Special Article

Polydactyly and Genes

Shubha R. Phadke and V.H. Sankar1
Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow; 1Department of Pediatrics, Government Medical College, Thiruvananthapuram, Kerala, India

ABSTRACT
Pediatricians deal with cases with the congenital malformations and malformation syndromes interest many of them. A lot
of information about genes involved in development is available now. Genetics of hand development and genes involved in
polydactyly syndromes is discussed in this article as a prototype to know about genetics of malformations: how it is studied
and what is known. Genetic and chromosomal defects are often associated with congenital malformations. Polydactyly is
one of the commonly seen malformations and genetic defects of many malformation syndromes associated with
polydactyly are known. The role of genetic defect in polydactyly syndromes and the correlation between genotypes and
phenotypes is discussed in this review article. [Indian J Pediatr 2010; 77 (3) : 277-281] E-mail: shubha@sgpgi.ac.in

Key words: Polydactyly; Genes in polydactyly; Limb development; Genetics; GLI3

Malformations affecting the limbs and particularly the

number of digits are the most frequent congenital
malformation in human occurring in about one in 1000
neonates. 1 Polydactyly implies the occurrence of
supernumerary digits whereas oligodactyly indicates
severe underdevelopment or less than normal number
of digits. The anomalies of number of digits can be
isolated or can occur in association with other
anomalies as a part of a syndrome. London
Dysmorphology Database lists 221 syndromes with
polydactyly and 120 syndromes with oligodactyly. The
commonly seen syndromes with digit anomalies are
Greig syndrome, Bardet Biedl syndrome, Cornelia de
Lange syndrome, ectrodactyly ectodermal dysplasia
clefting syndrome (EEC), oro-facio-digital syndromes
and short rib polydactyly syndromes. Many of these
syndromes have some common features. Syndromes of
polydactyly associated with midline malformation
include Pallister Hall syndrome, acrocallosal syndrome,
orofaciodigital syndromes, hydrolethalus syndrome,
pseudotrisomy syndrome and short rib polydactyly
syndromes. Cases with features overlapping with two
or more syndromes have been reported. 2 The clinical
similarity indicates possibility of a common causative
gene or genes involved in a common pathway. The

Correspondence and Reprint requests : Dr. Shubha R. Phadke,

Professor, Department of Medical Genetics, Sanjay Gandhi
Postgraduate Institute of Medical Sciences, Lucknow-226014,
UP, India.
[DOI-10.1007/s12098-010-0033-1]
[Received April 16, 2008; Accepted August 26, 2008]

Indian Journal of Pediatrics, Volume 77March, 2010

identification of causative genes for malformation

syndromes and study of function of these genes are
important ways to know about normal organogenesis
and genes involved in the development. At present a lot
of information is available about genetics of limbs
development. We shall review the approaches to study
developmental genetics, limb development and genes
identified in syndrome with polydactyly.
AN APPROACH TO THE MOLECULAR BASIS OF
DEVELOPMENT
Molecular basis of genetic syndromes and
polydactyly: The complete information regarding
sequence of human genome is available now. Using this
information and various gene mapping strategies like
linkage analysis, positional cloning and use of
chromosomal anomalies associated with malformation
syndromes, number of genes causing limb anomalies
were identified (Table 1). At present, 84 genes
associated with syndromes with limb defects are
identified. Out of these, 15 genes are associated with
syndromes of polydactyly. 2 The other approach to
understand developmental genetics is animal studies.
Mouse mutants carrying individual human mutation
team up to provide understanding of vertebrate limb
development. These mouse mutants are obtained by
knocking out (mutating) a gene to be studied and then
analyzing the phenotype of the knock out mouse.
Animal studies also provide an opportunity to study
expression of genes in various parts of the body at
277

Shubha R. Phadke and V.H. Sankar

different periods of organogenesis and thus provide
information regarding functions of various genes and
their role in development.
Genetics of hand development

Using the various approaches mentioned above

considerable amount of information is available about
development of limbs3, 4, 5 and also of heart,6 brain,7,8 and
vertebral column. 9,10 The limbs develop from an

TABLE 1. Syndromes with Polydactyly and Oligodactyly Along with the Causative Genes
Sl No Syndrome

Gene

Limb phenotype

Associated features

1.

