Trichorhinophalangeal Syndrome, Type Ii

A number sign (#) is used with this entry because trichorhinophalangeal syndrome type II (TRPS2), also known as Langer-Giedion syndrome, is a contiguous gene syndrome on 8q24.1, involving loss of functional copies of the TRPS1 (604386) and EXT1 (608177) genes.

TRPS type II combines the clinical features of trichorhinophalangeal syndrome type I (190350) and multiple exostoses type I (133700), which are caused by mutations in the TRPS1 and EXT1 genes, respectively.

See also Cornelia de Lange syndrome-4 (CDLS4; 614701), caused by mutation in the RAD21 gene (606462), which lies on 8q24 between TRPS1 and EXT1.

Clinical Features

Hall et al. (1974) described a condition that they called the Langer-Giedion syndrome in which affected individuals had multiple dysmorphic facial features including large, laterally protruding ears, a bulbous nose, an elongated upper lip, as well as sparse scalp hair, winged scapulae, multiple cartilaginous exostoses, redundant skin, and mental retardation. Kozlowski et al. (1977) reported 2 unrelated patients, a girl and a boy, and suggested that the condition may have been described by Ale and Calo (1961). Murachi et al. (1981) described affected father and daughter, suggesting autosomal dominant inheritance. The father was mildly mentally retarded. They noted previous reports of 9 cases, all sporadic.

Langer et al. (1984) described in detail 4 patients who were not mentally retarded, but who did have mental impairment. Delayed speech development and hearing loss were noted as features. They pointed out that most reported cases had been sporadic. They suggested that the term 'tricho-rhino-phalangeal syndrome with exostoses' be used. They also provided a detailed clinical review of 32 previously reported cases.

Brenholz et al. (1989) reported LGS in 2 brothers whose mother appeared to have been affected. The maternal grandmother and a maternal first cousin may have been affected.

Fryns et al. (1983) and Partington et al. (1991) described hydrometrocolpos and hematometra as complications of this syndrome. Kozlowski et al. (1977) and Partington et al. (1991) described ureteral reflux requiring reimplantation of the ureters in the bladder. In a patient with Langer-Giedion syndrome and interstitial 8q deletion, Ramos et al. (1992) found persistent cloaca and the prune belly sequence (100100). Morioka et al. (1999) described a patient with Langer-Giedion syndrome associated with submucous cleft palate.

Stevens and Moore (1999) described a girl with Langer-Giedion syndrome with deletion of 8q and the unusual findings of bilateral tibial hemimelia (275220) and unilateral absence of the ulna. Turleau et al. (1982) had reported an 8-year-old boy with LGS and bilateral tibial hemimelia. Although no genes involving limb development in the human had been identified in the 8q24.1 critical LGS region, 2 mouse syndromes that involve limb abnormalities mapped to the homologous chromosome region, 9A1-A4: 'luxoid' (absent toes, radial and tibial hemimelia, preaxial polydactyly, bent tail, and oligospermia) and 'aft' (abnormal feet and tail).

Riedl et al. (2004) described a girl with TRPS II and growth hormone deficiency (see 262400) causing pronounced short stature (-4.8 SD). The patient had an interstitial deletion at 8q24.1 of 12 to 15 Mb. The deletion spanned all genes from CSMD3 (608399) to at least ANXA13 (602573), including the TRPS1 (604386) and EXT1 (608177) genes. Growth hormone deficiency was indicated by diminished response in 3 stimulation tests and a striking response to growth hormone therapy. This was apparently the first observation of combined TRPS II and growth hormone deficiency.

Schinzel et al. (2013) reported follow-up of 4 persons with TRPS2 into adulthood and reviewed the limited available literature on adults with TRPS2. Most patients had borderline or mild cognitive impairment, with a few with normal intelligence; patients with TRPS2 performed better in practical skills than their academic achievement would suggest. Some patients developed seizures at variable ages. Scoliosis was most often mild. Exostoses typically did not progress further after puberty, and in some patients, became less prominent. However, serious complications related to cervical spinal exostoses, including stroke and spinal cord compression, were occasionally reported. No cases with malignant transformation of exostoses were identified, although the number of patients followed was too low to define malignancy risk. Almost all males lost their hair at or soon after puberty, and some developed gynecomastia. Growth hormone deficiency was infrequently observed. Serious complications related to the eye, ear, and heart were rare.

Cytogenetics

Buhler et al. (1980) reported the case of a teenage girl with features suggestive of Langer-Giedion syndrome associated with terminal deletion of 8q: the band q24 was missing from one chromosome 8. Pfeiffer (1980) described deletion of a segment (q13-22) of the long arm of chromosome 8 in a mentally retarded boy with Langer-Giedion syndrome. Additional features included colobomata of the iris and defect of the fourth and fifth fingers. Wilson et al. (1981) found interstitial deletion of 8q22.8-q24.1 in a 17-year-old patient with multiple exostoses and developmental delay. Exostoses were first apparent at age 4 years. The patient lacked the typical nose and coned epiphyses of the Langer-Giedion syndrome. Gorlin et al. (1982) found normal chromosomes on prophase banding in 2 patients. Turleau et al. (1982) concluded that 8q23 is the 'critical segment,' not 8q22. Zaletajev and Marincheva (1983) attributed LGS in their patient to interstitial deletion of 8q22. Bowen et al. (1985) described an 18-year-old intellectually normal male with LGS and a small deletion of bands 8q24.11-q24.12. In addition, he had an apparently balanced de novo translocation (2;9)(q21;q13). Neither abnormality was found in the parents. The risk of LGS in any child of the proband would presumably be 50%.

