What is syndactyly

Syndactyly is one of the most common hereditary limb malformations depicting the fusion of certain fingers and/or toes ¹. The involvement of feet is more frequent than the involvement of hands, and males are affected twice as frequently as females ². Syndactyly appears in the medical literature under several synonyms. For example, adherent fingers ³, fingers coated with common skin ⁴, coherence of fingers ⁵, fingers grown together ⁶, fingers knit together ³, skin fusion, digits in stocking ⁷, fingers stuck together ⁸, symphalanginae, symphalangus syndactylous ⁹, syndactylia, syndactylous ossification ⁹, webbed toes ¹⁰ and zygodactyly ¹¹.

Ambroise Pare (1510–1590) in the sixteenth century described syndactyly as fingers stuck together and polydactyly as superfluous fingers, respectively ⁸. Thus, it was established quite early that webbed fingers are not infrequent, appear in various forms, usually without the involvement of other organ systems but frequently witnessed with extra digits ³. Minor webbing types could be easily overlooked; however, severe types required surgical corrections.

Syndactyly is one of the most common hereditary limb malformations depicting a prevalence of 3–10 in 10 000 births, though higher estimates ranging from 10–40/10 000 have been reported ¹². Syndactyly may occur as an isolated entity or a component of more than 300 syndromic anomalies. Syndactylies exhibit great inter- and intra-familial clinical variability. Even within a subject, phenotype can be unilateral or bilateral and symmetrical or asymmetrical. At least nine non-syndromic syndactylies with additional sub-types have been characterized. Most of the syndactyly types are inherited as autosomal dominant but two autosomal recessive and an X-linked recessive entity have also been described ¹. Whereas the underlying genes/mutations for types II-1, III, IV, V, and VII have been worked out, the cause and molecular basis of the other syndactyly types remain unknown. Despite considerable progress in the understanding of syndactyly at clinical and molecular levels, fundamental questions regarding the disturbed developmental mechanisms leading to fused digits, remain to be answered ¹.

Clinically syndactyly is one of the most heterogeneous developmental deformities known in the medical literature. A number of combinations are possible in which the adjacent fingers and/or toes remain connected by a web. It may be unilateral or bilateral, and symmetrical or asymmetrical. Furthermore, inter- and intra-familial phenotypic variability is quite common. The condition is so variable that the same individual may exhibit asymmetrical phenotypes in the upper and lower, and right and left limbs. Syndactyly can be identified as partial or complete, cutaneous or bony, and involving only the phalanges or further extending up to metacarpal/metatarsal or carpal/tarsal levels, sometimes even proximating the distal end of forearm/foreleg. On the minimal extreme, a milder phenotype may only be recognized by the alterations in interphalangeal creases and peculiarities in dermatoglyphics ¹³.

Syndactyly may segregate as an isolated clinical phenotype. There are at least nine well-characterized syndactylous entities with subdivisions, the majority of which have non-syndromic nature. Most of these entities segregate in Mendelian dominant fashion. However, two autosomal recessive and an X-linked recessive type have also been described. Generally, autosomal dominant phenotypes are rather less severe and demonstrate widely variable expressivity and incomplete penetrances. On the other hand, autosomal recessive syndactylies are clinically more severe with rather consistent phenotypes.

Syndactyly causes

Syndactyly is a failure in the separation of developing digits during organogenesis. Syndactyly may occur as an isolated entity or a component of more than 300 hereditary syndromic malformations ¹ or nonsyndromic, existing as 1 of 9 nonsyndromic forms ¹⁴. Beyond the well-characterized syndactylies that have genetic etiology there are syndactyly types that occur with congenital ring constrictions, that is, acrosyndactyly/pseudosyndactyly ².

New syndromes, genes and causative loci are being found as research continues into congenital hand defects and it appears that each new finding gives as many further avenues for further investigation as answers in this field.

Man et al ¹⁵ conducted a study which reports a probable association with these conditions and maternal smoking and there are suggestions that syndactyly occurrence is associated with lower nutritional and economic status, including increased meat and egg intake whilst pregnant, although more research is required before suggesting these are causative factors ¹⁶.