Greig Cephalopolysyndactyly

GLI 3

Hands and feet: syndactyly,

Feet: preaxial polydactyly,
Hands: rare, post axial
polydactyly minumus

Frontal bossing

2.

Pallister Hall syndrome

GLI 3

Central or more rarely postaxial

polydactyly and syndactyly
laryngeal cleft, ets.

Hypothalamic hamartoma,
Multiple malformations of gut,

3.

Postaxial polydactyly type A1

GLI3

Postaxial polydactyly

Nil

4.

Preaxial polydactyly type IV

GLI3

Preaxial polydactyly

Nil

5.

Smith Lemli Opitz syndrome

DHCR7

Postaxial polydactyly, syndactyly

of toes II-III

Growth/mental retardation,
multiple malformations,
dysmorphism, ambiguous
genitalia (in male)

6.

Ellis Van Crevald syndrome

EVC, EVC2

Short limbs, postaxial polydactyly

Cardiac defects, dysplastic nails

and absent teeth, short ribs

7.

Ectrodactyly, Ectodermal
dysplasia, cleft/cleft palate
syndrome

TP63

Ectrodactyly(typically median
rays absent /hypoplasia in
hands and feet)

Ectodermal dysplasia,Cleft lip/

palate

8.

Split hand- feet malformation

(SHFM)

TP63

Ectrodactyly(typically median
rays absent /hypoplasia in
hands and feet)

Nil

9.

Acro-dermo-ungual-lacrimaltooth (ADULT) syndrome

TP63

EctrodactylySyndactyly

Ectodermal dysplasia,Hypoplastic
breasts and nipple, Freckling

10.

Ankyloblepharon- Ectodermal
dysplasia-clefting (AEC)
syndrome

TP63

Ectrodactyly

Ectodermal dysplasia,
Ankyloblepharon

11.

Acrodental syndrome

EVC

postaxial polydactyly

Dysplastic nails and teeth

12.

Oro-facial-digital syndrome 1

CXORF5

Postaxial polydactyly, syndactyly,

clinodactyly, brachydactyly

Mental retardation, multiple

frenulae, lobulated tongue

13.

Bardet- Biedl syndrome

BBS1,2,3,4,5,6 Post axial polydactyly

Mental retardation, pigmentary

retinopathy, Obesity,
hypogonadism

14.

McKusick-Kaufman syndrome

MKKS

Post axial polydactyly

Cardiac defects,
Hydrometrocolpos

15.

Gorlin syndrome

PTCH

Pre/ Post axial polydactyly,

syndactyly of toes II-III,
inconstant shortening of 4th
metacarpal

Nevoid basal cell carcinoma

16.

Synpolydactyly

HOXD13

poly/syndactyly numerous
carpal, metacarpal and
phalangeal abnormalities

17.

Rubinstein-Taybi syndrome

CREBBP

Broad, deviated thumbs and

great toes, Rare feet preaxial
polydactyly

Mental retardationTypical facial

dysmorphism

18.

