Polydactyly, Preaxial Ii

A number sign (#) is used with this entry because preaxial polydactyly II, triphalangeal thumb-polysyndactyly syndrome, and isolated triphalangeal thumb are all caused by heterozygous mutation in an SHH (600725) regulatory element (ZRS) that resides in intron 5 of the LMBR1 gene (605522) on chromosome 7q36.

Clinical Features

The thumb in this malformation is usually opposable and possesses a normal metacarpal. This form of polydactyly consists of duplication of the distal phalanx, giving a 'duck-bill' appearance. Reported families include the second in the paper by Haas (1939), and those described by Atwood and Pond (1917), Hefner (1940) and Ecke (1962). The proband of a family studied by Temtamy and McKusick (1978) had opposable triphalangeal thumbs, all 3 phalanges being well developed, and duplication of the great toes. The trait had passed through at least 6 generations.

Merlob et al. (1985) described a kindred in which persons in 4 and perhaps 5 generations had opposable triphalangeal thumbs associated with duplication of the great toe. They reviewed syndromes with triphalangeal thumbs and reemphasized the significant distinction between the opposable (true triphalangeal) and nonopposable (finger-like) thumb. The latter condition may require surgical pollicization for satisfactory function.

Radhakrishna et al. (1993) described a very extensive family from a village in the Rajkot district of Gujarat in India in which many members in 5 generations showed preaxial polydactyly with a well-formed extra digit, triphalangeal thumbs, and duplication of the big toes. They observed that 'the extra digit was functional and flexed like a normal finger.' Ray (1987) reported a large family from another area of India, Andhra Pradesh, with preaxial polydactyly and, in some persons, bilateral duplication of the big toe. Since the thumb was not triphalangeal, this may have been a different entity (174400).

Nicolai and Hamel (1988) described a large family in which multiple members exhibited a spectrum of pre- and postaxial anomalies of the limbs inherited as an autosomal dominant. In another study of this family, Tsukurov et al. (1994) found that the hand malformations were typically bilateral but usually asymmetric. Both pre- and postaxial polydactyly and syndactyly were present. In all affected individuals the thumb was triphalangeal and the index finger was normal. Malformations of the feet were present in some affected persons but were usually less severe than those observed in the hands. Variable expression of the disease gene was demonstrated by asymmetries in limb deformities of affected individuals and the differences observed between monozygotic twins.

Heutink et al. (1994) studied 2 large Dutch kindreds from 'a relatively isolated population' with an estimated prevalence of triphalangeal thumb of 1 in 1,000. Within the families the expression of thumb anomalies was highly variable and ranged from an opposable thumb with a delta phalanx to an extreme form of preaxial polydactyly with a triphalangeal index finger instead of a thumb, 2 extra hypoplastic rays radial to the 'thumb' (septadactyly), hypoplastic thenar muscles, and, occasionally, syndactyly between the fourth and fifth rays. The description suggested that of preaxial polydactyly II. Temtamy (1994) pointed out that dermatoglyphics can help differentiate preaxial polydactyly of a triphalangeal thumb from preaxial polydactyly of an index finger. A duplicate of the 'a' triradius and line is present in the latter. Zguricas et al. (1994) reported the phenotypic features of the families studied by Heutink et al. (1994).

Seidman (1994) indicated that polyphalangy seemed to be the most consistent feature in the families reported by Tsukurov et al. (1994) and Heutink et al. (1994); that the same haplotype was found in affected members of all 3 families, suggesting founder effect; and that a genealogic connection had been established between the 2 Dutch families. Hing et al. (1995) likewise cited evidence that further genealogic investigation of the kindreds described by Heutink et al. (1994), combined with haplotype analysis, demonstrated that they are part of a very large Belgian family and are probably carrying the same mutation.

Balci et al. (1999) described a Turkish family with triphalangeal thumb-polysyndactyly syndrome. Characteristic findings in this family were triphalangeal thumb, webbing between third, fourth, and fifth fingers associated with bony synostosis in the distal phalanges of the same fingers, and pre- and postaxial polysyndactyly of the feet. Some affected members of the family showed a more severe phenotype with complete syndactyly of all fingers giving a 'cup-like' appearance to the hands.

Kantaputra and Chalidapong (2000) reported a Thai man with triphalangeal thumb-polysyndactyly syndrome whose daughter had tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome (188740). The authors proposed that these conditions are actually the same disorder with wide variability. They suggested this condition be called 'tibial hemimelia-polysyndactyly-triphalangeal thumbs syndrome.'

Klopocki et al. (2008) described a large 4-generation family segregating an autosomal dominant phenotype comprising triphalangeal thumbs, preaxial and/or postaxial synpolydactyly, and cutaneous/osseous syndactyly of fingers III-V or IV/V. The phenotype varied among affected individuals, and the latter features occurred either in isolation or in combination. In general, the feet were less severely affected than the hands. There were no other organ anomalies or dysmorphic features.