Okuno et al. (1987) described a typical case with interstitial deletion of 8q24.13-q24.22. Zaletaev et al. (1987) found deletion in 8q in 3 unrelated patients with LGS. The 'critical' region was identified as 8q24.11-q24.13. The findings of Fennell et al. (1989) likewise supported the view that the critical segment for LGS is proximal to or involves a proximal part of 8q24.1.

Mapping

In reviewing 12 cases from the literature, Buhler and Malik (1984) suggested that the shortest region of overlap of the 8q deletion is in band 8q24.1. They raised the question of whether type I trichorhinophalangeal syndrome may be caused by mutation at the same locus or region. Supporting this suggestion was the description of TRPS I with probable deletion in the same region of 8q (Hamers et al., 1983) and appreciation that the presence or absence of exostoses may be the other 'symptom' that distinguishes types I and II. The fact that the multiple exostoses of LGS are indistinguishable in radiographic features and natural history from those of the long-recognized autosomal dominant disorder 'multiple hereditary exostoses' (see EXT, 133700) suggested that a locus for EXT was situated on 8q.

Brocas et al. (1986) showed that the thyroglobulin locus, located at 8q24, is intact in LGS. This confirmed the distal location previously defined for LGS and assigned the critical region for the disorder to the proximal part of band 8q24 (8q24.11-q24.13). 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. They described a case of TRPS I with a mosaic deletion of that band.

Ludecke et al. (1989) found 2 RFLPs in an anonymous DNA probe that defined the D8S48 locus within the Langer-Giedion syndrome chromosome region. Both polymorphisms were informative in the family of a Langer-Giedion patient carrying a de novo interstitial deletion 8q23-q24.1. Lack of transmission of a maternal haplotype indicated that the deletion occurred during maternal gametogenesis.

Ludecke et al. (1989) described the microdissection of the Langer-Giedion syndrome region on chromosome 8 from GTG-banded metaphase chromosomes (G-banding with trypsin-Giemsa) and the universal enzymatic amplification of the dissected DNA. Eighty percent of clones from this library (total yield 20,000) identified single-copy DNA sequences. Half of the clones detected deletions in 2 patients with LGS. Ten of the clones were assigned to the deleted region in Langer-Giedion syndrome (8q23.2-q24.11) based on Southern blot analysis of DNA from 2 patients. The results of Ludecke et al. (1989) demonstrated that thousands of region-specific probes can be isolated in a short period of time. Microdissection and microcloning have been applied successfully to various chromosome regions in Drosophila and mouse, but conventional microtechniques are too coarse and inefficient, especially on unbanded chromosomes, for analysis of the human genome. Ludecke et al. (1991) used 13 anonymous DNA markers from an 8q24.1-specific microdissection library, as well as MYC (190080) and TG (188450) gene probes, to map the deletion breakpoints in 16 patients with LGS. Twelve patients had a cytogenetically visible deletion, 2 had an apparently balanced translocation, and 2 had an apparently normal karyotype. In all cases except 1 translocation patient, loss of genetic material was detected. The DNA markers fell into 10 deletion intervals. Clone L48 (D8S51) defined the shortest region of deletion overlap, which was estimated to be less than 2 Mb. The clones that flanked the shortest region of deletion overlap recognized evolutionarily conserved sequences. Parrish et al. (1991) isolated 8 DNA clones that were found to lie within the deletion of at least 1 of 3 patients with LGS. One clone identified sequences that were missing from 1 copy of chromosome 8 in all 3 patients.

Molecular Genetics

Using YAC cloning, Southern blotting, PCR analysis, and fluorescence in situ hybridization in the study of chromosome 8 deletions, translocations, an inversion, and an insertion in patients with TRPS I, Langer-Giedion syndrome, or multiple exostoses type I, Ludecke et al. (1995) obtained information indicating that the TRPS1 gene (604386) maps more than 1,000 kb proximal to the EXT1 gene and that both genes are affected in Langer-Giedion syndrome. They concluded that the Langer-Giedion syndrome is not due to pleiotropic effects of mutations in a single gene, but that it is a true contiguous gene syndrome.

Hou et al. (1995) constructed a physical map covering 4 Mb of 8q24.1 and used this map to refine the location of the genes responsible for LGS. The map was composed of overlapping YAC clones that were identified and ordered in relation to sequence tagged sites mapped to the Langer-Giedion chromosomal region on somatic cell hybrids. The minimal region of overlap of LGS deletions, previously identified by analysis of 15 patients, was placed on the map by analysis of 2 patients whose deletions defined the end points. The chromosome 8 breakpoint of a balanced t(8;9)(q24.1;q33.3) translocation from a patient with TRPS I was found to be located just within the proximal end of the minimal deletion region. A deletion of 8q24.11-q24.3 in a patient with multiple exostoses was found to overlap the distal end of the LGS deletion region, indicating that the EXT1 gene is distal to the TRPS1 gene and providing further support for the hypothesis that LGS is due to loss of functional copies of both the TRPS1 and the EXT1 genes.