American Journal of Medical Genetics 126A:61–67 (2004)

A Novel Type of Autosomal Recessive Syndactyly:Clinical and Molecular Studies in a Familyof Pakistani Origin

Sajid Malik,1,2* Muhammad Arshad,2 Muhammad Amin-ud-Din,3 Frank Oeffner,1 Astrid Dempfle,4

Sayedul Haque,2 Manuela C. Koch,1 Wasim Ahmad,2 and Karl-Heinz Grzeschik1

1Zentrum fur Humangenetik, Philipps-Universitat Marburg, Marburg, Germany2Department of Biological Sciences, Quaid-I-Azam University, Islamabad, Pakistan3Department of Biology, Government College, DG Khan, Pakistan4Institut fur Medizinische Biometrie und Epidemiologie, Philipps-Universitat Marburg, Marburg, Germany

Non-syndromic syndactylies have been clas-sified into five major types (I–V), all showingautosomal dominant mode of inheritance.Later, the classification was extended andthree additional variants (VI–VIII) weredefined. Type VII, the Cenani–Lenz syndac-tyly, is the only non-syndromic, autosomalrecessive type. It is characterized by fusionof all phalanges with metacarpal synostosis,dislocated and dysplastic carpals and infre-quently, radio-ulnar fusion. Here, we pre-sent a Pakistani family with a novel non-syndromic autosomal recessive syndactylymanifesting a unique combination of clinicalfeatures. In both hands, reduction of certainphalanges is evident. Radiological examina-tion shows synostosis of third and fourthmetacarpals bearing single phalanges. Thefirst three toes are webbed, with hypoplas-tic terminal phalanx in all the toes. BesidesCenani–Lenz syndactyly, the phenotypesegregating in our family is the secondwell-documented autosomal recessive, non-syndromic syndactyly. A phenotype similarto our family was described in a Turkishkindred but was considered to be a homo-zygous expression of type I syndactyly. Sincethe clinical features in our family had mini-mal overlap with syndactyly types I, II, and

III, we have performed microsatellite mar-ker screening to look for the cosegregation ofthis phenotype with any of the known loci forthese respective types. We show that thephenotype in our family is not linked tochromosomal regions 2q34-q36, 2q31, and6q22-q23 encompassing loci for syndactylytypes I, II, and III. � 2003 Wiley-Liss, Inc.

KEY WORDS: autosomal recessive syndac-tyly; Pakistani family; link-age analysis; 2q34-q36; 2q31;6q22-q23

INTRODUCTION

Non-syndromic syndactyly is a common, heteroge-neous hereditary condition of webbed fingers and/ortoes. The malformation can be unilateral or bilateral,and the fusionwithin thewebmay be cutaneous or bony.Castilla et al. [1986] reported a prevalence of 3 per10,000 births in a Latin-American study. Temtamy andMcKusick [1978] reviewed the reported cases andidentified five major variants (type I–V), dependingupon different combinations of involved fingers andtoes. All variants were reported to exhibit autosomaldominant inheritance with variable expression andincomplete penetrance. Fifteen years later, Winterand Tickle [1993] proposed an alternative classifica-tion based on normal or abnormal patterning of thelimb during development. Goldstein et al. [1994] re-viewed and extended the Temtamy and McKusickclassification and defined three additional variants(type VI–VIII).

Type VII of the Goldstein classification is a totalsyndactylywithmetacarpal synostosis, namedCenani–Lenz syndactyly [MIM 212780]. This type, to the best ofour knowledge, hitherto is the only well-documentednon-syndromic, autosomal recessive form (Table I).Here we present a family from Pakistan with anothernon-syndromic, autosomal recessive syndactyly. Since

Grant sponsor: Deutsche Forschungsgemeinschaft; Grantnumber: GRK 767; Grant sponsor: Higher Education Commission,Islamabad Pakistan (to WA).

*Correspondence to: Sajid Malik, Zentrum fur Humangenetik,Philipps-Universitat Marburg, Bahnhofstr. 7, 35037 Marburg,Germany. E-mail: malik@staff.uni-marburg.de

Received 15 May 2003; Accepted 16 July 2003

DOI 10.1002/ajmg.a.20555

� 2003 Wiley-Liss, Inc.

affected individuals in the family show a relatively widephenotypic spectrum with some overlap with featuresobserved in other syndactylies, we reasoned that themalformation could be an allelic phenotypic variant ofeither syndactyly type I, II, or III. Since for these threetypes, chromosomal locations are known (2q34-q36,2q31, 6q22-q23), we performed linkage analysis usinghighly polymorphic microsatellite markers from theseregions to look for cosegregation of the phenotype withany of these loci. Our findings indicate that thephenotype in our family is not linked to these loci.