Syndactyly genetics

The genes involved in syndactyly and polydactyly tend to affect specific bodily regions, including the zone of polarizing activity (ZPA): an area that controls limb structure and positional identity ¹⁷. The zone of polarizing activity (ZPA) disappears by day 44 of embryonic development, after which time the phalanges form.10 Aside from the ZPA, which is on the posterior embryo and produces fibroblast growth factor 8 (FGF8), the apical ectodermal ridge, which is on the dorsal-ventral margin and produces FGF8, also aids in limb development.

The HOX genes, hedgehog pathways [Sonic Hedgehog (SHH) and Indian hedgehog (IHH)], FGFs, bone morphogenetic proteins (BMPs), and cartilage-derived morphogenetic proteins are also involved ¹¹.

Thirty-nine HOX genes exist in humans; the HOXA and HOXD clusters have been associated with syndactyly and polydactyly ¹⁸. Genes within the HOXD cluster and locus chr2q31 seem to be involved in syndactyly ¹⁹: the HOXD13 gene, for example, is linked to syndactyly type V (SD5) and a brachydactyly-syndactyly syndrome ²⁰.

The Sonic Hedgehog (SHH) signaling pathway plays key roles in limb development ²¹. Sonic Hedgehog (SHH) is affected by—or affects—several transcription factors, namely HAND2, GLI3, ALX4, and certain BMP antagonists (formin and gremlin), changes to which have led to syndactyly and polydactyly ¹⁰. If disrupted, as if ZPA activity is impacted, then Sonic Hedgehog (SHH) cannot lead to normal limb development; this often results in syndactyly ²².

The IHH signaling pathway may influence later development, considering its roles in chondrocyte differentiation and ossification ²³. Further, IHH is repressed by fibroblast growth factor (FGF) receptors ²⁴, functioning at a different time than WNTs and FGFs, which are involved in the final stages of mesenchymal ossification ²⁵; later, in the last stage of digit formation, there is down-regulation of gremlin and restriction of FGF8 expression ²⁶.

Wingless-type mouse mammary tumor virus integration sit family members 6 and 10B (WNT6, WNT10B) are involved in the developing limb bud and related to the chr2q35 region [a locus implicated in syndactyly type I (SD1)] ²⁷. BMPs and their antagonist noggin (NOG), when blocked, also lead to syndactyly ²⁸. GLI3 may also contribute ²⁹: it is involved in a range of syndromes, and a GLI3 missense mutation led to syndactyly and polydactyly ³⁰. N-Myc and zinc-finger transcription factors have caused soft-tissue syndactyly in mice ³¹.

Syndactylies and polydactylies also vary in their patterns of inheritance. Most syndactyly types follow autosomal dominant inheritance ³², but SD7 and SD9 are autosomal recessive ³³, and SD5 is X-linked recessive ³⁴. Generally, autosomal dominant phenotypes are less severe with variable expressivity and incomplete penetrance.

Syndactyly classification

The ‘current classification scheme’ of syndactyly is an adaptation and extension of Temtamy-McKusick system by incorporating into it the clinical, genetic, and molecular developments in this field. The syndactyly types identified according to the current classification are described below.