Semerci et al. (2009) reported a large partially consanguineous 3-generation Turkish family in which 22 individuals had triphalangeal thumb-preaxial polydactyly syndrome affecting only the hands. Eleven individuals were evaluated clinically. There was some intrafamilial variability: all had 3 phalanges in the thumb and 6 metacarpals. Three had triphalangism in an extra digit. Other affected members had an extra hypoplastic digit with 2 phalanges. Molecular analysis identified a heterozygous mutation in the ZRS of intron 5 of the LMBR1 gene (605522.0012). One affected individual was homozygous for the mutation, born of consanguineous affected parents, but did not have a more severe phenotype.

Mapping

In the family originally reported by Nicolai and Hamel (1988), Tsukurov et al. (1994) found linkage of the malformation to a highly polymorphic locus containing a short tandem repeat sequence (STR), D7S550, located at 7q36; maximum lod score = 6.85 at theta = 0.0. This region is homologous to a segment of mouse chromosome 5 where 2 nonallelic mutations, 'hammer-toe' (Hm) and 'hemimelic extra toes' (Hx), have been mapped.

In 2 large Dutch kindreds, Heutink et al. (1994) studied the transmission and linkage relationships of triphalangeal thumb. Using microsatellite DNA polymorphisms, they demonstrated that the locus, which they symbolized TPT, maps near the telomere of 7q. The combined maximum lod score for the 2 families was 12.61 at theta = 0.0 with marker D7S559.

Hing et al. (1995) used the designation preaxial polydactyly type II for the disorder they studied in a 6-generation North American Caucasian kindred of presumed English descent. They demonstrated linkage to the 7q36 region and identified a submicroscopic chromosomal deletion segregating with the phenotype, which they symbolized PPD2. Comparison of the haplotypes in this kindred with those in the previously described ones yielded evidence of an independent mutational event. The chromosomal deletion was demonstrated by absence of a parental allele or loss of heterozygosity for the D7S594 marker in PPD2 individuals. To facilitate mapping the boundaries of the chromosome 7 deletion, Hing et al. (1995) constructed human/rodent hybrid cell lines to segregate the human chromosome 7 containing the PPD2 allele (an apparent deletion) from the normal chromosome 7 allele. They concluded that the deletion was in-phase with the anomalous phenotype (and the causative mutation) but not causative of the abnormality.

Zguricas et al. (1999) reported linkage analysis of 12 families of different ethnic origin with preaxial polydactyly. The 2 Dutch families reported by Heutink et al. (1994) and Zguricas et al. (1994) were supplemented by 7 additional Dutch families, a British family, a Turkish family, and 2 Cuban families, 1 of which (Cuban family A) exhibited tibial aplasia in addition to preaxial polydactyly and triphalangeal thumbs (see 188740). Eleven of the kindreds investigated were found to be linked to chromosome 7q36, and haplotype analysis showed recombination events with markers D7S550 and D7S2423, reducing the critical region to 1.9 cM.

Heus et al. (1999) constructed a detailed physical map of the candidate region for this form of preaxial polydactyly. They used a combination of methods to identify and position 11 transcripts within this map. By recombination analysis on families with preaxial polydactyly, they reduced the candidate region to approximately 450 kb. Mapping to the refined candidate region were the homeobox gene HLXB9 (142994), a putative receptor (LMBR1; 605522), and 2 transcripts of unknown function. All 4 transcripts were analyzed and sequenced in patients with preaxial polydactyly, but no pathogenic mutations were identified.

In a Turkish family with triphalangeal thumb-polysyndactyly syndrome, Balci et al. (1999) found linkage of the disorder to 7q36.

Dobbs et al. (2000) performed linkage analysis in 2 Iowa kindreds with triphalangeal thumb and found a maximum lod score of 6.23 at marker D7S559 on chromosome 7q36.

In a Chinese family segregating triphalangeal thumb-polysyndactyly syndrome, Wang et al. (2007) identified a 1.7-cM candidate region between markers D7S2465 and D7S2423.

Molecular Genetics

Lettice et al. (2003) showed that chromosome 7q36-associated preaxial polydactyly II results from point mutations in an SHH (600725) regulatory element. SHH, normally expressed in the zone of polarizing activity (ZPA) posteriorly in the limb bud, is expressed in an additional ectopic site at the anterior margin in mouse models of PPD. Lettice et al. (2003) identified an enhancer element that drives normal SHH expression in the ZPA. The regulator, designated ZPA regulatory sequence (ZRS), lies within intron 5 of the LMBR1 gene, 1 Mb from the target gene SHH. The ZRS contained point mutations that segregated with polydactyly in 3 unrelated families with PPD2 (605522.0002, 605522.0004, and 605522.0005) and in 1 family with tibial hypoplasia with polydactyly (see 188740 and 605522.0003) as well as in the Hx mouse mutant.