MOLECULAR METHODSAND GENOTYPING

Genomic DNA was purified from peripheral bloodlymphocytes according to standard SDS-proteinase-Kand phenol/chloroform extraction method [Sambrookand Russel, 2001]. For genomic study of the puta-tive candidate regions, highly polymorphic microsatel-lite markers were selected from Marshfield MedicalCenter [http://research.marshfieldclinic.org/genetics/].All markers were 50-end-labeled with fluorescent dyes:6-FAM, TET, or HEX. Polymerase chain reactions wereperformed in a total volume of 20 ml, containing 25 ng ofgenomic DNA, 2 ml PCR buffer (Qiagen, Hilden,Germany), 1.8 mMMgCl2, 5 mMdNTPs, 12.5 ng of eachmarker, and 0.5 U of Taq DNA polymerase (Qiagen,Hilden, Germany). The PCR reaction started with aninitial 5 min denaturation step at 948C, followed by 30–35 cycles of 25 sec denaturation (948C), 25 sec annealing(53–578C), and 30 sec extension (728C), ending with afinal extension step of 5 min at 728C. The PCR wascarried out on a GeneAmp PCR systems 9600 machine(Applied Biosystems, Foster City, CA, USA). PooledPCR (1.4 ml) products were mixed with 1.6 ml loadingbuffer containing formamide, blue dextran, andGS500XL, the internal lane standard (Applied Biosys-tems), and analyzed on 6% denaturing polyacrylamidegel (Rotiphorese1NF-Acrylamide/Bis,CarlRoth,Karls-ruhe) in an ABI 377 automated sequencer (AppliedBiosystems, Foster City, CA, USA). Fragment analysiswas performed using GeneScan (ver 3.1.2) and Genoty-per (ver 2.0) software. Pedigree and genotype data weremanaged and recorded for linkage analysis usingCyrillic version 2.13 [1997] [www.cherwell.com]. Fileformatting was done by using MAKEDATA software(Dr. Yurii Aulchenko, Rotterdam) and Mega2 [Mukho-padhyay et al., 1999].

Two-point LOD scores were calculated using theMLINKprogramofLINKAGEsoftwarepackageversion5.1 [Lathrop et al., 1984] and FASTLINK version 4.1[Cottingham et al., 1993]. Multipoint analysis andhaplotyping was performed using SIMWALK2 version2.83 [Sobel and Lange, 1996]. An autosomal recessivemodelwith a penetrance of 0.99 (phenocopy rate of 0.001for homozygous normal and heterozygous individuals)and disease allele frequency of 0.001 was assumed. Themutation rate was set to zero and equal recombinationrates betweenmalesand femaleswereassumed.Markerallele frequencies were taken from Marshfield humandiversity panel (Pakistan (Asia) population, based on

TABLE

I.Com

parisonof

Phen

otypein

thePresentFamilyandSelectedSyndactylies

Type

Description

Key

features

Inheritance

Locus

Referen

ce

IZygod

actyly,SD1

Web

bingof

3rd

and4th

fingersand/or2ndor

3rd

toes

AD

2q34-q36

Bosse

etal.[2000]

IISynpolydactyly,SPD

Web

bingof

3rd

and4th

fingers,

duplication

offingersin

theweb

,web

bingof

4–5–6toes

AD

2q31,(H

OXD13)

Muragakiet

al.[1996]

III

Ringandlittle

finger

syndactyly,ODD

aWeb

bingof

4th

and5th

fingers

AD

6q22-q23,(G

JA1)

Pazn

ekaset

al.[2003]

VPostaxialsyndactyly

withmetacarp

al

synostosis

Fusion

of4th

and5th

metacarp

als,soft

tissue

syndactyly

oftoes

AD

Rob

inow

etal.[1982]

VII

Cen

ani–

Len

ztype

Gross

metacarp

als

andcarp

als

fusion

,radio-ulnar

synostosis,

spoon-shaped

hand

AR

Cen

ania

ndLen

z[1967]

Turk

ishfamily

Synostosisof

3rd

and4th

metacarp

als,h

ypop

lasia/

aplasiaof

thumbsandhallucesand2ndand5th

fingers,

toes

syndactyly

AD?

2q31ex

clusion

Percin[1998]

Presentfamily

Synostosisof

3rd

and4th

metacarp

als,reduction

ofphalanges,preaxialweb

bingof

toes

AR

2q34-q36,2q31,6q22-q23

exclusion

aOcu

loden

todigital(O

DD)syndrome.

