lucky AW, et al.

213. Sloan GM, Reinisch JF, Nichter LS, Saber WL, Lew Am J Ophthalmol. 1996;121(6):638 – 642
Prevalence of adrenal insuf fi ciency following
K, Morwood DT. Intralesional corticosteroid therapy
224. Egbert JE, Paul S, Engel WK, Summers CG. High systemic glucocorticoid therapy in infants with
for infantile hemangiomas. Plast Reconstr Surg.
injection pressure during intralesional injection of hemangiomas. Arch Dermatol. 2009; 145(3):262 – 266
corticosteroids into capillary hemangiomas. Arch
1989;83(3):459 – 467
Ophthalmol. 2001; 119(5):677 – 683
214. Chowdri NA, Darzi MA, Fazili Z, Iqbal S.
236. Boon LM, MacDonald DM, Mulliken JB.
Intralesional corticosteroid therapy for childhood
Complications of systemic corticosteroid therapy
cutaneous hemangiomas.
225. Elsas FJ, Lewis AR. Topical treatment of periocular for problematic hemangioma. Plast Reconstr
Ann Plast Surg. 1994;33(1):46 – 51
capillary hemangioma. Surg.
215. Chen MT, Yeong EK, Horng SY. Intralesional J Pediatr Ophthalmol Strabismus. 1994; 31(3):153 – 156 1999;104(6):1616 – 1623
corticosteroid therapy in proliferating head and
237. Kelly ME, Juern AM, Grossman WJ, Schauer DW,
neck hemangiomas: a review of 155 cases.
226. Cruz OA, Zarnegar SR, Myers SE. Treatment of Drolet BA. Immunosuppressive effects in infants
periocular capillary hemangioma with topical treated with corticosteroids for infantile
J Pediatr Surg. 2000;35(3):420 – 423
clobetasol propionate. Ophthalmology. 1995; hemangiomas. Arch Dermatol.
216. Buckmiller LM, Francis CL, Glade RS. 102(12):2012 – 2015
Intralesional steroid injection for 2010;146(7):767 – 774