Table 1. Current classification of well-characterized syndactyly types

ID	Type/description	Fingers webbing	Toes webbing	Inheritance	Locus/gene
I-a	ZD1; Zygodactyly; Weidenreich type	Normal	2/3 Toes only	AD	3p21.31
I-b	SD1; Lueken type	3/4 Fingers, cutaneous/bony	2/3 Toes, cutaneous	AD	2q34-q36
I-c	Montagu type	3/4 Fingers only, cutaneous/bony	Normal	AD
I-d	Castilla type	Normal	4/5 Toes only, cutaneous	AD?
II-a	SPD1; Vordingborg type	SPD, mesoaxial (3/4 fingers)	SPD, postaxial (4/5 toes)	AD	2q31; HOXD13
II-b	SPD2; Debeer type	SPD is central and postaxial	Postaxial syndactyly	AD	22q13.3; FBLN1
II-c	SPD3; Malik type	SPD is central	SPD postaxial	AD	14q11.2-q13
III	SDTY3; ODDD; Johnston-Kirby type	4/5 Fingers; fifth finger short	Normal	AD	6q21-q23; GJA1
IV-a	SDTY4; Haas type	All fingers webbed; pre-/post-axial polydactyly, cup-shaped hand	Normal	AD	7q36; ZRS (LMBR1)
IV-b	Andersen-Hansen type	All fingers webbed; pre-/post-axial polydactyly, cup-shaped hand	Variable webbing of toes with polydactyly
V	SDTY5; Dowd type	4/5 Fingers with metacarpals fusion; hypoplastic metacarpals 4/5	Mesoaxial webbing	AD	2q31; HOXD13
VI	Mitten type	2/5 Fingers	2/5 Toes	AD
VII-a	Cenani-Lenz type; spoon-hand type	Total synostotic syndactyly with metacarpals fusion, spoon-head shape	Total synostotic syndactyly with metatarsals fusion	AR	11p12-p11.2; LRP4.
VII-b	Oligodactyly type	Few deformed digits	Variable syndactyly of toes	AD	15q13.3; GREM1-FMN1
VIII-a	Orel-Holmes type	4/5 Metacarpal fusion	Normal	X-R
VIII-b	Lerch type	4/5 Metacarpal fusion	Normal	AD
IX	MSSD; Malik-Percin type	Mesoaxial synostotic syndactyly with phlanageal reduction	Preaxial webbing; distal phalangeal hypoplasia	AR	17p13.3

Abbreviations: SPD = synpolydactyly; AD = autosomal dominant; AR = autosomal recessive

[Source ¹ ]

Figure 1. Syndactyly types – schematic diagrams of syndactyly types (I-a–III).

Footnote: Shaded digits depict cutaneous fusion only, while bony synostosis is represented by black digital elements within the shaded area. The grey digital elements show hypoplastic phalanges or clinodactyly/brachydactyly. The digital elements with amorphous borders symbolize dysplastic bones.

[Source ¹ ]

Figure 2. Syndactyly types – schematic diagrams of syndactyly types (IV-a–IX).

[Source ¹ ]

Syndactyly type I

Of all the known non-syndromic syndactylies, type I syndactyly is one of the most common types. It demonstrates mesoaxial webbing: fusion of third and fourth fingers, and/or second and third toes. Several characteristic phenotypic and genetic variants within this type witnessed in distinct families have led to the suggestion of four subtypes for type I syndactyly ³⁵.

Syndactyly type I-a

Syndactyly type I-a (Weidenreich type; zygodactyly; 2/3 toes syndactyly) is an autosomal dominant entity was originally named zygodactyly by Weidenreich ¹¹. Zygodactyly is a minor and least conspicuous type, and often goes unnoticed in the clinical practice. It has an estimated prevalence of 4 in 10 000 men and accounts for 70% of all non-syndromic syndactyly cases ².

Zygodactyly is characterized by bilateral cutaneous webbing of second and third toes without the involvement of hands (Figure 1). Rarely, other toes are also affected. The phenotype in both feet is usually concordant ³⁶. In its mildest forms, it gives the impression of slight ascent of interdigital web between second and third toes, or it may only be detected by abnormal dermatoglyphics ¹³. In its extreme form, the web reaches up to phalangeal tips, a rather intimate fusion is witnessed at nails, and the second toe depicts varus inclination. First molecular evidence of zygodactyly being a distinct genetic entity was provided by Malik et al ³² by a mapping study on a large Pakistani family. Cosegregation of zygodactyly was shown with ZD1 locus at chromosome 3p21-p31. However, genetic heterogeneity has been suggested from the linkage data of a German kindred ³².

Syndactyly type I-b

Syndactyly type I-b (Lueken type; 3/4 fingers and 2/3 toes syndactyly) subtype is characterized by bilateral webbing of third and fourth fingers, and second and third toes (Figure 1). Finger’s webbing may exhibit osseous fusion in the form of a bony bridge at the phalangeal tips. In more severe cases, additional fingers from second to fifth and toes from first to fifth may be involved. Reduplication of any fused digit is not a characteristic of this type. In the family reported by Lueken, this dominant phenotype was mapped to the SD1 locus at chromosome 2q34-q35 ³⁷.