Meckel- Gruber syndrome

MKS1

Polydactyly (usually postaxial),

talipus equino varus

Occipital encephalomeningocele,
Microphthalmia,Renal dysplasia

278

Indian Journal of Pediatrics, Volume 77March, 2010

Polydactyly and Genes

embryonic limb bud. Limb development includes limb
initiation and growth (proximo-distal axis) and its
polarization in anteroposterior and dorsoventral axis. It
involves several coordinated processes characterized
by a constant equilibrium between cell mitotic activity
and programmed cell death. Limb bud formation and
growth (proximo-distal axis) are due to rapid cell
proliferation in the progress zone (PZ) induced by the
overlying apical ectodermal ridge (AER). The proximodistal growth is closely linked to polarization along the
anteroposterior axis (under control of zone of
polarizing activity, ZPA) and the dorosoventral axis
(limb patterning). The limb development involves
coordinated functioning of various interlinked genes
which work by forming network of signals.
In the mouse, HOXb5 inactivation results in
displacement of the shoulder to rostral positions,
indicating that it may be playing an important role in
positioning of limb. Fibroblast growth factors (FGFs) are
known to play an important role in limb initiation and
growth. In FGF-10 deficient mice, limb bud formation is
initiated but AER and ZPA are not formed resulting in
complete truncation of limbs. The important gene in
establishment of anteroposterior polarity is sonic
hedgehog (SHH) gene.11 Its expression is confined to the
ZPA. A number of molecules involved in SHH pathway
are known, and include patched-1, smoothened, GL1-1,
GLI-2, GLI-3 and twist. 12 The disorders caused by
mutations in these genes include holoprosencephaly,
syndrome of polydactyly (discussed later), Rubinstein
Taybi syndrome and Saethre-Chotzen syndrome (of
carniosynostosis) and also include various cancers
namely, basal cell carcinoma, glioblastoma, medulloblastoma, osteosarcoma, rhabdomyosarcoma etc. The
SHH protein needs addition of a cholesterol moiety for
activation and defects in biosynthesis of cholesterol
leads to Smith-Lemli-Opitz syndrome which has
polydactyly as a feature similar to disorders caused by
mutations in SHH pathway.
As compared to anteroposterior axis, little is known
about dorsoventral axis. A double dorsal phenotype is
observed in the case of an engrailed (En1) mutations13
and double ventral phenotype in case of Wingless
related MMTV integration site 7A (wnt 7A) or LIM
homeobox transcription factor-1 (Lmx1b) mutation.
LMX1B mutation has been identified in nail patella
syndrome in humans.14
The other genes involved in morphogenesis and
patterning of limb include T-box transcription factors
(TBX), bone morphogenetic proteins (BMP), homebox
genes (HOXD9, HOXD13, HOXA), noggin, cartilage
derived morphogenetic protein (CDMP1) or growth
differentiation factor 5 (gdf5). Mutations in T-box genes
are associated with Holt Oram syndrome (TBX5) and
Ulnar Mammary syndrome (TBX3).6 In transgenic mice
Indian Journal of Pediatrics, Volume 77March, 2010

with homozygous deletion of noggin (NOG), the bud

cartilage hypertrophies and joints fail to develop. In
humans heterozygous mutation of noggin have been
identified in syndrome with joint synostosis namely,
proximal symphalangism, multiple synostosis and
tarsal- carpal coalition syndrome. 15 Mice with
homozygous mutation of Gdf5 have abnormal length
and number of distal limb bones and the Gdf5 mutation
in humans are responsible for syndromes with
shortening of digital limb segments and digits namely
acromesomelic dysplasia, Grebe dysplasia and
brachydactyly type C.16
Polydactyly and genes
Polydactyly affecting thumb or great toe is classified as
preaxial or radial/tibial while presence of extra digit on
ulnar side is labeled as postaxial or ulnar/fibular
polydactyly. Temtamy and Mckusick have classified
ulnar polydactyly into types A and B, based on the extra
digit being either well developed or rudimentary. 17
Mirror image polydactyly is duplication of ulna/ fibula
and there is agenesis of radius/tibia. Autosomal
recessively inherited unusual type of complex hand
malformation (OMIM No.607539) associated with
polydactyly arising from dorsum of hand is also
reported.18 Synpolydactyly is an autosomal dominant
type of hand malformation caused by mutation in
HOXD13 gene. 19
Oligodactyly
Oligodactyly is the severe underdevelopment or
absence of one or more digits. Ectrodactyly is
synonymously used with split hand/foot malformation
to describe absence of central digital rays. Oligodactyly
occurs as an isolated finding or as a feature of many
syndromes. Some conditions are clearly genetic in
origin while in others it is a sporadic developmental
abnormality and may be a result of a disruptive process.
Teratogenic insults, impaired blood flow, and amniotic
bands are important causes of oligodactyly.
The list of genes associated with limb malformation
is available on http://www.ijdbchu.as/abstract.0207/
esm1grzeschik.htm. 3 Biesecker has compiled list of
syndromes associated with polydactyly along with the
causative genes. 2 Among 39 entries associated with
known causative mutations, 36 are syndromic and 3
are non syndromic. It has become clear that similar
phenotypes can be caused by mutations in different
genes, the example being Bardet Biedl syndrome (BBS).
Six loci for BBS have been identified till date. 20 This is
known as genetic heterogeneity. On the other hand
different mutations in a single gene can give rise to
clinically different diseases. GL1-3 mutations can cause
Greig cephalopolysyndactyly syndrome (GCPS),
Pallister Hall syndrome (PHS) and postaxial
polydactyly type A/B and non syndromic preaxial
279

