Achondroplasia

DISPROPORTIONATE SHORT
STATURE

PROSES PERTUMBUHAN NORMAL

Pertumbuhan tulang
Pusat osifikasi
primer
Pusat osifikasi sekunder

PROSES PERTUMBUHAN NORMAL

Pertumbuhan tulang

PERAWAKAN
PERAWAKANPENDEK
PENDEK
PATOLOGIS
PATOLOGIS
PROPORSIONAL
PROPORSIONAL
BB/TB
BB/TB

ENDOKRIN
ENDOKRIN
DEFISIENSI
DEFISIENSIGH
GH
HIPOTROID
HIPOTROID
KORTISOL
KORTISOL
PSEUDOHIPOP
PSEUDOHIPOP
ARATIROID
ARATIROID

DISPROPORSIONAL
DISPROPORSIONAL
BB/TB
BB/TB

MALNUTRISI
MALNUTRISI
INFEKSI
INFEKSIKRONIS
KRONIS
PENYAKIT
PENYAKIT
KRONIS
KRONIS
(ORGANIK)
(ORGANIK)
PSIKOSOSIAL
PSIKOSOSIAL
IUGR
IUGR

KELAINAN
KELAINAN
DISMORFIK
DISMORFIK

Po
Pr
en
stn
ata

Ma
U
GR
nu
ris

Klasifikasi perawakan pendek (COWELL,1995)

Pe
ny
aki

kro
nis

Perawakan pendek
Patologis

Variasi normal
Familial short stature
Constitutional growth delay

Proporsional

Disproporsional

Displasia skeletal
Riketsia

Idiopatik

Prenatal
IUGR
Faktor ibu
Penyakit plasenta
Infeksi
Terarogen
Sindrom dismorfik
Kelainan kromosom

Postnatal
Malnutrisi
Penyakit Kronis
Gastrointestinal
Kardioipulmonal
Infeksi
Ginjal
Hematologi
Obat obatan
Kelainan psikososial
Kelainan endokrin

AKONDROPLASIA
Sindrom
klinis
Perawakan
Pendek
abnormal
Skeletal
displasia

Dan lain-lain
Gangg sint kolagen

Osteogenesis I

Osteodisplasia
Kondrodisplasia
AKONDROPLASIA
Hipokondroplasia
SADAN
DAN LAIN-LAIN

Insiden 1/15.000 s/d

1/40.000 kelahiran
Autosomal dominan
75 80 % mutasi baru
Angka mutasi 1,72
5,57 x 10-5
gamet/generasi

Achondroplasia

most common form of short-limbed non-lethal dwarfism

autosomal dominant disorder
1 in 15.000
80 to 90% of cases sporadic
Gene chromosome 4p16.3 (Fibroblast Growth Factor
Receptor 3 - FGFR3); identified > 99% ACH patients
FGFR3 is expressed in cartilage and brain
In mouse homologue FGFR3 mediate the effect of
fibroblast growth factor on chondrocytes.

Molecular Genetic

mutations involve substitution of an arginine for a

glycine at amino acid position 380 in the protein
(nucleotide position 1138)

Transition: major mutation (97% of cases) is a G to A.

Transversion: minor mutation (2.5% of cases) is a G to
C.

Molecular genetic

Gene chromosome 4p16.3 (Fibroblast

Growth Factor Receptor 3 - FGFR3);
identified > 99% ACH patients
FGFR3 is expressed in cartilage and brain
In mouse homologue FGFR3 mediate
the effect of fibroblast growth factor on
chondrocytes.

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

ACHONDROPLASI
A

Mudah dikenal
Intelegensi & harapan hidup : normal
MASALAH

Komplikasi
Psikososial
Genetik, dll

PERLU
PERLU
PEMAHAMAN
PEMAHAMANPENYAKIT
PENYAKIT
AGAR
AGAR
TUMBUH
TUMBUHKEMBANG
KEMBANG
OPTIMAL
OPTIMAL

Morbiditas / mortalitas

Kematian mendadak (<3%)

Angular deformitas ekstremitas
Prematur degeneratif joint
Kelainan spinal, cervical instability
Obesitas
Gangguan pernafasan (<5%)
OMSK
Arrested hidrocepalus

GAMBARAN KLINIK

Perawakan pendek
Rhizomelia
Midfacial hypoplasia, frontal bossing
Prominent foerhead
Gibbus torakolumbal
Megalencepahly, contracted skull base
Penyempitan ruang interpedikel
Brachidactily, trident hand

