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journal homepage: www.elsevier.com/locate/survophthal

Major review

Ophthalmological manifestations of
Parry-Romberg syndrome

Franziska Bucher, MD*, Julia Fricke, MD, Antje Neugebauer, MD,

Claus Cursiefen, MD, Ludwig M. Heindl, MD
Department of Ophthalmology, University of Cologne, Cologne, Germany

article info abstract

Article history:
Received 10 December 2015
Received in revised form 22 March
2016
Accepted 24 March 2016
Available online 1 April 2016
Keywords:
Parry-Romberg syndrome
hemiatrophia faciei
progressive hemifacial atrophy
scleroderma
linear scleroderma en coup de sabre
morphea
Parry-Romberg syndrome is a rare disease characterized by slowly progressive atrophy
affecting facial subcutaneous tissues, including the underlying muscles and osteocartila-
ginous structures. Various periocular, ocular, and neuro-ophthalmological manifestations
have been described in Parry-Romberg syndrome. The most common periocular disorders
include enophthalmos, eyelid, and orbit alterations. The most frequent ocular disorders
include corneal and retinal changes, and the most common neuro-ophthalmological dis-
orders involve optic nerve, ocular motor and pupillary dysfunction. Besides the charac-
teristic facial abnormalities, systemic manifestations may occur, including neurologic,
dermatologic, cardiac, endocrine, infectious, orthodontic, and maxillofacial disorders. So
far, mainly brief case reports describe these ophthalmological findings. Therefore, we
summarize the ocular, periocular, and neuro-ophthalmological findings in detail, describe
diagnostic modalities, and outline therapeutic options.
ª 2016 Elsevier Inc. All rights reserved.

1. Introduction centuries ago by the neurologists Parry in 182579 and Romberg

Parry-Romberg syndrome (PRS) is a rare disease characterized
by slowly progressive atrophy affecting facial subcutaneous
tissues, muscles, osteocartilaginous structures, and possible
cerebral involvement.32,34,84 Although bilateral cases have
been described,34,98 diagnosis is often possible because of the
characteristic hemifacial atrophy and resulting facial asym-
metry at later stages of the disease (Fig. 1).
Studies of mummy portraits from the beginning of the first
millennium, combined with a computerized tomography scan
of the skull in one of the cases, led to the conclusion that PRS
already existed at that time.4,34 PRS was described almost 2
in 1846.87 In 1871, Eulenberg renamed the disease progressive
hemifacial atrophy.36 Since then, there are various terms used
for PRS, for example, progressive hemifacial atrophy, pro-
gressive facial hemiatrophy, idiopathic hemifacial atrophy, or
hemiatrophia faciei (progressiva).14,36
PRS can be categorized as one subset of linear morphea, a
type of localized scleroderma, a condition of unknown etiol-
ogy showing thickening and hardening of the skin from
increased collagen production.2 Linear scleroderma en coup
de sabre (LSCS) is another subset of linear morphea and refers
to a lesion mostly located in the frontoparietal scalp and/or
the paramedian forehead, often resembling a scar from a

