Clin Genet 2008: 73: 113–120
Printed in Singapore. All rights reserved
#2007 The Authors
Journal compilation#2007 Blackwell Munksgaard
Synpolydactyly: clinical and
Malik S, Grzeschik K-H. Synpolydactyly: clinical and molecular
Clin Genet 2008: 73: 113–120.#Blackwell Munksgaard, 2008
Synpolydactyly (SPD) is a rare limb deformity showing a distinctive
combination of syndactyly and polydactyly. Of the nine non-syndromic
syndactylies, it is clinically and genetically one of the most heterogeneous
malformation. SPD families may show clinical features consistent with
the Temtamy and McKusick criteria as well as additional phenotypic
variants, which vary from case to case. In certain instances, these variants
predominate in a given family, while the typical SPD features remain less
explicit. We have reviewed all the clinical variants occurring in well-
documented SPD families. We conclude that typical SPD features can be
delineated from minor clinical variants. Then, we propose to lump all the
phenotypic variants, manifesting themselves in SPD families into three
categories: (i) typical SPD features, (ii) minor variants, and (iii) unusual
phenotypes. Next, we discuss the likely reasons for the occurrence of
minor variants and the obvious lack of penetrance in SPD families.
Finally, we show that for the SPD phenotype associated with HOXD13
mutations, a straightforward genotype–phenotype correlation is weak.
Our lumping and splitting scheme for SPD phenotypic variants could be
useful for the understanding of this interesting malformation.
S Malika,band K-H Grzeschika
aZentrum fu ¨r Humangenetik, Philipps-
Universita ¨t Marburg, Bahnhofstr. 7,
Marburg, Germany, andbDepartment of
Animal Sciences, Faculty of Biology,
Quaid-I-Azam University Islamabad,
45320 Islamabad, Pakistan
Key words: clinical heterogeneity –
genetic heterogeneity – HOXD13
morphopathies – synpolydactyly
Corresponding author: Dr Sajid Malik,
Zentrum fu ¨r Humangenetik, Philipps-
Universita ¨t Marburg, Bahnhofstr. 7,
35037 Marburg, Germany.
Tel.: 149 6421 286 4082;
fax: 149 6421 286 8920;
Received 14 August 2007, revised and
accepted for publication 30 October
Synpolydactyly (SPD) (MIM 186000) is a rare
limb deformity, showing a distinctive combina-
tion of syndactyly and polydactyly, segregating in
an autosomal dominant fashion. In fact, of the
nine non-syndromic syndactylies known, it is
clinically and genetically one of the most hetero-
geneous malformations. The cardinal features of
SPD are the webbing of 3/4 fingers and 4/5 toes,
with partial or complete digital duplication within
the syndactylous web. Furthermore, SPD depicts
incomplete penetrance estimated from 86% to
97% (1, 2). Finally, three genetically distinct SPD
malformations are now known and have been
designated as SPD1, SPD2 and SPD3 (Table 1),
but a characteristic clinical delineation between
these entities has not been appreciated.
In the non-syndromic syndactyly nomenclature
by Temtamy and McKusick (3), SPD has been
categorized as ?type II syndactyly’. Since the pro-
posal of this purely clinical classification, a sub-
stantial amountof clinical and molecular datahas
been accumulated on syndactylies and SPD being
the most cited type. The limitation of this
classification scheme emerges from the evaluation
of recent reports, where the SPD phenotype
indeed overlaps with other clinically and geneti-
cally well-characterized syndactyly types (2, 4, 5).
Additionally, advancesin moleculargenetics have
shown that there are at least three distinct genetic
entities showing similar SPD features (6–8).
Therefore, it necessitates that the classical defini-
tion of the SPD phenotype can be revised and
extended on the basis of recent clinical and
Hence, in this communication, we intend to
review the major and minor phenotypic manifes-
tations established in SPD families, the clinical
overlap of SPD phenotype with other distinct
limb malformations and the problems with the
diagnosis. Then, we discuss its obvious lack of
penetrance, genetic heterogeneity and genotype–
phenotype correlation. Finally, we propose lum-
ping and splitting within the SPD phenotypic
spectrum and put upan alternative scheme for the
identification and classification of this interesting
The problem of clinical heterogeneity: which
syndactyly type is this?
