European Journal of Human Genetics (2012) 20, 817–824

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REVIEW
Syndactyly: phenotypes, genetics and current classification
Sajid Malik*,1

Syndactyly is one of the most common hereditary limb malformations depicting the fusion of certain fingers and/or toes.
It 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.
Whereas the underlying genes/mutations for types II-1, III, IV, V, and VII have been worked out, the etiology and molecular basis of the
other syndactyly types remain unknown. In this communication, based on an overview of well- characterized isolated syndactylies, their
cardinal phenotypes, inheritance patterns, and clinical and genetic heterogeneities,
a ‘current classification scheme’ is presented. 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.
European Journal of Human Genetics (2012) 20, 817–824; doi:10.1038/ejhg.2012.14; published online 15 February 2012

Keywords: syndactyly; syndactyly classification; clinical heterogeneity; genetic heterogeneity; webbed digits

INTRODUCTION penetrances. On the other hand, autosomal recessive syndactylies are

Syndactyly (Greek Syn¼together; Dactylos¼digit) is a digital malfor- clinically more severe with rather consistent phenotypes.
mation in which adjacent fingers and/or toes are webbed because they In this communication, first a review of classification schemes
fail to separate during limb development. It is one of the most proposed by various authors for syndactyly is given. Then, the ‘current
common hereditary limb malformations depicting a prevalence classification’ is presented, which is a revised and extended version
of 3–10 in 10 000 births, though higher estimates ranging from 10– of the scheme put forward by Temtamy and McKusick. 3 It is
40/10 000 have been reported.1,2 supported by snapshots of hallmark features as well as examples of
Clinically syndactyly is one of the most heterogeneous develop- clinical and genetic heterogeneity of each syndactyly. Finally, the
mental deformities known in the medical literature. A number of key questions in syndactyly research, which remain to be answered,
combinations are possible in which the adjacent fingers and/or toes have been highlighted.
remain connected by a web. It may be unilateral or bilateral, and
symmetrical or asymmetrical. Furthermore, inter- and intra-familial SYNDACTYLY: APPRECIATION AND DEVELOPMENT OF
phenotypic variability is quite common. The condition is so variable CLASSIFICATION
that the same individual may exhibit asymmetrical phenotypes in Syndactyly appears in the medical literature under several
the upper and lower, and right and left limbs. Syndactyly can be synonyms. For example, adherent fingers,4 fingers coated with
identified as partial or complete, cutaneous or bony, and involving common skin,5 coherence of fingers,6 fingers grown together,3,5 fingers
only the phalanges or further extending up to metacarpal/metatarsal knit together,4 skin fusion, digits in stocking,7 fingers stuck together,8
or carpal/ tarsal levels, sometimes even proximating the distal end of symphalanginae, symphalangus syndactylous,9 syndactylia,
forearm/ foreleg. On the minimal extreme, a milder phenotype may syndactylous ossification, webbed toes,10 and zygodactyly.11 The
9

only be recognized by the alterations in interphalangeal creases and earliest appreciation of syndac- tyly as a birth anomaly or burn-trauma
peculia- rities in dermatoglyphics.3 can be traced back to a famous Andalusian surgeon in the middle
Syndactyly may segregate as an isolated clinical phenotype. There ages named Al-Zahrawi Abulcasis (936–1013).12,13 Ambroise Pare
are at least nine well-characterized syndactylous entities with (1510–1590) in the sixteenth century described syndactyly as
subdivi- sions, the majority of which have non-syndromic nature. fingers stuck together and polydactyly as superfluous fingers,
Most of these entities segregate in Mendelian dominant fashion. respectively.8,4 Thus, it was established quite early that webbed
However, two autosomal recessive and an X-linked recessive type fingers are not infrequent, appear in various forms, usually without
have also been described. Generally, autosomal dominant phenotypes the involvement of other organ systems but frequently witnessed
are rather less severe and demonstrate widely variable expressivity with extra digits (Bell4 and references therein). Minor webbing types
and incomplete could be easily overlooked; however, severe types