Gurnett et al. (2007) studied 4 families with triphalangeal thumb and preaxial polydactyly, 2 of which were previously reported by Dobbs et al. (2000), and identified 2 mutations in 3 families (605522.0007 and 605522.0008, respectively). At least 1 affected member in each of the 3 families with mutations had preaxial polydactyly in addition to triphalangeal thumb; the affected mother and son in the fourth family had only triphalangeal thumb. A genotype/phenotype correlation was suggested by the 5-generation family, which showed reduced penetrance with 4 unaffected carriers who had affected offspring, and a milder phenotype with 18 of 19 affected members manifesting only triphalangeal thumb.

In 9 affected members of a large 4-generation family segregating autosomal dominant triphalangeal thumb-polysyndactyly syndrome, Klopocki et al. (2008) identified heterozygosity for a 589-kb duplication encompassing the ZRS in the LMBR1 gene (605522.0009). The duplication was not found in 6 clinically unaffected family members.

In 5 Han Chinese families with triphalangeal thumb-polysyndactyly syndrome (TPT-PS), some of which also had features of syndactyly type IV (186200), Sun et al. (2008) identified heterozygous duplications involving the ZRS, ranging from 131 kb to 398 kb (see, e.g., 605522.0006 and 605522.0010). Using quantitative PCR assays, the authors defined a common overlapping segment of 32,757 bp, which contains the ZRS enhancer. The duplications cosegregated with the limb phenotype in all 5 families and were not found in unaffected family members or in 50 unrelated Han Chinese controls. One of the families with TPT-PS had been previously studied by Wang et al. (2007) and found to have a point mutation (see 605522.0006) in intron 5 of the LMBR1 gene. Sun et al. (2008) suggested that the point mutation might represent a rare polymorphism.

Furniss et al. (2008) identified a mutation in the ZRS (295T-C; 605522.0011) in the LMBR1 gene in 3 unrelated probands from southern England with bilateral triphalangeal thumb, 1 of whom also had unilateral preaxial polydactyly. The mutation was found in heterozygous state in all affected individuals except for the mother of 1 proband, who was homozygous for the mutation, and it was also detected in 4 unaffected obligate carriers and 1 unaffected individual at 50% prior risk; it was not found in 381 ethnically matched controls. Analysis of the 3 pedigrees demonstrated a common haplotype at 4 flanking microsatellite loci, indicating a likely founder effect for the 295C allele. Furniss et al. (2008) concluded that 295T-C is a dominant mutation with reduced penetrance and is a common cause of triphalangeal thumb in southern England.

In the proband of the Turkish family with triphalangeal thumb-polysyndactyly syndrome mapping to chromosome 7q36 that was originally studied by Balci et al. (1999), Wieczorek et al. (2010) used a qPCR technique for CNV detection and identified a duplication involving the LMBR1 gene, including the ZRS region, that was subsequently detected in 8 affected family members but was not present in unaffected family members or in 35 Turkish controls. The 276-kb duplication was designated arr7q36.3(156,061,302x2,156,088,827-156,354,638x3,156,354,579x2). 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 members of 2 unrelated French families with preaxial polydactyly II, Albuisson et al. (2011) identified 2 different heterozygous mutations in the ZRS region of the LMBR1 gene (297G-A; 605522.0013 and 334T-G; 605522.0014, respectively) that occurred in highly conserved nucleotides within predicted binding sites for the transcription factors SOX9 (608160) and PAX3 (606597), respectively. The mutations were fully penetrant in both families. In mouse, both Sox9 and Pax3 are concomitantly expressed with Shh in the embryonic developing limb bud at the time of digit patterning. Albuisson et al. (2011) suggested that SOX9 and PAX3 may regulate SHH from the ZRS.

VanderMeer et al. (2014) studied 2 large unrelated 5-generation Mexican kindreds segregating autosomal dominant triphalangeal thumb and and/or preaxial polydactyly. In the first family, 31 affected individuals had isolated triphalangeal thumb, 14 had preaxial polydactyly with triphalangeal thumbs, and the proband had tibial and radioulnar hypoplasia with preaxial polydactyly of the hands and feet as well as short triphalangeal thumbs. In the second family, 6 affected individuals had isolated triphalangeal thumbs, 2 had preaxial polydactyly, 2 had preaxial polydactyly and triphalangeal thumbs, and 2 had mild radioulnar synostosis. In both families, affected individuals were heterozygous for a point mutation in the ZRS region of LMBR1 (c.402C-T; 605522.0021) except for the more severely affected proband in the first family, who was homozygous for the mutation, suggestive of a dosage effect.