62 Malik et al.

approximately 190 individuals) or from CEPH database[http://www.cephb.fr/].

FAMILY DESCRIPTION

The family originates from the North-Western part ofPakistan. A pedigree of the family was constructed byinterviewing the elders of the family. The informationwas cross-checked by interviewing relatives.

Five affected and six normal subjects of the familywere examined by at least two of the authors (SM, MA,WA). Photographs of three individuals (V-2, V-7, V-9)andX-rayfilmsof two subjects (IV-6,V-9)were obtained.Six phenotypically normal parents, in three consangui-neous loops (III-3 and III-4; IV-1 and III-5; IV-5 andIV-6), had eight affected (five males and three females),and eight normal offspring. This situation makes an

autosomal recessive inheritance most likely (Fig. 1).Peripheral blood samples from four affected and fivenormal subjects were obtained. All material wascollected after informed consent according to theHelsinki II declaration.

CLINICAL REPORT

The propositus (V-9), a 27-year-old male, is one of thethree affected sibs of related, phenotypically normalparents. The propositus has four ‘fingers,’ which didnot hamper in his day-to-day life (Fig. 2A). Digits losttheir shape and identity, except both thumbs. Radio-graphs show synostosis of third and fourth metacarpals(Fig. 2B). The fused third and fourth metacarpal gen-erated a single, broad, and conical proximal phalanx,ending in dysplastic middle and terminal phalanx. In

Fig. 1. Pedigree of the Pakistani family with syndactyly. Haplotypes for the critical regions are given; horizontal bars on symbols denote individualswho were physically examined.

A Pakistani Family With Recessive Syndactyly 63

Fig. 2. Photographs and radiographs showing the syndactyly phenotype.A,B andC,D: Hands and feet of themale propositus (V-9); (E) hands of femalesubject, V-7; (F) hands of male subject, V-2. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

64 Malik et al.

the right hand, the index finger was more like a middlefinger, while in left hand the index finger was stumped,bending at 908 on the radial side. The distal head ofproximal phalanx of second phalange showed mildhypertrophy, while in the left hand, this proximalphalanxwas drastically reduced in to a triangular bone,bearing remnants of middle phalanx on the radial side.In fifth fingers, there was bilateral clinodactyly alongwith symphalangism of distal phalanx. Distal heads ofmetacarpals generally showed hypoplasia. There wascrowding of carpal bones, scaphoid, and trapeziumshowing slight misalignment. Radial and ulnar headsseemed to be normal.

First three toes were webbed bilateraly (Fig. 2C).Radiological study did not show any bony fusion, yetthere was hypoplasia of middle and distal phalanx of alltoes (Fig. 2D). First metatarsals in both feet appearedbroad with signs of distortion at the distal heads. Therewas symphalangism of proximal and distal phalanx ofhalluces. All the metatarsals generally showed hypo-plastic distal heads.

Severe aplasia of digits was observed in his sister(V-7, age 29 years) and relative (V-2, age 33 years). Inthese two subjects, the defect not only affects themesoaxial fingers but also ranges on either side ofthemesoaxial skeletal rays. In subject V-7 (Fig. 2E), the

mesoaxial digits 2–3–4 were reduced to one or twodysplastic fingers in the right and left hand, respec-tively. In the right hand, the thumb seemed bifid atthe terminal phalanx but this was not confirmed byradiographs. The brother (V-11) of the propositusreportedly has hand involvement and his feet are saidto be normal.

Subject V-2 (Fig. 2F) shows on the right hand ahypoplastic thumb, a single phalange representing thethird and fourth fingers and clinodactyly of the fifthfinger. However, on the left hand, severe reduction of allfingers except the thumb was observed, the fifth fingerremains as a peg. His feet were found to be normal onclinical examination. His sister V-1 and one brother(V-4) had the same phenotype.

Dermatoglyphic changes characteristic of syndac-tyly were observed in the hands of the examinedsubjects, showing replacement of triradii by single orbifurcating horizontal or oblique lines. The affectedindividuals had normal intelligence and no otherassociated defects including craniofacial symptomswere observed.

Six other subjects (III-5, III-7, IV-1, IV-6, V-6, V-12)were examined and found to be phenotypically normal.X-ray films of subject (IV-6) did not show the presence ofany type of pathological findings.

