Syndactyly, Mesoaxial Synostotic, With Phalangeal Reduction

A number sign (#) is used with this entry because of evidence that mesoaxial synostotic syndactyly with phalangeal reduction (MSSD) is caused by homozygous mutation in the BHLHA9 gene (615416) on chromosome 17p13.

Homozygous mutation in BHLHA9 also causes complex camptosynpolydactyly (CCSPD; 607539). A form of split-hand/foot malformation with long bone deficiency (SHFLD3; 612576) is associated with telomeric duplications of chromosome 17p13 involving BHLHA9.

Description

Mesoaxial synostotic syndactyly with phalangeal reduction (MSSD) represents a distinctive combination of clinical features that includes mesoaxial osseous synostosis at a metacarpal level, reduction of one or more phalanges, hypoplasia of distal phalanges of preaxial and postaxial digits, clinodactyly of fifth fingers, and preaxial fusion of toes (Malik et al., 2014).

Clinical Features

Percin et al. (1998) described a large inbred Turkish pedigree in which 9 affected individuals had type I syndactyly (see 185900). The pedigree also included 3 individuals, born to first-cousin affected parents, who were found to have a severe form of mesoaxial syndactyly, the characteristic features of which were complete syndactyly and synostosis of the third and fourth fingers with severe bone reduction in the proximal phalanges, hypoplasia of the thumbs and halluces, aplasia/hypoplasia of the middle phalanges of the second and fifth fingers, and complete or partial soft tissue syndactyly of the toes. Percin et al. (1998) suggested that the severe clinical phenotype might be the result of homozygosity for syndactyly type I.

Malik et al. (2004) reported a consanguineous Pakistani family with nonsyndromic, autosomal recessive syndactyly. Limb findings included mesoaxial reduction of the fingers, synostoses of the third and fourth metacarpals with associated single phalanges, fifth finger clinodactyly, and preaxial webbing of the first 3 toes with a hypoplastic terminal phalanx in all toes. The authors noted the similarities between the phenotype in this family and that of the severely affected individuals of the Turkish kindred described by Percin et al. (1998).

Malik et al. (2014) reported 4 additional families with mesoaxial synostotic syndactyly with phalangeal reduction. In the first family, a brother and sister, born of consanguineous Turkish parents, had only 4 fingers bilaterally, with radial diversion of the index finger and replacement of the third and fourth fingers by a single thick digit. The fifth digit showed clinodactyly, and there was partial cutaneous webbing of toes 1 through 4. In the second family, the proband was a 50-year-old Italian woman with chronic pain and severe functional limitation of the thumbs due to bilateral rhizarthrosis of the trapeziometacarpal joint. She had congenital bilateral syndactyly of the third and fourth fingers with synostosis of the corresponding metacarpals, mild phalangeal shortening of all digits, fifth finger clinodactyly, and bilateral syndactyly of the second and third toes. Her parents were first cousins, and no other family members were affected. In the third family, a 24-year-old woman, born of consanguineous parents from southern Pakistan, had only hand involvement, exhibiting 4 hypoplastic radially deviated digits bilaterally, with tapering fingertips and hypoplastic nail plates that were reduced to small islands in the second and fourth digits. The fourth family was a consanguineous pedigree from northern Pakistan with affected sibs. The affected sister was deceased, and the 23-year-old brother exhibited bilateral short thumbs, index fingers with valgus deviation at the terminal phalanx, replacement of third and fourth digits with a single broad proximal phalanx and a hypoplastic and club-shaped terminal phalanx with a reduced nail, and dysplastic fifth fingers with clinodactyly. The palmar surface of his hands showed characteristic dermatoglyphic changes, including grossly distorted triradii and decreased interdigital flexion creases. His feet showed hallux varus, cutaneous syndactyly of the second and third toes, shortening of the fourth toes, and hypoplastic nails on the second to fourth toes.

Mapping

Malik et al. (2005) performed a genomewide screen on 4 affected individuals from the Pakistani family reported by Malik et al. (2004) and identified a single autozygous region on 17pter-p13, with an approximately 10-Mb critical interval spanning markers D17S643 and D17S1828. Two-point linkage analysis showed a maximum lod score of 3.47 for marker D17S1528 (theta = 0.00); multipoint analysis yielded a lod score of 3.29. Analysis of the 3 severely affected members of the Turkish family described by Percin et al. (1998) showed a homozygous region flanked by markers D17S1866 and D17S831, with a maximum 2-point lod score of 1.89 for marker D17S153 (theta = 0.00). When Malik et al. (2005) analyzed the affected individuals from both families together, a maximum 2-point lod score of 4.97 was obtained at marker D17S695 (theta = 0.00). Combined multipoint analysis showed a lod score of 5.1 at 17p13.3, with an approximately 6.6-Mb homozygous region in both families spanning markers D17S643 and D17S831. The 9 individuals from the Turkish kindred with type I syndactyly were excluded from the chromosome 17p13.3 locus under an autosomal dominant model; Malik et al. (2005) suggested that 2 different types of syndactyly were segregating in that family, autosomal recessive type IX syndactyly, which maps to chromosome 17p13.3, and an autosomal dominant type I-like syndactyly.

In a Turkish family in which a brother and sister had MSSD, Malik et al. (2014) identified homozygosity for microsatellite markers D17S849 and D17S1533 in the affected sibs, whereas 2 unaffected sibs and their unaffected parents were heterozygous. Combining data from this family with data from 2 previously reported families (Malik et al., 2005) slightly improved the lod scores in the critical interval on chromosome 17p13.3, with the highest pairwise lod scores at D17S1533, D17S695, and D17S926.

Exclusion Studies

By single-strand conformation polymorphism (SSCP) and linkage analysis, Percin et al. (1998) excluded HOXD13 (142989) and other relevant genes at 2q31 as candidates for syndactyly in a Turkish kindred.

By microsatellite marker screening of a Pakistani family with syndactyly, Malik et al. (2004) found no evidence for linkage to known syndactyly loci on 2q34-q36, 2q31, and 6q22-q23.

Molecular Genetics

In affected members of 6 families with MSSD, including the Turkish family originally reported by Percin et al. (1998) and the Pakistani family reported by Malik et al. (2004), Malik et al. (2014) identified homozygosity for missense mutations in the BHLHA9 gene (615416.0001-615416.0003). No unaffected family members were homozygous for the mutations, which were not found in 280 control chromosomes or in the dbSNP, 1000 Genomes Project, HapMap, or Exome Variant Server databases.