238. Aviles R, Boyce TG, Thompson DM. Pneumocystis 250. Perez Payarols J, Pardo Masferrer J, Gomez 5% imiquimod cream. Arch Dermatol.
carinii pneumonia in a 3-month-old infant Bellvert C. Treatment of lifethreatening infantile 2002;138(7):881 – 884; discussion: 884
receiving high-dose corticosteroid therapy for hemangiomas with vincristine. N Engl J Med. 1995;
262. Ho NT, Lansang P, Pope E. Topical imiquimod in
airway hemangiomas. Mayo Clin Proc. 2004; 333(1):69
the treatment of infantile hemangiomas: a
79(2):243 – 245
retrospective study.
251. Enjolras O, Brevière GM, Roger G, et al. J Am Acad Dermatol. 2007;56(1):63 – 68
239. Maronn ML, Corden T, Drolet BA. Vincristine treatment for function- and
263. Czernik A, Bystryn JC. Does imiquimod work in
Pneumocystis carinii pneumonia in infant life-threatening infantile hemangioma.
infantile hemangiomas? J Am Acad Dermatol. 2007;57(3):535;
treated with oral steroids for hemangioma. Arch Arch Pediatr. 2004;11(2):99 – 107
– author reply: 536
Dermatol. 2007; 143(9):1224 – 1225
252. Pérez-Valle S, Peinador M, Herraiz P, Saénz P,
Montoliu G, Vento M. Vincristine, an ef fi cacious
264. McCuaig CC, Dubois J, Powell J, et al. A phase II,
240. Pokorny JJ, Roth F, Balfour I, Rinehart G. An alternative for diffuse neonatal haemangiomatosis
open-label study of the ef fi cacy and safety of
unusual complication of the treatment of a [in French]. Acta Paediatr. 2010;99(2): 311 – 315
imiquimod in the treatment of super fi cial and
hemangioma. Ann Plast Surg. 2002;48(1):83 – 87
mixed infantile hemangioma. Pediatr Dermatol. 2009;26(2):203
– 212
241. Toogood JH, Markov AE, Baskerville J, Dyson C. 253. Mabeta P, Pepper MS. Hemangiomas —
Association of ocular cataracts with inhaled and current therapeutic strategies. Int J Dev Biol. 2011;55(4-5):431
265. Jayson GC, Hicklin DJ, Ellis LM. Antiangiogenic
oral steroid therapy during long-term treatment of – 437
therapy — evolving view based on clinical trial
asthma.
254. Greinwald JH Jr, Burke DK, Bonthius DJ, Bauman results. Nat Rev Clin Oncol. 2012;9(5):297 – 303
J Allergy Clin Immunol. 1993;91(2): 571 – 579
NM, Smith RJ. An update on the treatment of
hemangiomas in children with interferon alfa-2a. Arch
266. Mahajan D, Miller C, Hirose K, McCullough A,
242. Carnahan MC, Goldstein DA. Ocular Otolaryngol Head Neck Surg. 1999; 125(1):21 – 27
Yerian L. Incidental reduction in the size of liver
complications of topical, peri-ocular, and
hemangioma following use of VEGF inhibitor
systemic corticosteroids. Curr Opin Ophthalmol. 2000;11(6):478
bevacizumab. J Hepatol. 2008; 49(5):867 – 870
– 483
255. Barlow CF, Priebe CJ, Mulliken JB, et al. Spastic
243. Razeghinejad MR, Katz LJ. Steroidinduced diplegia as a complication of interferon alfa-2a
iatrogenic glaucoma. treatment of hemangiomas of infancy. J Pediatr.
267. Greenberger S, Yuan S, Walsh LA, et al.
Ophthalmic Res. 2012;47(2):66 – 80
Rapamycin suppresses self-renewal and
1998;132(3 pt 1):527 – 530
244. Yamashita T, Kodama Y, Tanaka M, Yamakiri K, vasculogenic potential of stem cells isolated from
Kawano Y, Sakamoto T. Steroid-induced 256. Wörle H, Maass E, Köhler B, Treuner J. Interferon infantile hemangioma.
glaucoma in children with acute lymphoblastic alpha-2a therapy in haemangiomas of infancy: J Invest Dermatol. 2011;131(12): 2467 – 2476
leukemia: a possible complication. J Glaucoma. spastic diplegia as a severe complication. Eur J
Pediatr. 1999;158(4):344
268. Ashinoff R, Geronemus RG. Capillary
2010;19(3):188 – 190
hemangiomas and treatment with the
245. Al-Shahwan S, Khan AO. Buphthalmos following 257. Dubois J, Hershon L, Carmant L, Bélanger S, fl ash lamp-pumped pulsed dye laser.
systemic steroid treatment. Leclerc JM, David M. Toxicity pro fi le of interferon Arch Dermatol. 1991;127(2):202 – 205
J Pediatr Ophthalmol Strabismus. 2006; 43(5):311 – 312 alfa-2b in children: a prospective evaluation. J
269. Barlow RJ, Walker NP, Markey AC. Treatment of
Pediatr.
proliferative haemangiomas with the 585 nm pulsed
1999;135(6):782 – 785
246. Kushner BJ, Lemke BN. Bilateral retinal dye laser. Br J Dermatol. 1996;134(4): 700 – 704
embolization associated with intralesional 258. Li VW, Li WW, Talcott KE, Zhai AW. Imiquimod as
corticosteroid injection for capillary hemangioma an antiangiogenic agent.
of infancy. J Drugs Dermatol. 2005;4(6):708 – 717
270. Garden JM, Bakus AD, Paller AS. Treatment of
J Pediatr Ophthalmol Strabismus. 1993; 30(6):397 – 399
259. Majewski S, Marczak M, Mlynarczyk B, cutaneous hemangiomas by the fl ashlamp-pumped
Benninghoff B, Jablonska S. Imiquimod is a pulsed dye laser: prospective analysis. J Pediatr.
247. Kushner BJ. Hemangiomas. Arch strong inhibitor of tumor cellinduced
Ophthalmol. 2000;118(6):835 – 836 angiogenesis. Int J Dermatol. 1992;120(4 pt 1):555 – 560
2005;44(1):14 – 19
248. Mabeta P, Pepper MS. A comparative study on the 271. Glassberg E, Lask G, Rabinowitz LG, Tunnessen
anti-angiogenic effects of DNA-damaging and 260. Sidbury R, Neuschler N, Neuschler E, et al. WW Jr. Capillary hemangiomas: case study of a
cytoskeletaldisrupting agents. Angiogenesis. 2009; Topically applied imiquimod inhibits vascular novel laser treatment and a review of therapeutic
12(1):81 – 90 tumor growth in vivo. options. J Dermatol Surg Oncol. 1989;15(11):1214
J Invest Dermatol. 2003;121(5): 1205 – 1209 – 1223
249. Ghadially FN. Ultrastructural Pathology

of the Cell and Matrix. 3rd ed. London, United 261. Martinez MI, Sanchez-Carpintero I, North PE, 272. Haywood RM, Monk BE, Mahaffey PJ. The
Kingdom: Butterworths; 1988 Mihm MC Jr. Infantile hemangioma: clinical treatment of early cutaneous capillary
resolution with haemangiomata (strawberry

