Synpolydactyly 1

A number sign (#) is used with this entry because of evidence that synpolydactyly-1 (SPD1) is caused by heterozygous mutation in the HOXD13 gene (142989) on chromosome 2q31. Some more severely affected individuals are homozygous for mutations in HOXD13.

Description

Synpolydactyly (SPD), or syndactyly type II, is defined as a connection between the middle and ring fingers and fourth and fifth toes, variably associated with postaxial polydactyly in the same digits. Minor local anomalies and various metacarpal or metatarsal abnormalities may be present (summary by Merlob and Grunebaum, 1986).

In some families with SPD, the foot anomalies are characterized by preaxial as well as postaxial polydactyly, and appear to be fully penetrant. The more severe features of classic SPD, involving 3/4 synpolydactyly in the hands and 4/5 synpolydactyly in the feet, also occur, but at reduced penetrance. This foot phenotype is not seen in patients with classic SPD due to HOXD13 polyalanine tract expansions (Goodman et al., 1998).

Malik (2012) reviewed the syndactylies, noting that the extreme phenotypic heterogeneity observed in SPD families consists of approximately 18 clinical variants that can be 'lumped' into 3 categories: typical SPD features, minor variants, and unusual phenotypes.

Genetic Heterogeneity of Synpolydactyly

See also SPD2 (608180), caused by mutation in the fibulin-1 gene (FBLN1; 135820) on chromosome 22q13, and SPD3 (610234), which has been mapped to chromosome 14q11.2-q12.

Nomenclature

In their review of synpolydactyly, Malik and Grzeschik (2008) listed the many designations given to the various facets of the same heterogeneous condition, including syndactyly Vordingborg type; zygodactyly, syndactyly, and polydactyly; syndactyly type A2; syndactyly type II; novel foot malformation; atypical synpolydactyly; variable hand but consistent foot malformation; and hypoplastic synpolydactyly. Malik and Grzeschik (2008) stated that this situation indicated a general lack of consensus in the recognition and naming of this phenotype by clinicians and geneticists, and noted that Zhao et al. (2007) had proposed the term 'HOXD13 limb morphopathies' to represent the spectrum of limb disorders caused by HOXD13 mutations.

Clinical Features

Thomsen (1927) described an extensive pedigree in which 31 males and 11 females in 7 generations had syndactyly type II. Other kindreds were reported by Alvord (1947) and Pipkin and Pipkin (1946) among others. Cross et al. (1968) observed a kindred with 27 affected persons. Two persons transmitted the trait without showing any effects themselves. All persons with clinically evident malformation in the hand showed anomalous palmar dermatoglyphics. No linkage with any of 12 loci was demonstrable. An excess of affected males has been a consistent feature. Cross et al. (1968) found, in the literature and in their kindred, 133 females and 174 males affected. The 'original' case of Fabry disease (301500) reported by Anderson (1898) had this anomaly: 'The fingers of both hands are contracted at the middle and distal phalanges of the fourth finger on each hand are duplicated, the two digits being enclosed in one cutaneous investment....his mother and sister, and three out of four of his children, had congenital deformities like his own.' Merlob and Grunebaum (1986) found the anomaly in 16 persons in 6 generations of a family.

Camera et al. (1995) described a family with 8 affected members in 4 generations. There were at least 3 instances of male-to-male transmission. Aplasia/hypoplasia of the middle phalanges of the toes was also noted. Camera et al. (1995) suggested that this anomaly is a frequent manifestation of synpolydactyly. No other major skeletal or extraskeletal manifestations were present.

In an extensive Turkish kindred, Sayli et al. (1995) observed (or obtained information on) 182 persons with synpolydactyly distributed over 7 generations. Founder effect accounted for this extensively affected kindred originating from the village of Derbent, Afyon. The inheritance was autosomal dominant with variable expressivity and an estimated penetrance of 96%. Penetrance differed between the upper (96%) and lower (69.5%) limbs. The sex ratio was equal. Four different phenotypes were observed in various branches of the Derbent kindred: (1) subjects presenting typical features of SPD; (2) subjects exhibiting both pre- and post-axial polydactyly; (3) persons manifesting postaxial polydactyly type A (174200); and (4) subjects born to 2 affected parents and apparently homozygous for the mutation resulting in severe hand and foot deformities previously described in SPD families. A total of 27 affected offspring were born to couples of whom both were affected. In 7 of them the phenotype was very severe, consistent with homozygosity (Akarsu et al., 1995).