Shubha R. Phadke and V.H. Sankar

polydactyly.21, 22, 23 The phrase GL13 morphopathies
was coined to describe the phenotypes caused by GL13 mutations.24 Some amount of genotype phenotype
correlation has been observed in GLI-3 morphopathies.
Mutations in first third of GLI3 gene cause GCPS and
those in second third of gene cause PHS. 22 TP63 gene
and syndromes caused by mutation in it, namely, spilt
hand foot malformation (SHFM), ectrodactyly
ectodermal dysplasia (EEC), Acro-dermo-unguallacrimal-tooth (ADULT) syndrome, ankyloblepharonectodermal dysplasia-clefting (ACE) syndrome is
another example of one gene - multiple phenotype.25
The observation of one gene-many phenotypes and
one phenotype-many genes has been observed in
polydactyly syndromes. Similar observation in other
genetic disorders has brought out the limitations of
present disease nomenclature. So it has become
essential to incorporate phenotype label along with
genotype into the diagnosis of a patient to avoid
confusion.2 One more interesting concept of genetics
has been identified through genetics of polydactyly
syndromes. This is the concept of triallelic inheritance
which is a type of non Mendelian inheritance. 26 BBS
was considered to be inherited in autosomal recessive
manner. But two allelic mutations on one BBS gene and
a third mutation in another BBS gene are required for
the disease phenotype to manifest. This was described
as recessive inheritance with a modifier penetrance
by Burghes et al.27 Triallelic inheritance may represent a
transmission model that bridges classic Mendelian
disorder with complex traits.27

2.
3.

4.

5.
6.

7.

8.

9.
10.

11.

12.

13.

14.

CONCLUSION
15.

Human limb malformations, like other congenital

anomalies are frequently associated with defects in
other organs. This is because they are caused by
mutations that affect important signaling pathways
repetitively used during embryonic development at
different times and different locations. 1, 3, 5 The
identification of genes for malformation syndrome
provides an opportunity to peep into the complex
developmental processes involved in limb
development. Key genes and some of their interactions
have been identified. How many genes are involved in
limb development is yet to be known. 2 Various
phenotypes in humans, knock out animal models and
studies on animal embryos are the important tools to
understand the developmental biology.
Conflict of Interest: None.

16.
17.

18.

19.

20.

21.

Role of Funding Source : None.

22.

REFERENCES
1. Manouvrier-Hanu S. Limb developmental anomalies:

