MARFANS SYNDROME

Marfan Syndrome

Marfan Syndrome

Introduction
Marfan syndrome is an inherited connectivetissue disorder :autosomal dominant trait. Pleiotropic manifestations Cardinal features : tall stature, ectopia lentis, al valve prolapse, mitr aortic root dilatation, and aortic dissection. About three quarters of patients have an affected parent; new mutations + Marfan syndrome is fully penetrant with marked interfamilial and intrafamilial variability.

Example: Marfan Syndrome

What is the probability that this pending pregnancy will be affected?

Pathophysiology
Mutations in the fibrillin-1 (FBN1) gene on chromosome 15, which encodes for the glycoprotein fibrillin. Fibrillin is 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. Abnormalities involving microfibrils weaken the aortic wall. Likewise, deficient fibrillin deposition leads to reduced structural integrity of the lens zonules, ligaments, lung airways, and spinal dura.

Epidemiology
1 in 10,000 individuals3 and perhaps as many as 1 in 3000-5000 (united states) No sex predilection is known. Marfan syndrome is panethnic. may be diagnosed prenatally, at birth, or well into adulthood

diagnosis
At this time, the diagnosis of Marfan syndrome remains mainly clinical. using criteria based on an evaluation of the family history, molecular data, and 6 organ systems. Berlin criteria, involvement of the skeletal system and 2 other systems, with the requirement of at least one major manifestation (ie, ectopia lentis, aortic dilatation or dissection, or dural ectasia).

The major criteria

A first-degree relative (parent, child, or sibling) meets the diagnostic criteria Presence of an FBN1 mutation Inheritance of an FBN1 haplotype known to be associated with unequivocally diagnosed Marfan syndrome in the family In family members, major involvement in one organ system and involvement in a second organ system

Clinical presentations :
Delayed of gross and fine motor milestones (ligamentous laxity ) A decrescendo diastolic murmur from aortic regurgitation An ejection click at the apex followed by a holosystolic highpitched murmur from mitral prolapse and regurgitation Dysrhythmia (a primary feature) Abrupt onset of thoracic pain, which occurs in more than 90% of patients with aortic dissection Low back pain near the tailbone, burning sensation and numbness or weakness in the legs in serious dural ectasia

Skeletal findings (mayor criteria)

Pectus excavatum requiring surgery or pectus carinatum Taller and thinner , dolichostenomeli, arachnodactyly, Positive wrist (Walker) and thumb (Steinberg) signs Medial displacement of the medial malleolus, resulting in pes planus Protrusio acetabuli :hip joint stiffness , progressive limitation in activity related to joint pain, a waddling gait, limited range of motion, flexion contracture, majority :diagnosed <10 years,

Positive wrist (Walker) sign.

Positive thumb (Steinberg) sign.

arachnodactily

MARFAN SYNDROME

Skeletal (Minor criteria)

Pectus excavatum of moderate severity Scoliosis less than 20 Thoracic lordosis Highly arched palate Dental crowding Typical facies (dolichocephaly, malar hypoplasia, enophthalmos, retrognathia, down-slanting palpebral fissures)

at least 2 major criteria or 1 major criterion plus 2 minor criteria must be present.

Hypermobility of finger joints.

Ocular
major criteria :ectopia lentis(50% ), usually superior and temporal. Minor criteria : Flat cornea (measured by keratometry), cataract (nuclear sclerotic), hypoplastic iris or hypoplastic ciliary Refraction error is myopia due to elongated globe and amblyopia. Glaucoma (patients <50 y) , retinal detachment. At least 2 minor criteria must be present.