1
Human Genetics Program, Department of Animal Sciences, Quaid-i-Azam University Islamabad, Islamabad, Pakistan
*Correspondence: Dr S Malik, Human Genetics Program, Department of Animal Sciences, Quaid-i-Azam University Islamabad, 45320 Islamabad, Pakistan. Tel: +92 51 9064 3158; Fax: +92 51 260
1176; E-mail: [email protected]
Received 7 October 2011; revised 3 January 2012; accepted 6 January 2012; published online 15 February 2012
 Syndactyly: phenotypes, genetics and classification
S Malik

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Table 1 Classification schemes proposed for syndactylies

Author Syndactyly type identified Description

Anatomical approach
Roblot (1906)14 Complete vs partial Based on the extent of webbing; also observed syndromic vs non-syndromic
Weidenreich (1923)11 Zygodactyly Identified two types for 2/3 toes webbing; partial vs complete; and common vs rare type
Bell (1953)4 A1, A2, B1, C; and subgroups Each type is unique but combination of various types are possible
Kelikian (1974)15 One to eight categories Considers cutaneous/bony fusion, number of involved digits, and other digital insults
Woolf and Cone (1977)16 Division of type I (Ia, Ib) Type Ia shows 2/3 toes webbing; type Ib has 2/3 toes; and 3/4 fingers involvement
Lenz and Majewski (1981)17 Syndactyly type Ia Separated Lueken type from syndactyly type I

Descriptive and embryological classification

Swanson (1976)18 Simple vs complicated Based on failure of differentiation (separation of digits)
Winter and Tickle (1993)19 Pre-, meso-, post-axial, and total Based on normal/abnormal patterns and secondary limb modeling during development;
syndactyly types preaxial, mesoaxial, postaxial, and total syndactyly types
Stoll et al (1998)20 Radial, central, ulnar, complex types A descriptive system to classify limb defects

Clinical, genetic and molecular approach

Temtamy and McKusick (1978)3 Five types (I—V) Based on the combination of fused digits and inheritance pattern
Goldstein et al (1994)21 Eight types (I—VIII) Extension of Temtamy-McKusick, types VI–VIII were introduced
Malik et al (2004, 2005)22,23 Nine types (I—IX) Extension of Temtamy-McKusick, recessive type IX syndactyly was introduced
Harpf et al (2005)24 Subgroups in type VII Identified ‘spoon hand type’ and ‘oligodactyly type’ within type VII
Malik et al (2005)25 Syndactyly type I extended Four subdivisions proposed for type I syndactyly (I-1 to I-4)
Malik et al (2006)26 Syndactyly type II extended Splitting type II syndactyly (SPD1, SPD2, SPD3)
Malik and Grzeschik (2008)27 Clinical variants in Type II Identified typical features, minor variants, and unusual phenotypes in type II

required surgical corrections. As the number of reports regarding system. However, it is not always possible to comprehend all digit
the deformity grew into the medical and anthropological records, it malformations on the basis of morphogenesis and gene
permitted a systematic evaluation of various types. Hence, several function.20
attempts were made to classify webbing of digits which, depending
upon the approach taken, fall into three categories (summary in
Table 1):

Simple anatomical classification systems

The classical approach has been a simple anatomical categorization
depending upon the digits within the web, number of digits
involved, and also, the extent of webbing. In this context, the
systems intro- duced by Roblot,14 Weidenreich,11 Bell,4 Kelikian,15
and Lenz and Majewski17 are worth mentioning (Table 1). Of
particular interest is the classification system proposed by Bell4 who
identified four major types (A1, A2, B1, and C). However, there were
types with overlapping features and still others that remained
unclassified (reviewed in Malik et al28).

