3

Osteogenesis
imperfecta
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 Osteogenesis imperfecta (OI)
 disorder of congenital
bone fragility caused by
mutations in the genes
that codify for type I
procollagen (ie, COL1A1
and COL1A2).
 4 types of OI :
 Type I - Mild forms
 Type II - Extremely severe
 Type III - Severe
 Type IV - Undefined
Pathophysiology
 Type I collagen fibers are found in the
bones, organ capsules, fascia, cornea,
sclera, tendons, meninges, and dermis.
 Type I collagen, which constitutes
approximately 30% of the human body by
weight, is the defective protein in OI.
 In structural terms, type I collagen fibers
are composed of a left-handed helix
formed by intertwining of pro-alpha 1 and
pro-alpha 2 chains.
 Mutations in the loci that encode these
chains cause OI (ie, COL1A1 on band
17q21 and COL1A2 on band 7q22.1,
respectively).
 Other mutations : bone fragility(rapuh)
associated with distinctive clinical or
histologic features (eg,
redundant/b’lebihan callus/jalinan tlg yg
tdk teratur formation,
pseudoglioma/menyerupai
retinoblastoma, defective mineralization of
bone).
 These conditions have been grouped as
syndromes resembling OI.
 Cartilage-associated protein (CRTAP) is a
protein required for prolyl 3-hydroxylation.
Loss of CRTAP in mice causes an
osteochondrodysplasia characterized by
severe osteoporosis and decreased osteoid
production.
 In humans, CRTAP mutations may be
associated with syndromes resembling
osteogenesis imperfecta, including
recessive forms of lethal syndromes
resembling OI and syndromes resembling
OI with redundant callus formation.
Resembling of OI
Congenital brittle bones with rhizomelia (panggul)
 short humerus and femora, and recessive inheritance Fractures
may be present at birth., the genetic defect has been mapped to the
short arm of chromosome 3, where no genes codify type I
procollagen.

Congenital brittle bones with redundant callus formation

 hyperplastic calluses in long bones after having a fracture or
orthopedic surgery. Mutations in the type I procollagen genes have
not been found Inheritance appears to be autosomal dominant.
 presentation : OI with bone fragility/rapuh and deformity, patients
develop hard, painful, and warm swellings over long bones Patients
with this condition have white sclera and normal teeth.
 On radiographs, a redundant callus can be observed around some
fractures.
Osteoporosis pseudoglioma syndrome
 an autosomal recessive . Bone fragility is mild to moderate.
Blindness/kebutaan is due to hyperplasia of the vitreous, to
corneal opacity, and to secondary glaucoma. The genetic
defect has been identified and mapped to chromosomal
region 11q12-13. The defect is specifically in the LRP5 gene
that encodes for the low-density lipoprotein receptor-related
protein 5.

Other ocular forms

 At least 2 other forms with ocular involvement are described
in the literature. One variant includes optic atrophy,
retinopathy, and severe psychomotor retardation; another
variant includes microcephaly and cataracts.
 etc
Epidemiology
 The prevalence of OI : 1 per 20,000 live births;
however, the mild form is underdiagnosed, and
the actual prevalence may be higher.
 Prevalences appear to be similar worldwide,
increased rate in Zimbabwe.
 No differences based on race and sex
 Th e age begin widely varies.
 mild forms may not have fractures until
adulthood, or they may present with fractures in
infancy.
 severe cases present with fractures in utero.
 Patients often have a family history of osteogenesis
imperfecta (OI), but most cases are due to new
mutations.
 Patients most commonly present with fractures after
minor trauma.
 In severe cases, prenatal screening ultrasonography
performed during the second trimester may show
bowing of long bones, fractures, limb shortening, and
decreased skull echogenicity. Lethal OI cannot be
diagnosed with certainty in utero.
 Patients may bruise easily.
 Patients may have repeated fractures after mild trauma.
However, these fractures heal readily.
 Deafness is another feature. About 50% of patients with
type I OI have deafness by the age 40.
Type I - Mild forms
 Patients have no long-bone deformity.
 The sclera can be blue or white.
 Dentinogenesis imperfecta may be present.
 Over a lifetime, numbers of fractures can range from 1-60.
 Height is usually normal in individuals with mild forms of OI.
 People with OI have a high tolerance for pain.
 Exercise tolerance and muscle strength are significantly
reduced in patients with OI
 Fractures are most common during infancy
 Other possible findings : kyphoscoliosis (lengkungan k blkg & k
samping pd columna vertebra), hearing loss, premature arcus
senilis, and easy bruising/memar.
Type II - Extremely severe
 Type II is often lethal.
 Blue sclera may be present.
 Patients may have a small nose, micrognathia/rahang
kecil, or both.
 All patients have in utero fractures, which may involved
the skull/tlg tengkorak, long bones, and/or vertebrae.
 The ribs/tlg iga are beaded, and the long bones are
severely deformed.
 Causes of death include extreme fragility of the ribs,
pulmonary hypoplasia, and malformations or
hemorrhages of the CNS.
Type III - Severe
 joint hyperlaxity, muscle weakness, chronic unremitting(tak
brkurang) bone pain, and skull deformities (eg, posterior
flattening) due to bone fragility during infancy.
 Deformities of upper limbs may compromise function and
mobility.
 dentinogenesis imperfecta
 The sclera have variable hues.
 In utero fractures are common.
 Limb shortening and progressive
deformities
 triangular face with frontal
bossing(dahiny menonjol kluar).
 Basilar invagination uncommon/luar
biasa, but potentially fatal
occurrence/kejadian in OI.
 Vertigo is common
 Hypercalciuria : 36% of patients
 Respiratory complications secondary to
kyphoscoliosis
 Constipation and hernias
Type IV - Undefined