Syndactyly type I-c

Syndactyly type I-c (Montagu type; 3/4 fingers syndactyly) is a rare autosomal dominant type is characterized by bilateral cutaneous/bony fusion of third and fourth fingers with normal feet (Figure 1) ³⁸. A large Chinese family reported by Hsu ³⁹ had 23 affected subjects demonstrating variable degree of bilateral osseous fusion of third and fourth or third, fourth and fifth fingers. Only one subject also had partial fusion of toes from third to fifth.

Syndactyly type I-d

Syndactyly type I-d (Castilla type; 4/5 toes syndactyly) subtype depicts bilateral cutaneous webbing of fourth and fifth toes (Figure 1) and has been reported to be the second most common type of isolated webbing of toes with a frequency of 0.22 in 10 000 subjects ². Occasionally, the fifth toe is tucked inside the fibular aspects of the fourth toe, and thus any minor form of webbing could be easily overlooked in the clinical practice. This is particularly the case when the fifth toe is disfigured due to faulty footwear. The inheritance pattern and penetrance estimates for this subtype have not been worked out.

Syndactyly type II

Type II syndactyly/SPD (Vordingborg type; 3/4 fingers and 2/3 toes synpolydactyly), a well-described entity, is clinically and genetically one of the most heterogeneous types. The hallmark features of SPD are cutaneous/bony fusion of third and fourth fingers and second and third toes with partial or complete reduplication of a digital ray within the syndactylous web (Figure 1) ⁴⁰. It is the only syndactyly type with a mesoaxial superfluous finger. The extreme phenotypic heterogeneity in SPD families has led to the lumping of all clinical variants (∼18 types) into three categories: (A) typical SPD features; (B) minor variants; and (C) unusual phenotypes ⁴⁰. SPD segregates as an autosomal dominant entity with reduced penetrance. Three SPD loci have been discovered (SPD1-3), however, these entities have not yet been clinically delineated (Table 1) ³⁴. Additionally, detailed clinical and mutation data are available only for SPD1 linked to HOXD13.

Syndactyly type III

Syndactyly type III (Johnston–Kirby type; 4/5 or 3/4/5 fingers fusion) type of syndactyly affects fourth and fifth or third, fourth and fifth fingers (Figure 1). The middle phalanx of the fifth finger is hypoplastic ⁴¹. The fourth finger shows valgus deviation in order to accommodate the webbing with little finger particularly when the fusion is complete ¹³. There is adduction of fused fingers, and the nails of the syndactylyous fingers are fused medially. The fusion may involve a bony bridge at the distal phalanges. The feet are generally unaffected. This type shows an autosomal dominant mode of inheritance with incomplete penetrance.

The fusion of fourth and fifth fingers is, likewise, a feature of ODDD (oculodentodigital dysplasia), which exhibits additional symptoms of eyes, ears, and orofacial region. Schrander–Stumpel et al ⁴² proposed that oculodentodigital dysplasia and pure syndactyly type III are the respective ends of a clinical spectrum as variable expression of a contiguous gene deletion syndrome. Interestingly, molecular studies revealed that type III syndactyly and/or oculodentodigital dysplasia are caused by mutations in GJA1, a pleiotropic gene encoding connexin 43 ⁴³.

Syndactyly type IV

Syndactyly type IV (Haas type; complete syndactyly of all fingers) has a prevalence of 1/300 000 and segregates in an autosomal dominant fashion ². It manifests itself as complete cutaneous fusion of all fingers accompanied by the presence of extra digital pre- or postaxial ray(s) in the web (Figure 2) ⁴⁴. The nails may be fused completely or give an impression of separation by a groove only. Flexion of fingers is limited and the union of contiguous fingers gives the hand a cup-shaped appearance. Phalanges may fuse as a conglomerate mass of bones; however, metacarpal synostosis is absent.