Available at: www.pediatrics.org/cgi/
naevi) with the tunable dye laser. Br J Plast Surg. 2000;53(4):302 orbit in infancy. Am J Ophthalmol. 1977; 83(1):52 – 58
– 307 content/full/128/5/e1053
273. Landthaler M, Hohenleutner U, el-Raheem 284. Smit JM, Bauland CG, Wijnberg DS, Spauwen PH. 296. Stigmar G, Crawford JS, Ward CM, Thomson HG.
TA. Laser therapy of childhood Pulsed dye laser treatment, a review of indications Ophthalmic sequelae of infantile hemangiomas of
haemangiomas. Br J Dermatol. 1995;133(2):275 and outcome based on published trials. Br J Plast the eyelids and orbit. Am J Ophthalmol. 1978;85(6):
– 281 Surg. 2005;58(7):981 – 987 806 – 813
274. Poetke M, Philipp C, Berlien HP.

Flashlamp-pumped pulsed dye laser for 285. Anderson RR. Infant hemangiomas: a 297. von Noorden GK. Application of basic research
hemangiomas in infancy: treatment of super fi cial controversy worth solving. Lasers Surg Med. 2006;38(2):92 data to clinical amblyopia.
vs mixed hemangiomas. – 93 Ophthalmology. 1978;85(5):496 – 504
Arch Dermatol. 2000;136(5):628 – 632

286. Wareham WJ, Cole RP, Royston SL, Wright PA. 298. Schwartz SR, Kodsi SR, Blei F, Ceisler E, Steele M,
275. Scheepers JH, Quaba AA. Does the pulsed tunable Adverse effects reported in pulsed dye laser Furlan L. Treatment of capillary hemangiomas
dye laser have a role in the management of treatment for port wine stains. Lasers Med Sci. 2009;24(2): causing refractive and occlusional amblyopia.
infantile hemangiomas? Observations based on 3 241 – 246
years ’ experience. Plast Reconstr Surg. 1995;95(2):305 J AAPOS. 2007;11(6):577 – 583
– 312
287. Mulliken JB, Fishman SJ, Burrows PE. Vascular 299. Kushner BJ. Intralesional corticosteroid injection for
anomalies. Curr Probl Surg. infantile adnexal hemangioma. Am J Ophthalmol. 1982;
276. Waner M, Suen JY, Dinehart S. Treatment of 2000;37(8):517 – 584 93(4):496 – 506
hemangiomas of the head and neck. Laryngoscope. 1992;102(10):

288. Greene AK. Management of hemangiomas and
1123 – 1132
other vascular tumors. Clin Plast Surg. 2011;38(1): 300. Morrell AJ, Willshaw HE. Normalisation of refractive
45 – 63 error after steroid injection for adnexal
277. Waner M, Suen JY, Dinehart S, Mallory SB. Laser haemangiomas. Br J Ophthalmol. 1991;75(5):301 – 305
photocoagulation of super fi cial proliferating 289. Arneja JS, Mulliken JB. Resection of amblyogenic
hemangiomas. periocular hemangiomas: indications and 301. Plager DA, Snyder SK. Resolution of astigmatism
J Dermatol Surg Oncol. 1994;20(1): 43 – 46 outcomes. Plast Reconstr Surg. 2010;125(1):274 – 281 after surgical resection of capillary hemangiomas
in infants.
278. Anderson RR, Parrish JA. Selective Ophthalmology. 1997;104(7):1102 – 1106

