Genotypic and phenotypic spectrum in tricho-rhino-phalangeal syndrome types I and III

Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial an d skeletal abnormalities. Three subtypes have been described: TRPS I, cause d 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 seve re brachydaayly, due to short metacarpals, and severe short stature, but wi thout exostoses. To investigate whether TRPS III is caused by TRPS1 mutatio ns and to establish a genotype-phenotype correlation in TRPS, we performed extensive mutation analysis and evaluated the height and degree of brachyda ctyly 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 TRP S1 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. Evalu ation 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 o f the TRPS spectrum and that it is most often caused by a specific class of mutations in the TRPS1 gene.