SPECIAL TOPIC

Hand/Peripheral Nerve
Genetic Overview of Syndactyly and Polydactyly
Humayun Ahmed, BA*†
Hossein Akbari, MD‡ Summary: Syndactyly and polydactyly—respectively characterized by fused and
Abdolhasan Emami, MD‡ supernumerary digits—are among the most common congenital limb malforma-
Mohammad R. Akbari, MD, tions, with syndactyly presenting at an estimated incidence of 1 in 2,000–3,000
PhD*†§ live births and polydactyly at a frequency of 1 in approximately 700–1,000 live
births. Despite their relatively regular manifestation in the clinic, the etiologies
of syndactyly and polydactyly remain poorly understood because of their pheno-
typic and genetic diversity. Further, even though concrete knowledge of genotypic
links has been established for some variants of syndactyly and polydactyly, there
appears to be no single comprehensive published summary of all syndromic and
nonsyndromic syndactyly and polydactyly presentations, and there is decidedly no
resource that maps all syndromic and nonsyndromic syndactylies and polydactylies
to their genetic bases. This gap in the literature problematizes comprehensive car-
rier screening and prenatal diagnosis and complicates novel diagnostic attempts.
This review thus attempts to collect all that is known about the genetic bases of
syndromic and nonsyndromic syndactylies and polydactylies, as well as to highlight
the dactyly manifestations for which no genetic bases are as yet known. Then, hav-
ing established a summation of existing and missing knowledge, this work briefly
outlines the diagnostic techniques that a genetics-reinforced understanding of syn-
dactyly and polydactyly could inform. (Plast Reconstr Surg Glob Open 2017;5:e1549;
doi: 10.1097/GOX.0000000000001549; Published online 2 November 2017.)

SYNDACTYLY AND POLYDACTYLY 5 digits per limb). Like syndactyly, polydactyly is pheno-
PHENOTYPES typically variable3 in terms of the limb affected (hand or
Syndactyly (ie, digit fusion, typically via webbing) is a foot),4 its severity, and its syndromicity or lack thereof.3
common inherited and clinically heterogeneous malfor- Though syndactyly and polydactyly are phenotypically
mation.1 It can be syndromic, comprising more than 300 well understood, their genetic bases have not been synthe-
distinct anomalies,1 or nonsyndromic, existing as 1 of 9 sized in writing and remain unclear for some types. This
nonsyndromic forms.2 It also varies phenotypically between study reviews the current knowledge on the genetics of
families. Even a single patient’s phenotype may be severe or these anomalies.
mild, unilateral or bilateral, symmetrical or asymmetrical,
complete or incomplete, cutaneous or bony, and involving SYNDACTYLY AND POLYDACTYLY
many distinct bones, with inter-limb phenotypic variation.1 GENETICS
Polydactyly is another hereditary limb malformation, Given the aforementioned morphological variation, it
characterized by supernumerary digits (ie, more than is not surprising that the genetic bases of syndactyly and
polydactyly are diverse, polygenic,5 and as yet unclear in
From the *Women’s College Research Institute, Women’s College some cases. New causative genes and mutations are being
Hospital, University of Toronto, Toronto, Canada; †Institute discovered with advances in sequencing technology.
of Medical Science, University of Toronto, Toronto, Canada; The genes involved in syndactyly and polydactyly tend
‡Department of Plastic and Reconstructive Surgery, Hazrat Fatemeh to affect specific bodily regions, including the zone of po-
Hospital, Burn Research Center, Iran University of Medical Sciences, larizing activity (ZPA): an area that controls limb structure
Tehran, Iran; and §Dalla Lana School of Public Health, University and positional identity.6–9 The ZPA disappears by day 44
of Toronto, Toronto, Canada. of embryonic development, after which time the phalan-
Received for publication March 6, 2017; accepted September 6, ges form.10 Aside from the ZPA, which is on the posterior
2017. embryo and produces fibroblast growth factor 8 (FGF8),
Copyright © 2017 The Authors. Published by Wolters Kluwer Health, the apical ectodermal ridge, which is on the dorsal-ventral
Inc. on behalf of The American Society of Plastic Surgeons. This is margin and produces FGF8, also aids in limb development.
an open-access article distributed under the terms of the Creative
Commons Attribution-Non Commercial-No Derivatives License 4.0
(CCBY-NC-ND), where it is permissible to download and share the Disclosure: The authors have no financial interest to d­ eclare
work provided it is properly cited. The work cannot be changed in in relation to the content of this article. The Article Processing
any way or used commercially without permission from the journal. Charge was paid for by the authors.
DOI: 10.1097/GOX.0000000000001549

