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Special Article

Malformations affecting the limbs and particularly thenumber of digits are the most frequent congenitalmalformation in human occurring in about one in 1000neonates.1 Polydactyly implies the occurrence ofsupernumerary digits whereas oligodactyly indicatessevere underdevelopment or less than normal numberof digits. The anomalies of number of digits can beisolated or can occur in association with otheranomalies as a part of a syndrome. LondonDysmorphology Database lists 221 syndromes withpolydactyly and 120 syndromes with oligodactyly. Thecommonly seen syndromes with digit anomalies areGreig syndrome, Bardet Biedl syndrome, Cornelia deLange syndrome, ectrodactyly – ectodermal dysplasia –clefting syndrome (EEC), oro-facio-digital syndromesand short rib polydactyly syndromes. Many of thesesyndromes have some common features. Syndromes ofpolydactyly associated with midline malformationinclude Pallister Hall syndrome, acrocallosal syndrome,orofaciodigital syndromes, hydrolethalus syndrome,pseudotrisomy syndrome and short rib polydactylysyndromes. Cases with features overlapping with twoor more syndromes have been reported.2 The clinicalsimilarity indicates possibility of a common causativegene or genes involved in a common pathway. The

Polydactyly and Genes

Shubha R. Phadke and V.H. Sankar1

Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow; 1Depart-ment 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 lotof information about genes involved in development is available now. Genetics of hand development and genes involved inpolydactyly syndromes is discussed in this article as a prototype to know about genetics of malformations: how it is studiedand what is known. Genetic and chromosomal defects are often associated with congenital malformations. Polydactyly isone of the commonly seen malformations and genetic defects of many malformation syndromes associated withpolydactyly are known. The role of genetic defect in polydactyly syndromes and the correlation between genotypes andphenotypes is discussed in this review article. [Indian J Pediatr 2010; 77 (3) : 277-281] E-mail: [email protected]

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

identification of causative genes for malformationsyndromes and study of function of these genes areimportant ways to know about normal organogenesisand genes involved in the development. At present a lotof information is available about genetics of limbsdevelopment. We shall review the approaches to studydevelopmental genetics, limb development and genesidentified in syndrome with polydactyly.

AN APPROACH TO THE MOLECULAR BASIS OFDEVELOPMENT

Molecular basis of genetic syndromes andpolydactyly: The complete information regardingsequence of human genome is available now. Using thisinformation and various gene mapping strategies likelinkage analysis, positional cloning and use ofchromosomal anomalies associated with malformationsyndromes, number of genes causing limb anomalieswere identified (Table 1). At present, 84 genesassociated with syndromes with limb defects areidentified. Out of these, 15 genes are associated withsyndromes of polydactyly.2 The other approach tounderstand developmental genetics is animal studies.Mouse mutants carrying individual human mutationteam up to provide understanding of vertebrate limbdevelopment. These mouse mutants are obtained byknocking out (mutating) a gene to be studied and thenanalyzing the phenotype of the knock out mouse.Animal studies also provide an opportunity to studyexpression of genes in various parts of the body at

Correspondence and Reprint requests : Dr. Shubha R. Phadke,Professor, Department of Medical Genetics, Sanjay GandhiPostgraduate Institute of Medical Sciences, Lucknow-226014,UP, India.

[DOI-10.1007/s12098-010-0033-1]

[Received April 16, 2008; Accepted August 26, 2008]

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278 Indian Journal of Pediatrics, Volume 77—March, 2010

different periods of organogenesis and thus provideinformation regarding functions of various genes andtheir role in development.

Genetics of hand development

Using the various approaches mentioned aboveconsiderable amount of information is available aboutdevelopment of limbs3, 4, 5 and also of heart,6 brain,7,8 andvertebral 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, Frontal bossingFeet: preaxial polydactyly,Hands: rare, post axialpolydactyly minumus

2. Pallister Hall syndrome GLI 3 Central or more rarely postaxial Hypothalamic hamartoma,polydactyly and syndactyly Multiple malformations of gut,laryngeal cleft, ets.