There is a broad spectrum of inter- and intra-
unique, non-overlapping clinical categories have
been recognized in large families linked to
HOXD13 mutations (i.e. SPD1). Interestingly,
different families with SPD1 show a different set
of clinical categories. For example, Sayli et al. (1)
and Akarsu et al. (9) reported a large Turkish
family with 182 affected subjects showing four
unique clinical categories (Fig. 1):
(1) Subjects representing typical features of SPD
(Fig. 1, A1–A4).
(2) Subjects exhibiting both pre- and post-axial
polydactyly in one or the other foot simul-
(3) Post-axial polydactyly type A [later on shown
to be a separate entity linked to chromosome
(4) Severe phenotype, homozygous expression
(Fig. 1, A5, A6).
Then, a second instance of further clinical
heterogeneity was observed in a panel of SPD1
families recruited by Goodman et al. (2). Besides
the typical SPD features (Fig. 1, A1–A4), the
authors also remarked the presence of milder
phenotypes in the affected subjects (Fig. 1):
(1) Webbing of 3/4 fingers (Fig. 1, B1).
(2) Minor webbing of 2/3 toes (Fig. 1, B5).
(3) Brachydactyly of fifth toe (Fig. 1, B6).
(4) An over-riding fourth or fifth toe (Fig. 1, B6).
(5) Isolatedfourthfingerbrachydactyly(Fig. 1,C2).
was depicted in two more families in which
classical SPD features were present only in a few
subjects, while an apparently novel foot pheno-
type was segregating in all of the affected subjects
(11). Therefore, the clinical categories in these
(1) Rudimentary extra digits between 1/2 meta-
tarsals and often between 4/5 metacarpals
(Fig. 1, B7).
(2) Classical SPD phenotype, less frequent
(Fig. 1, A1, A3).
The authors held that this novel phenotype
phenotypic spectrum seen in SPD’ (11). In fact,
this phenotype had also been witnessed in the
Turkish family reported by Sayli et al. (1) and was
considered as a part of clinical category ?a’.
Next, the clinical spectrum of SPD was further
broadened by a report on a large family showing
a similar ?foot phenotype’ with a combination of
bilateral clinodactyly of the fifth finger (7). The
classical SPD phenotype was less obvious (3/16)
(1) Clinodactyly of fifth fingers (Fig. 1, B3) and
partial duplication of the base of the second
metatarsals (Fig. 1, B7).
(2) Typical SPD phenotype, less frequent
(Fig. 1, A1, A3).
Then, Kjaer et al. (4) reported detailed clinical
presentation of four SPD1 families. Besides the
subjects with typical SPD features, the following
of the milder phenotypic manifestations were
(1) Single or a few abnormal flexion creases on
the hands (Fig. 1, B10).
(2) Minor symphalangism and/or camptodactyly
of first, second or third finger (Fig. 1, B8).
(3) Single over-riding toe (Fig. 1, B6).
(4) Malformed middle phalanx of the second toe
(Fig. 1, B9).
(5) Large distance between the first and second
toe (Fig. 1,B9).
Finally, Malik et al. (5) described two Asian
SPD families and identified four distinctive
clinical categories (Fig. 1):
(1) Typical SPD features (Fig. 1, A2–A4).
(2) Severe phenotype, a likely homozygous
expression (Fig. 1, A5, A6).
Table 1. Clinical features and the known loci/genes for synpolydactylies (SPDs)
Type Cardinal featuresLocus GeneOMIM
SPD is central in hands and post-axial in feet
SPD is central and post-axial in hands, post-axial syndactyly of feet
SPD is central in hands and post-axial in feet
Malik and Grzeschik
Fig. 1. Schematic diagrams of unilateral hand and foot showing three clinical categories (A, B, C) established for the
phenotypic variants observed in the reported synpolydactyly families. The shaded digits depict cutaneous fusion only. Bony
synostosis is represented by black digital elements within the shaded area. The grey digital elements show clinodactyly,
brachydactyly or hypoplastic phalanges. The digital elements with amorphous borders symbolize dysplastic bones.
(3) Partial duplication of second metatarsal in
the first metatarsal spaces (Fig. 1, B7).
(4) Cutaneous webbing of 3/4 fingers only
(Fig. 1, B1).