Descriptive and embryological approaches of classification

These approaches rely on the grouping of similar patterns of limb
deficiencies due to embryological failures. They consider, for
instance, whether the insult involves soft/skeletal tissue or only the
dermo- myofascial structure.18 One of the prime objectives of these
classifica- tion schemes has been to help adopt best surgical and
treatment methods to restore the correct digit number, size of
individual rays, and digit shape.29 Additionally, these schemes were
based on the observations of sporadic cases and post-traumatic
syndactylies.
Winter and Tickle19 based their classification essentially on the
mechanism of pattern formation and secondary modeling of limb
bud during development. Hence, they categorized syndactylies as
preaxial, mesoaxial, postaxial, and total webbing types (Table 1). A
relatively similar scheme was introduced by Stoll et al20 by
emphasizing more on descriptive nomenclature. The original idea
was to introduce the emerging molecular data into the classification

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Clinical and genetic approach 8

Temtamy and McKusick3 proposed a classification essentially based on
the phenotypic presentation (ie, site and nature of digit
involvement) as well as the pattern of disease segregation in large
families. They identified five discrete and isolated syndactylies, in
addition to a few unclassified types (Table 1). Since then it has been
the most widely used scheme by the geneticists and clinicians.

CURRENT SYNDACTYLY CLASSIFICATION: CLINICAL,

GENETIC, AND MOLECULAR APPROACH
The Temtamy-McKusick classification has been a well-appreciated
scheme for a number of reasons. First, the majority of the reported
isolated syndactyly phenotypes in families/subjects can be easily
typed with this scheme.28 Second, novel syndactyly phenotypes
could be easily accommodated by extending the existing
classification system.21–23 Third, subgroups could be introduced with
equal flexibility as fresh dysmorphology data emerged.23,25 Fourth,
and importantly, the molecular data have been integrated into the
classification system without disturbing the original scheme. Finally,
the OMIM catalogue, which is the most widely used unified and
consolidated dysmorphol- ogy resource for geneticists, clinicians,
and genetic counselors, adopts this scheme.
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 step-by-step progress in this scheme is summarized in
Table 1. The syndactyly types identified according to the current
classification are described below (Figures 1 and 2; Supplementary
Figure 1; Table 2):

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

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I-a I-b

Cutaneous webbing of 2/3 toes only Cutaneous webbing of 3/4 fingers, 2/3 toes

I-c I-d

Cutaneous webbing of 3/4 fingers only Cutaneous webbing of 4/5 toes

II-a II-b

Typical SPD; Cutaneous bony

Synpolydactyly, mesoaxial in hand, postaxial in foot
fusionof 3/4 fingers, webbing of 4/5 toes

II-c III

Severe manifestation of SPD

Fusion of 4/5 fingers, 5th finger short

Figure 1 Schematic diagrams of syndactyly types (I-a–III). 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 (adapted from Malik and Grzeschik).27

witnessed in distinct families have led to the suggestion of four estimated prevalence of 4 in 10 000 men and accounts for 70% of
subtypes for type I syndactyly (Table 2):25 all non-syndromic syndactyly cases.2,47
Zygodactyly is characterized by bilateral cutaneous webbing of
Syndactyly type I-a (Weidenreich type; zygodactyly; 2/3 toes second and third toes without the involvement of hands (Figure 1).
syndactyly) Rarely, other toes are also affected. The phenotype in both feet is
This autosomal dominant entity was originally named zygodactyly usually concordant.48 In its mildest forms, it gives the impression of
by Weidenreich.11 Zygodactyly is a minor and least conspicuous slight ascent of interdigital web between second and third toes, or it
type, and often goes unnoticed in the clinical practice. It has an may only be detected by abnormal dermatoglyphics.3 In its extreme

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IV-a IV-b

Complete polysynactyly, cup shaped hand Complete syndacactyly of hands and feet

V VI

Postaxial Mesoaxial Syndactyly of all fingers; several toes in the web

metacarpal fusion in hands cutaneous in feet

VII-a VII-b

Classic Cenani-Lenz type; Oligodactyly type; total synostotic

Spoon-head type syndactyly and metacarpal/metatarsal fusion

VIII IX

Synostosis of 4/5 metacarpals Mesoaxial synostotic fusion in hands

preaxial cutaneous webbing in toes

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

form, the web reaches up to phalangeal tips, a rather intimate fusion is Syndactyly type I-b (Lueken type; 3/4 fingers and 2/3
witnessed at nails, and the second toe depicts varus inclination.25 toes syndactyly)
First molecular evidence of zygodactyly being a distinct genetic This subtype is characterized by bilateral webbing of third and
entity was provided by Malik et al25 by a mapping study on a large fourth fingers, and second and third toes (Figure 1). Finger’s
Pakistani family. Cosegregation of zygodactyly was shown with ZD1 webbing may exhibit osseous fusion in the form of a bony bridge at
locus at chromosome 3p21-p31. However, genetic heterogeneity the phalangeal tips. In more severe cases, additional fingers from
has been suggested from the linkage data of a German kindred.25 second to fifth and toes from first to fifth may be involved.