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 Growth/mental retardation,of toes II-III multiple malformations,

dysmorphism, ambiguousgenitalia (in male)

6. Ellis Van Crevald syndrome EVC, EVC2 Short limbs, postaxial polydactyly Cardiac defects, dysplastic nailsand absent teeth, short ribs

7. Ectrodactyly, Ectodermal TP63 Ectrodactyly(typically median Ectodermal dysplasia,Cleft lip/dysplasia, cleft/cleft palate rays absent /hypoplasia in palatesyndrome hands and feet)

8. Split hand- feet malformation TP63 Ectrodactyly(typically median Nil(SHFM) rays absent /hypoplasia in

hands and feet)

9. Acro-dermo-ungual-lacrimal- TP63 EctrodactylySyndactyly Ectodermal dysplasia,Hypoplastictooth (ADULT) syndrome breasts and nipple, Freckling

10. Ankyloblepharon- Ectodermal TP63 Ectrodactyly Ectodermal dysplasia,dysplasia-clefting (AEC) Ankyloblepharonsyndrome

11. Acrodental syndrome EVC postaxial polydactyly Dysplastic nails and teeth

12. Oro-facial-digital syndrome 1 CXORF5 Postaxial polydactyly, syndactyly, Mental retardation, multipleclinodactyly, brachydactyly frenulae, lobulated tongue

13. Bardet- Biedl syndrome BBS1,2,3,4,5,6 Post axial polydactyly Mental retardation, pigmentaryretinopathy, Obesity,hypogonadism

14. McKusick-Kaufman syndrome MKKS Post axial polydactyly Cardiac defects,Hydrometrocolpos

15. Gorlin syndrome PTCH Pre/ Post axial polydactyly, Nevoid basal cell carcinomasyndactyly of toes II-III,inconstant shortening of 4th

metacarpal

16. Synpolydactyly HOXD13 poly/syndactyly numerouscarpal, metacarpal andphalangeal abnormalities —

17. Rubinstein-Taybi syndrome CREBBP Broad, deviated thumbs and Mental retardationTypical facialgreat toes, Rare feet preaxial dysmorphismpolydactyly

18. Meckel- Gruber syndrome MKS1 Polydactyly (usually postaxial), Occipital encephalomeningocele,talipus equino varus Microphthalmia,Renal dysplasia



embryonic limb bud. Limb development includes limbinitiation and growth (proximo-distal axis) and itspolarization in anteroposterior and dorsoventral axis. Itinvolves several coordinated processes characterizedby a constant equilibrium between cell mitotic activityand programmed cell death. Limb bud formation andgrowth (proximo-distal axis) are due to rapid cellproliferation in the progress zone (PZ) induced by theoverlying apical ectodermal ridge (AER). The proximo-distal growth is closely linked to polarization along theanteroposterior axis (under control of zone ofpolarizing activity, ZPA) and the dorosoventral axis(limb patterning). The limb development involvescoordinated functioning of various interlinked geneswhich work by forming network of signals.

In the mouse, HOXb5 inactivation results indisplacement of the shoulder to rostral positions,indicating that it may be playing an important role inpositioning of limb. Fibroblast growth factors (FGFs) areknown to play an important role in limb initiation andgrowth. In FGF-10 deficient mice, limb bud formation isinitiated but AER and ZPA are not formed resulting incomplete truncation of limbs. The important gene inestablishment of anteroposterior polarity is sonichedgehog (SHH) gene.11 Its expression is confined to theZPA. A number of molecules involved in SHH pathwayare known, and include patched-1, smoothened, GL1-1,GLI-2, GLI-3 and twist.12 The disorders caused bymutations in these genes include holoprosencephaly,syndrome of polydactyly (discussed later), Rubinstein –Taybi syndrome and Saethre-Chotzen syndrome (ofcarniosynostosis) and also include various cancersnamely, basal cell carcinoma, glioblastoma, medullo-blastoma, osteosarcoma, rhabdomyosarcoma etc. TheSHH protein needs addition of a cholesterol moiety foractivation and defects in biosynthesis of cholesterolleads to Smith-Lemli-Opitz syndrome which haspolydactyly as a feature similar to disorders caused bymutations in SHH pathway.

As compared to anteroposterior axis, little is knownabout dorsoventral axis. A double dorsal phenotype isobserved in the case of an engrailed (En1) mutations13

and double ventral phenotype in case of Winglessrelated MMTV integration site 7A (wnt 7A) or LIMhomeobox transcription factor-1 (Lmx1b) mutation.LMX1B mutation has been identified in nail patellasyndrome in humans.14

The other genes involved in morphogenesis andpatterning of limb include T-box transcription factors(TBX), bone morphogenetic proteins (BMP), homeboxgenes (HOXD9, HOXD13, HOXA), noggin, cartilagederived morphogenetic protein (CDMP1) or growthdifferentiation factor 5 (gdf5). Mutations in T-box genesare associated with Holt Oram syndrome (TBX5) andUlnar Mammary syndrome (TBX3).6 In transgenic mice

with homozygous deletion of noggin (NOG), the budcartilage hypertrophies and joints fail to develop. Inhumans heterozygous mutation of noggin have beenidentified in syndrome with joint synostosis namely,proximal symphalangism, multiple synostosis andtarsal- carpal coalition syndrome.15 Mice withhomozygous mutation of Gdf5 have abnormal lengthand number of distal limb bones and the Gdf5 mutationin humans are responsible for syndromes withshortening of digital limb segments and digits namelyacromesomelic dysplasia, Grebe dysplasia andbrachydactyly type C.16