Akarsu et al. (1995) described the clinical features of the homozygous individuals in the kindred reported by Sayli et al. (1995): (1) short hands with wrinkled fatty skin and short feet; (2) complete soft tissue syndactyly involving all 4 limbs; (3) polydactyly of the preaxial, mesoaxial, and postaxial digits of the hands; (4) loss of the normal tubular shape of the carpal, metacarpal, and phalangeal bones, resulting in polygonal structures; (5) loss of the typical structure of the cuboid and all 3 cuneiform bones while the talus, calcaneus, and navicular bones remained intact; (6) large bony islands instead of metatarsals, most probably because of cuboid-metatarsal and cuneiform-metatarsal fusions; and (7) severe middle phalangeal hypoplasia/aplasia as well as fusion of some phalangeal structures that are associated with the loss of normal phalangeal pattern. Three subjects with this phenotype from 3 different branches of the large SPD pedigree exhibited the same phenotype with minimal variation. Akarsu et al. (1995) stated that the polysyndactyly (Ps) mutation in mice shows a pattern of synpolydactyly very similar to that of human SPD and may be a homologous mutation.

Muragaki et al. (1996) examined 3 families with manifestations of SPD. In 2 families there were typical manifestations of SPD. In 1 family, in which the mother and father were first cousins, the mother had typical manifestations of SPD, but her daughter showed a somewhat different and more severe phenotype in that the hands and feet were very small, the digits were very short, and fusion of digits 3, 4 and 5 occurred. The metacarpals and metatarsals were very short and the carpal bones were abnormal. Muragaki et al. (1996) suggested that this individual was homozygous and that 1 of her parents was a nonpenetrant heterozygote.

Al-Qattan (2011) reported 2 families with synpolydactyly exhibiting intrafamilial variability. In the first family, in which the parents were unrelated, a mother and 3 children were affected. All affected individuals had normal feet, and 1 child had isolated synpolydactyly of the little finger of the left hand, concurrent with synpolydactyly of the third web in the right hand. In the second family, the parents were first cousins and the family had a several-generation history of synpolydactyly. Both parents had isolated clinodactyly of the little finger, and 4 of their 6 children were affected: the 2 boys had bilateral involvement of their hands and feet, with severe brachydactyly and hypoplasia of the middle phalanges, polygonal ulnar metacarpals as well as some metatarsals, bilateral accessory carpal and tarsal bones, bilateral thumb clinodactyly, and tarsometatarsal fusion. The 2 girls had only hand involvement, with 1 hand showing the classic synpolydactyly of the third web and the other showing only syndactyly; both also had bilateral clinodactyly of the little fingers. Al-Qattan (2011) reviewed and tabulated reported variations of familial synpolydactyly and concluded that such variations are common. (Al-Qattan (2011) referred to this disorder as 'synpolydactyly type II.')

Brison et al. (2012) studied an affected mother and son from a consanguineous Pakistani family with SPD1. The mother exhibited only fifth-finger camptodactyly and discrete shortening and external rotation of the fourth and fifth toes, whereas her son was born with severe bilateral hand and foot anomalies. He had bilateral cutaneous and osseous syndactyly between the third and fourth fingers and absent or rudimentary nails in the syndactylous web and in the right fifth finger. Radiography revealed a complex type II SPD showing clinical overlap with brachydactyly types A1 (BDA1; 112500) and B (see 113000). He also had broadening of the left metacarpals, a supernumerary digit in the syndactylous web that was fused to the third digit, and bilateral osseous fusions of the distal phalanges. All fingers were short, with small or absent middle phalanges and a rudimentary distal phalanx of the first finger of the right hand. His feet had short, medially deviated halluces, and there was plantar flexion of the syndactylized mass of the fourth and fifth toes. Brison et al. (2012) concluded that affected members of this family exhibited some of the classic features of SPD as well as frequently associated minor variants such as camptodactyly and clinodactyly, but also showed signs of overlap with brachydactyly type B, since the proband displayed rudimentary or hypoplastic distal phalanges and absent or underdeveloped nails.

