Trichorhinophalangeal Syndrome, Type I

A number sign (#) is used with this entry because trichorhinophalangeal syndrome type I (TRPS1) is caused by heterozygous mutation in the TRPS1 gene (604386) on chromosome 8q23. Mutation in the same gene has been found to cause TRPS III (TRPS3; 190351).

Description

Trichorhinophalangeal syndrome type I is a malformation syndrome characterized by distinctive craniofacial and skeletal abnormalities and is inherited as an autosomal dominant (Momeni et al., 2000). TRPS I patients have sparse scalp hair, bulbous tip of the nose, long flat philtrum, thin upper vermilion border, and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations, and short stature.

Clinical Features

Giedion (1966) delineated a syndrome consisting of thin and slowly growing hair, pear-shaped nose with high philtrum, brachyphalangy with deformation of the fingers and wedge-shaped epiphyses. Giedion's patient, a girl, had 2 supernumerary incisors. He found 2 previous reports, each describing 2 affected sibs. Furthermore, the parents were consanguineous in 1 case. One of the pairs of affected sibs was reported as pseudo-pseudohypoparathyroidism (van der Werff Ten Bosch, 1959). Hussels (1971) observed affected brother and sister whose parents were not related and allegedly were unaffected, but the father was not available for examination. While showing that in most instances inheritance is autosomal dominant, Giedion et al. (1973) concluded that a recessive form probably exists. Gonadal mosaicism is a frequent phenomenon, however, and it is probably noteworthy that there was so little evidence for a recessive form.

Autosomal dominant inheritance seemed unequivocal in light of a family in which affected grandfather, son, and grandson were observed (Murdoch, 1969; McKusick, 1972). The earliest affected male died at age 43 years of a cerebrovascular accident. Beals (1973) described a family in which the father and 2 of 4 children, a male and a female, were affected. Three Japanese families with 19 affected persons in a clear autosomal dominant pedigree pattern were reported by Sugiura et al. (1976).

Izumi et al. (2010) reported a 31-year-old man of Native American and Puerto Rican descent who presented with adult-onset chronic joint pain in his neck, back, hips, knees, and ankles. Physical and radiographic examination showed facial and skeletal features consistent with TRPS type I, and the diagnosis was confirmed by molecular testing. Facial features included low-set, posteriorly rotated ears, prominent malar eminence and orbital ridge, bulbous nose, hypoplastic nasi alae nasi, hypotrichosis, and long philtrum. He also had brachydactyly, wide halluces, and flat arches. Radiographs showed vertebral spondylosis, scoliosis, spondylolisthesis, shortening of the phalanges, osteophyte formation, osteopenia, and secondary arthritic changes. Cone-shaped epiphyses were not observed. Family history revealed that his mother had alopecia and chronic multiple joint pain. The proband had clinical evidence of hypogonadism and mild vitamin D insufficiency, which could contribute to osteopenia, but Izumi et al. (2010) concluded that the skeletal features were secondary to TRPS type I. The findings suggested that progressive osteopenia and osteoarthritis are part of the phenotype in older patients with TRPS type I.

Clinical Variability

Armour et al. (2016) reevaluated 2 male twins who were originally reported by Fitzsimmons and Guilbert (1987) as having early-onset slowly progressive spastic paraplegia, dysarthria, and low-normal intellectual capacity. In addition, both patients had skeletal abnormalities of the hands and feet: brachydactyly, cone-shaped epiphyses, and an abnormal metaphyseal-phalangeal pattern profile. Fitzsimmons and Guilbert (1987) concluded that the patients had a novel syndrome, which was later designated 'Fitzsimmons-Guilbert syndrome;' however, exome sequencing performed by Armour et al. (2016) found that the patients were compound heterozygous for mutations in the SACS gene, resulting in the correct diagnosis of autosomal recessive spastic ataxia-6 (SACS, SPAX6; 270550). In addition, the patients carried a heterozygous truncating mutation in the TRPS1 gene (604386), consistent with a diagnosis of type I trichorhinophalangeal syndrome. Thus, the patients had 2 different genetic diseases that explained the unusual phenotype.

Cytogenetics

Booth and Maurer (1981) described a sporadic case of this disorder in a girl with de novo 9;11 translocation (p22;q21).

Trichorhinophalangeal syndrome type II (TRPS2), or Langer-Giedion syndrome (150230), a similar disorder with the additional features of multiple exostoses and mental retardation, often has abnormality of chromosome 8.

