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Dyggve-Melchior-Clausen syndrome (DMC) (MIM 223800) and Smith-McCort dysplasia (SMC) (MIM 607326) are rare allelic autosomal recessive spondylo-epi-metaphyseal dysplasias (SEMDs) characterized by similar skeletal manifestations. Both phenotypes have been mapped to chromosome 18q21.1 and mutations in the DYM (dymeclin) gene were identified in 13 families with DMC and in two families with SMC. Most mutations identified in DMC predict a loss of function, while those identified in SMC are mainly missense mutations, presumably associated with residual DYM activity and a less severe phenotype. We studied three consanguineous families from Turkey, Lebanon, and Georgia, one with SMC and two with DMC and identified different homozygous DYM mutations (IVS3 194-1G > A, 938₉₄₂delTGTCT) in the DMC families. No mutation was identified in the SMC family, possibly suggesting genetic heterogeneity of this disorder. Show less

Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities. Three subtypes have been described: TRPS I, caused by mutations in the TRPS1 gene on chromosome 8; TRPS II, a microdeletion syndrome affecting the TRPS1 and EXT1 genes; and TRPS III, a form with severe brachydactyly, due to short metacarpals, and severe short stature, but without exostoses. To investigate whether TRPS III is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, we performed extensive mutation analysis and evaluated the height and degree of brachydactyly in patients with TRPS I or TRPS III. We found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicates that TRPS1 is the major locus for TRPS I and TRPS III. We did not find any mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the five missense mutations alter the GATA DNA-binding zinc finger, and six of the seven unrelated patients with these mutations may be classified as having TRPS III. Our data indicate that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in the TRPS1 gene. Show less