Dai et al. (2014) reported 2 multigenerational Chinese families with what the authors designated as 'syndactyly type 1-c.' One was a 5-generation family in which 14 of 19 affected individuals examined had complete bilateral webbing of the third and fourth fingers, with fusion of the nails, and normal feet. In addition, there were 2 patients with unilateral cutaneous 3/4 webbing of the fingers, 1 patient with a mild SPD phenotype of the hands with normal feet, and 2 patients with an atypical abnormality of the feet but no hand anomalies. In an unrelated 3-generation Chinese family, 5 of 7 affected individuals had complete bilateral 3/4 webbing of the fingers with normal feet, 1 of whom also had fifth-finger clinodactyly. Another patient had unilateral 2/3 webbing of the fingers with normal feet, and 1 affected family member had unilateral 4/5 synpolydactyly of the toes and unilateral cutaneous 3/4 webbing of the fingers. Dai et al. (2014) tabulated the clinical features of reported patients with HOXD13 mutations, and concluded that 'HOXD13 limb morphopathies' was the most appropriate term to represent the continuum of phenotypes observed in those patients.

Mapping

Sarfarazi et al. (1995) used 62 meioses from the kindred reported by Sayli et al. (1995) and Akarsu et al. (1995) to map the SPD locus to 2q31, approximately 1.7 cM (lod score = 12.96) centromeric to a HOXD8 (142985) intragenic marker. They speculated that a mutation in a member of the HOXD cluster is a likely site for the SPD mutation. A single recombinant with HOXD8 excluded the most 3-prime end of the HOXD cluster as the site for SPD, but a mutation in the 5-prime end of the HOXD cluster, especially in HOXD13 (142989), EVX2 (142991), or DLX2 (126255)/DLX1 (600029) was not excluded.

Using linkage analysis, Muragaki et al. (1996) showed that the SPD region is closely linked to the HOXD region on chromosome 2q31-q32.

Molecular Genetics

Muragaki et al. (1996) selected 3 possible candidate genes for SPD in the HOXD region on chromosome 2q31-q32 on the basis of their expression in the distal limb bud. Sequencing of the homeodomains of the 3 genes, each of which was located at the 3-prime end of the gene, revealed no abnormalities. Sequencing of the 5-prime gene regions revealed that the HOXD13 protein contains 2 serine stretches and 1 alanine stretch. Amplification of the gene region encoding the alanine stretch showed an additional larger band in the affected individuals in all 3 pedigrees. Muragaki et al. (1996) noted that the mutation found in these pedigrees did not disrupt an evolutionarily conserved domain.

Akarsu et al. (1996) reported results of analysis of the HOXD13 gene in the family studied by Sayli et al. (1995). Through direct comparison of DNA sequences at the 5-prime end of the HOXD13 gene in normal and homozygous affected individuals, Akarsu et al. (1996) identified a 27-bp duplication (142989.0001) of the normal sequences that encode for a polyalanine tract in the affected individuals. In normal individuals, a stretch of 15 alanine residues were identified 145 bp downstream from the initiation codon. Homozygous affected individuals had a total of 24 polyalanine residues. Akarsu et al. (1996) identified 2 affected individuals who had the polyalanine duplication described above and who were recombinant at the HOXD13 CA repeat. In these 2 individuals, there was therefore a recombination event within a 1.5-kb region between the HOXD13 CA repeat and the HOXD13 polyalanine duplication. Akarsu et al. (1996) documented nonpenetrance of this disorder. In their haplotype analysis of 2 Turkish families with 169 members (105 affected) they noted that 164 expressed the disorder phenotypically as predicted by their genotype. Gene expression was approximately 97%; 3% of individuals were gene carriers who did not express the defect.