* Corresponding author: Franziska Bucher, MD, Department of Ophthalmology, University of Cologne, Kerpener Strasse 62, 50937
Cologne, Germany.
E-mail address: franziskabucher@yahoo.de (F. Bucher).
0039-6257/$ e see front matter ª 2016 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.survophthal.2016.03.009
694 s u r v e y o f o p h t h a l m o l o g y 6 1 ( 2 0 1 6 ) 6 9 3 e7 0 1
Fig. 1 e Characteristic hemifacial atrophy of subcutaneous
tissue of the left side of the face and anisocoria.17
sword.2 Several studies support that PRS and LSCS exist on a
spectrum of localized scleroderma as a single entity27 because
both of them have a similar clinicopathological appearance,
sometimes making the differentiation between them chal-
lenging.15 Up to 28% of patients with LSCS show features of
PRS such as progressive hemifacial atrophy or histopatho-
logical similarities in skin biopsies.2,8 Even conversion from
LSCS to PRS occurs, making the differentiation more com-
plex.34,58 There is a controversy, however, whether these 2
entities are linked or whether they have to be seen as distinct
conditions. The deeper structures of the head and neck are
usually not involved in LSCS, in contrast to PRS.58,100 Ocular
involvement in children with localized scleroderma include
eyelid abnormalities, dry eye, and anterior uveitis.102
The disease is not always restricted to one side, as bilateral
facial or cerebral atrophy may occur29,50,98; however, bilateral
occurrence is sometimes classified as Barraquer-Simons
syndrome.89
Incidence has been estimated to be at least 1 per 700.000,96
with women being more often affected by PRS than
men.34,95,98,100 Most cases start in the first decade of life,32,34,65
although neonatal onset21 and late onset cases occur.66,95
Disease progression may vary between 2 to 20 years until
stabilization is reached.32,36,65,70,79,87 Initial diagnosis of PRS
can be difficult, often taking years, and has to include medical
history, examination, exclusion of other causes, sometimes
with the aid of imaging or histopathology.100
We provide an overview on the clinical characteristics of
this rare condition, as well as on the pathogenesis and the
ophthalmological and systemic manifestations of PRS.
Currently, (peri)ocular findings are described in case reports,
and no major ophthalmological review exists. Our purpose is
to summarize these periocular and ocular findings in detail, to
describe recommendable diagnostic modalities, and to outline
therapeutic options.
2. Pathogenesis
The exact pathogenesis of PRS remains unclear, but seems to be
heterogeneous. There are various proposed causes for this self-
limiting disease: congenital mechanisms, disturbance of fat
metabolism, trauma, infectious agents, heredity, cranial vascular
malformations, immune-mediated processes, hyperactivity of
the brain stem sympathetic centers, cervical sympathetic
dysfunction, and trigeminal neurovasculitis.31,32,34,42,45,62,64
Trauma is a cause of PRS in 24%e34% of patients,7,22 PRS also
occurring after surgical6 or obstetric trauma.89
Familial PRS is described, but our review of the literature
reveals no clear pattern of inheritance or evidence of one
specific genetic defect.3,63
An immune-mediated process has been hypothesized and
is supported by inflammatory changes detected in brain bi-
opsies, frequent association with autoimmune diseases (e.g.
lupus erythematosus), finding of autoantibodies, cerebrospi-
nal fluid oligoclonal bands, and improvement of the lesions
following immunosuppression.8,15,32,45,46,65,71,89
Hemifacial atrophy has also been associated with benign
tumors such as orbital neurinomas, mandibular odontogenic
fibromas, and hamartomas.28 The coexistence with migraine
and intracranial aneurysms raises the possibility of a neural
crest migration disorder, from which affected tissues in PRS
(e.g. craniofacial bone and cartilage, smooth muscles, and
cranial vessels) take origin.34,80,89
In some cases, an infectious cause (e.g. herpes infection,
Lyme disease) seems possible.90
Underlying mechanisms of this syndrome have been
studied by clinical, electrophysiological, and neuroimaging
tools.7,18,49,84 Despite hemifacial atrophy and changes in the
brain, ocular motor cranial nerve palsies may be present in
PRS (III, IV, and VII nerves).34,95 Involvement of the trigeminal
nerve may present as chronic facial pain and trigeminal
neuralgia.17,24,30,37 In vivo confocal microscopy of the cornea
may show reduction of trigeminal nerve endings of the
affected side compared to the unaffected side.17
The cervical sympathetic trunk seems to play a role in the
pathogenesis of PRS as well.6 The hypothesis of sympathetic
dysfunction is supported by experimental studies in animals
that demonstrate clinical features of PRS (i.e., hemifacial at-
rophy, enophthalmos, and bone atrophy on the side of the
sympathectomy) after ablation of the superior cervical gan-
glion.6,22,72,83 Some patients even may show signs of auto-
nomic dysfunction (e.g. ipsilateral Horner syndrome).8,44
Others, however, show normal responses to autonomic
function testing.6 In some cases, sympathectomy has halted
disease progression, supporting the hypothesis that sympa-
thetic irritation leads to facial hemiatrophy.34 Although many
approaches try to elucidate the pathogenesis of PRS, the exact
mechanisms causing the periocular, ocular, and systemic
manifestations remain unclear.
3. Periocular manifestations (including
disorders of the eyelids and orbit)
The periorbital region is often affected by facial atrophy in
PRS. Changes in periocular structures may be an early symp-
tom in PRS, making it important for ophthalmologists to be
aware of this disease (Table 1).
One of the most frequent periocular signs is enoph-
thalmos, mainly due to fat atrophy of retrobulbar fat tissue.38
 s u r v e y o f o p h t h a l m o l o g y 6 1 ( 2 0 1 6 ) 6 9 3 e7 0 1 695