www.PRSGlobalOpen.com 1
 PRS Global Open • 2017

The HOX genes, hedgehog pathways [Sonic Hedge- been identified. It has been explored in a large Pakistani
hog (SHH) and Indian hedgehog (IHH)], FGFs, bone family.29 Subtype 2 (Lueken type, type Ib) is usually bilat-
morphogenetic proteins (BMPs), and cartilage-derived eral, in both the hands and feet, and can be either bony or
morphogenetic proteins are also involved.11 cutaneous. It is associated with the chr2q34-q36 locus and
Thirty-nine HOX genes exist in humans; the HOXA has been studied in German and Iranian families.30 The dis-
and HOXD clusters have been associated with syndactyly ease-causing gene has not been identified. Subtype 3 (type
and polydactyly.12 Genes within the HOXD cluster and Ic, Montagu type) involves the third and fourth fingers, is
locus chr2q31 seem to be involved in syndactyly13: the typically bilateral, and can be either bony or cutaneous. It
HOXD13 gene, for example, is linked to syndactyly type V is linked to the chr2q31-q32, and mutations p.R306Q and
(SD5) and a brachydactyly-syndactyly syndrome.14 p.R306G in HOXD13. It has been studied in 2 Chinese fam-
The SHH signaling pathway plays key roles in limb de- ilies.31 Finally, subtype 4 (type I-d, Castilla type) involves the
velopment.15 SHH is affected by—or affects—several tran- fourth and fifth toes and is typically bilateral and cutane-
scription factors, namely HAND2, GLI3, ALX4, and certain ous.1 Little is known about its genetic basis, but it is typically
BMP antagonists (formin and gremlin), changes to which inherited in an autosomal dominant manner.28,30
have led to syndactyly and polydactyly.10 If disrupted, as if
ZPA activity is impacted, then SHH cannot lead to normal Syndactyly Type II
limb development; this often results in syndactyly.16 Syndactyly type II (SPD) is one of the most heteroge-
The IHH signaling pathway may influence later de- neous nonsyndromic types.1,10,29 Like SD1, SPD tends to in-
velopment, considering its roles in chondrocyte differ- volve the third and fourth fingers.1 However, unlike SD1,
entiation and ossification.17 Further, IHH is repressed by SPD is also associated with the fifth toe.10 SPD manifests
fibroblast growth factor (FGF) receptors,18 functioning at itself in 3 types: SPD1 (Vordingborg type), SPD2 (Debeer
a different time than WNTs and FGFs, which are involved type), and SPD3 (Malik type). In SPD1, both the HOXA
in the final stages of mesenchymal ossification19; later, in and the HOXD clusters are involved; often, a polyalanine
the last stage of digit formation, there is down-regulation expansion on HOXD13 is present.30 The locus affected is
of gremlin and restriction of FGF8 expression.20 usually chr2q31 on HOXD13. In SPD2, it is usually fibu-
Wingless-type mouse mammary tumor virus integra- lin-1 (FBLN1) on chromosome 12 that is modified, and
tion sit family members 6 and 10B (WNT6, WNT10B) are the locus involved is usually chr22q13.3.28 The mutations
involved in the developing limb bud and related to the responsible for SPD2 are usually missense mutations or
chr2q35 region [a locus implicated in syndactyly type I deletions. Finally, in SPD3, the chr14q11.2-q13 locus is
(SD1)].21 BMPs and their antagonist noggin (NOG), when affected. SPD as a whole is characterized by incomplete
blocked, also lead to syndactyly.10 GLI3 may also contrib- penetrance and high variability and has been studied in
ute22: it is involved in a range of syndromes, and a GLI3 Turkish,32 Greek, Pakistani, Chinese, and Belgian fami-
missense mutation led to syndactyly and polydactyly.23 N- lies,30 as well as in mice.33 SPD is inherited in an autosomal
Myc and zinc-finger transcription factors have caused soft- dominant manner with reductive penetrance.1
tissue syndactyly in mice.24
Syndactylies and polydactylies also vary in their patterns Syndactyly Type III
of inheritance. Most syndactyly types follow autosomal Syndactyly type III (SD3; Johnston-Kirby type, 4/5 fin-
dominant inheritance,25 but SD7 and SD9 are autosomal gers or 3/4/5 fingers fusion) usually involves soft tissue
recessive,1 and SD5 is X-linked recessive.26 Generally, auto- and only the hands1: specifically, there is complete, bilat-
somal dominant phenotypes are less severe with variable eral syndactyly between the fourth and fifth fingers, the
expressivity and incomplete penetrance. fifth finger is often shortened, and the middle digit may
be missing or underdeveloped.10 SD3 usually involves the
connexin-43 (GJA1) gene at the chr6q21-3 and sometimes
NONSYNDROMIC DACTYLIES: PHENOTYPES chr6q22-24 loci.30 SD3 has been studied in a Pakistani fam-
AND GENETICS ily.30 This type exhibits autosomal dominant inheritance
with complete penetrance.1
Syndactyly
Nonsyndromic syndactyly manifests itself as 9 distinct Syndactyly Type IV
types; at least 11 loci and 8 relevant genes have been iden- Syndactyly type IV (SD4; Haas type1) is very rare.34 It is
tified27 (Fig. 1). complete and bilateral12; often, polydactyly is associated.10
No associated conditions of the feet or bone fusion have
Syndactyly Type I been mentioned.10 SD4 involves a range of genes, including
SD1 is one of the most common nonsyndromic syndac- the SHH signaling pathway, limb development membrane
tylies28 and is associated with the third and fourth fingers or protein 1 (LMBR1), and the zone of polarizing activity
the second and third toes.28 SD1 is so diverse that it can be (ZPA) regulatory sequence (ZRS) locus at chr7q36.3.30 It
divided into 4 subtypes.28 Subtype 1 (Weidenreich type or can also further be divided into 2 subtypes: SDTY4 (Haas
zygodactyly) accounts for 70% of nonsyndromic syndactyly type) and Andersen-Hansen type. The former usually in-
cases1,29; it is bilateral, symmetrical, found exclusively in the volves the ZRS locus and LMBR1, while the genetic basis of
feet, and free of bone involvement. Subtype 1 is associated the latter is not known.30 This syndactyly has been studied
with the 3p21.31 locus, but no disease-causing gene has in Chinese families.35 SD4 is autosomal dominant.1