Marfan Syndrome
Subluxation

cardiovasculer
Major criteria
Aortic root dilatation (70-80%). A diastolic murmur over the aortic valve may be present. Aortic dissections involving the ascending aorta

Minor criteria
Mitral valve prolapse (prevalence, 55-69%): highpitched late-systolic murmur, a holosystolic murmur. Dilatation of proximal main pulmonary artery in the absence of peripheral pulmonic stenosis Calcification of mitral annulus Dilatation of abdominal or descending thoracic aorta

Marfan Syndrome
Aortic Dissection

Pulmonary
only minor criteria are noted. a minor criterion must be present. Spontaneous pneumothorax (occurs in about 5% of patients) Apical blebs (on chest radiography)

Skin
only minor criteria are noted. a minor criterion must be present. 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

Stretch marks (striae atrophicae) in the lower back.

Dural ectasia in the lumbosacral region.

Dura
For the dura, only 1 major criterion exists; dural ectasia must be present and be confirmed by CT scan or MRI. (65-92%). ballooning or widening of the dural sac, often associated with herniation of the nerve root sleeves out of the associated foramina

Differentials diagnosis:
- Ehlers-Danlos Syndrome - Homocystinuria - Gigantism and acromegaly - Hyperpituitarism - Hyperthyroidism - Klinefelter Syndrome

Treatment:
Therapy focuses on prevention of complications and genetic counseling -Adrenergic blocker (propanolol or atenolol) slows the progression of aortic dilatation Progesterone and estrogen therapy Myopia is treatable with refraction

Surgery
Cardiovascular Scoliosis Pectus repair Ocular

Prognosis:
Prognosis depends on severity of cardiovascular complications

Osteogenesis imperfecta

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 :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.

 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 cause excess posttranslational modification of collagen, and may be associated with syndromes resembling osteogenesis imperfecta,

Resembling of OI
Congenital brittle bones with redundant callus formation hyperplastic calluses in long bones after having a fracture or orthopedic surgery, autosomal dominant. presentation : OI with bone fragility and deformity, white sclera and normal teeth. On radiographs, a redundant callus can be observed

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. Congenital brittle bones with rhizomelia short humerus and femora, and recessive inheritance Fractures may be present at birth

Epidemiology
OI : 1 per 20,000 live births; to be similar worldwide No differences based on race No differences based on sex The age when symptoms (ie, fractures) begin widely varies. Patients with severe cases present with fractures in utero.

 often have a family history of osteogenesis imperfecta (OI), but most cases are due to new mutations. present with fractures after minor trauma. In severe cases, prenatal screening Patients may bruise easily. repeated fractures after mild trauma. these fractures heal readily. Deafness is another feature.

Type I - Mild forms

Patients have no long-bone deformity. The sclera can be blue or white. Dentinogenesis imperfecta numbers of fractures from 1-60. Height is normal in mild forms of OI. high tolerance for pain. Exercise tolerance reduced Fractures most common during infancy kyphoscoliosis, hearing loss, premature arcus senilis, and easy bruising.

Type II - Extremely severe

Type II is often lethal.Blue sclera may be + small nose, micrognathia, or both. 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) Deformities of upper limbs dentinogenesis imperfecta The sclera have variable hues. In utero fractures Limb shortening and progressive deformities can occur. Patients may have a triangular face with frontal bossing. Basilar invagination is an uncommon Vertigo is common in patients with severe OI. 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

 Obtain a radiographic skeletal survey after birth. In mild (type I) OI, thinning of the long bones with thin cortices. In type II, beaded ribs, broad bones, fractures with deformities of the long bones. types III and IV, cystic metaphyses, or a popcorn appearance of the growth cartilage. Fractures may cause deformities of the long bones. Old rib fractures may be present. Vertebral fractures are common. Prenatal ultrasonography decreased mineralization of calvaria (also calvarial compressibility), bowing of the long bones, decreased bone length (especially of the femur), and multiple rib fractures.

Laboratory Studies
ruling out other metabolic bone diseases.
Collagen synt :culturing dermal fibrblasts

negative in syndromes resembling OI Prenatal DNA mutation analysis (chorionic villus cells). Bone mineral density, : dual-energy x-ray absorptiometry (DEXA), is low

Histologic Findings
the width of the cortex, and the volume of cancellous bone are decreased in all types of OI. 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
Arm span

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

Upper (U) Lower (L)

ACHONDROPLASIA