Temtamy Preaxial Brachydactyly Syndrome

A number sign (#) is used with this entry because of evidence that Temtamy preaxial brachydactyly syndrome (TPBS) is caused by homozygous mutation in the CHSY1 gene (608183) on chromosome 15q26.

Clinical Features

Temtamy et al. (1998) described a 10-year-old Egyptian boy with a syndrome characterized by multiple congenital anomalies, mental retardation, sensorineural deafness, talon cusps of upper central incisors, growth retardation, and bilateral symmetric digital anomalies mainly in the form of preaxial brachydactyly and hyperphalangism of digits 1-3. Talon cusp malformation (talonism) is a markedly enlarged cingulum, on the maxillary or mandibular incisors, primary or permanent. It prominently projects from the lingual surface of the incisors resembling an eagle's talon in shape. Temtamy et al. (1998) pointed out similarities to several other syndromes, but thought the differences sufficient to consider the disorder in this family to be distinct. They noted that talon cusps have been reported in Rubinstein-Taybi syndrome (180849) and in Mohr syndrome (252100). Because the boy had a similarly affected brother and his parents were second cousins, the authors suggested autosomal recessive inheritance, but stated that X-linked recessive inheritance could not be excluded.

Clarkson et al. (2004) reported a girl, born of consanguineous parents, who had cleft palate, micrognathia, sensorineural hearing loss, and abnormal hands and feet. Radiographic examination of the hands revealed ulnar deviation of the fifth fingers and accessory ossicles of digits 2-5 and abnormal proximal phalanges of the thumbs. Examination of the feet showed short halluces, a short left fourth toe, and medial deviation of most toes, with anomalies of the metatarsals and phalanges on x-ray. Clarkson et al. (2004) suggested that this child represented an extension of the Catel-Manzke phenotype (616145); however, Temtamy (2005) stated that this child had hand and foot anomalies identical to those of the patient described by Temtamy et al. (1998).

Race et al. (2010) described a girl (patient 1), born to first-cousin Sri Lankan parents, and 2 sisters and a brother (patients 2-4, respectively), born to consanguineous Pakistani parents, with symmetric hand and foot anomalies and the same unusual combination of preaxial brachydactyly, phalangeal duplication, symphalangism and hyperphalangism of digits 1-3. Patient 1 also had facial dysmorphism, sensorineural deafness, and dental anomalies; in addition, she had proximal radioulnar synostosis, a feature not previously described. Patients 1 and 2 had carpal/tarsal fusions. Patient 2 had hypodontia, and patients 3 and 4 had sensorineural hearing loss. Race et al. (2010) suggested that these anomalies are remarkably similar to those of the patient described by Temtamy et al. (1998).

Tian et al. (2010) studied a consanguineous Jordanian family in which a brother and sister had symmetric and bilateral preaxial brachydactyly, micrognathia, short stature, and variable degrees of learning disability. Radiography revealed unified capitate and hamate bones, and partial duplication of the proximal phalanges of digits 1 to 3, suggestive of hyperphalangism. Tian et al. (2010) noted that the clinical features of the sibs were similar to those described previously by Temtamy et al. (1998) in a consanguineous Egyptian family. In addition, Tian et al. (2010) observed that both affected sibs exhibited macrophthalmia accompanied by bilateral blue sclerae, with remnants of pupillary membrane over the crystalline lens and tilted optic discs in both eyes.

Inheritance

Race et al. (2010) described 4 children from 2 consanguineous families with anomalies remarkably similar to those of the patient described by Temtamy et al. (1998) and suggested that autosomal recessive inheritance of this disorder is likely.

Mapping

Li et al. (2010) genotyped DNA samples from the consanguineous Egyptian family with Temtamy preaxial brachydactyly syndrome (TPBS) originally described by Temtamy et al. (1998) and another consanguineous Egyptian family with TPBS, and obtained lod scores of 2.37 and 2.51 at chromosomes 1p33 and 15q26, respectively. Analysis of microsatellite markers mapped the locus to chromosome 15q26-qter between SNPs rs1480952 and rs352744, defining a shared homozygous 3.8-Mb critical interval and excluding the 1p33 region. Mapping data from an additional Turkish TPBS family confirmed the TPBS locus without reducing the critical region.

Molecular Genetics

In 5 consanguineous families with Temtamy preaxial brachydactyly syndrome (TPBS), including the Egyptian family originally described by Temtamy et al. (1998) and 2 TPBS families from Sri Lanka and Pakistan that were previously reported by Race et al. (2010), Li et al. (2010) analyzed the candidate gene CHSY1 (608183) and identified 5 different homozygous mutations (608183.0001-608183.0005, respectively), that cosegregated with disease in each family and were not found in more than 150 controls.

In a consanguineous Jordanian family in which 2 sibs had TPBS, Tian et al. (2010) performed homozygosity mapping and identified 4 candidate regions. Targeted genomic loci capture followed by high-throughput resequencing revealed 2 homozygous mismatches in an affected sib, only 1 of which cosegregated with disease in the family: a 1-bp deletion in the CHSY1 gene (608183.0006). Tian et al. (2010) noted that hemizygous deletions of CHSY1 occur in the chromosome 15q26-qter deletion syndrome (612626), which shares some phenotypic features in common with TPBS.