Polydactyly and genes

Polydactyly affecting thumb or great toe is classified aspreaxial or radial/tibial while presence of extra digit onulnar side is labeled as postaxial or ulnar/fibularpolydactyly. Temtamy and Mckusick have classifiedulnar polydactyly into types A and B, based on the extradigit being either well developed or rudimentary.17

Mirror image polydactyly is duplication of ulna/ fibulaand there is agenesis of radius/tibia. Autosomalrecessively inherited unusual type of complex handmalformation (OMIM No.607539) associated withpolydactyly arising from dorsum of hand is alsoreported.18 Synpolydactyly is an autosomal dominanttype of hand malformation caused by mutation inHOXD13 gene.19

Oligodactyly

Oligodactyly is the severe underdevelopment orabsence of one or more digits. Ectrodactyly issynonymously used with split hand/foot malformationto describe absence of central digital rays. Oligodactylyoccurs as an isolated finding or as a feature of manysyndromes. Some conditions are clearly genetic inorigin while in others it is a sporadic developmentalabnormality and may be a result of a disruptive process.Teratogenic insults, impaired blood flow, and amnioticbands are important causes of oligodactyly.

The list of genes associated with limb malformationis available on http://www.ijdbchu.as/abstract.0207/esm1grzeschik.htm.3 Biesecker has compiled list ofsyndromes associated with polydactyly along with thecausative genes.2 Among 39 entries associated withknown causative mutations, 36 are syndromic and 3are non syndromic. It has become clear that similarphenotypes can be caused by mutations in differentgenes, the example being Bardet Biedl syndrome (BBS).Six loci for BBS have been identified till date.20 This isknown as genetic heterogeneity. On the other handdifferent mutations in a single gene can give rise toclinically different diseases. GL1-3 mutations can causeGreig cephalopolysyndactyly syndrome (GCPS),Pallister Hall syndrome (PHS) and postaxialpolydactyly type A/B and non syndromic preaxial

Shubha R. Phadke and V.H. Sankar

280 Indian Journal of Pediatrics, Volume 77—March, 2010

polydactyly.21, 22, 23 The phrase “GL13 morphopathies”was coined to describe the phenotypes caused by GL1-3 mutations.24 Some amount of genotype – phenotypecorrelation has been observed in GLI-3 morphopathies.Mutations in first third of GLI3 gene cause GCPS andthose in second third of gene cause PHS.22 TP63 geneand syndromes caused by mutation in it, namely, spilthand foot malformation (SHFM), ectrodactylyectodermal dysplasia (EEC), Acro-dermo-ungual-lacrimal-tooth (ADULT) syndrome, ankyloblepharon-ectodermal dysplasia-clefting (ACE) syndrome isanother example of one gene - multiple phenotype.25

The observation of one gene-many phenotypes andone phenotype-many genes has been observed inpolydactyly syndromes. Similar observation in othergenetic disorders has brought out the limitations ofpresent disease nomenclature. So it has becomeessential to incorporate phenotype label along withgenotype into the diagnosis of a patient to avoidconfusion.2 One more interesting concept of geneticshas been identified through genetics of polydactylysyndromes. This is the concept of triallelic inheritancewhich is a type of non Mendelian inheritance.26 BBSwas considered to be inherited in autosomal recessivemanner. But two allelic mutations on one BBS gene anda third mutation in another BBS gene are required forthe disease phenotype to manifest. This was describedas “recessive inheritance with a modifier penetrance”by Burghes et al.27 Triallelic inheritance may represent atransmission model that bridges classic Mendeliandisorder with complex traits.27

CONCLUSION

Human limb malformations, like other congenitalanomalies are frequently associated with defects inother organs. This is because they are caused bymutations that affect important signaling pathwaysrepetitively used during embryonic development atdifferent times and different locations.1, 3, 5 Theidentification of genes for malformation syndromeprovides an opportunity to peep into the complexdevelopmental processes involved in limbdevelopment. Key genes and some of their interactionshave been identified. How many genes are involved inlimb development is yet to be known.2 Variousphenotypes in humans, knock out animal models andstudies on animal embryos are the important tools tounderstand the developmental biology.

Conflict of Interest: None.

Role of Funding Source : None.

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