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Ahmed et al. • Genetics of Polydactyly and Syndactyly

Fig. 1. Summary of nonsyndromic and selected syndromic syndactyly with their known causal genes.

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Syndactyly Type V with chr17p13.3. No causative gene has been pinpointed.31

Syndactyly type V (SD5; Dowd type) is another rare It has been studied in Turkish and Pakistani families.42 SD9
form of syndactyly. This syndactyly is usually complete is inherited in an autosomal recessive fashion.1
and involves fusion of both cutaneous and bony tissue.10 Novel cases may necessitate expanded classification
Soft-tissue syndactyly affects the third and fourth fingers schemes. For example, Avina and Hernandez43 described
and the second and third toes; conversely, the metacar- a case they believe constitutes a new nonsyndromic syn-
pals and metatarsals are most commonly fused in the case dactyly.
of the fourth and fifth or third and fourth digits.10 Some-
times, this syndactyly exists without metatarsal fusion, but Polydactyly
in this case, there are usually other foot abnormalities.10 Polydactyly is classified into 3 main phenotypes: pre-
SD5, like SD1 and SPD, usually involves HOXD13 (namely axial, central, and postaxial44 (Fig. 2). Preaxial polydactyly
a c.950A>G mutation or a polyalanine expansion as per (medial ray polydactyly) usually includes the thumb44 and
SPD). The locus affected is usually chr2q31.30 This syndac- can manifest itself in 1 of 4 types (types 1, 2, 3, and 4).45 It
tyly has been studied in a Han Chinese family.14 SD5 is in- tends to be associated with GLI3 on chr7p13 and SHH on
herited in an autosomal dominant manner.1 chr7q36. Central polydactyly (also “central ray” polydac-
tyly) is associated with syndactyly and cleft hand.45 It domi-
Syndactyly Type VI nantly appears syndromically. Finally, postaxial polydactyly
Syndactyly VI (SD6; mitten hand syndactyly) is perhaps (lateral ray polydactyly) is characterized by a hypoplastic
the least researched type. It is typically unilateral36; as its
or fully developed little finger, is often bilateral, can be
name suggests, it affects the second through fifth digits,36
simple or complex, and tends to be associated with foot
generating a mitten-like appearance. The genetic basis of
deformations44a; it can also manifest in 2 types (types A
SD6 is unknown.30 It has an autosomal dominant mode of
and B).46 It is associated with GLI3 on chr7p13, and PAPA2
inheritance with reductive penetrance.1
and PAPA3 on chr13q21-q32 and chr19p13.2-p13.1, re-
Syndactyly Type VII
spectively. It is also associated with SHH mutations, MI-
Syndactyly VII (SD7) is another very rare phenotype.1 POLI, and PITXI.30
It is similar to Apert syndrome but includes additional,
severe shortening and fusion of the ulna and radius, as SYNDROMIC DACTYLIES: PHENOTYPES
well as fusion of the metacarpals and disorganized pha- AND GENETICS
langeal development.10 The SD7 syndactyly group appears
to contain 2 phenotypes: one involving a “spoon hand,” Acrocephalosyndactyly
and the other an oligodactyly.37 It is sometimes similar Acrocephalosyndactyly syndromes are characterized