in their shape and volume may also be present because of

Table 1 e Periocular findings in Parry-Romberg syndrome
atrophy of underlying tissue.61,82
Periocular structure Periocular manifestations The eyelids may be affected, with retraction, lagoph-
Skin Hyperpigmentation/depigmentation23,71 thalmos, atrophy, or pseudoptosis.8,43,76 Late-onset develop-
Eyebrows/lashes Alopecia34 ment of ipsilateral upper eyelid pseudocoloboma has been
Asymmetry61,82 described.52,92
Eyelid Retraction13 One characteristic facies is the deviation of mouth and
Lagophthalmos13
nose toward the affected side.51 Orbital computerized to-
Atrophy56
mography scan and MRI may reveal alterations of the orbital
Pseudoptosis76
Pseudocoloboma52,92 wall, retro-ocular structures, or orbital tumors, for example,
Orbit Enophthalmos due to retroorbital orbital neurinoma.9,28,38
fat atrophy38 Periocular manifestations might present initially with only
Enophthalmos due to bone atrophy9 slight alterations, with worsening during the course of the
Alterations of orbital wall and retroocular disease. Particularly in patients presenting with progressive
structures38
enophthalmos and eyelid alterations, the diagnosis of PRS
Orbital tumors28
Mouth and nose Deviation toward the affected side of
should be considered (Fig. 2).
hemifacial atrophy51

4. Ocular manifestations (including

Changes in the bony structures of the orbit may also occur,
causing enophthalmos.9 Shrinkage of the globe may be
mistaken for enophthalmos as well.10
Periocular skin may show hyperpigmentation or depig-
mentation,23,71 or even alopecia.34 Asymmetries of eyebrows
disorders of cornea, uvea, lens, ciliary body,
retina, and vitreous)
Ophthalmological findings occur in 10%e35% of patients,
mainly in the ipsilateral orbit; however, also the contralateral

Fig. 2 e Periocular findings in PRS. A: Characteristic enophthalmos of the left eye.82 B: Photograph showing en coup de
sabre.33 Black arrow pointing at lesion on paramedian forehead. C: Pigmentation and atrophy of the left periocular region.9
D: Hemifacial atrophy of the right side of the face with deviation of mouth and nose toward the affected side.39 PRS, Parry-
Romberg syndrome.
696 s u r v e y o f o p h t h a l m o l o g y 6 1 ( 2 0 1 6 ) 6 9 3 e7 0 1

