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: [email protected]

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]

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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 77—March, 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 77—March, 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.

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5. 6.

7.

8.

9. 10.

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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.

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