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8 Reduplication of any fused

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Table 2 Current classification of well-characterized syndactyly types

Key
ID Type/description OMIM Fingers webbing Toes webbing Inheritance Locus/gene reference

I-a ZD1; Zygodactyly; 609815 Normal 2/3 Toes only AD 3p21.31 25

Weidenreich type
I-b SD1; Lueken type 185900 3/4 Fingers, cutaneous/bony 2/3 Toes, cutaneous AD 2q34-q36 30,31
I-c Montagu type 3/4 Fingers only, cutaneous/bony Normal AD 32
I-d Castilla type Normal 4/5 Toes only, cutaneous AD? 2

II-a SPD1; Vordingborg type 186000 SPD, mesoaxial (3/4 fingers) SPD, postaxial (4/5 toes) AD 2q31; HOXD13 33
II-b SPD2; Debeer type 608180 SPD is central and postaxial Postaxial syndactyly AD 22q13.3; FBLN1 34
II-c SPD3; Malik type 610234 SPD is central SPD postaxial AD 14q11.2-q13 26

III SDTY3; ODDD; 186100 4/5 Fingers; fifth finger short Normal AD 6q21-q23; GJA1 35
Johnston-Kirby type

IV-a SDTY4; Haas type 186200 All fingers webbed; pre-/post-axial Normal AD 7q36; ZRS 36,37
polydactyly, cup-shaped hand (LMBR1)
IV-b Andersen-Hansen type All fingers webbed; pre-/post-axial Variable webbing of toes with 38
polydactyly, cup-shaped hand polydactyly

V SDTY5; Dowd type 186300 4/5 Fingers with metacarpals fusion; Mesoaxial webbing AD 2q31; HOXD13 39,40
hypoplastic metacarpals 4/5

VI Mitten type 2/5 Fingers 2/5 Toes AD 3

VII-a Cenani-Lenz type; 212780 Total synostotic syndactyly with Total synostotic syndactyly with AR 11p12-p11.2; 41,42;
spoon-hand type metacarpals fusion, spoon-head metatarsals fusion LRP4.
shape
VII-b Oligodactyly type Few deformed digits Variable syndactyly of toes AD 15q13.3; 43
GREM1-FMN1

VIII-a Orel-Holmes type 309630 4/5 Metacarpal fusion Normal X-R 44,45
VIII-b Lerch type 4/5 Metacarpal fusion Normal AD 46

IX MSSD; Malik-Percin type 609432 Mesoaxial synostotic syndactyly with Preaxial webbing; distal phalan- AR 17p13.3 22,23
phlanageal reduction geal hypoplasia
Abbreviation: SPD, synpolydactyly.

digit is not a characteristic of this type. In the family reported by genetically one of the most heterogeneous types. The hallmark features
Lueken, this dominant phenotype was mapped to the SD1 locus at
chromosome 2q34-q35.30,31

Syndactyly type I-c (Montagu type; 3/4 fingers syndactyly)

This rare autosomal dominant type is characterized by bilateral
cutaneous/bony fusion of third and fourth fingers with normal feet
(Figure 1).32 A large Chinese family reported by Hsu49 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 (Castilla type; 4/5 toes syndactyly)

This 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 (Vordingborg type; 3/4 fingers and 2/3

toes synpolydactyly, SPD)
Type II syndactyly/SPD, a well-described entity, is clinically and

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8 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).27 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 (B18
types) into three categories: (A) typical SPD features; (B)
minor variants; and (C) unusual phenotypes.27 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 2).33,34,26 Additionally, detailed clinical and mutation data
are available only for SPD1 linked to HOXD13.