eye can be affected (Table 2).100 Ocular manifestations can
develop before, during, or after facial atrophy. Case reports
describe a great variety of different ocular manifestations, but
unfortunately, there is no large study available on ocular pa-
thologies found in PRS.
Abnormal pigmentation of the palpebral conjunctiva of the
affected side developed in 1 patient with PRS.9 Corneal epithe-
lium, stroma, or endothelium may show different pathologies:
for example, corneal band keratopathy, exposure keratopathy,
decrease of corneal nerves, reduced corneal sensation, flourlike
stromal deposits, primary corneal endothelial failure, and
discrete, irregularly round, glassy precipitates.5,17,40,47,68,74
Refractive changes may be the initial sign of PRS,55 and some
patients suffer from photophobia.38,68 In addition, severe com-
plications such as spontaneous scleral melting occur in PRS.52
The iris may show signs of anterior uveitis or atrophy.38,98
Iris crystalline deposits and Fuchs heterochromic iridocyclitis
have been observed.47,61,74,98 Ciliary body inflammation,
hypotony, and phthisis occur as well.39,53,59 The vitreous may
show bilateral vitritis.54
Chorioretinal changes may include retinal vasculitis, telan-
giectasia, pigment epithelial changes, retinal edema, retinitis
pigmentosa, retinal detachment, Coats disease, sectional cho-
rioretinal atrophy, and central retinal artery occlusion (even in
children).10,13,33,56,67,69,73,74,95 Phthisis may be another reason
for choroidal and retinal folding and hyperopia (Fig. 3).10
PRS can lead to a variety of ocular pathologies, making
interdisciplinary care indispensable for these patients.
5. Neuro-ophthalmological manifestations
(including disorders of the optic nerve and
extraocular muscles)
The neuro-ophthalmic examination may reveal third nerve
palsy, optic neuropathy, Horner syndrome, and tonic pupil
(Table 3).5,8,34,44 The optic nerve may show papillitis and
neuroretinitis.26,88 There may be pupillary disturbances, ani-
socoria with mydriasis or miosis on the affected side, in some
cases.17,38,40
Diplopia in PRS has been attributed not only to enoph-
thalmos or progressive atrophy of the orbit but also to limi-
tation of eye motility based on ocular motor nerve
dysfunction, extraocular muscle thinning, or vertical and
horizontal restrictive strabismus.10,28,81,95,103 A muscle biopsy
in a patient with PRS and an eye movement disorder showed
fibrosis.103
6. Systemic associations (including
neurologic, dermatologic, cardiac, endocrine,
infectious, orthodontic, and maxillofacial
disorders)

Systemic associations include neurologic, dermatologic, car-

Table 2 e Ocular manifestations in Parry-Romberg diac, rheumatologic, endocrine, infectious, orthodontic, and
syndrome maxillofacial manifestations.1,12,19,34,42,98 Neurologic abnor-
Ocular structure Ocular manifestations malities, such as involvement of limbs, seizures,71
Conjunctiva Palpebral pigmentation9 migraine,30,80,95 facial pain,24,99 intraparenchymal calcifica-
Cornea Band keratopathy5,47 tions, intracranial vasculature abnormalities, meningeal
Exposure keratopathy43 enhancement,48 cerebral atrophy,71 Rasmussen encephalitis,19
Decreased corneal nerves17 and sympathetic dysfunction,50 may occur in up to 15% of pa-
Reduced corneal sensation5 tients.50 Dermatological findings include skin hyperpigmenta-
Flourlike stromal deposits68
tion or depigmentation,23,71 cicatricial alopecia, and mostly
Primary corneal endothelial failure40
unilateral subcutaneous facial atrophy.34 PRS has been associ-
Discrete, irregularly round, glassy
precipitates11 ated with hypertrophic cardiomyopathy,12 congenital heart
Refractive changes55 disease,91 rheumatologic diseases (with positive ANA and
Photophobia38,68 rheumatoid factor),45 thyroid dysfunction including Hashimoto
Sclera Spontaneous scleral melting52 thyroiditis.22,34 Hyperthyroidism and metabolic disorder was
Iris/Uvea Anterior uveitis38,101 thought to cause facial atrophy, lipodystrophy, and diencephalic
Iris atrophy38
tissue melting (Fig. 4).34 Different studies hypothesize a corre-
Iris crystalline deposits11,47
Fuchs heterochromic iridocyclitis47,61
lation with viral or bacterial infections (e.g. herpes and Borrelia
Panuveitis25 burgdorferi) as possible causes for PRS,35,90 although this cau-
Ciliary body Inflammation53 sality is uncertain.14,89,93 Otitis, dental infections, diphtheria,
Hypotony/Phthisis53,59 syphilis, rubella, and tuberculosis have been associated with the
Vitreous (Bilateral) vitritis54 development of PRS.34,83,89,94 Oral manifestations of PRS include
Retina Retinal vasculitis13,74
unilateral tongue atrophy, deficiency of soft and hard palate, jaw
Retinal telangiectasia10,76
hypoplasia, and abnormal dental development.1,41,97 In addi-
Retinal pigment epithelial changes95
Retinal edema95 tion, cases of facial cleft malformation support the hypothesis of
Retinitis pigmentosa69 the disturbance of neural crest cell development.97
Retinal detachment67
Coats disease67,73,78
Sectional chorioretinal atrophy56 7. Treatment
Central retinal artery occlusion33
Choroidal/retinal folding and hyperopia
Little is known about the efficacy of agents used to treat this
due to phtisis10
disease.98 Moreover, the success of a therapy is difficult to
 s u r v e y o f o p h t h a l m o l o g y 6 1 ( 2 0 1 6 ) 6 9 3 e7 0 1 697