290. Arneja JS, Chim H, Drolet BA, Gosain AK. The
photothermolysis: precise Cyrano nose: re fi nements in surgical technique and 302. Ni N, Guo S, Langer P. Current concepts in the
microsurgery by selective absorption of pulsed treatment approach to hemangiomas of the nasal management of periocular infantile (capillary)
radiation. Science. 1983; 220(4596):524 – 527 tip. Plast Reconstr Surg. 2010;126(4): 1291 – 1299 hemangioma. Curr Opin Ophthalmol. 2011;22(5):419
– 425
279. Alora MB, Anderson RR. Recent 303. Claerhout I, Buijsrogge M, Delbeke P, et al. The
developments in cutaneous lasers. 291. Soltani AM, Reinisch JF. Algorithmic approach to use of propranolol in the treatment of periocular
Lasers Surg Med. 2000;26(2):108 – 118 the management of hemangiomas. J Craniofac infantile haemangiomas: a review. Br J
Surg. 2011; 22(2):585 – 588 Ophthalmol. 2011;95(9):1199 – 1202
280. Batta K, Goodyear HM, Moss C, Williams HC, Hiller
L, Waters R. Randomised controlled study of early
pulsed dye laser treatment of uncomplicated 292. Li WY, Chaudhry O, Reinisch JF. Guide to early 304. Al Dhaybi R, Superstein R, Milet A, et al. Treatment
childhood haemangiomas: results of a 1-year surgical management of lip hemangiomas based on of periocular infantile hemangiomas with
analysis. Lancet. 2002; 360(9332):521 – 527 our experience of 214 cases. Plast Reconstr Surg. 2011; propranolol: case series of 18 children. Ophthalmology.
128(5):1117 – 1124
2011;118(6):1184 – 1188
281. Kolde G. Early pulsed-dye laser treatment of 293. Mulliken JB, Rogers GF, Marler JJ. Circular 305. Ceisler EJ, Santos L, Blei F. Periocular
childhood haemangiomas. excision of hemangioma and purse-string hemangiomas: what every physician should
Lancet. 2003;361(9354):348 – 349; author reply: 349 closure: the smallest possible scar. Plast know. Pediatr Dermatol. 2004; 21(1):1 – 9
Reconstr Surg.
2002;109(5):1544 – 1554; discussion: 1555
282. Rizzo C, Brightman L, Chapas AM, et al. Outcomes 306. Bullock JD, Warwar RE, Green WR. Ocular
of childhood hemangiomas treated with the explosion during cataract surgery: a clinical,
pulsed-dye laser with dynamic cooling: a 294. Haik BG, Jakobiec FA, Ellsworth RM, Jones IS. histopathological, experimental, and
retrospective chart analysis. Dermatol Surg. 2009;35(12): Capillary hemangioma of the lids and orbit: an biophysical study.
1947 – 1954 analysis of the clinical features and therapeutic Trans Am Ophthalmol Soc. 1998;96(12): 243 – 276;
results in 101 cases. Ophthalmology. 1979;86(5): discussion: 276 – 281
760 – 792
283. Flick RP, Katusic SK, Colligan RC, et al. Cognitive 307. Cogen MS, Elsas FJ. Eyelid depigmentation
and behavioral outcomes after early exposure to following corticosteroid injection for infantile
anesthesia and surgery. Pediatrics. 2011;128(5). 295. Robb RM. Refractive errors associated with ocular adnexal hemangioma. J Pediatr
hemangiomas of the eyelids and