 This type of OI is not clearly defined.

 Whether patient have normal height or whether
scleral hue defines the type has not been
established in consensus.
 Dentinogenesis imperfecta may be present.
 Fractures usually begin in infancy, but in utero
fractures may occur. The long bones are usually
bowed.
Other Problems to Be Considered
 Camptomelic = melengkung dysplasia
 Achondrogenesis type I
 Congenital hypophosphatasia
 Steroid induced osteoporosis
 Battered child syndrome (syndrome X)
 Idiopathic juvenile osteoporosis
Laboratory Studies
 routine laboratory studies are normal
 Collagen synthesis is performed by culturing
dermal fibroblasts.
 Results are negative in syndromes resembling
OI
 Prenatal DNA mutation analysis can be
performed in pregnancies (chorionic villus cells).
 Bone mineral density, as measured with dual-
energy x-ray absorptiometry (DEXA), is low in
children and adults with OI despite the severity.
Histologic Findings
 the width of the cortex, and the volume of
cancellous bone are decreased
 thickness of trabeculae are reduced.
 defects in modeling of external bone in
terms of the size and shape,
 OI might be regarded as a disease of the
osteoblast.
 Bone formation is quantitatively
decreased,
Medical Care
OI is a genetic condition, it has no cure.
 Cyclic administration of intravenous
pamidronate reduces the incidence of
fracture and increases bone mineral
density,
 Nutritional evaluation and intervention are
paramount to ensure appropriate intake of
calcium and vitamin D. Caloric
management is important, particularly in
adolescents and adults with severe forms
of OI.
.
Surgical Care
 Orthopedic surgery is one of the pillars of
treatment for patients with OI. Surgical
interventions include intramedullary rod
placement, surgery to manage basilar
impression, and correction of scoliosis
Consultations
 Care of OI patients is
multidisciplinary. Team members
may include an occupational
therapist (OT), a physical therapist
(PT), nutritionist, an audiologist, an
orthopedic surgeon, neurosurgeon,
pneumologist, and nephrologist,
among others.
 Offer genetic counseling to the
parents of a child with OI
Diet
 Adequate calcium, vitamin D, and
phosphorus intake are paramount.
 Caloric management is necessary in
nonambulatory patients with severe OI.

Activity
 Parents need special instructions in
handling affected children.
 Parents need to know how to position the
child in the crib and how hold the child to
avoid causing fractures while maintaining
bonding and physical stimulation.
Complications
 Recurrent Pneumonia
 Heart Failure
 Brain Damage
 Permanent deformity
 Breathing Problems
 Hearing lost
OSSIFIKASI ENDOKONDRAL PADA
ZONA TULANG RAWAN EPIFISIS