Fig. 3 e Ocular manifestations of PRS. A: Slit-lamp photography showing abnormal pigmentation of the tarsal conjunctiva.9
B: Ocular hypotony causing chorioretinal folds.59 C: Fundus photograph showing an elevated optic disc, tortuosity of retinal
vessels, macular folds, and pigment changes.39 D: Cherry red spot after retinal artery occlusion.33 E: Exudative detachment
of the inferior retina and macula caused by telangiectatic retinal vessels.78 F: Fluorescein angiography showing extensive
staining of the retina due to telangiectasia and leakage from peripheral retinal capillaries.78 PRS, Parry-Romberg syndrome.

assess, as the disease stabilizes spontaneously.100 Therefore,
systemic medications used to treat other forms of linear
scleroderma are commonly used for PRS.98 There are no ran-
domized controlled trials for the treatment of PRS, and only case
reports describe the effect of different agents. Suggested treat-
ments include antimalarials, methotrexate, local or systemic
steroids, tetracycline, and cyclophosphamide (Table 4).34,71,98
Sympathectomy appears to have halted disease progression in
some cases.34,86
Local therapeutic options include emollients,14 vitamin D3
analogues (þPUVA [Psoralen plus ultraviolet A]),14,98 and
phototherapy.14 Hemicranial pain syndrome in PRS has been
treated successfully by repetitive local botulinum toxin A
injections.16
Ophthalmological treatment concentrates on stabilization
or rehabilitation of (peri)ocular complications. Eyelid retraction
and lagophthalmos can be treated by recession of the levator
muscle to abolish corneal exposure, and pseudocoloboma can
be closed surgically.43,92 External eye muscle surgery and
frontalis suspension may be indicated to correct eye motility
disorder and ptosis.88 Primary corneal endothelial failure was
treated with repeated penetrating keratoplasty after graft fail-
ure.40 Scleral melting may require scleral grafting.52 Anterior
uveitis is treated with standard measures, starting with topical
steroids and mydriatics.38,101 In 1 case at 1-month follow-up,
the keratic precipitates and inflammatory cells in the anterior
chamber had resolved.101 Another case with panuveitis and
papillitis was treated with local and systemic steroids.25 Retinal
arteriolar leakage may be treated by laser coagulation. In some
cases, pars plana vitrectomy was necessary because of sub-
retinal exudates and retinal telangiectatic vessels.26,61,78 Ocular
inflammation may require immunosuppressive therapy.13
698 s u r v e y o f o p h t h a l m o l o g y 6 1 ( 2 0 1 6 ) 6 9 3 e7 0 1

Table 3 e Neuro-ophthalmological manifestations in Table 4 e Therapeutic options for Parry-Romberg

