Syndactyly, Type Iv

A number sign (#) is used with this entry because type IV syndactyly (SDTY4) is caused by heterozygous mutation in an SHH (600725) regulatory element (ZRS) that resides in intron 5 of the LMBR1 gene (605522).

Clinical Features

Haas (1940) reported this type of syndactyly in a mother and her 2 children. The syndactyly was complete, affecting the fingers of both hands, and there was polydactyly, with 6 metacarpals and 6 digits. Flexion of the fingers gave the hands a cup-shaped form. In contradistinction to the type of syndactyly in Apert syndrome (101200), there was no bone fusion. There was no mention of the condition of the feet and there were no associated malformations.

Gillessen-Kaesbach and Majewski (1991) described an affected 2-month-old girl with complete cutaneous syndactyly and hexadactyly of both hands. Partial cutaneous syndactyly of toes 2 and 3, involving the proximal segment, was present on both feet. Although neither parent had syndactyly, 2 brothers of the mother and the maternal grandmother showed complete bilateral cutaneous syndactyly of the second and third toes. Development was otherwise normal. Each hand had 1 supernumerary ray, which may have been pre- or postaxial.

Rambaud-Cousson et al. (1991) described type IV syndactyly with bilateral hexadactyly of the hands and feet in 6 members of 3 generations with 1 instance of male-to-male transmission. The proband also had unilateral absence of the tibia. The possibility was raised that syndactyly type IV with hexadactyly of the feet is in fact a complex entity which can include a variety of lower limb malformations.

Sato et al. (2007) reported a 5-generation Chinese family segregating autosomal dominant nonsyndromic syndactyly, which was clinically diagnosed as type IV because 1 of the 6 living affected members had complete syndactylism of all fingers and toes accompanied by polydactyly; flexion of the fingers together with cutaneous syndactyly gave his hands a cup-shaped appearance. This patient and 1 other in the family also had tibial hemimelia.

Mapping

Sato et al. (2007) performed linkage and haplotype analysis of a 5-generation Chinese family segregating autosomal dominant type IV syndactyly and obtained a maximum 2-point lod score of 1.613 for a 17.39-cM region on chromosome 7q36 flanked by markers D7S3070 and D7S559.

Molecular Genetics

In a 5-generation Chinese family diagnosed with type IV syndactyly mapping to chromosome 7q36, Sato et al. (2007) directly sequenced the SHH (600725) and LMBR1 (605522) genes, including the conserved ZPA regulatory sequence (ZRS) within intron 5 of LMBR1, but found no pathogenic mutations.

In a Han Chinese mother and daughter with type IV syndactyly, Sun et al. (2008) identified a 235-kb duplication in intron 5 of the LMBR1 gene (605522.0010) involving the ZRS. The duplication was not found in unaffected family members or in 50 unrelated Han Chinese controls.

In the Chinese family with type IV syndactyly and tibial hypoplasia previously studied by Sato et al. (2007), Wu et al. (2009) identified a 97-kb duplication involving the LMBR1 gene that segregated with the limb phenotype in the family and was not found in 50 unrelated ethnically matched controls. Wu et al. (2009) concluded that SDTY4 with tibial hypoplasia is a severe clinical subtype of SDTY4.

By array CGH analysis in the female patient with complete cutaneous syndactyly and hexadactyly of both hands who was originally reported by Gillessen-Kaesbach and Majewski (1991), Wieczorek et al. (2010) identified a 73-kb duplication involving the ZRS region of the LIMBR1 gene (605522.0016) that they designated arr7q36.3(156,265,512x2,156,265,453-156,354,638x3,156,354,579x2). Wieczorek et al. (2010) stated that because of the complex and repetitive nature of this genomic region, they were unable to determine the exact orientation of the duplication.

In affected individuals from 2 families with type IV syndactyly, Lohan et al. (2014) identified heterozygosity for microduplications in the ZRS region of LMBR1, measuring approximately 255 kb and 179 kb, respectively. Lohan et al. (2014) noted that the 255-kb duplication, present in a Peruvian boy who had complete syndactyly of the hands with no other anomalies, encompassed the entire LMBR1 gene as well as several exons of the adjacent RNF32 gene (610241).