Sanchez et al. (1985) described a complex chromosome rearrangement in a boy with TRPS I. Skeletal x-rays were normal. The breakpoints in chromosome 8 were at p22 and q13. Goldblatt and Smart (1986) reported a case of TRPS I without exostoses and with a partial microdeletion of 8q23. This is further support for the notion that the Langer-Giedion syndrome is the consequence of deletion or other mutation of 2 or more independent loci, one of which 'causes' exostoses and the other TRPS. Fryns and Van den Berghe (1986) reported a patient with TRPS I and a small interstitial deletion of 8q24.12. Buhler et al. (1987) concluded that the Langer-Giedion syndrome is due to a deletion extending from 8q24.11 to 8q24.13, whereas TRPS I is caused by an even smaller deleted segment, namely, 8q24.12. Buhler et al. (1987) described a case of TRPS I with a mosaic deletion of that band.

Haan et al. (1989) studied a family with an inherited rearrangement of 8q in which persons with the chromosome abnormality had manifestations of both TRPS and the branchiootic syndrome (113650). One breakpoint in the abnormality in this family involved 8q24.11, which is consistent with the previously deduced location of the TRPS gene. Haan et al. (1989) suggested that the gene for the branchiootic syndrome may map to either 8q13.3 or 8q21.13, the 2 other breakpoint sites in this family's chromosome aberration. It was thought that there was no deleted material in this family. Yamamoto et al. (1989) found no evidence of deletion in a study of the chromosomes at the 850-bands stage in a patient with typical familial TRPS I. Naritomi and Hirayama (1989) described a mother and daughter with mild features of TRPS I. Neither had exostosis, microcephaly, or mental retardation. The mother was a mosaic for an 8q23.3-q24.13 deletion. The daughter had a more complex rearrangement of chromosome 8 resulting in partial trisomy of distal 8q. The daughter, however, showed no features of the trisomy 8 syndrome and was a little more affected than the mother.

Yamamoto et al. (1989) and Hamers et al. (1990) independently reported cases of TRPS I with severe mental retardation but without multiple exostoses; in both cases an interstitial deletion of 8q was found. The findings were interpreted to support the suggestion that TRPS II is due to deletion of 8q24.11-q24.13; that TRPS I patients have a deletion of band 8q24.12; and band 8q24.13 is involved in the development of exostoses. Mental retardation seems to be correlated with the size of the interstitial 8q deletion. Marchau et al. (1993) reported the cases of a brother and sister with TRPS I and an apparently balanced translocation involving 1 breakpoint at 8q24.11. The photograph of the father, who had died from an accident, showed very sparse scalp hair and a bulbous pear-shaped nose. He had short stature.

Ludecke et al. (1995) and Hou et al. (1995) presented evidence that the Langer-Giedion syndrome is a contiguous gene syndrome due to loss of functional copies of both the TRPS1 and the EXT1 gene (608177) and that the EXT1 gene is distal to the TRPS1 gene.

In contrast to TRPS I patients, most TRPS II (Langer-Giedion syndrome) patients have cytogenetically visible deletions and are often mentally retarded. Using Southern blot and fluorescence in situ hybridization analysis, Nardmann et al. (1997) searched for submicroscopic deletions in 12 patients with TRPS I and an apparently normal karyotype. One patient of normal intelligence was found to have a deletion of approximately 5 Mb. This suggested that mental retardation in TRPS is caused by genes outside the 5-Mb region. Using 3 Langer-Giedion critical region microsatellite markers, they determined the paternal origin of this TRPS I deletion and of 8 TRPS II deletions. In 6 patients, the deletion was of paternal origin and in 3 patients it was of maternal origin.

Mapping

Ludecke et al. (1995) and Hou et al. (1995) assigned the TRPS1 locus to 8q24. It maps centromeric to the EXT1 gene, which is mutant in multiple exostoses type I (133700); EXT1 is deleted in all patients with TRPS type II, or Langer-Giedion syndrome (150230), which combines features of TRPS I and multiple exostoses.

Molecular Genetics

Starting from the location of the TRPS1 gene on 8q24, Momeni et al. (2000) positionally cloned a gene that spans the chromosomal breakpoint of 2 patients with TRPS I and was deleted in 5 patients with TRPS I combined with an interstitial deletion. In 10 unrelated patients, Momeni et al. (2000) identified 6 different nonsense mutations in the TRPS1 gene (604386). The findings suggested that haploinsufficiency for this putative transcription factor causes TRPS I.

Although Giedion et al. (1973) concluded that a recessive form of TRPS I probably exists, the isolation of TRPS1, a putative transcription factor zinc finger protein that shows its effects in single dose, indicates that haploinsufficiency of this gene causes the condition which, therefore, is inherited as an autosomal dominant. Of the 6 patients in whom mutations were identified by Momeni et al. (2000), 3 were familial and 3 were sporadic; all 6 showed heterozygosity for a mutation.

Trichorhinophalangeal syndrome type III (TRPS3; 190351) differs from TRPS I by the presence of severe brachydactyly, due to short metacarpals, and severe short stature. To investigate whether TRPS III is caused by TRPS1 mutations 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 44 of 51 unrelated patients. The detection rate (86%) indicated that TRPS1 is the major locus for TRPS I and TRPS III. 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 short 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.