SD1 is characterized by involvement of the third and fourth finger web space and/or the web between the second and third toes. The most common non-syndromic presentation of syndactyly, it has been described with involvement of other digits and the underlying bones [69]. It is also known under the name zygodactyly.

The phenotype of zygodactyly has been seen to vary. It has been seen to affect the upper or lower limb, both simultaneously and independently. SD1 appears to be inherited only as an autosomal dominant trait. Initial genetic studies localized the 2q34-q36 region of the second chromosome, mapped during studies involving both a large German and a non-related Iranian family [70, 71]. This locus has also been linked to a Philadelphia type of craniosynostosis with associated syndactyly [72, 73].

Mouse studies have shown a chemically induced mutation on the chromosome 6 causes syndactyly of digits 2 and 3 of the hind legs (Sndy Jrt/Sndy +). This varies from simple complete to incomplete phenotype, and although sparing the front limbs appears to correlate well with the characteristics of SD1. The homologous region of this chromosomal mutation in humans would be found on 3p25.1 [74].

Malik et al. [75] postulated that SD1 can be further divided into four subtypes:

They designated the 3p21.31 locus to be specific for this first subtype and named it zygodactyly 1 (ZD1). This appeared to be a new locus for the same phenotype previously described in the German family by Bosse et al. [70].

Synpolydactyly (SPD) is, in terms of both genetic and clinical terms, one of the most heterogeneous malformations of the non-syndromic syndactyly types. It appears to lack penetrance within SPD-affected families, with its typical signs including third and fourth finger syndactyly associated with varying degrees of polydactyly of the fourth finger web space. Polydactyly of the fifth toe is often seen.

SPD has been categorized several times in the literature. There is agreement that SPD is inherited in an autosomal dominant manner. Subtypes have been constructed as new genetic sources have been found.

The Homeobox family of genes were the first group to be acknowledged in relation to Synpolydactyly. Located on the 5′ region of the A- and D-clusters of human chromosomes 7 and 2, respectively, several distinct genes have been recognized [39]. These genes appear to influence limb patterning and of particular interest is the Homeobox D gene (HOXD), and precisely that related to the loci at 2q31 [76].

Following this theory, research into the HOXD13 gene found in one family a relation to polyalanine expansion [77–81]. Specifically, the N terminal region of the protein, involved in binding to DNA, is disturbed. With this there appears to be a correlation between expansion size and the appearance and severity of the SPD phenotype in affected patients, with a greater number of limb involvement seen with increasing expansion size [82]. It has correspondingly been found that minimal duplication does not seem to cause the phenotypical deformity [83]. Since its finding, HOXD13 has been linked with multiple limb deformities including SD5, brachydactyly, and several syndromic forms of syndactyly [84, 85].

The HOXD13 gene link has been supplemented by the discovery that a translocation between Chromosomes 12 and 22 resulting in a defect in the Fibulin gene, normally located on the latter, was found to cause SPD [86, 87]. Debeer and Schoenmakers team published further papers examining this translocation within the FBLN1 gene and localized specific involvement of an area represented by EST R72964, as well as ruling out several previously characterized genes [88].

This finding initially complicated the SPD phenotype, and resulted in the commonly recognized classification SPD 1–3. With this description, SPD 3 correlates to the more classical presentation of SPD and has been linked to the 14q11.2-q12 loci [89].

Likewise, the grouping of phenotype to gene of SPD 2 to the Fibulin 1 gene on Chromosome 12 (MIM 608180) and SPD 1 with Homeobox D13 (MIM 186000) is now widely accepted. SPD2 is generally thought to include synostosis of the metacarpal and metatarsal bones.

A more recent paper [90] has stated that SPD should be sub-classed more specifically relating to phenotype, stating genotype–phenotype correlation is weak when looking only at the HOXD13 mutation. They propose the phenotypic variant being classed as (1) typical SPD features, (2) minor variants, and (3) unusual phenotypes.

A further SPD subtype is described by one paper [91] where a new distinct clinical form involving a complicated and distinctive hypoplastic synpolydactyly was found. This currently does not appear to have been investigated on a genetic basis, and further research into this will help define this new phenotype as a new or mixed entity.

Continuing research has led to other genes being suggested as causative in SPD, although all of these have been found to involve the Shh pathway on one level or another [92].

In syndactyly type III, the typical and first described phenotype involves complete and bilateral syndactyly between the fourth and fifth fingers. This is a soft tissue syndactyly but has been seen with the distal phalanges fused. An absent or rudimentary middle phalanx results in an often seen shorter fifth digit. The feet are generally not affected. Johnston and Kirby [93] presented a family which was one of the largest fully described pedigrees, involving seven affected males and seven affected females over five generations in a pattern compatible with an autosomal dominant inheritance [65].

Other papers to describe SD3 as a single entity, as opposed to as being part of a syndrome include De Smet et al. [94].

Isolated SD3 appears to be in a disease spectrum that includes oculodentodigital dysplasia (ODDD; MIM 164200), which commonly involves digit as well as craniofacial dysmorphia and neurological degeneration [95]. ODDD has complete penetrance but a varying phenotype. Gene research has led to the locus 6q21-q23 being associated with SD3, with significant crossover of the locus 6q22-q24, linked to ODDD, and in particular the Connexin 43 (Cx43) gene and its involvement with the gap junction protein, alpha 1 (GJA1) [96–98].