Parry-Romberg syndrome syndrome
Structure Neuro-ophthalmological Systemic therapy Local therapy Ophthalmic surgical
manifestations procedures

Optic nerve Papillitis/neuroretinitis26,88 Procaine penicillin14 Emollients14 Ptosis surgery88

Optic neuropathy44 D-penicillamine98 Vitamin D Eyelid retraction
Extraocular muscles Thinning10,76 analog14 repair43
Fibrosis81 Antimalarials14,98 Vitamin D Pseudocoloboma
Vertical and horizontal analogþ closure92
restrictive strabismus81 Corticosteroids14,98 PUVA98 Strabism surgery88
Third nerve paresis66 Vitamin E98 Topical steroids98 Keratoplasty40
Other neuro-ophthalmic Third nerve palsy66 Retinoids14 Botulinum Scleral grafting52
disorders Horner syndrome8 toxin A16,98
Adie pupil34 Cyclosporine14 Phototherapy14 Panretinal laser
Anisocoria (mydriasis or miosis on coagulation26,61
the affected side)17,38,40 Tetracycline98 Pars plana vitrectomy78
Amblyopia57 Cyclophosphamide14 Enophthalmos
Blindness67,74 correction76
Metotrexate14,98 Adipose stem cell
injection20,60,100
Metotrexateþ Lipofilling49
After stabilization, surgical reconstruction using silicone
Pulse oral steroids98 Autologous lipofilling85
implants, muscle flap grafts, galeal flaps, fat grafts, bone and
Plastic reconstructive
cartilage grafts, or injectable dermal filler are used to restore surgery (i.e.,
natural facial contours.75,77,85,98,100 These techniques can be free flap)100
successfully applied to treat enophthalmos and pseu-
PUVA, Psoralen plus ultraviolet A.
doptosis.49,76 The most promising cosmetic results recently
described are autologous fat grafting with adipose-derived
stem cells.20,60,77,100
9. Methods and literature search

8. Conclusions Pubmed electronic search was performed in September and

PRS is a rare progressive degenerative disorder of unknown
etiology. Besides characteristic facial hemiatrophy, PRS pre-
sents with a variety of ophthalmological manifestations.
Progressive enophthalmos or eyelid alterations may be one of
many periocular signs. All ocular structures may be involved,
mainly on the affected side, but also bilaterally.
October 2015 without any date restrictions. We included peer-
reviewed literature to be of clinical importance and relevance
to the subject. Furthermore, references from within these
articles were also included. Key words used in the search
included Parry-Romberg syndrome, progressive hemifacial
atrophy, progressive facial hemiatrophy, idiopathic hemi-
facial atrophy, or hemiatrophia faciei.

Fig. 4 e Systemic manifestations in PRS. A: Magnetic resonance imaging demonstrating right cerebral atrophy (axial T1 with
contrast).71 B: Right cerebral atrophy and T2 hyperintensities (coronal FLAIR).71 PRS, Parry-Romberg syndrome.
 s u r v e y o f o p h t h a l m o l o g y 6 1 ( 2 0 1 6 ) 6 9 3 e7 0 1
10. Disclosures
The authors report no proprietary or commercial interest in
any product mentioned or concept discussed in this article.
Funding was given from German Research Foundation [FOR
2240 “(Lymph-) Angiogenesis and Cellular Immunity in In-
flammatory Diseases of the Eye” (to Claus Cursiefen and
Ludwig M. Heindl); HE 6743/2-1 and HE 6743/3-1 to Ludwig M.
Heindl; CU 47/6-1 to Claus Cursiefen]; GEROK-Program Uni-
versity Hospital of Cologne (to Franziska Bucher and Ludwig
M. Heindl); EU FP7 STRONG (to Claus Cursiefen and Franziska
Bucher); UoC grant (to Franziska Bucher); German Cancer Aid
(to Claus Cursiefen and Ludwig M. Heindl).
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