In a study of affected individuals from the large family with syndactyly type II originally described by Thomsen (1927), Kjaer et al. (2002) detected a 9-triplet polyalanine expansion within HOXD13 (142989.0001). The phenotypic spectrum in mutation carriers ranged from severe to inapparent bone malformations detected only by examination of dermatoglyphics. Kjaer et al. (2005) restudied the kindred reported by Thomsen (1927) and demonstrated that the duplication of 27 bp in the HOXD13 gene extended the polyalanine coding repeat from 15 to 24 residues. They also found the 27-bp duplication in 2 other Danish families.

In their Figure 3, Goodman et al. (2002) diagrammed the cluster of HOXD genes extending from HOXD1 at the telomeric end to HOXD13 at the centromeric end. EVX2 (142991) is located at the centromeric side of HOXD13, and farther centromerically there are 7 regulatory elements, designated R1 to R7, counting from the telomeric end toward the centromere. Goodman et al. (2002) reported a father and daughter with synpolydactyly who carried a 117-kb microdeletion at the 5-prime end of the HOXD cluster. They showed that the microdeletion removed only HOXD9 (142982) through HOXD13, extending centromerically to include the EVX2 gene, the 7 regulatory elements, and part of a LINE-1 element at the centromeric end. They also reported a girl with bilateral split foot and a chromosome deletion that included the entire HOXD cluster and extended approximately 5 Mb centromeric to it. These findings indicated that haploinsufficiency for the 5-prime HOXD genes causes not split-hand/foot malformation (SHFM; see 183600) but SPD. The deletion in the girl with SHFM was related to a novel locus for SHFM, SHFM5 (606708), in the 5-Mb interval centromeric to EVX2.

Goodman et al. (1998) described 2 families with features of classic synpolydactyly in the hands and feet as well as a novel foot phenotype. All carriers of 1 of 2 deletion mutations in the HOX13 gene (see 142989.0002 and 142989.0003) had a rudimentary extra digit between the first and second metatarsals and often between the fourth and fifth metatarsals as well. Kan et al. (2003) described a family in which a typical synpolydactyly phenotype was absent in the hands and the foot anomaly was similar to that described by Goodman et al. (1998). A deletion in an acceptor splice site was found in the HOXD13 gene (142989.0006).

Fantini et al. (2009) described a Greek family with syndactyly type II, fifth finger campto-clinodactyly, and occasional fifth toe camptodactyly, wherein affected family members were heterozygous for a mutation (G220V; 142989.0011). The authors concluded that the G220V mutation did not produce a dominant-negative effect or a gain-of-function, but represented a dominant loss-of-function mutation revealing haploinsufficiency of HOXD13.

Kurban et al. (2011) studied a large consanguineous Pakistani family with SPD1, in which 10 of 16 affected individuals examined had a typical SPD1 phenotype, whereas the remaining 6 patients showed a milder phenotype, restricted to the toes and consisting mainly of 2/3 or 4/5 webbing. The authors obtained a significant nonparametric linkage analysis score (Z = 3.15) at chromosome 2q22.3-q34, and microsatellite mapping identified a common haplotype that overlapped the HOXD13 gene for which the 10 severely affected family members were homozygous. Direct sequencing of HOXD13 revealed homozygosity for a nonsense mutation (Q248X; 142989.0013) in all 10 individuals with severe SPD; 12 more family members were heterozygous, of whom 6 were affected and exhibited the milder SPD phenotype. Kurban et al. (2011) stated that this was the first report of a nonsense mutation in the HOXD13 gene causing a severe form of SPD in the homozygous state, and a milder form of SPD with approximately 50% penetrance in the heterozygous state. In a mildly affected mother and severely affected son from a consanguineous Pakistani family with SPD1, Brison et al. (2012) identified heterozygosity and homozygosity, respectively, for a missense mutation in the HOXD13 gene (G11A; 142989.0014). The mother exhibited only fifth-finger camptodactyly and discrete shortening and external rotation of the fourth and fifth toes, whereas her son was born with severe bilateral hand and foot anomalies. Brison et al. (2012) noted that in addition to the classic features of SPD and associated minor variants, the phenotype in this family showed signs of overlap with brachydactyly type B, since the proband displayed rudimentary or hypoplastic distal phalanges and absent or underdeveloped nails.