It should be borne in mind that all the above
stated families belong to SPD1 (i.e. linked to
HOXD13 mutations). These instances show that
SPD phenotype has expanded dramatically, and
there is an array of clinical variants existing in
various combinations in different families, result-
ing in a hotchpotch of clinical presentations
The problem of clinical overlap with other
Phenotypic heterogeneity may lead to a clinical
misclassification (7, 12). Few of the clinical
categories reported in SPD1 families phenotypi-
cally superimpose on the other distinct syndactyly
2/3 toes (Fig. 1, C5) observed in the affected
subjects of SPD1 families by Goodman et al.,
Kjaer et al. (4) and Horsnell et al. (13) also occurs
as a separate entity and is classified as syndactyly
type I (zygodactyly, MIM 609815) (3, 14).
Likewise, another well-characterized syndactyly
type, isolated soft tissue webbing of 3/4 fingers,
was observed in SPD1 family subjects reported
by Goodman et al. (2). This variant was also
witnessed in few of the affected subjects, in two
Asian families segregating with SPD1 (Fig. 1, B1)
(5). This phenotype is the second most frequent
non-syndromic syndactyly type (15) and has been
regarded as a part of type I syndactyly (OMIM
185900) (3, 16).
The problem of reduced penetrance
Reduced penetrance is an inherent problem in
families with SPD that adds another level of
complexity to the question. Non-penetrant muta-
tion carriers have been repeatedly observed in
SPD1 families (2, 5, 7, 9). The estimates vary from
96% to 70% in upper and lower limbs, respec-
tively (9). However, an overall penetrance of 95%
has been calculated when very mild manifesta-
tions were also included in large families (4). The
marked lack of penetrance, in certain cases, could
be explained because of bias of ascertainment (5).
Furthermore, because of the prismatic nature of
SPD, it is quite likely that the minor phenotypes
are overlooked, which is readily possible when
radiograms are not available for all family
subjects. There are instances where dermatogly-
phics (abnormal flexion creases) aloneshowed the
genetic status of subjects (4, 17).
In addition, the carrier status remains unspec-
ified unless detailed molecular analyses have
estimate the penetrance because not all subjects of
the family are available at the time of clinical and
molecular examination. Even though, all the non-
penetrant subjects could not be explained purely
on difficulties with clinical phenotyping, and
genetic or other reasons should be involved.
Reduced penetrance may compromise the genetic
analysis and have implications in the genetic
counselling and risk estimation.
The problem of genetic heterogeneity
SPD remains the first to be genetically defined
For SPD1, expansion mutations in HOXD13
Fig. 2. (a) Phenotypic overlap of SPD1 clinical variants
with other well-characterized limb malformations. The
extent of overlap is depicted as circles. It is evident that
zygodactyly features are completely shared by SPD1 minor
variants, while only few of the clinical symptoms are
common for type I syndactyly and brachydactyly types.
(b) The clinical overlap within the known SPDs (i.e. SPD1,
SPD2 and SPD3) is illustrated. Interestingly, SPD3 also
shows features of syndactyly type V. SPD, synpolydactyly.
Malik and Grzeschik
polyalanine repeat (PolAR) have been identified
in several independent studies (2, 9, 18).
For the second genetic entity, SPD2 (complex
type of 3/3#/4 SPD), only one family has been
described (19, 20). It was initially diagnosed as
Cenani–Lenz syndactyly (12) but was later shown
to be a case of misclassification (19, 20). In
addition to the typical SPD features, the affected
subjects also depicted synostosis between 4/5
metacarpals, shortening of third and fourth
metatarsals, over-riding third toe and proximal
implantation of fourth toe. This condition was
subsequently associated with a disrupted gene,
FBLN1 (7). Clinically, this condition showed
minimal divergence from SPD1. However, the
is considered as a key feature of type V syndactyly
Finally, another genetic entity has been estab-
lished, SPD3, segregating in a large Pakistani
kindred and mapped on chromosome 14q11.2-
q12 spanning an interval of approximately
Temtamy and McKusick diagnostic criteria,
being essentially indistinguishable from SPD1
phenotype. One of the affected family subjects
did not harbour the disease haplotype and was
explained as a phenocopy (8). Replication of this
study might provide useful data for the clinical
appreciation and may also refine the disease
clinical delineation between these three entities
(i.e. SPD1–3) has not been established. This issue
is further aggravated by the likelihood that other
SPD loci/genes might have yet to be identified,
genetic data are available only for SPD1 linked to
The problem of nomenclature – how many
names are there for synpolydactyly?
