Trichorhinophalangeal Syndrome, Type Iii

A number sign (#) is used with this entry because of evidence that type III TRPS is caused by heterozygous mutation in the TRPS1 gene (604386) on chromosome 8q23. Mutation in the same gene has been found to cause type I TRPS (190350).

Clinical Features

Sugio and Kajii (1984) described a kindred in which 9 persons in 4 generations showed a syndrome of sparse hair, beaked nose, long upper lip, and severe metacarpophalangeal shortening. They reported the condition as an example of Ruvalcaba syndrome (180870); however, as pointed out by Hunter (1985), the disorder could be differentiated from Ruvalcaba syndrome by the absence of mental retardation and microcephaly and the presence of other changes resembling those of trichorhinophalangeal syndrome I (190350). The abnormalities of the hands and feet present in the patients of Sugio and Kajii (1984) were more severe, however, than those of TRPS1 patients. Niikawa and Kamei (1986) reported on a sporadic case who had similar manifestations and proposed that the condition should be recognized as a new syndrome known as TRPS type III, or Sugio-Kajii syndrome. Nagai et al. (1994) added another family in which 4 persons in 3 generations were affected with 1 instance of male-to-male transmission. The sparse hair, 'pear-shaped nose' clearly demonstrated in the figures, and cone-shaped epiphyses were features like those of TRPS types I and II (TRPS2; 190350), but the presence of severe generalized shortening of all phalanges and metacarpals differentiated the condition from TRPS1 and the absence of mental deficiency and exostoses from TRPS2.

Vilain et al. (1999) reported a case of TRPS III in a patient of European descent. The patient had typical features of TRPS I as well as severe brachydactyly. The case was sporadic, consistent with a new mutation. The authors believed this to be the first reported case of TRPS III in a western European patient.

Molecular Genetics

To investigate whether TRPS III is caused by mutations in the TRPS1 gene and to establish a genotype-phenotype correlation in TRPS, Ludecke et al. (2001) performed extensive mutation analysis and evaluated height and degree of brachydactyly in patients with TRPS I or TRPS III. They found 35 different mutations in TRPS1 in 44 of 51 unrelated patients with TRPS I or TRPS III. The detection rate (86%) indicated that TRPS1 is the major locus for both type I and type III TRPS. They found no 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 5 missense mutations altered the GATA DNA-binding zinc finger, and 6 of the 7 unrelated patients with these mutations could be classified as having TRPS III because they had severe brachydactyly, due to generalized shortness of all phalanges and metacarpals, and severe short stature. The data indicated 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.