TABLE II. Pairwise LOD Scores Between the Phenotype and Markers on Chromosome 2q and 6q

Gene Locus cM Marker

Recombination fraction (y)

0.00 0.01 0.05 0.1 0.2 0.3 0.4

Chromosome 22q12.2 118.16 D2S436 �4.48 �3.68 �1.86 �1.04 �0.38 �0.13 �0.02

125.18 D2S410 �5.07 �3.55 �2.13 �1.46 �0.78 �0.38 �0.132q21.1 134.45 D2S2215 �0.03 0.21 0.52 0.58 0.49 0.31 0.13

142.83 D2S114 �0.70 0.14 0.63 0.71 0.61 0.39 0.17145.08 D2S1334 �5.14 �3.63 �1.98 �1.13 �0.39 �0.09 0.01147.40 D2S442 �3.45 �2.33 �1.24 �0.73 �0.28 �0.09 �0.01149.89 D2S1326 �2.30 �0.66 0.42 0.76 0.84 0.65 0.35161.81 D2S418a 0 0 0 0 0 0 0

HOXD13173.00 D2S1776 �3.20 �1.99 �0.90 �0.46 �0.13 �0.02 0

2q31!186.21 D2S1391 �2.88 �1.77 �0.71 �0.29 �0.01 0.04 0.03200.43 D2S1384 �3.37 �2.65 �1.56 �0.93 �0.39 �0.17 �0.05205.00 D2S1649a �2.85 �2.09 �1.15 �0.58 �0.13 0 0.03215.78 D2S434 �5.90 �3.90 �2.24 �1.45 �0.70 �0.33 �0.12

2q34-q36! 227.00 D2S1363 �6.41 �3.17 �1.73 �1.08 �0.51 �0.24 �0.08240.79 D2S1279 �6.85 �4.59 �2.33 �1.39 �0.63 �0.32 �0.14240.79 D2S206 �6.44 �3.51 �1.93 �1.26 �0.65 �0.32 �0.12250.54 D2S338 �5.79 �3.92 �2.08 �1.26 �0.53 �0.21 �0.06

2q37.3 260.63 D2S125 �5.17 �3.39 �2.38 �1.91 �1.11 �0.57 �0.23Chromosome 6

6q11.1 80.45 D6S1053 �7.41 �5.13 �3.43 �2.31 �1.09 �0.50 �0.1888.63 D6S1031 �6.89 �4.13 �2.07 �1.20 �0.50 �0.24 �0.11

6q14.3 92.85 D6S1270 �0.47 �0.22 0.09 0.18 0.15 0.06 0.01102.81 D6S1056 �6.23 �2.70 �1.32 �0.71 �0.23 �0.05 0.00112.20 D6S1021 �2.77 �2.23 �1.35 �0.89 �0.42 �0.17 �0.04

GJA1

118.64 D6S474 �4.20 �3.58 �2.38 �1.61 �0.84 �0.43 �0.17

6q22-q23! 128.93 D6S1040 �5.03 �4.11 �3.12 �2.52 �1.48 �0.77 �0.31137.74 D6S1009 �6.41 �4.51 �2.48 �1.54 �0.70 �0.30 �0.09144.46 D6S1003 �6.37 �4.81 �2.81 �1.80 �0.83 �0.35 �0.10159.98 D6S1007 �4.98 �3.35 �2.08 �1.30 �0.55 �0.20 �0.04166.39 D6S305 �3.10 �2.12 �0.77 �0.19 0.17 0.21 0.12

6q26 173.31 D6S1277 �0.73 �0.47 �0.10 0.04 0.10 0.08 0.04

aMicrosatellite markers not present in Marshfield map.

A Pakistani Family With Recessive Syndactyly 65

LINKAGE RESULTS

We evaluated this family for the possibility that thephenotype is linked to the known loci for syndactyly,namely 2q34-q36, 2q31, and 6q22-q23 (loci for syndac-tyly type I, type II, and type III). Two point linkageanalysis yielded significant negative (less than �2.0)LOD scores at y¼ 0.0 (Table II), which was confirmed bymultipoint analysis (Fig. 3). Haplotypes constructedfor the critical regions do not show homozygosity inthe affected individuals (Fig. 1). Our results exclude allcritical regions for syndactylies type I, II, and III,flanked by markers D2S1776-D2S1391, D2S434-D2S1279, and D6S474-D6S1003. Analyses wererepeated with equal marker allele frequencies, whichhad no significant effect on results and did not alter theconclusions.

