AchondroplasiaDISPROPORTIONATE SHORT STATURE

PROSES PERTUMBUHAN NORMALPertumbuhan tulangPusat osifikasi primerPusat osifikasi sekunder

PROSES PERTUMBUHAN NORMALPertumbuhan tulang

PERAWAKAN PENDEKPATOLOGISPROPORSIONALBB/TB ENDOKRINDEFISIENSI GHHIPOTROIDKORTISOLPSEUDOHIPOPARATIROIDBB/TB MALNUTRISIINFEKSI KRONISPENYAKIT KRONIS (ORGANIK)PSIKOSOSIALIUGR

KELAINAN DISMORFIKDISPROPORSIONAL

Perawakan pendekPatologisVariasi normalFamilial short statureConstitutional growth delayIdiopatikDisproporsionalProporsionalDisplasia skeletalRiketsiaPrenatalIUGRFaktor ibuPenyakit plasentaInfeksiTerarogenSindrom dismorfikKelainan kromosom

Klasifikasi perawakan pendek (COWELL,1995)

PrenatalIUGR :

PostnatalMalnutrisiPenyakit kronis:

PostnatalMalnutrisiPenyakit KronisGastrointestinalKardioipulmonalInfeksiGinjalHematologiObat obatanKelainan psikososialKelainan endokrin

Insiden 1/15.000 s/d 1/40.000 kelahiranAutosomal dominan75 80 % mutasi baruAngka mutasi 1,72 5,57 x 10-5 gamet/generasiPerawakan PendekabnormalSindromklinisSkeletaldisplasia Osteodisplasia Kondrodisplasia

AKONDROPLASIA

Hipokondroplasia SADAN DAN LAIN-LAIN AKONDROPLASIA Osteogenesis I Gangg sint kolagen Dan lain-lain

Achondroplasiamost common form of short-limbed non-lethal dwarfismautosomal dominant disorder1 in 15.000 80 to 90% of cases sporadicGene chromosome 4p16.3 (Fibroblast Growth Factor Receptor 3 - FGFR3); identified > 99% ACH patientsFGFR3 is expressed in cartilage and brainIn 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 geneticGene chromosome 4p16.3 (Fibroblast Growth Factor Receptor 3 - FGFR3); identified > 99% ACH patientsFGFR3 is expressed in cartilage and brainIn mouse homologue FGFR3 mediate the effect of fibroblast growth factor on chondrocytes.

KONDROBLASTZONAPROLIFERASIZONAHIPERTROFIZONA KALSIFIKASIZONAOSIFIKASIOSSIFIKASI ENDOKONDRAL PADAZONA TULANG RAWAN EPIFISISOsteoblastmenyusupAKONDROPLASIAXMENINGKATKAN KOLAGEN & MATRIXFGFNORMAL:KECEPATAN PROLIFERASI& DESTRUKSI, SEIMBANG

ACHONDROPLASIA

Mudah dikenalIntelegensi & harapan hidup : normal

KomplikasiPsikososial Genetik, dll

PERLU PEMAHAMAN PENYAKIT AGAR TUMBUH KEMBANG OPTIMALMASALAH

Morbiditas / mortalitasKematian mendadak (

GAMBARAN KLINIKPerawakan pendekRhizomeliaMidfacial hypoplasia, frontal bossingProminent foerhead

Gibbus torakolumbalMegalencepahly, contracted skull basePenyempitan ruang interpedikelBrachidactily, trident hand

Kepala bentuk kubahDahi menonjolPangkal hidung datar

Punggung : lordosis, gibusEkstremitas : segmen atas pendekReflek : normalTangan : trident hand

TRIDENT HANDKepalaBentuk kubah

Dahi menonjol

Pangkal hidungDatar

rhizomelia

ANTROPOMETRIBB : 4,8 KGPB : 60 CMLK : 44 CM

Tinggi duduk : 42 cmArm span : 52 cmPanjang lengan 13 cm( segmen atas ( 6 cm )Panjang tungkai 22 cm( segmen atas 12 cm )Arm spanUpper( U )Lower( L )

DEVELOPMENTLarge head, poor muscle tone, loose joints delayed in sitting, standing and walking often thought MRPsychosocial problemsNormal life spanNormal IQ

DIAGNOSISAnamnesis Riwayat tumbuh kembangAnamnesis komplikasiOtitis media, ketulianGangguan tidurDeteksi keluarga berisikoPemeriksaan fisikAntropometri & tanda2 khasPencitraan

Pre natallimb 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).

