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 associated
with distinctive clinical or histologic
features (eg, redundant callus formation,
pseudoglioma, 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
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 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 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 11q1213. 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, hearing loss,
premature arcus senilis, and easy bruising.

Type II - Extremely severe

Type II is often lethal.

Blue sclera may be present.
Patients may have a small nose, micrognathia, or both.
All patients have in utero fractures, which may involved
the skull, long bones, and/or vertebrae.
The ribs 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 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.
Basilar invagination uncommon, but
potentially fatal occurrence 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 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 dualenergy 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
PROLIFERASI

AKONDROPLASIA

ZONA
HIPERTROFI

ZONA
KALSIFIKASI
Osteoblast
menyusup

ZONA
OSIFIKASI

FGF

MENINGKATKAN
KOLAGEN &
MATRIX

NORMAL:
KECEPATAN PROLIFERASI
& 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
Tinggi duduk : 42 cm
Arm span : 52 cm
Panjang lengan 13 cm
( segmen atas ( 6 cm )
Panjang tungkai 22 cm
( segmen atas 12 cm )

Arm span

Upper
(U)
Lower
(L)

ACHONDROPLASI
A

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)

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.

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 of the aorta near the heart
Leakage 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

Minor criteria :

Aortic root dilatation involving the sinuses of Valsalva ( 7080%)

A diastolic murmur over the aortic valve.
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 requiring surgery or pectus carinatum

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, downslanting 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.

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