Kepala bentuk kubah

Dahi menonjol
Pangkal hidung datar

Punggung : lordosis,
gibus
Ekstremitas : segmen atas
pendek
Reflek : normal
Tangan : trident hand

Kepala
Bentuk kubah
Dahi menonjol
Pangkal hidung
Datar
rhizomelia

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)

DEVELOPMENT

Large head, poor muscle tone, loose joints

delayed in sitting, standing and walking
often thought MR
Psychosocial problems
Normal life span
Normal IQ

DIAGNOSIS

Anamnesis

Pemeriksaan fisik

Riwayat tumbuh kembang

Anamnesis komplikasi
Otitis media, ketulian
Gangguan tidur
Deteksi keluarga berisiko
Antropometri & tanda2 khas

Pencitraan

Prenatal

limb shortening usually becomes apparent

only > 22 weeks gestation.
Prenatal diagnosis DNA analysis of fetal
blood, amniotic fluid, CVS in cases of
suspicious USG findings.
If both parents have achondroplasia,

25% chance the fetus is homozygous state

lethal condition (short limbs and narrow thorax).

GROWTH

Final Height

Males 131 ( 118 145 ) cm

Females 121 (112 136)
cm

Growth velocity in the 1st

year of life is normal
(Horton et al, 1978)
Special Growth Chart

PENCITRAAN

USG kepala usia; 2, 4 6 bulan

USG jika

fontanel melebar,
lingkar kepala meningkat
Gejala hidrocepalus

CT scan
MRI

Radiologicalfeatures

Narrowing of the
interpediculate
distance of the caudal
spine
Notch-like sacroiliac
groove
Circumflex or chevron
seat on the metaphysis
Langer et al 1967, Hall 1988

Radiologicalfeatures

Pedicles are
short and
thick

elephant
ears

from Adam Greenspan, Orthopedic Radiology, Third edition, p909-910

trumpet-like
metaphysis

from Adam Greenspan, Orthopedic Radiology,

Third edition, p908

Br
15 cm
( N 13,2)

KRANIUM MEMBESAR
DASAR KECIL

H
15 cm
(N 12,4 cm)

L
17,5 cm
( N 15,8)

Modulus =
(L+H+Br)/3 = 15,8
( N 12,9 15,3 )
Chepalik indeks =
(Br/L) x 100 = 85,7
( N 75 84 )

MAKROCHEPAL
BRACHICEPHAL

Sternum melebar
Iga pendek
Konkavitas ke anterior

Jarak interpedikel
Lumbal I-V berkurang
Pedikel kecil
Diameter sempit

Sayap os ilium
Square
Ronga pelvis :
Chmapagne glass

Tulang panjang
melengkung
metafisis
melebar

Jari melebar
Pendek
(BRACHIDACTILY)

Vent lat & II lebar

Sulci frontalis melebar
Giri mengkrut

TATALAKSANA

Pemantauan, tiap tahun ;

Pertumbuhan, U/L ratio

Berat badan
Lingkar kepala

Pemeriksaan neurologik berkala

Atasi OMSK, pertumbuhan gigi crowded
Kontrol obesitas
Jika perlu tindakan bedah
Konsultasi : bedah saraf, THT, genetik

COMPLICATIONS

Hypotonia psychomotor delay

Spinal compressions
Brain stem and spinal abnormalities
Sleep apnea

REKURENSI
ANGKA MUTASI BARU = 1:50.000 ANAK

POPULASI
10.000.000

200 akondroplasia akibat mutasi baru

Jika kawin dengan
orang normal
40

80% akondroplasia
Gagal jadi anak

20%( akondroplasia yg hidup )

Jika kawin dengan
orang normal

Suami istri normal yg mempunyai anak akondroplasia,

anak berikutnya normal

Anak laki-laki, 2 th 5 bl, OI tipe III,

sudah diketahui sejak dalam kandungan,
fraktur sejak usia 2 bulan (5 kali), sklera biru (+)
Riwayat keluarga disangkal

Marfansyndrome

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.

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 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

Skeletalsystem

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)

skinandintegument

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.

Diagnostic
Involve;
Family history
Genetics
Ocular
cardiovascular
Skeletal
Pulmonary
Skin
CNS

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