Polydactyly, Preaxial Iv

A number sign (#) is used with this entry because of evidence that some cases of preaxial polydactyly type IV are caused by heterozygous mutation in the GLI3 gene (165240) on chromosome 7p14.

Description

Although both preaxial polydactyly and syndactyly are cardinal features of this malformation, it is classified as a form of polydactyly because syndactyly does not occur in the absence of polydactyly (McClintic, 1935), the opposite not being true. On the other hand, polysyndactyly is here classified as a type of syndactyly because polydactyly (of the third or fourth fingers and fifth toes) does not occur in the absence of syndactyly. The thumb shows only the mildest degree of duplication, and syndactyly of various degrees affects fingers 3 and 4. The foot malformation is more constant and consists of duplication of part or all of the first or second toes and syndactyly affects all of the toes, especially the second and third.

Clinical Features

Thomsen (1927) described 10 affected females and 5 affected males in 5 generations. McClintic (1935) observed 15 affected in 5 generations, and Goodman (1965) 5 affected in 3 generations.

Baraitser et al. (1983) pointed out that the digital changes of this disorder are identical to those of Greig syndrome (GCPS; 175700); that the facial features of Greig syndrome can be so mild as to be indistinguishable from the normal; and, therefore, that delineation of type IV preaxial polydactyly (uncomplicated polysyndactyly) as a distinct entity (Temtamy and McKusick, 1978) is not certain. Reynolds et al. (1984) reported 21 affected persons in 5 generations. Variability in expression without apparent sex influence and with complete penetrance was noted. The deformities were more severe in the feet than in the hands. Anteroposterior flatness of the thumbs was the only manifestation of the trait in the hands of several affected family members. X-rays of the thumbs in a pictured case showed dysplastic distal phalanges with a central hole--a most curious and perhaps specific finding of type IV preaxial polydactyly.

It is possible that this is the same disorder as that called type I crossed polydactyly (CP1) by Ishikiriyama et al. (1991). Crossed polydactyly (CP) is defined as coexistence of preaxial and postaxial polydactyly with discrepancy in the axes of polydactyly between hands and feet. CP is divided into 2 types: in type I, postaxial polydactyly of the hands is combined with preaxial polydactyly of the feet; in type II, the opposite is found. CP is often associated with congenital malformation syndromes, while nonsyndromic CP is rare. McClintic (1935), Goodman (1965), and Giorgini et al. (1979) reported families with CP type I. Abnormal earlobes were present in the family reported by Goldberg and Pashayan (1976); see 186350. Most patients in these families showed not only preaxial polydactyly of the feet but also syndactyly of toes II-V. In the family studied by McClintic (1935), there were 6 fingers and 7 toes. Ishikiriyama et al. (1991) described a Japanese mother and son with CP type I. Unlike the affected members of the previously reported families, syndactyly of the toes was not present.

Radhakrishna et al. (1999) described a large family from the Gujarat state in western India in which 22 affected individuals over 4 generations exhibited preaxial polydactyly type IV. Most had bilateral anomalies of the feet, although their hands were less severely affected, and some individuals had apparently normal hands. Foot polydactyly was the only abnormality in 12 of the 22 affected individuals. The anomaly ranged from duplication of the great toe ('double toes') to syndactyly of toes with postaxial polydactyly. Hand polydactyly was not observed without foot polydactyly. The more severely affected individuals with hand/foot polydactyly had bilateral duplication of the fifth fingers and nails and unilateral triplication of the fifth finger. There were no craniofacial signs, such as frontal bossing, macrocephaly, hypertelorism, or broad base of the nose, in any individuals with digital anomalies.

Mapping

In a large 4-generation family from the Gujarat state in western India segregating autosomal dominant preaxial polydactyly type IV, Radhakrishna et al. (1999) performed linkage analysis in a candidate region of chromosome 7p and obtained a maximum lod score of 3.91 for marker D7S521 (theta = 0.00). Using 2 microsatellite polymorphisms within the GLI3 gene, they obtained a Z(max) score of 5.51, suggesting GLI3 as a strong candidate gene for the phenotype in this family.

Molecular Genetics

In a large 4-generation family from the Gujarat state in western India with preaxial polydactyly type IV mapping to chromosome 7p, Radhakrishna et al. (1999) identified heterozygosity for a 1-bp insertion in the GLI3 gene (165240.0005) that segregated with disease.

In a father and son with preaxial polydactyly type IV, Fujioka et al. (2005) identified heterozygosity for a nonsense mutation in the GLI3 gene (R290X; 165240.0014). The authors noted that the son also had syndactyly of the third and fourth fingers on his left hand, whereas his father had no abnormalities of his hands, indicating that phenotypic variation may be seen between cases of preaxial polydactyly with identical mutations in GLI3.

Biesecker and Johnston (2005) raised the question of whether there was sufficient phenotypic evidence to rule out a diagnosis of GCPS in the father and son reported by Fujioka et al. (2005). Fujioka and Ariga (2005) noted that Baraitser et al. (1983) had reported that facial features of Greig syndrome can be so mild as to be indistinguishable from normal and had suggested that preaxial polydactyly type IV may be Greig syndrome.