Disorders Involving Cartilage Matrix Proteins

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Chapter 686 Disorders Involving Cartilage Matrix Proteins

Functional disturbances of cartilage matrix proteins result in several bone and joint disorders. They fall into five groups corresponding primarily to the defective proteins: three collagens and the noncollagenous proteins COMP (cartilage oligomeric matrix protein), matrilin 3, and aggrecan. The clinical phenotypes differ between and within the groups, especially the spondyloepiphyseal dysplasia (SED) group. In some groups, there is substantial variation in clinical severity.

Spondyloepiphyseal Dysplasias

The term spondyloepiphyseal dysplasia refers to a heterogeneous group of disorders characterized by shortening of the trunk and, to a lesser extent, the limbs. Severity ranges from achondrogenesis type II to the slightly less severe hypochondrogenesis (these two types are lethal in the perinatal period) to SED congenita and its variants, including Kniest dysplasia (which are apparent at birth and are usually nonlethal), to late-onset SED (which might not be detected until adolescence or later). The radiographic hallmarks are abnormal development of the vertebral bodies and of epiphyses, the extent of which corresponds to the clinical severity. Most of the SEDs result from heterozygous mutations of COL2A1; they are autosomal dominant disorders. The mutations are dispersed throughout the gene; there is a poor correlation between the mutation’s location and the resultant clinical phenotype. For familial cases, prenatal diagnosis is possible if the mutation is identified. Schimke immuno-osseous dysplasia may be an exception because it is an autosomal recessive disorder characterized by short stature, hyperpigmented macules, unusual facies, proteinuria and progressive renal failure, cerebral ischemia, and a T-cell defect with lymphopenia and recurrent infections.

Lethal Spondyloepiphyseal Dysplasias

Achondrogenesis type II (OMIM 200610) is characterized by severe shortening of the neck and trunk and especially the limbs and by a large, soft head. Fetal hydrops and prematurity are common; infants are stillborn or die shortly after birth. Hypochondrogenesis (OMIM 200610) refers to a clinical phenotype intermediate between achondrogenesis type II and SED congenita. It is typically lethal in the newborn period.

The severity of radiographic changes correlates with the clinical severity (Fig. 686-1). Both conditions produce short, broad tubular bones with cupped metaphyses. The pelvic bones are hypoplastic, and the cranial bones are not well mineralized. The vertebral bodies are poorly ossified in the entire spine in achondrogenesis type II and in the cervical and sacral spine in hypochondrogenesis. The pedicles are ossified in both.