Schmid type of metaphyseal chondrodysplasia and COL10A1 mutations--findings in 10 patients.

The Schmid type of metaphyseal chondrodyplasia (MCDS) is characterized by short stature, widened growth plates, and bowing of the long bones. It results from autosomal dominant mutations of COL10A1, the gene which encodes alpha1(X) chains of type X collagen. We report the clinical and radiographic findings in 10 patients with MCDS and COL10A1 mutations. Six patients had lower limb deformities, which necessitated orthopedic surgeries in all of them. One patient demonstrated no deformities and normal stature at age 11 years (height -1.2 SDS) while the others manifested severe short stature (<-3.5 SDS). Radiographs showed metaphyseal changes which were most pronounced at the hips and knees. Five of the identified 10 mutations in COL10A1 were novel. Six mutations resulted in truncation of the NC1 domain while four mutations were single amino-acid substitutions. Our findings suggest that COL10A1 mutations result in a uniform pattern of growth plate abnormalities. However, the clinical variability in severity among affected individuals is greater than previously thought.

A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey disease) expands the spectrum of collagen-related disorders.

Infantile cortical hyperostosis (Caffey disease) is characterized by spontaneous episodes of subperiosteal new bone formation along 1 or more bones commencing within the first 5 months of life. A genome-wide screen for genetic linkage in a large family with an autosomal dominant form of Caffey disease (ADC) revealed a locus on chromosome 17q21 (LOD score, 6.78). Affected individuals and obligate carriers were heterozygous for a missense mutation (3040Ctwo head right arrowT) in exon 41 of the gene encoding the alpha1(I) chain of type I collagen (COL1A1), altering residue 836 (R836C) in the triple-helical domain of this chain. The same mutation was identified in affected members of 2 unrelated, smaller families with ADC, but not in 2 prenatal cases and not in more than 300 chromosomes from healthy individuals. Fibroblast cultures from an affected individual produced abnormal disulfide-bonded dimeric alpha1(I) chains. Dermal collagen fibrils of the same individual were larger, more variable in shape and size, and less densely packed than those in control samples. Individuals bearing the mutation, whether they had experienced an episode of cortical hyperostosis or not, had joint hyperlaxity, hyperextensible skin, and inguinal hernias resembling symptoms of a mild form of Ehlers-Danlos syndrome type III. These findings extend the spectrum of COL1A1-related diseases to include a hyperostotic disorder.