Ophthalmol Strabismus. 1989;26(1): 35 – 38 318. Sherrington CA, Sim DK, Freezer NJ, Robertson CF. literature review. Arch Otolaryngol Head Neck
Subglottic haemangioma. Surg. 2011;137(5):517 – 521
Arch Dis Child. 1997;76(5):458 – 459
308. Vazquez-Botet R, Reyes BA, VazquezBotet M. 329. Vijayasekaran S, White DR, Hartley BE, Rutter MJ,
Sclerodermiform linear atrophy after the use of 319. Sie KC, McGill T, Healy GB. Subglottic hemangioma: Elluru RG, Cotton RT. Open excision of subglottic
intralesional steroids for periorbital ten years ’ experience with the carbon dioxide laser. Ann hemangiomas to avoid tracheostomy. Arch
hemangiomas: a review of complications. J Otol Rhinol Laryngol. 1994;103(3):167 – 172 Otolaryngol Head Neck Surg. 2006;132(2):159 – 163
Pediatr Ophthalmol Strabismus. 1989;26(3): 124 – 127
320. Longstreet B, Bhama PK, Inglis AF Jr, Saltzman 330. Rahbar R, Nicollas R, Roger G, et al. The biology
B, Perkins JA. Improved airway visualization and management of subglottic hemangioma: past,
309. Droste PJ, Ellis FD, Sondhi N, Helveston EM. Linear during direct laryngoscopy using self-retaining present, future.
subcutaneous fat atrophy after corticosteroid laryngeal retractors: a quantitative study. Otolaryngol Laryngoscope. 2004;114(11):1880 – 1891
injection of periocular hemangiomas. Am J Head Neck Surg. 331. Mistry N, Tzifa K. Use of propranolol to treat
Ophthalmol. 1988;105(1):65 – 69 multicentric airway haemangioma. J Laryngol Otol. 2010;
2011;145(2):270 – 275 124(12):1329 – 1332
310. Sutula FC, Glover AT. Eyelid necrosis following 321. Parhizkar N, Manning SC, Inglis AF Jr, Finn LS,
intralesional corticosteroid injection for Chen EY, Perkins JA. How airway venous 332. Maturo S, Hartnick C. Initial experience using
capillary hemangioma. malformations differ from airway infantile propranolol as the sole treatment for infantile
Ophthalmic Surg. 1987;18(2):103 – 105 hemangiomas. airway hemangiomas. Int J Pediatr
Arch Otolaryngol Head Neck Surg. 2011; 137(4):352 – Otorhinolaryngol. 2010;74(3): 323 – 325
311. Chambers CB, Katowitz WR, Katowitz JA,
357
Binenbaum G. A controlled study of topical 0.25%
timolol maleate gel for the treatment of cutaneous 322. Drolet BA, Dohil M, Golomb MR, et al. Early stroke 333. Buckmiller LM, Munson PD, Dyamenahalli U, Dai Y,
infantile capillary hemangiomas. Ophthal Plast and cerebral vasculopathy in children with facial Richter GT. Propranolol for infantile hemangiomas:
Reconstr Surg. 2012;28(2):103 – 106 hemangiomas and PHACE association. Pediatrics. early experience at a tertiary vascular anomalies
center. Laryngoscope. 2010; 120(4):676 – 681
2006;117(3):959 – 964
312. Schneider D, Lee MS, Harrison AR, Sidman J.
Excision of periorbital hemangiomas to correct 323. Badi AN, Kerschner JE, North PE, Drolet BA,
visual abnormalities. Arch Facial Plast Surg. Messner A, Perkins JA. Histopathologic and 334. Manunza F, Syed S, Laguda B, et al. Propranolol
immunophenotypic pro fi le of subglottic for complicated infantile haemangiomas: a case
2011;13(3):195 – 198 hemangioma: multicenter study. Int J Pediatr series of 30 infants. Br J Dermatol. 2010;162(2):
Otorhinolaryngol. 2009;73(9):1187 – 1191 466 – 468
313. Deans RM, Harris GJ, Kivlin JD. Surgical dissection
of capillary hemangiomas: an alternative to
intralesional corticosteroids. Arch Ophthalmol. 1992; 324. Zur KB, Wood RE, Elluru RG. Pediatric 335. Jephson CG, Manunza F, Syed S, Mills NA,
110(12):1743 – 1747 postcricoid vascular malformation: a diagnostic Harper J, Hartley BE. Successful treatment of
and treatment challenge. isolated subglottic haemangioma with propranolol
Int J Pediatr Otorhinolaryngol. 2005; alone.

314. Perkins JA, Duke W, Chen E, Manning S. Emerging
69(12):1697 – 1701 Int J Pediatr Otorhinolaryngol. 2009;
concepts in airway infantile hemangioma
73(12):1821 – 1823
assessment and management. Otolaryngol Head 325. Feuerstein SS. Subglottic hemangioma in infants. Laryngoscope.
Neck Surg. 2009;141(2):207 – 212 1973;83(4): 466 – 475 336. Denoyelle F, Leboulanger N, Enjolras O, Harris R,
Roger G, Garabedian EN. Role of propranolol in
the therapeutic strategy of infantile laryngotracheal
315. Perkins JA, Oliaei S, Garrison MM, Manning SC, 326. Truong MT, Perkins JA, Messner AH, Chang KW.
hemangioma. Int J Pediatr Otorhinolaryngol. 2009;73(8):1168
Christakis DA. Airway procedures and Propranolol for the treatment of airway – 1172
hemangiomas: treatment patterns and outcome in hemangiomas: a case series and treatment
U.S. pediatric hospitals. Int J Pediatr algorithm.
337. Parikh SR, Darrow DH, Grimmer JF, Manning SC,
Otorhinolaryngol. 2009;73(9):1302 – 1307 Int J Pediatr Otorhinolaryngol. 2010; 74(9):1043 –
Richter GT, Perkins JA. Propranolol use for
1048
infantile hemangiomas: American Society of
316. Shikhani AH, Jones MM, Marsh BR, Holliday 327. Hoeve LJ, Küppers GL, Verwoerd CD. Pediatric Otolaryngology Vascular Anomalies Task
MJ. Infantile subglottic hemangiomas. An Management of infantile subglottic Force practice patterns.
update. Ann Otol Rhinol Laryngol. 1986;95(4 hemangioma: laser vaporization, submucous
pt 1): 336 – 347 resection, intubation, or intralesional steroids? Int JAMA Otolaryngol Head Neck Surg.
J Pediatr Otorhinolaryngol. 1997;42(2):179 – 186 2013;139(2):153 – 156
317. Bitar MA, Moukarbel RV, Zalzal GH. Management 338. Denoyelle F, Garabédian EN. Propranolol may
of congenital subglottic hemangioma: trends and 328. Sierpina DI, Chaudhary HM, Walner DL, Aljadeff G, become fi rst-line treatment in obstructive subglottic
success over the past 17 years. Otolaryngol Head Dubrow IW. An infantile bronchial hemangioma infantile hemangiomas. Otolaryngol Head Neck
Neck Surg. 2005;132(2):226 – 231 unresponsive to propranolol therapy: case report Surg. 2010;142(3):463 – 464
and