Syndactyly type III (Johnston–Kirby type; 4/5 or 3/4/5

fingers fusion)
This type of syndactyly affects fourth and fifth or third, fourth
and fifth fingers (Figure 1). The middle phalanx of the fifth
finger is hypoplastic.35 The fourth finger shows valgus deviation
in order to accommodate the webbing with little finger
particularly when the fusion is complete.3 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 inheri- tance with
incomplete penetrance.
The fusion of fourth and fifth fingers is, likewise, a
feature of ODDD (oculodentodigital dysplasia), which exhibits
additional

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symptoms of eyes, ears, and orofacial region. Schrander–Stumpel similar to upper limbs and certain digital rays may be absent.
et al50 proposed that ODDD and pure syndactyly type III are the Additionally, there is rare involvement of craniofacial and
respective ends of a clinical spectrum as variable expression of a nephrological features.53,42
contiguous gene deletion syndrome. Interestingly, molecular studies
revealed that type III syndactyly and/or ODDD are caused by muta-
tions in GJA1, a pleiotropic gene encoding connexin 43.51

Syndactyly type IV (Haas type; complete syndactyly of all fingers)

Haas type syndactyly 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).36 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 2).52 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.38,37

Syndactyly type V (Dowd type; fusion of 4/5 metacarpals)

The hallmark of this type 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.39 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.40

Syndactyly type VI (Mitten type; fusion of 2/5 fingers and 2/3 toes)
Temtamy and McKusick3 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 (Cenani–Lenz syndactyly, CLS; severe

bony fusion of all digits and deformed hand)
This 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. 3 Lower limbs show changes

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8 Harpf et al24 suggested that there exist two grossly different

clinical features in Cenani–Lenz type: (a) spoon-head type, and (b)
oligo- dactyly type (Table 2). They also differentiated between
consistent and inconsistent feature for CLS. Recently, Li et al42 have
shown that CLS, 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/b-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 rearran- gements of GREM1-FMN1 locus on
chromosome 15q13.3.43

Syndactyly type VIII (Orel-Holmes type; metacarpals 4/5 fusion;

X-linked recessive)
It 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 meta-
carpals 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. 54,45 This
entity shows X-linked recessive inheritance.54,44 However, there is at
least one report depicting autosomal dominant segregation for this
phenotype (Table 2).46

Syndactyly type IX (Malik–Percin type; fusion of 3/4 metacarpals

with a reduction of mesoaxial finger, and preaxial syndactyly
of toes)
Percin et al55 and Malik et al22 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 CLS 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 17p13.3.23

DISCUSSION
Syndactyly is a failure in the separation of developing digits during
organogenesis. Being an explicit limb phenotype, it comes to
immedi- ate medical attention at child’s birth, particularly when it
appears in the upper limbs. The involvement of feet is more
frequent than the involvement of hands, and males are affected
twice as frequently as females.2,3,56
Syndactyly is a common feature of more than 300 hereditary
syndromic malformations (OMIM) and it provides additional help
in the ascertainment of these malformations (eg, F-syndrome, Apert
syndrome, Seathre–Chotezen syndrome) (Supplementary Table 1).
Beyond the well-characterized syndactylies that have genetic etiology
there are syndactyly types that occur with congenital ring constric-
tions, that is, acrosyndactyly/pseudosyndactyly.2
Typing of syndactyly can be quite puzzling. For instance, intra-
familial and individual-specific clinical variability may result in
phenotypic overlap with other entities. Identification of syndactyly
is particularly daunting when only few affected individuals are
encountered with a particular phenotype, and other occasional digit
malformations (ectro-, poly-, brachy-, campto-dactyly, etc) also
accompany the syndactylous condition.57 Various other factors
complicate the understanding and pathomorphology of syndactyly.