In the literature, at least two variants of type IV syndactyly have been reported: (a) typical Haas type without involvement of feet; and (b) complete fusion of all fingers with variable fusion of all five digits in feet (Table 1) ⁴⁵. Haas type syndactyly has been shown to be allelic to triphalangeal thumb polysyndactyly, which is present at a milder end of phenotype. Both entities are caused by mutations in the ZRS locus at chromosome 7q36 (LMBR1), encompassing a long-range regulator of SHH ⁴⁶.

Syndactyly type V

The hallmark of syndactyly type V (Dowd type; fusion of 4/5 metacarpals) is the fusion of fourth and fifth metacarpals (Figure 2). Additional symptoms may involve shortening of fused fourth and fifth metacarpals, ulnar deviation of fingers from second to fifth, interdigital cleft between third and fourth fingers, camptodactyly of fifth finger, short distal phalanges, and absent distal interphalangeal creases of the affected fingers ⁴⁷. In the feet, there is hyperplasia of first ray/metatarsal, and shortening of metatarsals from second to fifth, resulting in varus deviation of metatarsals and valgus deviation of toes/phalanges. Type V syndactyly is inherited as an autosomal dominant entity, and it has been attributed to a missense mutation in homeodomain of HOXD13 in a Chinese family ⁴⁸.

Syndactyly type VI

Syndactyly type VI (Mitten type; fusion of 2/5 fingers and 2/3 toes). Temtamy and McKusick ¹³ described a family in which the index subject had fusion of fingers from second to fifth in his right hand, whereas distal and terminal phalanges were amalgamated in a knot-like structure (Figure 2). The feet showed syndactyly involving second and third toes. The maternal second cousin also had the same deformity. Other family members, however, showed only webbing between second and third toes without involvement of fingers. An autosomal dominant mode of inheritance with reduced penetrance and variable expressivity has been suggested for this rare type.

Syndactyly type VII

Syndactyly type VII (Cenani–Lenz syndactyly, CLS; severe bony fusion of all digits and deformed hand) is an autosomal recessive entity manifests severe abnormalities of all digital elements. It is characterized by gross disorganization of all bones of hand to such an extent that no phalangeal element is identifiable (Figure 2).41 The carpals, metacarpals and phalanges show irregular synostosis giving an impression of ‘hands-in-stockings’. The anomaly may involve radius and ulna that are either fused, short, or rudimentary resulting in luxation of the radial head and mesomelic shortening of forearm ¹³. Lower limbs show changes similar to upper limbs and certain digital rays may be absent. Additionally, there is rare involvement of craniofacial and nephrological features ⁴⁹.

Harpf et al ³¹ suggested that there exist two grossly different clinical features in Cenani–Lenz type: (a) spoon-head type, and (b) oligodactyly type (Table 1). They also differentiated between consistent and inconsistent feature for Cenani-Lenz syndactyly. Recently, Li et al ⁴⁹ have shown that Cenani-Lenz syndactyly, both spoon-head and oligodactyly types, and with or without kidney malformations are caused by mutations in LRP4 (chromosome 11p11.2), which is involved in Wnt/β-Catenin signaling. Interestingly, another molecular study showed that Cenani–Lenz phenotype with renal defects and hearing loss, and an autosomal dominant Cenani–Lenz-like non-syndromic oligodactyly are caused by genomic rearrangements of GREM1-FMN1 locus on chromosome 15q13.3 ⁵⁰.

Syndactyly type VIII

Syndactyly type VIII (Orel-Holmes type; metacarpals 4/5 fusion; X-linked recessive) is characterized by the fusion of fourth and fifth metacarpals with a marked ulnar deviation of the little finger and with no other abnormality (Figure 2). There are shortened fourth and fifth metacarpals with excessive separation between their distal ends, and inability to bring the affected fingers in parallel to other fingers. Fifth metacarpal is hypoplastic and tri-radii c and d are absent ⁵¹. This entity shows X-linked recessive inheritance.54, 44 However, there is at least one report depicting autosomal dominant segregation for this phenotype (Table 1) ⁵².

