Achondroplasia

DISPROPORTIONATE SHORT
STATURE
 PROSES PERTUMBUHAN NORMAL
Pertumbuhan tulang
Pusat osifikasi primer
Pusat osifikasi sekunder
PROSES PERTUMBUHAN NORMAL
Pertumbuhan tulang
 PERAWAKAN PENDEK

PATOLOGIS

PROPORSIONAL
DISPROPORSIONAL

BB/TB BB/TB

KELAINAN
ENDOKRIN MALNUTRISI DISMORFIK
DEFISIENSI GH INFEKSI KRONIS
HIPOTROID PENYAKIT
KORTISOL KRONIS
(ORGANIK)
PSEUDOHIPOP
ARATIROID PSIKOSOSIAL
IUGR
P
or
se
tn
a
n
Klasifikasi perawakan pendek (COWELL,1995)
at
ta
al
lI
U
M
aG
lR
Perawakan pendek
n:
u
t
r
i Patologis Variasi normal Idiopatik
s
i
Familial short stature
P Constitutional growth delay
e
n
y
a Proporsional
k
i
Disproporsional
t Prenatal Postnatal
k Malnutrisi
r IUGR
o Faktor ibu Penyakit Kronis
n
Penyakit plasenta Gastrointestinal
i
Infeksi Kardioipulmonal
s
:
Displasia skeletal Terarogen Infeksi
Riketsia Sindrom dismorfik Ginjal
Kelainan kromosom Hematologi
Obat obatan
Kelainan psikososial
Kelainan endokrin
 AKONDROPLASIA

Sindrom
klinis Dan lain-lain
Gangg sint kolagen
Perawakan Insiden 1/15.000 s/d
Pendek Osteogenesis I
abnormal 1/40.000 kelahiran
Osteodisplasia
Skeletal Autosomal dominan
displasia
Kondrodisplasia 75 80 % mutasi baru
AKONDROPLASIA
Angka mutasi 1,72
5,57 x 10-5
Hipokondroplasia
gamet/generasi
SADAN

DAN LAIN-LAIN
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
X
PROLIFERASI

AKONDROPLASIA
ZONA
HIPERTROFI
MENINGKATKAN

ZONA
FGF KOLAGEN &
MATRIX
KALSIFIKASI

Osteoblast NORMAL:
ZONA KECEPATAN PROLIFERASI
menyusup
OSIFIKASI & DESTRUKSI, SEIMBANG
ACHONDROPLASIA
 Mudah dikenal
Intelegensi & harapan hidup : normal

MASALAH

Komplikasi
Psikososial
Genetik, dll PERLU
PEMAHAMAN PENYAKIT
AGAR
TUMBUH KEMBANG
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 TRIDENT HAND

Dahi menonjol

Pangkal hidung
Datar

rhizomelia
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 )
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
Riwayat tumbuh kembang
Anamnesis komplikasi
Otitis media, ketulian
Gangguan tidur
Deteksi keluarga berisiko
Pemeriksaan fisik
Antropometri & tanda2 khas
Pencitraan
Pre natal
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
Radiological features
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
Radiological features
 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 MAKROCHEPAL
( N 12,9 15,3 )

Chepalik indeks = BRACHICEPHAL

(Br/L) x 100 = 85,7
( N 75 84 )
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 200 akondroplasia akibat mutasi baru

10.000.000
Jika kawin dengan
orang normal

40 20%( akondroplasia yg hidup )

Jika kawin dengan
80% akondroplasia
orang normal
Gagal jadi anak
8

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
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.
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
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 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, 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
 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