When it comes to assign a title to SPD phenotype,
of titles: ?syndactyly Vordingborg type’ (17, 21),
?zygodactyly, syndactyly, and polydactyly’ (22),
?syndactyly type II’ (3), ?novel feet malformation’
(11), ?atypical synpolydactyly’ (26), ?variable
hand but consistent foot malformation’ (27), or
?hypoplastic synpolydactyly’ (28), representing
various facets of the same heterogeneous condi-
tion. Quite often, the naming comes after the
most common clinical variant encountered in the
family that varies from case to case. Alternatively,
it may also depend upon the proportion of
the affected family members and/or loop of the
family available for clinical evaluation. In any
case, it shows a general lack of consensus, both
between clinicians and the geneticists, in the
naming and appreciation of this heterogeneous
Subjects and methods
In order to appreciate the minor secondary
clinical and molecular data was available. The
clinical variants fulfilling the Temtamy and
McKusick criteria are defined as the core or
typical SPD features, all other variants as minor
secondary features. All the secondary variants
were documented and categorized on the basis of
their recurrence and consistency, especially in
large families and were compared with the pheno-
type characteristic of other well-characterized
syndactyly types (3, 16).
Results and discussion
Clinical categories for SPD phenotype
The clinical survey of 32 SPD1 families has shown
that the typical SPD phenotype fulfilling the
Temtamy and McKusick criteria can be distin-
guished from minor secondary features. The
minor clinical features customarily accompany
SPD phenotype in various combinations and differ
from case to case. Few of the minor variants may
occur as a predominant feature in a given family,
while the typical SPD features remain less explicit.
Based on this observation we, therefore, propose
to lump all the clinical variants occurring in SPD
(A) Typical SPD phenotypes (fulfilling the
Temtamy and McKusick criteria):
(1) Osseous synostosis of 3/4 fingers (Fig. 1,
(2) Mesoaxial osseous synostosis in hands
with extra digital elements (Fig. 1, A2).
(3) Fusion of 4/5 toes with an additional
post-axial toe (Fig. 1, A3).
(4) Combination of above said conditions
113 (Fig. 1, A11A3), or 213 (Fig. 1,
(5) Metacarpals/metatarsals involvement,
duplication, branching approaching
more proximally (Fig. 1, A4).
(6) Severe phenotypes (homozygous mani-
festations) showing bizarre arrangement
of all digital elements, loss of identity/
pattern and the malformation reaching as
for as carpals and tarsals (Fig. 1, A5, A6).
(B) Minor variants (features frequently associ-
ated with SPD):
(1) Isolated, cutaneous webbing of 3/4
fingers (Fig. 1, B1) or partial webbing
of 3/4/5 fingers (Fig. 1, B2).
(2) Clinodactyly of fifth fingers, may
include camptodactyly, brachydactyly
or symphalangism of this digit; brachy-
dactyly A3 (Fig. 1, B3).
(3) Isolated cutaneous webbing of 4/5 toes
(Fig. 1, B4).
(4) Isolated cutaneous webbing of 2/3 toes,
zygodactyly (Fig. 1, B5).
(5) Over-riding fourth or fifth toes, or
brachydactyly of fifth toe (Fig. 1, B6).
(6) Presence of partially developed metatar-
sals between first and/or fourth web
spaces (Fig. 1, B7).
(7) Symphalangism or camptodactyly of
first, second or fifth fingers (Fig. 1, B8).
(8) Radial deviation of hallux and/or mal-
formed middle phalanx of second toe,
brachydactyly A2 (Fig. 1, B9).
(9) Broad halluces, hypoplasia/aplasia of
middle phalanges of toes (Fig. 1, B10).
(10) Malformed dermatoglyphics, unusual
pattern of palmar creases (Fig. 1, B10).
(C) Unusual phenotypes:
(1) Post-axial polydactyly of hands, pre-
axial polydactyly of feet (Fig. 1, C1).
(2) Brachydactyly type C, D, E (Fig. 1, C2).
There is no specific explanation, thus far, for
the presence of minor clinical variants in SPD
families. However, variations in the genetic back-
grounds reflecting the presence of modifier loci in
different families or in different loops of the same
family could be involved. A roughly constant
amount of major gene product (e.g. HOXD13)
interacting with fluctuating quantitative ampli-
for the unique minor clinical variants existing in
different families. It is quite likely that the second
gene/locus does not harbour any rare disease-
causing mutation but sequence polymorphisms.
