Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (453 page)

   Individual targeted gene sequencing, deletion/duplication testing, ethnicitybased testing

Suggested Reading

Reiners J, et al. Molecular basis of human Usher syndrome: deciphering the meshes of the Usher protein network provides insights into the pathomechanisms of the Usher disease.
Exp Eye Res.
2006;83(1):97–119.

   
SKELETAL DYSPLASIA

ACHONDROPLASIA (ACH)

MIM #100800

   Definition

Achondroplasia (ACH) is the most frequent form of short-limb dwarfism, with clinical manifestations including short stature, shortening of the limbs, frontal bossing, lumbar lordosis, genu varum, and trident hand. ACH is an autosomal dominant disorder, caused by mutations in the fibroblast growth factor receptor-3 gene (FGFR3; 4p16.3), with the majority of cases resulting from de novo mutations.

   Relevant Tests and Diagnostic Value

Targeted sequencing mutation analysis of
FGFR3
exons 10, 13, and 15 detects the majority of ACH mutations, as well as many mutations associated with hypochondroplasia; sequence analysis of the entire coding region.

Suggested Reading

Shiang R, et al. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia.
Cell.
1994;78:335–342.

ELLIS-VAN CREVELD (EVC MIM #225500) AND WEYERS ACROFACIAL DYSOSTOSIS (MIM #193530)

MIM #193530 AND #193530

   Definition

Ellis-van Creveld syndrome is an autosomal recessive skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly, and dysplastic nails and teeth. Congenital cardiac defects, most commonly a defect of primary atrial septation producing a common atrium, occur in 60% of affected individuals. Weyers acrofacial dysostosis (Curry-Hall syndrome) is an autosomal dominant inheritance syndrome of postaxial polydactyly with anomalies of the lower jaw, dentition, and oral vestibule. Both EVC and Weyers are caused by mutations in the EVC1 and/or EVC2 genes.

   Relevant Tests and Diagnostic Value

Sequencing of the EVC1 and EVC2 genes identifies mutations in individuals with EVC and Weyers acrofacial dysostosis in about 70% of cases.

Suggested Reading

Galdzicka M, England JA., Ginns EI. EVC and EVC2 and Ellis-van Creveld Syndrome, Second Edition of CJ Epstein, RP Erickson, A Wynshaw-Boris (eds.) Inborn Errors of Development: the molecular basis of clinical disorders of morphogenesis, Oxford University Press, New York (2008).

OSTEOGENESIS IMPERFECTA (OI; BRITTLE BONE DISEASE)

MIM #166200

   Definition

Osteogenesis imperfecta type I (OI) is a generalized connective tissue disorder characterized by bone fragility and blue sclerae. Mutations in the collagen, type I, alpha-1 (COL1A1; 17q21.33) or the collagen, type I, alpha-2 (COL1A2; 7q21.3) gene result in OI, but lack of finding a mutation does not rule out OI.

   Relevant Tests and Diagnostic Value

Protein analysis demonstrating reduced amounts of normal collagen I.

Suggested Reading

Kuivaniemi H, et al. Mutations in fibrillar collagens (types I, II, III, and XI), fibril-associated collagen (type IX), and network-forming collagen (type X) cause a spectrum of diseases of bone, cartilage, and blood vessels.
Hum Mutat.
1997;9:300–315.

   
CONNECTIVE TISSUE DISORDERS

MARFAN SYNDROME (MFS)

MIM #154700

   Definition