KONDROBLAST

ZONA
X
PROLIFERASI

AKONDROPLASIA
ZONA
HIPERTROFI
MENINGKATKAN

ZONA
FGF KOLAGEN &
MATRIX
KALSIFIKASI

Osteoblast NORMAL:
ZONA KECEPATAN PROLIFERASI
menyusup
OSIFIKASI & DESTRUKSI, SEIMBANG
GAMBARAN KLINIK
 Perawakan pendek
 Rhizomelia
 Midfacial hypoplasia, frontal bossing
 Prominent foerhead

 Gibbus torakolumbal
 Megalencepahly, contracted skull base
 Penyempitan ruang interpedikel
 Brachidactily, trident hand
ANTROPOMETRI
BB : 4,8 KG
PB : 60 CM
LK : 44 CM
Arm span
Tinggi duduk : 42 cm
Arm span : 52 cm Upper
Panjang lengan 13 cm (U)
( segmen atas ( 6 cm )
Panjang tungkai 22 cm Lower
(L)
( segmen atas 12 cm )
ACHONDROPLASIA
Marfan syndrome
 Marfan syndrome is an inherited connective
tissue
 transmitted as an autosomal dominant trait.
 Inherited connectice tissue disorders
 Bones

 Ligaments

 Eyes

 Lung

 Blood vessels

 Heart (weakness of the aorta)

 Cardinal features of the disorder include tall
stature, ectopia lentis, mitral valve prolapse, aortic
root dilatation, and aortic dissection.
 3/4 of patients have an affected parent; new
mutations account for the remainder of cases.
 Marfan syndrome is fully penetrant with marked
interfamilial and intrafamilial variability.
MARFAN SYNDROME
Pathophysiology **
 mutations in the fibrillin-1 (FBN1) gene ( chromosome
15q21.1)
 The gene encodes the glycoprotein fibrillin, a major
building block of microfibrils, which constitute the
structural components of the suspensory ligament of the
lens and serve as substrates for elastin in the aorta and
other connective tissues.
 Fibrillin-1 ( a large glycoprotein ) is a main component of
the 10-12 nm extracellular microfibrils that are important
for elastogenesis, elasticity, and homeostasis of elastic
fibres.
 Abnormalities involving microfibrils weaken the aortic wall.
Progressive aortic dilatation and eventual aortic dissection occur
because of tension caused by left ventricular ejection impulses.
Likewise, deficient fibrillin deposition leads to reduced structural
integrity of the lens zonules, ligaments, lung airways, and spinal
dura.
 Production of abnormal fibrillin-1 monomers from the
mutated gene disrupts the multimerization of fibrillin-1
and prevents microfibril formation.
 Cultured skin fibroblasts from patients with Marfan
syndrome produce greatly diminished and abnormal
microfibrils.
Manifestations
 Tall, arachnodactyly , long fingers and hypermobile joints, is
seen in the majority of patient.
 Feet are flat
 Spine may be curved, Low back pain near the tailbone
 Face; long & narrow, high palate
 Crowded teeth
 Dislocation of the eye lens
 Enlarged/m’besarkn of the aorta near the heart
 Leakage/bocor of the aortic valve, a decrescendo diastolic
murmur, dysrhythmia
 Dyspnea, severe palpitations, and substernal pain in severe
pectus excavatum
 Breathlessness, often with chest pain, in spontaneous
pneumothorax
**
 Diagnosis of Marfan syndrome currently is made
using a set of diagnostic criteria that is based on
evaluation of family history, molecular data, and 6
organ systems.
 Berlin criteria, the diagnosis of Marfan syndrome
diagnosed was based on involvement of the
skeletal system and 2 other systems, with the
requirement of at least 1 major manifestation
(ectopia lentis, aortic dilatation or dissection, or
dural ectasia).3,9
Skeletal system
 Marfan syndrome diagnosed was based on
involvement of the skeletal system and 2
other systems, with the requirement of at
least 1 major manifestation (ectopia lentis,
aortic dilatation or dissection, or dural
ectasia).
Ocular

 major criteria: ectopia lentis. About 50% of

patients have lens dislocation.
 Minor criteria : Flat cornea (measured by
keratometry) , The most common refraction
error is myopia due to elongated globe and
amblyopia. Glaucoma (patients <50 y) , retinal
detachment.
 At least 2 minor criteria must be present.
cardiocascular
 Major criteria
 Aortic root dilatation involving the sinuses of Valsalva ( 70-
80%)
 A diastolic murmur over the aortic valve.
 Minor criteria :
 Mitral valve prolapse (prevalence, 55-69%)
 Dilatation of proximal main pulmonary artery
 Calcification of mitral annulus (patients <40 y)
 Dilatation of abdominal or descending thoracic aorta
(patients <50 y)
 For the cardiovascular system to be involved, a
minor criterion must be present.
Pulmonary

