Polydactyly, Postaxial, Type A8

A number sign (#) is used with this entry because of evidence that postaxial polydactyly type A8 (PAPA8) is caused by homozygous mutation in the GLI1 gene (165220) on chromosome 12q13.

Homozygous mutation in the GLI1 gene has also been reported to cause preaxial polydactyly type I (PPD1; 174400).

Description

Postaxial polydactyly type A8 is characterized by the presence of postaxial extra digits (hexadactyly) on the hands and/or the feet. The anomalous digits are well formed and have nails (Palencia-Campos et al., 2017).

For a discussion of genetic heterogeneity of postaxial polydactyly, see 174200.

Clinical Features

Palencia-Campos et al. (2017) studied 10 patients from 3 unrelated families with postaxial polydactyly. The first family was an extended multiply consanguineous Turkish pedigree in which the proband was a male infant who exhibited bilateral postaxial hexadactyly of hands and feet, as well as mild nail dysplasia, short stature, shortening of the long bones of the lower extremities, and atrial septal defect. The authors considered these features to be 'reminiscent of' Ellis-van Creveld syndrome (EVC; see 225500). An 8-year-old boy and his 2-year-old male cousin, who were distant relatives of the proband, also had bilateral postaxial polydactyly of the hands; their heights were in the 10th to 25th percentile. Another distant female relative was reported to have had either unilateral or bilateral postaxial floating sixth finger that was surgically treated in infancy, and multiple affected members with only hand involvement were reported over 3 generations of another branch of the family. In an unrelated Turkish family, 2 brothers born of second-cousin parents had bilateral hexadactyly of the hands and feet, short stature, and genu valgum. The authors stated that although an extra metatarsal was reported to be present in the brothers' feet, there was no extra metacarpal in their hands. The third family was a consanguineous Pakistani pedigree in which 4 affected individuals with normal stature exhibited bilateral postaxial polydactyly of the feet, with 1 patient also showing postaxial polydactyly of the left hand. The authors stated that no metacarpal/metatarsal duplications were detected. No associated anomalies were reported in the Pakistani patients.

Molecular Genetics

In a consanguineous Turkish pedigree with postaxial polydactyly, in which the proband was negative for mutation in the EVC (604831), EVC2 (607261), and WDR35 (613602) genes, Palencia-Campos et al. (2017) performed homozygosity mapping using SNP arrays as well as whole-exome sequencing, and identified homozygosity for a nonsense mutation in the GLI1 gene (W780X; 165220.0001) in the proband (patient 1) and an affected 8-year-old boy who was a distant relative (patient 2). Another affected distant relative, a 2-year-old boy (patient 3), was heterozygous for the variant, whereas a distantly related female patient (patient 4) did not carry the mutation. Sequencing of GLI1 in 27 unrelated individuals with EVC or an EVC-like phenotype identified the proband of a consanguineous Turkish family (patient 5) with postaxial polydactyly and genu valgum who was homozygous for a different nonsense mutation in GLI1 (Q644X; 165220.0002), which was also found in homozygosity in his similarly affected brother (patient 6). Homozygosity for a third nonsense mutation in GLI1 (R113X; 165220.0003) was identified in 4 affected individuals from 2 sibships of a large consanguineous Pakistani pedigree (patients 7 to 10) with postaxial polydactyly. The proband of the original Turkish family, who exhibited additional features 'reminiscent of' EVC, also carried 2 heterozygous missense variants of unknown significance in the GLI2 gene (165230), which the authors suggested might account for his more severe phenotype.