DISCUSSION

The phenotype observed in the present Pakistanifamily is not in complete agreement with any of the

described syndactylies. All affected subjects are theproduct of consanguineous loops, making a dominantinheritance with non-penetrance highly improbable.Therefore, an autosomal recessive inheritance is themost likely explanation. The OMIM catalogue [http://www.ncbi.nlm.nih.gov/Omim/] documents 109 entriesfor autosomal recessive syndactylies. All except Cenani–Lenz syndactyly [MIM 212780] are reported to besyndromic conditions. Cenani–Lenz type is a ‘total’digit syndactyly with extensive metacarpal and carpalfusions, often accompanied by partial or complete radio-ulnar synostosis, culminating in a sort of spoon-likehand. The feet are usually mildly affected [Cenani andLenz, 1967]. This makes our family phenotypicallydistinct from Cenani–Lenz type.

The phenotype in propositus (V-9), his sister (V-7),and relative (V-2) resembles the three severe cases in aTurkish family with syndactyly type I (SD1) reportedbyPercin et al. [1998]. The authors pointed out that sucha severe phenotype is unusual for SD1 andhypothesizedhomozygosity for SD1 in that family due to the inbrednature of the pedigree. The mildly affected subjects inthe family, with only soft tissue syndactyly betweensecond and third toes were not documented in detail.This mild defect could be a common variant cosegregat-ing in the pedigree. An autosomal recessive mode ofinheritance for the severe phenotype is, therefore,equally likely.

The present Pakistani family shows a distinctivephenotypic manifestation and has minimal overlap ofclinical featureswith syndactylies type I, II, and III. Thedefect is predominantlymesoaxial andmore severe thanSD1. Therefore, it does not fit into type I syndactyly. Thesame is true for the involvement of index finger and firsttoe in the web in our family, which is an extremely rarefinding in SD1, as pointed out by Bosse et al. [2000].Since the classical features of type II syndactyly (SPD),mesoaxial polydactyly, are missing in all five affectedmembers of our family, it almost rules out the possibilityof being SPD (Table I). Our family does not show anycraniofacial symptoms like type III syndactyly (oculo-dentodigital, ODD) but it overlapswith this condition byshowing the involvement of mesoaxial skeletal rays. Wealso exclude type V because of its postaxial involvementof digits and occasional association of brachydactylyand camptodactlyly [Temtamy and McKusick, 1978;Robinow et al., 1982].

Although only minimal overlap with the clinicalfeatures of known syndactylies was observed in ourfamily, the phenotypic status might represent an allelicvariant of a previously described type. Therefore, weanalyzed whether the phenotype cosegregates with oneof the known loci for syndactylies.

The molecular etiology of type II syndactyly (synpo-lydactyly, SPD) has been revealed. Expansions of apolyalanine stretch in homeobox geneHOXD13 at 2q31have been implicated in this type [Akarsu et al., 1996;Muragaki et al., 1996; Kjaer et al., 2002]. Studies haveshown that type I syndactyly is also linked to the longarm of chromosome 2, in close vicinity of SPD locus at2q34-q36 [Bosse et al., 2000] and that, there is genetichomogeneity in syndactyly type I [Ghadami et al., 2001].

Fig. 3. Multipoint linkage analysis of candidate regions of chromosome2q (a) and 6q (b). Markers used are the same as listed in Table II.

66 Malik et al.

The underlying gene remains unknown. Type III syn-dactyly, which occurs as a part of a distinct entity, ODDsyndrome has been linked to 6q22-q23 [Boyadjiev et al.,1999] andmutations in connexin 43 (GJA1) protein havebeen recently observed [Paznekas et al., 2003].

Using a panel of highly polymorphic microsatellitemarkers, we excluded the critical regions for syndactylytype I, II, and III. Thus, the clinical impression of ourfamily not fitting into syndactyly type I, II, and III hasbeen proven by the exclusion of established candidateloci.

In summary, the remarkable clinical features in ourfamily and the exclusion results lead us to conclude thatwe are dealing with a unique entity, which is closelyrelated to the reported Turkish family of Percin et al.[1998]. Apart from type VII syndactyly (Cenani–Lenztype), our family and possibly the Percin et al. [1998]familyare theonlydocumentedrecessive,non-syndromicphenotypes in the literature. A genome-wide mappingstudy is underway to pinpoint a candidate locus region.

ACKNOWLEDGMENTS

We highly acknowledge the cooperation of the familyand Mr. Mansoor Qureshi for making contact with thefamily. We are grateful to Dr. Yurii Aulchenko,Rotterdam for making his MAKEDATA software avail-able to us.

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A Pakistani Family With Recessive Syndactyly 67