Xin et al. (2012) studied 7 affected members of a 5-generation Chinese family with SPD due to a heterozygous 8-ala expansion of the HOXD13 polyalanine tract. The 24-bp duplication was not found in unaffected family members or in 50 controls. Affected members of the younger generation exhibited a less severe phenotype than members of the older generations, and the authors suggested that the variable phenotypic expressivity might be due to genetic or environmental modifiers.

In 6 affected individuals from a 2-generation Chinese family with a variant form of mild SPD, Wang et al. (2012) identified heterozygosity for a missense mutation in the HOXD13 gene (R298Q; 142989.0015) that was not found in 2 unaffected family members or in 136 controls. The authors stated that the most distinctive manifestation of this mutation was bilateral clinodactyly of the second finger, seen in 3 of the 6 patients, 1 of whom also exhibited bilateral clinodactyly of the second toe.

In 5 affected members of a 4-generation Chinese family with SPD and cortical bone thinning of the proximal phalanges, Shi et al. (2013) identified heterozygosity for a splice site mutation (142989.0016) that was not found in 3 unaffected family members or in 60 ethnically matched controls. Shi et al. (2013) reviewed published x-ray films from 5 unrelated SPD1 families exhibiting foot anomalies (Calabrese et al., 2000; Debeer et al., 2002; Goodman et al., 1998; Goodman et al., 2002; Kan et al., 2003), and noted that all family members with broad hallux had a cortical shell of the proximal phalanges of the foot that became thinner as the proportion of cancellous bone increased. Shi et al. (2013) suggested that cortical bone thinning might be another cardinal foot feature of the atypical form of SPD1.

Zhou et al. (2013) reported a 3-generation Chinese family in which 4 of 5 affected individuals had bilateral 3/4 finger webbing and fifth finger clinodactyly, whereas 1 patient had 2/3/4 finger webbing; all had normal feet. Analysis of HOXD13 revealed that all affected members of the family were heterozygous for a missense mutation outside of the homeobox domain (G220A; 142989.0017).

In 2 unrelated multigenerational Chinese families in which affected individuals exhibited features of synpolydactyly and were known to be negative for mutation in the GJA1 gene (121014) and ZRS region (see 605522), Dai et al. (2014) sequenced the HOXD13 gene and identified 2 different heterozygous mutations at the same residue: R306Q (142989.0015) in the 5-generation family, and R306G (142989.0019) in the 3-generation family. Dai et al. (2014) noted that both mutations altered the highly conserved R31 residue in the homeodomain, and that these patients exhibited different features from the patients previously reported with mutations at R31 by Debeer et al. (2002) (see 142989.0007) and Wang et al. (2012) (see 142989.0015).

Genotype/Phenotype Correlations

Malik and Grzeschik (2008) reviewed all the clinical variants occurring in 32 well-documented synpolydactyly families and noted that, based on cases of SPD associated with HOXD13 mutations reported to that time, straightforward genotype/phenotype correlation was weak.

Brison et al. (2014) reviewed reported patients with HOXD13 mutations and concluded that the complexity of the clinical phenotype in SPD patients, as well as the overlap with other limb deformities, severely limits the interpretation of the genotype-phenotype relationship. In addition to the clinical heterogeneity of SPD, the reduced penetrance may also compromise genetic analysis and may have implications for risk estimation and genetic counseling.

Animal Model

Zakany and Duboule (1996) used embryonic stem cells and a site-specific recombination system to induce a mutation that eliminates the products of mouse Hoxd13, Hoxd12 (142988), and Hoxd11 (142986) genes simultaneously. They reported that mice homozygous for this deficiency showed small digit primordia, a disorganized cartilage pattern, and impaired skeletal mass. They noted that these alterations are similar to the defects seen in human synpolydactyly. Zakany and Duboule (1996) suggested that this syndrome, which is associated with a subtle mutation in human HOXD13, may involve the loss of function of several HOXD genes. They noted further that their studies have provided an animal model to study human digit malformations.