With six types, it has been found the Connexin family are key in forming gap junctions allowing small molecule and ion passage, with Cx43 being expressed in the developing limb bud and in particular relating to digit and cartilage condensation [99]. Further studies into both the phenotype and genetic regions above have found localized missense mutations causative for ODDD, of which over eight have been described, as well as tested in animal studies [100–104].

Dobrowolski et al. [105] have described ODDD phenotype in specific mutations (131M and G138R) whilst mutations at other points appear to result in no syndactyly (H194P) or solely facial abnormality (G143S). This has led to a belief that increased hemi-channel activity may strengthen ODDD phenotype in Cx43 gap junction deficient patients. Other studies have also confirmed a highly variable phenotype of Cx43 mutations which includes ODDD [106–108].

With only four reports in the literature, syndactyly type IV is rare [109–112].

Haas [109] was first to describe this phenotype, referred to as Haas type polysyndactyly, with the syndactyly described as complete, affecting the fingers of both hands, with associated polydactyly, generally involving six metacarpals and six digits. Flexion of the fingers results in the hands forming a cup shape. In contradistinction to the type of syndactyly in Apert syndrome, there is no bone fusion. In the reports, there is no mention of SD4 affecting the feet, with descriptions noting there were no associated malformations.

Following an autosomal dominant inheritance trait, 7q36 has been mapped as a locus for SD4 [110]. Shh regulation mutations have been found to be key in SD4 [113, 114], with one paper showing an involvement of an area on the limb region 1 (LMBR1) gene being causative [115].

Another rare form of syndactyly, SD5 is as a rule characterized by the presence of an associated metacarpal and metatarsal fusion. The fourth and fifth, or third and fourth, metacarpals and metatarsals are most commonly fused, with soft tissue syndactyly usually affecting the third and fourth fingers and the second and third toes. In this form, the syndactyly tends to be more extensive and complete. In 1932, Kemp and Ravn [116] described this anomaly in five generations of a family from the island of Seeland. Other descriptions without metatarsal fusion have been documented, but these are usually seen with other foot abnormalities [117].

Syndactyly type V has an autosomal dominant trait but has been described as X-linked recessive. Research has linked SD5 to the locus at 2q31-q32 as well as mutations in the HOXD13 gene, including the pathogenicity of a c.950A→G (p.Q317R) mutation [84]. In this paper, the authors called for a genotype classification of HOXD13 limb morphologies, again confusing the genotype-phenotype boundaries of the syndactylies.

Interestingly, as in SPD, evidence of HOXD13 polyalanine expansion has been found in the Seeland family [118].

Also known as mitten hand syndactyly, this form consists of unilateral syndactyly of digits 2–5 [65]. One family has been described with this anomaly, where an autosomal dominant inheritance, but with variable expression and incomplete penetrance, is likely. Tentamy and McKusick included this phenotype in their initial classification but, even since their description, due to its rarity it remains the least researched non-syndromic syndactyly.

In 1967 two brothers with an Apert syndrome-like form of syndactyly were described by Cenani and Lenz [119]. They noted however, that additional features including severe shortening of the ulna and radius with fusion, as well as fusion of the metacarpals and “disorganization” of phalangeal development were present. The feet of both brothers were less severely affected. They identified similar cases reported by Liebenam [120], Borsky [121], and Yelton [122].

Cenani–Lenz syndrome, named after the pair’s description, is a very rare phenotype and has been reported to show an autosomal recessive inheritance. There have been accounts of varying phenotypes, including a description of a patient with features consistent with Cenani–Lenz type but also displaying a severe form of SPD1 [69].

The LRP4 gene has been linked to syndactyly in cattle [123, 124], and it is reported with multiple mutations on Chromosome 11p12-p11.2 to be the causative factor in SD7 [125]. In the study group, two families did not exhibit LRP4 mutations, suggesting further gene involvement. Bachelli et al. found that this is unlikely to be related to the pathways involving Formin or Gremlin expression [126]. A more recent paper suggests a mutation involving the loci of these bmp antagonists can result in a phenotype similar to Cenani–Lenz syndrome [127].

Within the Cenani–Lenz syndactyly group, there appears to be two grossly variant phenotypes: one involving a spoon hand type, and the other an oligodactyly type [128].

Fusion of the fourth and fifth metacarpals is an uncommon presentation of syndactyly. First described by Orel in 1928 [129], it was thought to have an X-linked recessive trait, which has been supported by later papers [130, 131].

An autosomal dominant inheritance has been suggested by Lerch [132] after he found a family with male–male transmission as well as female member being affected.

Xq26 has been suggested as a starting point for analysis, a known mapped area for split-hand/foot malformation (SHFM2), with the gene allocated as MF4 (MIM 309630), although there is general consensus that this syndactyly needs further research before its relationship is fully understood [133].

Type IX, mesoaxial synostotic syndactyly (MSSD) has been described only in two families. The characteristic features consist of complete syndactyly and synostosis of the third and fourth fingers with severe bone reduction in the proximal phalanges, hypoplasia of the thumbs and halluces, aplasia/hypoplasia of the middle phalanges of the second and fifth fingers, and complete or partial soft tissue syndactyly of the toes. Percin initially believed, with family members known to have SD1 trait, this to be a severe form of SD1 having a possible homozygous origin [134].

Malik et al. [135] found similar findings in another family, with an autosomal recessive trait, and ruled out genome candidates at 2q34-q36, 2q31, and 6q22-q23. The previous family had also had HOXD13 and the genome associated with 2q31 disproved as causative by Percin et al. Merging the two families into one study has revealed a likelihood of a causal gene being mapped to chromosome 17p13.3 [67].