339. Waner M, Suen JY. Treatment options for the 349. Burgos L, López Gutiérrez JC, Andrés AM, et al. Suen JY, eds. Hemangiomas and Vascular
management of hemangiomas. In: Waner M, Early surgical treatment in nasal tip Malformations of the Head and Neck. New York,
Suen JY, eds. hemangiomas: 36 cases review [in Spanish]. Cir NY: Wiley-Liss; 1999:293 – 307
Hemangiomas and Vascular Malformations of Pediatr. 2007; 20(2):83 – 86
the Head and Neck.
360. Zide BM, Glat PM, Stile FL, Longaker MT. Vascular
New York, NY: Wiley-Liss Inc; 1999: 233 – 262
350. Hochman M, Mascareno A. Management of nasal lip enlargement: part I. Hemangiomas — tenets of
hemangiomas. Arch Facial Plast Surg. 2005;7(5):295 therapy. Plast Reconstr Surg. 1997;100(7):1664 – 1673
340. Pransky SM, Canto C. Management of subglottic – 300
hemangioma. Curr Opin Otolaryngol Head Neck
351. Perkins JA, Chen BS, Saltzman B, Manning SC, 361. Bouchard S, Yazbeck S, Lallier M. Perineal
Surg. 2004; 12(6):509 – 512
Parikh SR. Propranolol therapy for reducing the hemangioma, anorectal malformation, and
number of nasal infantile hemangioma invasive genital anomaly: a new association? J Pediatr
341. Cotton RT, Tew fi k TL. Laryngeal stenosis procedures. JAMA Otolaryngol Head Neck Surg.
following carbon dioxide laser in subglottic Surg. 2014;140(3):220 – 227 1999;34(7):1133 – 1135
hemangioma: report of three cases. Ann Otol
362. Kulungowski AM, Alomari AI, Chawla A,
Rhinol Laryngol. 1985; 94(5 pt 1):494 – 497
352. Eivazi B, Cremer HJ, Mangold C, Teymoortash A, Christison-Lagay ER, Fishman SJ. Lessons from
Wiegand S, Werner JA. Hemangiomas of the nasal a liver hemangioma registry: subtype classi fi cation.
342. Chatrath P, Black M, Jani P, Albert DM, Bailey CM. tip: an approach to a therapeutic challenge. Int J
A review of the current management of infantile Pediatr Otorhinolaryngol. 2011;75(3): 368 – 375 J Pediatr Surg. 2012;47(1):165 – 170
subglottic haemangioma, including a comparison
363. Rialon KL, Murillo R, Fevurly RD, Kulungowski
of CO 2 laser therapy versus tracheostomy. Int J
AM, Christison-Lagay ER, Zurakowski D, et al.
Pediatr Otorhinolaryngol. 2002;64(2):143 – 157
353. Faguer K, Dompmartin A, Labbé D, Barrellier MT, Risk factors for mortality in patients with
Leroy D, Theron J. Early surgical treatment of multifocal and diffuse hepatic hemangiomas. J
Cyrano-nose haemangiomas with Rethi incision. Br Pediatr Surg. 2015;50(5):837 – 41.