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For instance, inheritance pattern, incomplete penetrance, genetic also help to single out complex interlocking development plans. Finally,
heterogeneity, limited number of families linked to each syndactyly syndactyly is a very relevant
locus (except type II-1 and III), a large number of morphogens
involved in limb development, complex interactions between these
morphogens, and the involvement of modifier genes and/or long
range regulatory elements (eg, ZRS). For a correct typing in
syndactyly (and other developmental anomalies), more weight should
be given to the phenotypes in extended families. As a general rule,
the most common phenotype in particular kindred is considered
important for typing. The involvement of upper and/or lower limbs,
webbing pattern, and the ascent of web from phalanges up to
metacarpals/ metatarsal and carpals/tarsals are critical for
diagnosis.
A workable classification should employ a simple but meticulous
and itemized approach. It should allow the recording of common
clinical entities with minimal confusion, but yet permit the full
categorization of complex cases. 20 Thus, one approach could be the
grouping of malformations according to morphogenesis or to their
cause (ie, genes).19 However, genes cannot always be used to classify
morphogenesis,20 owing to the fact that the action of genes is over-
lapping. Moreover, mutations of different genes can lead to the
same phenotype (eg, type II syndactyly). Conversely, mutations in
the same gene can lead to different phenotypes (eg, HOXD13).
Thus, even after considerable advances in limb morphogenesis and
molecular embry- ology, it is still not possible to precisely correlate a
specific syndactyly/ limb anomaly to the underlying gene(s). Hence,
the current classifica- tion takes the advantage of clinical, genetic, and
molecular approaches, simultaneously (Supplementary Figure 1).
Before we can type syndactylies with confidence, there are still a
number of intriguing questions that await resolution. For instance,
a distorted sex ratio in certain syndactylies is very puzzling. 16 Large
epidemiological surveys in various populations would be helpful in the
evaluation of sex distortion and revisiting the prevalence estimates
of various syndactyly types. Additionally, it is not known how the
same underlying genetic factors may lead to dissimilar webbing in
hands and feet. Also, the extreme phenotypic variability observed in
certain types (eg, SPD) is difficult to explain on the basis of current
genetic and molecular data alone. Furthermore, it is also not clear why
certain web types (ie, fusion of second and third toes; third and
fourth fingers) are observed more frequently in isolated or
syndromic situations.2 For syndactylies with known underlying
genes, further studies on the allelic mutation series are required to
establish geno- type-phenotype correlation(s).
The study of syndactyly could contribute substantially in the
appreciation of limb developmental pathways. The three main inter-
locking developmental axis of the growing limb bud are the prox-
imodistal, running in the human arm from shoulder to digits; the
anteroposterior (AP), from thumb to the little finger; and dorsoven-
tral, from the back of the hand to the palm. The digit specification
and identity are mainly coordinated by the AP developmental
axis.58 Cutaneous syndactyly may result when the growing digits fail
to separate during the late stages of digit sculpting by interdigital
necrosis (for instance via BMP pathways). Experimental studies on
mice revealed that BMP pathway is necessary for apoptosis in the
develop- ing limb and the inhibition of BMP signaling caused
extensive soft tissue syndactyly and postaxial polydactyly.59 Osseous
fusion resulting in more intimate cohesion of digits and the
involvement of proximal segments of hand/foot would necessitate
gross irregularity in rather early developmental cascades. The
identification of novel genes for syndactyly could not only elucidate
the limb patterning and digit specification mechanisms but should

European Journal of Human Genetics

 Syndactyly: phenotypes, genetics and classification
S Malik

8 model to study the interaction of genetic mechanisms, 27 Malik S, Grzeschik KH: Synpolydactyly: clinical and molecular advances. Clin Genet
2008; 73: 113–120.
epigenetic events, pleiotropy and stochastic factors, which
generate extreme clinical heterogeneity in affected subjects and
families.60 The present review of classification of syndactyly
would be helpful in the apprecia- tion of syndactyly
malformation and defining its affinities with other digit
anomalies like polydactyly, oligodactyly, and brachydactyly.

CONFLICT OF INTEREST
The author declares no conflict of interest.

ACKNOWLEDGEMENTS
The helpful comments of Professors Karl-Heinz Grzeschik, Nurten
Akarsu and Mahmud Ahmad are highly acknowledged. The study was
supported by Higher Education Commission Pakistan, and Pakistan
Science Foundation, Islamabad.

WEB SOURCES
OMIM. Online Mendelian Inheritance in Man.
http://www.ncbi.nlm.nih.gov/ omim/.
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