280

Genetics. In Cooper David N, ed. Nature encyclopedia of the

human genome. Vol. 3., Macmillan Publishers Ltd, 2003;
696-703.
Biesecker LG. Polydactyly: how many disorders and how
many genes? Am J Med Genet 2002; 112: 279-283.
Grzeschik KH. Human limb malformations; an approach to
the molecular basis of development. Int J Dev Biol 2002;46:
983-991.
Talamillo A, Bastida MF, Fernandez-Teran M, Ros MA. The
developing limb and the control of the number of digits.
Clin Genet 2005; 67: 143-153.
Goodman FR. Congenital abnormalities of body patterning:
embryology revisited. Lancet 2003; 362: 651-662.
Isphording D, Leylek AM, Yeung J, Mischel A, Simon HG. Tbox genes and congenital heart/limb malformations. Clin
Genet 2004;66 : 253-264. Erratum in Clin Genet 2004; 66: 577.
Rice DP. Craniofacial anomalies: from development to
molecular pathogenesis. Curr Mol Med 2005; 5: 699-722.
Review.
Cohen MM Jr. Malformations of the craniofacial region:
evolutionary, embryonic, genetic, and clinical perspectives.
Am J Med Genet 2002; 115: 245-268. Review.
Pourquie O, Kusumi K. When body segmentation goes
wrong. Clin Genet 2001; 60: 409-416. Review.
Martinez-Frias ML. Segmentation anomalies of the vertebras
and ribs: one expression of the primary developmental
field. Am J Med Genet A 2004; 128: 127-131.
Nieuwenhuis E, Hui CC. Hedgehog signaling and
congenital malformations. Clin Genet 2005; 67: 193-208.
Review.
Villavicencio EH, Walterhouse DO, Iannaccone PM. The
sonic hedgehog-patched-gli pathway in human development and disease. Am J Hum Genet 2000; 67: 1047-1054.
Loomis CA, Kimmel RA, Tong CX, Michaud J, Joyner AL.
Analysis of the genetic pathway leading to formation of
ectopic apical ectodermal ridges in mouse Engrailed-1
mutant limbs. Development 1998; 125: 1137-1148.
Dreyer SD, Zhou G, Baldini A et al. Mutations in LMX1B
cause abnormal skeletal patterning and renal dysplasia in
nail patella syndrome. Nat Genet 1998; 19: 47-50.
Marcelino J, Sciortino CM, Romero MF et al. Human
disease-causing NOG missense mutations: effects on noggin
secretion, dimer formation, and bone morphogenetic protein
binding. Proc Natl Acad Sci USA 2001; 98: 11353-11358.
Epub 2001 Sep 18.
Luyten FP. Cartilage-derived morphogenetic protein-1. Int
J Biochem Cell Biol 1997; 29: 1241-1244.
Temtamy S, Mckussick V. Polydactyly as an isolated
malformation. In Temtamy S, Mckussick V, eds. The
genetics of hand malformations. Birth defects. New York: Alan
R Liss, Inc.,1978; 14: 364-392.
Phadke SR, Gautam P.Complex camptopolydactyly: an
unusual hand malformation. Am J Med Genet 1999; 83: 191192.
Muragaki Y, Mundlos S, Upton J, Olsen BR. Altered growth
and branching patterns in synpolydactyly caused by
mutations in HOXD13. Science 1996; 272: 548-551.
Katsanis N, Lupski JR, Beales PL. Exploring the molecular
basis of Bardet-Biedl syndrome. Human Molecular Genetics
2001; 10: 2293-2299.
Biesecker LG. What you can learn from one gene: GLI3. J
Med Genet 2006; 43: 465-469.
Johnston JJ, Olivos-Glander I, Killoran C, Elson E, Turner JT,
Peters KF et al. Molecular and clinical analyses of Greig
cephalopolysyndactyly and Pallister-Hall syndromes:
robust phenotype prediction from the type and position of
GLI3 mutations. Am J Hum Genet 2005; 76: 609-622.

Indian Journal of Pediatrics, Volume 77March, 2010

Polydactyly and Genes

23. Fujioka H, Ariga T, Horiuchi K, Otsu M, Igawa H,
Kawashima K et al. Molecular analysis of non-syndromic
preaxial polydactyly: preaxial polydactyly type-IV and
preaxial polydactyly type-I. Clin Genet 2005; 67: 429-433.
24. Radhakrishna U, Bornholdt D, Scott HS, Patel UC, Rossier
C, Engel H et al. The phenotypic spectrum of GLI3
morphopathies includes autosomal dominant preaxial
polydactyly type-IV and postaxial polydactyly type-A/B;
No phenotype prediction from the position of GLI3
mutations. Am J Hum Genet 1999; 65: 645-655.

Indian Journal of Pediatrics, Volume 77March, 2010

25. Brunner HG, Hamel BC, Bokhoven Hv H. P63 gene

mutations and human developmental syndromes. Am J
Med Genet 2002; 112: 284-290.
26. Burghes AH, Vaessin HE, de La Chapelle A.Genetics. The
land between Mendelian and multifactorial inheritance.
Science 2001; 293: 2213-2214.
27. Katsanis N, Ansley SJ, Badano JL, Eichers ER, Lewis RA,
Hoskins BE et al. Triallelic inheritance in Bardet-Biedl
syndrome, a Mendelian recessive disorder. Science 2001;
293(5538): 2256-2259.

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