343. Froehlich P, Stamm D, Floret D, Morgon J Plast Surg. 2002;55(6):498 – 503
A. Management of subglottic haemangioma. Clin
364. Horii KA, Drolet BA, Frieden IJ, et al; Hemangioma
Otolaryngol Allied Sci. 1995;20(4):336 – 339
Investigator Group. Prospective study of the
354. Pitanguy I, Machado BH, Radwanski HN, Amorim NF.
frequency of hepatic hemangiomas in infants with
Surgical treatment of hemangiomas of the nose. Ann
344. Bajaj Y, Hartley BEJ, Wyatt ME, Albert DM, Bailey multiple cutaneous infantile hemangiomas. Pediatr
Plast Surg.
CM. Subglottic haemangioma in children: Dermatol. 2011; 28(3):245 – 253
1996;36(6):586 – 592; discussion: 592 – 593
experience with open surgical excision. J Laryngol
Otol. 2006; 120(12):1033 – 1037 355. Demiri EC, Pelissier P, Genin-Etcheberry
T, Tsakoniatis N, Martin D, Baudet J. Treatment of
365. Huang SA, Tu HM, Harney JW, et al. Severe
facial haemangiomas: the present status of
345. O-Lee TJ, Messner A. Open excision of subglottic hypothyroidism caused by type 3 iodothyronine
surgery. Br J Plast Surg. 2001;54(8):665 – 674
hemangioma with microscopic dissection. Int J deiodinase in infantile hemangiomas. N Engl J
Pediatr Otorhinolaryngol. 2007;71(9):1371 – 1376 Med. 2000; 343(3):185 – 189
356. McCarthy JG, Borud LJ, Schreiber JS.
Hemangiomas of the nasal tip. Plast Reconstr
346. Waner M, Kastenbaum J, Scherer K. Hemangiomas 366. Mhanna A, Franklin WH, Mancini AJ. Hepatic
Surg. 2002;109(1):31 – 40
of the nose: surgical management using a modi fi ed infantile hemangiomas treated with oral
subunit approach. Arch Facial Plast Surg. 2008; 357. Jackson IT, Sosa J. Excision of nasal tip propranolol — a case series.
10(5):329 – 334 hemangioma via open rhinoplasty: a skin sparing Pediatr Dermatol. 2011;28(1):39 – 45
technique. Eur J Plast Surg. 1998;21(5):265 – 268
367. Mazereeuw-Hautier J, Hoeger PH, Benlahrech
347. Thomson HG, Lanigan M. The Cyrano nose: a S, et al. Ef fi cacy of propranolol in hepatic
clinical review of hemangiomas of the nasal tip. Plast 358. Chang CS, Wong A, Rohde CH, Ascherman JA, infantile hemangiomas with diffuse neonatal
Reconstr Surg. Wu JK. Management of lip hemangiomas: hemangiomatosis. J Pediatr. 2010; 157(2):340 – 342
1979;63(2):155 – 160 minimizing peri-oral scars. J Plast Reconstr
Aesthet Surg.
348. Koopmann CF Jr. The “ Pinocchio ” nasal
2012;65(2):163 – 168
deformity — hemangioma vs. angiolipoma: 368. Luu M, Frieden IJ. Haemangioma: clinical
esthetic correction and etiology. J Otolaryngol. 1988;17(4):359. Waner M, Suen JY. The treatment of course, complications and management. Br J
169 – 172 hemangiomas: hemangiomas requiring special Dermatol. 2013; 169(1):20 – 30
consideration. In: Waner M,

Diagnosis and Management of Infantile Hemangioma
Anthony J. Mancini, Amy J. Nopper and the
DERMATOLOGY, SECTION ON OTOLARYNGOLOGY-HEAD David H. Darrow, Arin K. Greene,
AND NECK SURGERY, and SECTION ON PLASTIC SURGERY SECTION ON
Pediatrics 2015;136;e1060
DOI: 10.1542/peds.2015-2485 originally published online September 28, 2015;
Updated Information & including high resolution figures, can be found at:
Services http://pediatrics.aappublications.org/content/136/4/e1060
References This article cites 352 articles, 36 of which you can access for free at:
http://pediatrics.aappublications.org/content/136/4/e1060#BIBL
Subspecialty Collections This article, along with others on similar topics, appears in the
following collection(s):
Current Policy
http://www.aappublications.org/cgi/collection/current_policy
Dermatology
http://www.aappublications.org/cgi/collection/dermatology_sub
Section on Dermatology
http://www.aappublications.org/cgi/collection/section_on_dermatolo
gy
Section on Otolaryngology-Head and Neck Surgery
http://www.aappublications.org/cgi/collection/section_on_otolaryng
ology-head_and_neck_surgery
Section on Plastic Surgery
http://www.aappublications.org/cgi/collection/section_on_plastic_su
rgery
Permissions & Licensing Information about reproducing this article in parts (figures, tables) or
in its entirety can be found online at:
http://www.aappublications.org/site/misc/Permissions.xhtml
Reprints Information about ordering reprints can be found online:

http://www.aappublications.org/site/misc/reprints.xhtml

Diagnosis and Management of Infantile Hemangioma
Anthony J. Mancini, Amy J. Nopper and the
DERMATOLOGY, SECTION ON OTOLARYNGOLOGY-HEAD David H. Darrow, Arin K. Greene,
AND NECK SURGERY, and SECTION ON PLASTIC SURGERY SECTION ON
Pediatrics 2015;136;e1060
DOI: 10.1542/peds.2015-2485 originally published online September 28, 2015;
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/136/4/e1060
Pediatrics. A monthly publication, it

Pediatrics is owned, published, and trademarked by Pediatrics is the official journal of the American Academy of
Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, has been published continuously since 1948.
60007. Copyright © 2015 by the American Academy of Pediatrics. All rights reserved. Print the American Academy of
ISSN: 1073-0397.

