SYNDACTYLY, TYPE II SYNPOLYDACTYLY WITH FOOT ANOMALIES, INCLUDED
SPD1
SD2a
Synpolydactyly, Vordingborg type
SPD, Vordingborg type
SD2, Vordingborg type
Synpolydactyly, 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 ... Synpolydactyly, 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).
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) ... 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.')
Malik and Grzeschik (2008) reviewed all the clinical variants occurring in 32 well-documented synpolydactyly families and grouped them into 3 categories: typical SPD features, minor variants, and unusual phenotypes. They demonstrated that, based on cases of SPD associated ... Malik and Grzeschik (2008) reviewed all the clinical variants occurring in 32 well-documented synpolydactyly families and grouped them into 3 categories: typical SPD features, minor variants, and unusual phenotypes. They demonstrated that, based on cases of SPD associated with HOXD13 mutations reported to date, straightforward genotype/phenotype correlation is weak.
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 ... 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). Again, a frameshift deletion 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.