Additionally, it cannot be ruled out that the
variants of other syndactyly loci (at chromo-
somes 2q34-q36, 3p21.31, 6q22.31, 14q11.2-q12,
22q13.31, or other genes) have functional cross-
families, as reported for SPD, it is conceivably
possible to identify a major as well as the minor
loci by molecular mapping. This area, however,
Furthermore, the phenotypic variability obser-
ved within the limbs of the same affected sub-
ject might well be because of the stochasticity in
HOXD13 dosage differences during development
extensive functional overlap between different
dose-dependent fashion (29). Likewise, this phe-
nomenon might also in part explain the lack of
penetrance for SPD1 in certain families. Finally,
there might be epigenetic changes during devel-
opment, which could account for the phenotypic
Clinical overlap with other limb malformations
The comparison of the SPD phenotype with other
well-characterized limb malformations showed
that clinical overlap is prominent for the ?minor
variants’ of SPD (here category B; Fig. 2), some
of which readily overlap with zygodactyly and
brachydactyly types. Nevertheless, the ?unusual
phenotypes’ (category C) also show overlap with
polydactyly and brachydactyly types (Fig. 2),
however, the typical SPD features remain unique.
This observation reinforces the fact that the
typical SPD phenotype can be separated from
minor variants and that the proposed phenotypic
grouping might be biologically relevant for the
appreciation of this condition.
A correlation has been proposed between the
severity and penetrance of SPD1 phenotype and
the size of PolAR expansion mutations in
HOXD13 (2, 4). Generally, three kinds of muta-
tions are observed in HOXD13 (i.e. PolAR
expansions, truncations, and homeodomain mis-
to the mutant protein and dictating a relatively
confined phenotype (31, 32). However, recent
reports have not only expanded the HOXD13
mutation spectrum but also have broadened the
associated phenotypic picture, which in turn has
lead to the suggestion to lump all the phenotypes
under the term ?HOXD13 morphopathies’ (33).
We have re-examined the proposed genotype–
phenotype correlation for HOXD13 in the light of
the clinical categories described above (Fig. 3).
Malik and Grzeschik
deletion mutations usually give rise to typical SPD
phenotypes, and the homeodomain missense
mutations cluster for brachydactyly types, a clear
genotype–phenotype correlation is weak (Fig. 3).
So much so that the families with brachydactyly
type C and D depicttypicalSPDfeatures,however
less prominent (32, 33). Additionally, the milder
SPD variants show a broad distribution irrespec-
tive of mutation type (Fig. 3). We, therefore,
suggest that a molecular classification of HOXD13
morphopathies might not be straightforward.
Despite recent advances, it may not be possible to
develop the ultimate classification system for
SPD; however, different patterns of lumping and
splitting may be useful for the clinicians, the
Lumping and splitting is a continuous process,
which evolves as fresh clinical and molecular data
emerge. Furthermore, certain individual cases
with unique features may never fit into any
particular category. For the nomenclature, we
propose that the name SPD need not change as it
is in itself very specific and self-explanatory.
We conclude that a typical SPD phenotype can
be separated from minor neighbouring features,
which are customarily accompanied with SPD in
various combinations. Additionally, no definite
boundary line could be drawn between the milder
SPD variants (Fig. 1, B1, B5) and the type I
syndactyly phenotypes. However, there are cer-
tain generalizations for SPD, which make it
unique from other entities. For example, SPD
primarily involves both upper and lower limbs;
the additional digit is mesoaxial in hands and
post-axial in feet; polydactyly does not exist
without syndactyly (3); shows metacarpals, meta-
tarsals involvement (1, 34); webbing is complete,
reaching the tips of involved digits; and the
Fig. 3. Mutation spectrum in HOXD13 morphopathies. Schematic diagram of HOXD13 cDNA and the reported disease-
causing mutations with their corresponding phenotypes. Only the typical synpolydactyly features fulfil the Temtamy and
McKusick criteria. HOXD13 protein contains a polyalanine stretch (hashed) and a homeodomain (dark). MIM, Mendelian
Inheritance in Man; SPD, synpolydactyly; PolAR, polyalanine repeat.
manifestation is never present in the feet, unless Download full-text
the hands are also affected (1, 25). Further studies
both on the clinical and on the molecular fronts
might increase our understanding of this unique
We are very grateful to Dr Nurten Akarsu for her useful
comments on the manuscript.
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