Darrow DH. Diagnosis and Management of Infantile Hemangioma .En - Id

Diunggah oleh

Informasi Dokumen

Judul Asli

Hak Cipta

Format Tersedia

Bagikan dokumen Ini

Bagikan atau Tanam Dokumen

Opsi Berbagi

Apakah menurut Anda dokumen ini bermanfaat?

Apakah konten ini tidak pantas?

Hak Cipta:

Format Tersedia

Darrow DH. Diagnosis and Management of Infantile Hemangioma .En - Id

Diunggah oleh

Hak Cipta:

Format Tersedia

LAPORAN KLINIK Pedoman untuk Clinician di Rendering Pediatric Perawatan

Diagnosis dan Penatalaksanaan infantil

dasar untuk pengambilan keputusan klinis dalam pengelolaan IH.

DOI: 10,1542 / peds.2015-2485

con fl ik kepentingan untuk mengungkapkan.

download dari www.aappublications.org/news oleh tamu di April 9, 2019

malformasi vaskular endotel yang melapisi GLUT1negative slitlike

download dari www.aappublications.org/news oleh tamu di April 9, 2019

EPIDEMIOLOGI dan setiap peningkatan risiko yang timbul

download dari www.aappublications.org/news oleh tamu di April 9, 2019

Meskipun sering disarankan sebagai faktor

• Insiden pada populasi umum adalah

download dari www.aappublications.org/news oleh tamu di April 9, 2019

mereka. Atas dasar proliferasi cepat dari sel endotel,

2,3-deoxygenase, protein berpikir untuk

IH. GLUT1, transporter glukosa fasilitatif digunakan pertumbuhan ke dalam jaringan

download dari www.aappublications.org/news oleh tamu di April 9, 2019

download dari www.aappublications.org/news oleh tamu di April 9, 2019

Untuk sebagian besar bayi dengan IH, involusi GAMBAR 6

Sebagai IHS rumit, kebanyakan lesi fl atten dan

download dari www.aappublications.org/news oleh tamu di April 9, 2019

• Super ﬁ cial IHs appear earlier and

• Segmental IHs are more

• The presence of more than 5 focal

Downloaded from www.aappublications.org/news by guest on April 9, 2019

been reported as a complication of segmental treatment. However, the mean size of

Ulceration was the most common complication

Downloaded from www.aappublications.org/news by guest on April 9, 2019

In a large prospective study of ulcerated IHs,

Feeding impairment can occur in infants with

Downloaded from www.aappublications.org/news by guest on April 9, 2019

• High-risk periocular IHs are those

Downloaded from www.aappublications.org/news by guest on April 9, 2019

TABLE 3 Consensus Diagnostic Criteria for PHACE Syndrome Organ System

Major Criteria Minor Criteria

Cerebrovascular anomalies, present in more

Adapted from ref 25.

Downloaded from www.aappublications.org/news by guest on April 9, 2019

common extracutaneous manifestation of PHACE arterial anomalies in patients with PHACE

Downloaded from www.aappublications.org/news by guest on April 9, 2019

administration, T2-weighted images with fat is better to assess extent of the

saturation, and ﬂ ow-sensitive sequences such lesion.

as gradient echo or MRA. 129 Proliferating IHs

ﬂ ow-sensitive sequences, along with

Downloaded from www.aappublications.org/news by guest on April 9, 2019

Whether IH affects the psychosocial well-being of

Downloaded from www.aappublications.org/news by guest on April 9, 2019

MANAGEMENT OF ULCERATED IHS

when surgery for IH is being considered. For

Downloaded from www.aappublications.org/news by guest on April 9, 2019

laser therapy with a mean number of Wound Care Adjuvant Therapies

Adapted from ref 368.

Downloaded from www.aappublications.org/news by guest on April 9, 2019

vascular lesions, including IHs refractory to treatment of IH is unknown. Proposed

A complete history and physical examination,

Downloaded from www.aappublications.org/news by guest on April 9, 2019

from ref 161. bradycardia (8 patients, including 1 considered

unremarkable cardiac history and propranolol has yet to be established, a

b- blockers can be also be associated with

Downloaded from www.aappublications.org/news by guest on April 9, 2019

• Contraindications to the use of

b- blocker therapy is risky or contraindicated. 203 One

Downloaded from www.aappublications.org/news by guest on April 9, 2019