to SPD1.38 SD7 usually involves formin 1 (FMN1) and by craniosynostosis (early fusion of skull bones) alongside
gremlin 1 (GREM1) on chr15q13.3 on,1 as well as low- syndactyly and polydactyly. Apert syndrome is primarily
density lipoprotein receptor–related protein 4 (LRP4) on characterized by craniosynostosis and syndactyly in which
chr11p12-p11.2. Specifically, SD7 can be subdivided into 2 fingers and toes are either entirely fused or webbed. At
types: Cenani-Lenz type (spoon-hand type) and oligodac-
minimum 3 digits on each hand and foot are fused to-
tyly type. The former is usually associated with LRP4 muta-
gether, though all digits can be fused. Polydactyly is less
tions, whereas the latter is usually associated with GREM1
commonly found in Apert. Apert is associated with FGFR2
and FMN1 mutations.29 This type has been studied in a
mutations on chr10q26.1346 and autosomal dominant in-
Pakistani family30; LRP4 mutations have been studied in
heritance.
cows, as well.39 This syndactyly type is autosomal recessive
in inheritance, but sometimes also autosomal dominant.1 Carpenter syndrome is another manifestation of cra-
niosynostosis, involving a pointed head (acrocephaly)
Syndactyly Type VIII and, severely, a cloverleaf skull. Typically, Carpenter syn-
Syndactyly VIII (SD8) is not common40 and involves fu- drome involves cutaneous syndactyly between 2 or more
sion of the fourth and fifth metacarpals.10 It can be divided fingers or toes, most commonly between the third and
into 2 subtypes: Orel-Holmes type and Lerch type. SD8 is fourth fingers. Polydactyly most often occurs next to the
associated with chrXq26 and the split hand/foot malfor- first or second toe or fifth finger. Carpenter syndrome is
mation type 2 (SHFM2) gene. It has also been associated typically associated with RAB23 at the chr6p11.2 locus47
with 2 nonsense mutations p.R179X and p.S157X in exon and is primarily autosomal recessive.
3 of the FGF16 gene on chrXq21.1.29 FGF16 is known to Pfeiffer syndrome, a third kind of craniosynostosis, re-
function in limb development. It has been studied in both sults in a misshapen head and face, and is most commonly
Polish and German families.41 SD8 is autosomal dominant associated with syndactyly. It is associated with FGFR1 on
in inheritance.1 chr8p11.23 and FGFR2 on chr10q26.1348 and presents
with autosomal dominant inheritance.
Syndactyly Type IX Finally, Saethre-Chotzen syndrome is dominantly char-
Finally, syndactyly IX (SD9; mesoaxial synostotic syndac- acterized by craniosynostosis but also involves syndactyly
tyly or Malik-Percin type) is another highly rare form and between the second and third fingers on each hand, and
has only been described in 2 families.10 SD9 is associated polydactyly involving a duplicated first toe. It is associated

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Ahmed et al. • Genetics of Polydactyly and Syndactyly

Fig. 2. Summary of nonsyndromic and selected syndromic polydactyly with their known causal genes.

with TWIST1 on chr7p21.1 and FGFR2 on chr10q26.1349 and IFT172 on chr2p23.3. These syndromes typically present
and presents with autosomal dominant inheritance. with autosomal recessive or digenic recessive inheritance.