Syndactyly type IX

Syndactyly type IX (Malik–Percin type; fusion of 3/4 metacarpals with a reduction of mesoaxial finger, and preaxial syndactyly of toes). Percin et al ⁵³ and Malik et al ⁵⁴ described a consanguineous Turkish and Pakistani family, respectively, in which the affected subjects showed mesoaxial reduction of fingers, osseous synostosis of third and fourth metacarpals culminating into a single digit, malformed thumbs, and hypoplasia and clinodactyly of the fifth finger (Figure 2). In addition, there was preaxial webbing of toes with terminal phalangeal hypoplasia of all toes. Clinically this type is less severe than Cenani–Lenz syndactyly as it is not extending beyond carpals/tarsals, and is not characterized by bizarre arrangement of skeletal elements of hand/foot. This entity segregated in autosomal recessive fashion and was mapped to chromosome 17p13.3 ³⁰.

Syndactyly treatment

The current mainstay for the treatment and management of syndactyly is surgery. The indications in general for hand anomalies run true with syndactyly and include ⁵⁵;

• Functional needs: The degree of function required by the patient; including whether delaying surgery may alter hand function and grip development.
• Aesthetic consideration: The appearance of the deformity and its subsequent effects on psychological and social aspects of the patient’s life.

It must be remembered that surgical intervention is not urgent. Despite this there are age related targets for reconstruction and dependency on the type of anomaly present.

Border digit syndactyly involving the thumb, index and ring fingers is felt to benefit from earlier release, usually between the ages of 6 to 12 months, and should always be released first in multiple digit involvement. The result in delayed surgery can involve deformity of the digit relating to forced flexion, angulation and/or rotation.

Long finger syndactyly usually involves similarly lengthened digits and for this reason is often delayed, and KettleKamp and Flatt ⁵⁶ found results to be better in those aged greater than 18 months, particularly with long term final appearance of the commissure.

Multiple digit involvement, as stated above, should involve in the first instance release of the border digits, with subsequent digit release after a 6-month waiting period. These subsequent releases involve either radial or ulnar sides of a finger as releasing both sides may endanger the digit viability.

It is generally regarded that operative therapy should be done pre-school age. The main reason for this is that interaction with other children whilst having the anomaly is thought to have potentially detrimental affects on the child’s social, functional and psychological development.

The main concern with surgical therapy is the fact that combined circumference of the two normal digits is approximately 1.4 times the circumference of the fused digits. Pre reconstruction it is felt that massaging the skin where the new web space will be constructed facilitates skin loosening and maximises potential soft tissue needed during the procedure.

Full thickness skin grafts are used for soft-tissue coverage in the majority of cases at present, with altering levels of flap use. The choice of flap, and consequent extra need for full thickness graft coverage, appears to be dependant on the surgeon’s preference, with multiple techniques and variances described in the literature. Several other methods have been used, including split thickness grafts ⁵⁷ and tissue expanders ⁵⁸. Both have suffered with less favourable outcomes and increased complications compared to the use of full thickness grafts and have hence failed to establish themselves as alternative techniques. The use of no graft is more common, but this appears only to be of use in mild cases of simple syndactyly.

Follow up should be until skeletal maturity, mainly due to the prevalence of web creep until this age. Complications of all the surgical techniques include web creep, finger deviation (particularly in complex syndactyly) as well as those complications associated with any surgical procedure. The greater the degree of syndactyly, the more need there is for the surgeon to be aware of neurovascular variance and this takes on greater importance in graft and flap survival.

In light of genetic and peri-natal investigations, both these fields have potential for future management input. Ultrasound has allowed earlier diagnosis and this can now be supplemented by genetic review of likely carriers. Constriction bands have been released in-utero allowing a more normal limb development and with minimal scarring ⁵⁹. However, in utero surgery at present is high risk and currently the benefit of operating does not outweigh the risks and associated complications for non-fatal conditions.

The continuing development in both the genetic basis of syndactyly, and the improvement in tissue bioengineering, bodes that in the future both these avenues will expand management options.

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