Connective tissue disorders

Question 1

CONGENITAL CONTRACTURAL ARACHNODACTYLY (Beals Syndrome)
Responsible gene:
Protein:
Cytogenetic locus:
Inheritance:
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:

Answer 1

Responsible gene: FBN2
Protein: Fibrillin-2
Cytogenetic locus: 5q23-q31
Inheritance: AD
Clinical Features and Diagnostic Criteria: Marfanoid appearance, long slender fingers and toes, crumpled ears, major joint contracture, muscle hypoplasia, kyphosis/scoliosis, Severe/lethal: aortic dilation, ASD, VSD, IAA, duodenal or esophageal atresia, malrotation
Clinical Tests: x-ray, echocardiogram, UGI with SBFT
Molecular Tests:FBN2sequencing (75%)
Disease Mechanism: Fibrillin 2 is a glycoprotein of the extracellular matrix microfibrils, it is co-distributed with fibrillin 1 in many tissues. The precise function is not known.
Treatment/Prognosis: PT for joint contracture, contracture surgical release, bracing and/or surgical correction of kyphoscoliosis. Echo every 2 years until it is clear the aorta is not involved. Annual exam for scoliosis/kyphosis.

Question 2

EHLERS-DANLOS SYNDROME
CLASSIC TYPE(Type I and Type II)
Responsible genes:
Proteins:
Cytogenetic loci:
Inheritance:
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:

other types are not included

Answer 2

Responsible genes: COL5A1 and COL5A2
Proteins: Collagen alpha-1 and alpha-2 (V) chain
Cytogenetic loci: 9334.2-q34.3 and 2q31
Inheritance: AD
Clinical Features and Diagnostic Criteria: skin hyperextensibility, widened atrophic scars, joint hypermobility, smooth velvety skin, molluscoidpseudotumors(heaped up scar-like lesions over pressure points), subcutaneous spheroids (cyst-like lesions, feel like grains of rice, over bony prominences of legs and arms, they are fibrosedand calcified fat globules), joint sprains/dislocations/subluxations, hypotonia, easy bruising, hernia, chronic pain, aortic root dilation
Clinical Tests: Ultrastructural studies by EM suggest disturbed collagen fibrillogenesis(“cauliflower” deformity is characteristic).
Molecular Tests:COL5A1 “null” allele testing on cultured fibroblasts (30%), COL5A1 and COL5A2 sequencing (50%)
Disease Mechanism: Dominant negative activity of abnormal Collagen alpha-1 or alpha-2 (V) chains (interfere with the utilization of normal protein from the normal allele)
Treatment/Prognosis: PT, non-weight-bearing muscular exercise, dermal wounds repaired with two layer closure without tension, if possible avoid joint surgery , baseline echo for aortic root assessment

Question 3

LOEYS-DIETZ SYNDROME
Responsible gene:
Protein:
Cytogenetic locus:
Inheritance:
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Disease Mechanism:

Answer 3

Responsible gene: TGFBR1, TGFBR2, SMAD3, TGFB2
Protein:TGF-betareceportype-1 and type-2, Mothers against decapentaplegichomolog 3, Transforming growth factor beta-2
Cytogenetic locus: 9q22.33, 3p24.1, 15q22.33, 1q41
Inheritance: AD
Clinical Features and Diagnostic Criteria: vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections) and skeletal manifestations (pectusexcavatumor pectuscarinatum, scoliosis, joint laxity, arachnodactyly, talipesequinovarus). 75% have LDS type I with craniofacial manifestations (ocular hypertelorism, bifid uvula/cleft palate, craniosynostosis); 25% have LDS type II with cutaneous manifestations (velvety and translucent skin; easy bruising; widened, atrophic scars).
Clinical Tests: Echocardiogram, MRA or CT scan for arterial aneurysm/tortuosity, spinal xrays
Molecular Tests:genesequencing and del/dup testing
Disease Mechanism: data demonstrate increased TGFβ signaling in the vasculature of persons with LDS
Treatment/Prognosis: Regular surveillance imaging of the vasculature, Beta blockers/Losartan for aortic root dilation, bracing/surgery for scoliosis

Question 4

MARFAN SYNDROME
Responsible gene:
Protein:
Cytogenetic locus: 15q21.1
Inheritance:
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:

Answer 4

Responsible gene: FBN1Protein: Fibrillin 1
Cytogenetic locus: 15q21.1 Inheritance: AD
Clinical Features and Diagnostic Criteria: Major involvement of 2 body systems and minor involvement of a 3rd. Major CriteriaCV: Dilation or dissection of the ascending aorta Skeletal: pectus carinatumor excavatum, reduced upper:lowersegment or arm span:ht, scoliosis, pes planus, high palate, reduced elbow extension, protrusioacetabulae, Eye: ectopialentis, Dura: lumbosacral duralectasia, FH: pathogenic FBN1mutation, 1stdegree relative with Marfansyndrome. Minor CriteriaCV: MV, MR, dilation of main PA, mitral annulus calcification, dilation or dissection of the descending thoracic or abdominal aorta ate age <50yrs, Skeletal: moderate pectus excavatum, joint hypermobility, high palate with crowding of teeth, typical facial features Eye: flat cornea, increased length of globe, decreased pupillary miosis, Lung:pneumothorax, apical lung blebs, Skin: skin striae, hernia
Clinical Tests: CXR: apical blebs, Echocardiogram: MVP, aortic measurements, CT or MRI: duralectasia
Molecular Tests:FBN1seqencing(70-90%)
Disease Mechanism: Dominant negative effect of mutant forms of fibrillin
Treatment/Prognosis: Beta blockers/Losartan for aortic root dilation, bracing/surgery for scoliosis, annual dilated eye exam, glasses for myopia