Bardet-Biedl Syndrome Greig Cephalopolysyndactyly Syndrome

Bardet-Biedl syndrome (BBS) is associated with syn- Greig cephalopolysyndactyly syndrome is another limb-
dactyly and polydactyly in both the fingers and the toes. anomaly-heavy disorder, involving the limbs, the head,
BBS can result from mutations in at least 20 genes. It is as- and the face. Polydactyly of the finger or toes as well as
sociated with CCDC28B on chr1p35.2, ARL6 on chr3q11.2, cutaneous syndactyly are common. Greig cephalopolysyn-
BBS1 on chr11q13.2, BBS2 on chr16q13, BBS6 (MKKS) dactyly is associated with GLI3 mutations on chr7p14.150
on chr20p12.2, BBS10 on chr12q21.2, BBS9 (PTHB1) on and is primarily autosomal dominant.
chr7p14.3, BBS4 on chr15q24.1, BBS7 on chr4q27, BBS5 on
chr2q31.1, MKS1 on chr17q22, BBS8 (TTC8) on chr14q31.3, McKusick-Kaufman Syndrome
SDCCAG8 on chr1q43-q44, LZTFL1 on chr3p21.31, WD- McKusick-Kaufman syndrome is characterized by 3 fea-
PCP on chr2p15, BBS4 on chr15q24.1, BBS12 on chr4q27, tures: heart defects, genital abnormalities, and polydacty-
TMEM67 on chr8q22.1, CEP290 on chr12q21.32, TRIM32 ly. McKusick-Kaufman syndrome is associated with MKKS
on chr9q33.1, BBIP1 on chr10q25.2, chr22q12.3 on IFT27, on chr20p12.251 and autosomal recessive inheritance.

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Fig. 3. The phenotypic manifestations of 2 of the 3 nonsyndromic polydactylies (preaxial and postaxial) and their subtypes. Adapted with
permission from Hand Malformations [Internet]. Gainesville: University of Florida. Available at https://www.peds.ufl.edu/divisions/genet-
ics/teaching/hand_malformations.htm.

Pallister-Hall Syndrome on chr15q13, and Ellis van Creveld syndrome is associ-

Pallister-Hall syndrome is characterized by an assortment ated with LBN (EVC) on chr4p16.2. Saldino-Noonan and
of developmental defects, including polydactyly and cuta- Majewski syndromes result from DYNC2H1 mutations on
neous syndactyly. Pallister-Hall syndrome is associated with chr11q22.3.54 These syndromes are typically digenic and
GLI3 on chr7p14.152 and autosomal dominant inheritance. autosomal recessive.

Poland Syndrome Smith-Lemli-Opitz Syndrome

Poland syndrome involves underdeveloped muscles Smith-Lemli-Opitz syndrome is characterized by several
and hand abnormalities, including syndactyly. The genetic affected body parts. Syndactyly primarily affects the second
basis of Poland syndrome appears to be unknown, but this and third toes, and polydactyly affects either fingers or toes.
syndrome exhibits autosomal dominant inheritance.53 This syndrome is associated with DHCR7 on chr11q13.455
and presents with autosomal recessive inheritance.
Short-Rib Polydactyly
Short-rib polydactyly syndromes are characterized Triphalangeal Thumb-Polydactyly Syndrome
by a narrow thorax as well as preaxial polydactyly. They Triphalangeal thumb-polydactyly syndrome is a hand-
include Jeune syndrome, Ellis van Creveld syndrome, foot malformation characterized by pre- and postaxial
Saldino-Noonan syndrome (Verma-Naumoff syndrome), polydactyly, isolated syndactyly, complex polydactyly, and
and Majewski syndrome. These syndromes are largely triphalangeal thumbs. Typically, the hands are more affect-
phenotypically heterogeneous but are all characterized ed. This syndrome is associated with LMBR1 on chr7q36.3
by polydactyly. Jeune syndrome is associated with ATD1 and presents with autosomal dominant inheritance.

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Ahmed et al. • Genetics of Polydactyly and Syndactyly

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