 only minor criteria are noted. For the

pulmonary system to be involved, a minor
criterion must be present.
 Minor criteria include the following:
 Spontaneous pneumothorax (occurs in about 5%
of patients)
 Apical blebs (on chest radiography)
skin and integument
 only minor criteria are noted. For the skin and
integument system to be involved, a minor criterion must
be present.
 Minor criteria include the following:
 Striae atrophicae in the absence of marked weight

changes, pregnancy, or repetitive stress: Stretch

marks usually are found on the shoulder, mid
back, and thighs.
 Recurrent or incisional hernia
dura
 by CT scan or MRI. ( dural ectasia) : 65-92%.
 Dural ectasia is defined as a ballooning or widening of
the dural sac, often associated with herniation of the
nerve root sleeves out of the associated foramina.
 Dural ectasia occurs most frequently in the lumbosacral
spine. Severity appears to increase with age,
 Dural ectasia also can be associated with conditions
such as Ehlers-Danlos syndrome, neurofibromatosis
type 1, ankylosing spondylitis, trauma, scoliosis, or
tumors.
 Differentials diagnosis:
 - Ehlers-Danlos Syndrome
 - Homocystinuria
 - Gigantism and acromegaly
 - Hyperpituitarism
 - Hyperthyroidism
 - Klinefelter Syndrome
Lab Studies:
 the fibrillin gene may be obtained in cases in
which Marfan syndrome
 is not yet generally available.
 No single gene probe or group of probes is
available to detect most FBN1 molecular.
 Metacarpal index
 measuring the lengths of the second to fifth
metacarpals and dividing by their breadths taken at
the exact mid-point
 In normal : the metacarpal index varies from 5,4 –
7,9; in arachnodactyly the range varies from 8,4 –
10,4.
Major criteria include :
 Pectus excavatum (funnel) requiring surgery or pectus
carinatum (pigeon)
 Reduced upper-to-lower body segment ratio (0.85 vs 0.93)
or arm span-to-height ratio greater than 1.05: Arms and legs
may be unusually long in proportion to torso.
 Positive wrist (Walker) and thumb (Steinberg) signs: Two
simple maneuvers may help demonstrate arachnodactyly.
 Scoliosis greater than 20°: More than 60% of patients have
scoliosis. Reduced extension of the elbows (<170°)
 Medial displacement of the medial malleolus, resulting in
pes planus
 Protrusio acetabula (intrapelvic protrusion of the
acetabulum) of any degree (ascertained on radiograph):
Prevalence is about 50%.
Minor criteria are as follows
 Pectus excavatum of moderate severity ,
scoliosis less than 20° , thoracic lordosis , joint
hypermobility , highly arched palate , dental
crowding , typical facies (dolichocephaly, malar
hypoplasia, enophthalmos, retrognathia, down-
slanting palpebral fissures).
 For the skeletal system to be involved, at least 2
major criteria or 1 major criterion plus 2 minor
criteria must be present.
Diagnostic
Involve;
Family history
Genetics
Ocular
cardiovascular
Skeletal
Pulmonary
Skin
CNS
Treatment
 Therapy focuses on prevention of
complications and genetic counseling.
 multidisciplinary center with experience in
the Marfan syndrome is advisable.
 Anticoagulant medications such as warfarin
 Intravenous antibiotic therapy to prevent bacterial
endocarditis.
 Progesterone and estrogen therapy have been used to
induce puberty and reduce ultimate height if hormonal
treatment is begun before puberty.
 Myopia is treatable with refraction.
 Patients with flat feet may wear shoes with adequate arch
support, although custom orthotics may be required.
 Psychological counseling is helpful for families coping with
feelings of denial, anger, blame, depression, or guilt.
Surgical Care:
 Cardiovasculer surgery
 Scoliosis
 Pectus repair
 Pneumothorax
 A Ocular
Genetic counseling
Prognosis
 Mainly determined by aortic root
abnormalities : aortic regurgitation
 Untreated : 40 years
 Both medical & surgical : 60 – 70 years