GROWTHFinal HeightMales 131 ( 118 145 ) cmFemales 121 (112 136) cmGrowth velocity in the 1st year of life is normal (Horton et al, 1978)Special Growth Chart

PENCITRAANUSG kepala usia; 2, 4 6 bulanUSG jika fontanel melebar, lingkar kepala meningkatGejala hidrocepalusCT scanMRI

Radiological featuresNarrowing 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

elephant earsfrom Adam Greenspan, Orthopedic Radiology, Third edition, p909-910Pedicles are short and thick

trumpet-like metaphysisfrom Adam Greenspan, Orthopedic Radiology, Third edition, p908

Br15 cm( N 13,2)KRANIUM MEMBESARDASAR KECIL

L17,5 cm( N 15,8)H15 cm(N 12,4 cm)Modulus =(L+H+Br)/3 = 15,8( N 12,9 15,3 )

Chepalik indeks =(Br/L) x 100 = 85,7( N 75 84 )MAKROCHEPALBRACHICEPHAL

Sternum melebarIga pendekKonkavitas ke anterior

Jarak interpedikelLumbal I-V berkurang

Pedikel kecilDiameter sempit

Sayap os ilium SquareRonga pelvis :Chmapagne glassTulang panjang melengkungmetafisis melebar

Jari melebarPendek(BRACHIDACTILY)

Vent lat & II lebarSulci frontalis melebarGiri mengkrut

TATALAKSANAPemantauan, tiap tahun ;Pertumbuhan, U/L ratioBerat badanLingkar kepala Pemeriksaan neurologik berkalaAtasi OMSK, pertumbuhan gigi crowdedKontrol obesitasJika perlu tindakan bedahKonsultasi : bedah saraf, THT, genetik

COMPLICATIONSHypotonia psychomotor delaySpinal compressionsBrain stem and spinal abnormalities Sleep apnea

REKURENSIANGKA MUTASI BARU = 1:50.000 ANAKPOPULASI10.000.000200 akondroplasia akibat mutasi baruJika kawin dengan orang normal20%( akondroplasia yg hidup )40Jika kawin dengan orang normal880% akondroplasiaGagal jadi anakSuami 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 syndromeMarfan syndrome is an inherited connective tissue transmitted as an autosomal dominant trait. Inherited connectice tissue disordersBonesLigamentsEyesLungBlood vesselsHeart (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.

Pathophysiologymutations 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.

ManifestationsTall, arachnodactyly , long fingers and hypermobile joints, is seen in the majority of patient. Feet are flatSpine may be curved, Low back pain near the tailbone Face; long & narrow, high palateCrowded teethDislocation of the eye lensEnlarged of the aorta near the heartLeakage of the aortic valve, a decrescendo diastolic murmur, dysrhythmia Dyspnea, severe palpitations, and substernal pain in severe pectus excavatumBreathlessness, 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 systemMarfan 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).

Ocularmajor 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

cardiocascularMajor 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 arteryCalcification of mitral annulus (patients

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 integumentonly 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

duraby 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 indexmeasuring the lengths of the second to fifth metacarpals and dividing by their breadths taken at the exact mid-pointIn 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 (

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.

DiagnosticInvolve;Family historyGeneticsOcularcardiovascularSkeletalPulmonarySkinCNS

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 surgeryScoliosisPectus repairPneumothoraxA OcularGenetic counseling

PrognosisMainly determined by aortic root abnormalities : aortic regurgitationUntreated : 40 yearsBoth medical & surgical : 60 70 years

*Prototype of chondroplasia in humans.* In early 1994, linkage studies placed the achondroplasia gene on the short arm of human chromosome 4, distal to an anonymous marker, D4S43. This region on chromosome 4 had been scrutinized for more than 10 years by scientists searching for the Huntington's disease gene, and among the genes already known to reside in this area was fibroblast growth factor receptor 3 (FGFR3). In early 1994, linkage studies placed the achondroplasia gene on the short arm of human chromosome 4, distal to an anonymous marker, D4S43. This region on chromosome 4 had been scrutinized for more than 10 years by scientists searching for the Huntington's disease gene, and among the genes already known to reside in this area was fibroblast growth factor receptor 3 (FGFR3). (A point mutation is called a "transition" when a purine replaces a purine or a pyrimidine replaces a pyrimidine; it is called a "transversion" when a purine replaces a pyrimidine or vice versa.) In early 1994, linkage studies placed the achondroplasia gene on the short arm of human chromosome 4, distal to an anonymous marker, D4S43. This region on chromosome 4 had been scrutinized for more than 10 years by scientists searching for the Huntington's disease gene, and among the genes already known to reside in this area was fibroblast growth factor receptor 3 (FGFR3).

*