CLINICAL REPORT

Autosomal Dominant Syndrome of Camptodactyly,Clinodactyly, Syndactyly, and Bifid ToesSajid Malik,1* Muhammad Afzal,1 Sumera Gul,1 Abdul Wahab,2 and Mahmud Ahmad1

1Human Genetics Program, Department of Animal Sciences, Quaid-i-Azam University Islamabad, 45320 Islamabad, Pakistan2Zoological Survey of Pakistan, Bhara Kahu, Islamabad, Pakistan

Received 2 April 2010; Accepted 19 May 2010

We report on a 25-year follow-up of a Pakistani kindred with a

unique combination of camptodactyly and clinodactyly of 5th

fingers, mesoaxial camptodactyly of toes, and ulnar deviation of

3rd fingers. The less common anomalies in the affected subjects

include syndactyly involving all digits, and bifid toes. This

condition is grossly bilateral, symmetrical, and affects upper

and lower limbs of the 26 affected subjects in the kindred. The

comparable number of affected male and female subjects

(c2¼ 0.154, P< 0.1), disease allele transmission by mother and

father, and the malformation segregation in four consecutive

generations are strongly suggestive of autosomal dominant

inheritance. Differential diagnosis considered syndactyly types

II, III, and V. Only type II syndactyly manifests noticeable

phenotypic overlap with the clinical presentation in this family;

however, the typical type II syndactyly changes are absent. To the

best of our knowledge, this autosomal dominant limb phenotype

has not been reported previously. � 2010 Wiley-Liss, Inc.

Key words: camptodactyly; clinodactyly; syndactyly; bifid toe;

synpolydactyly; Pakistani family

INTRODUCTION

Camptodactyly (OMIM 114200) is characterized by contracture

deformity of postaxial fingers at the proximal interphalangeal (PIP)

joints resulting in a permanent volar inclination of the affected

digits [Welch and Temtamy, 1966]. The little finger is most

frequently affected but other digits may be involved [Temtamy

and Mckusick, 1978]. Camptodactyly of feet which often affects the

second toe, is less common [Brites et al., 1998]. Camptodactyly may

occur as an isolated deformity as well as a part of >150 well-

characterized hereditary syndromes (OMIM). The isolated type is

an autosomal dominant entity and the first locus of 5th finger

camptodactyly was mapped to chromosome band 3q11.2-q13 in a

large German family [Malik et al., 2008].

Clinodactyly (OMIM 112700) (brachydactyly A3) refers to

a varus deviation of the distal phalanx of the 5th finger due

to shortness of metacarpal and the middle phalanx. Isolated

clinodactyly is an autosomal dominant trait. Camptodactyly

and clinodactyly accompany each other as minor clinical variants

in various limb anomalies such as syndactyly types II, III, and V

[Malik et al., 2005]. In addition, both malformations may occur

simultaneously in a number of syndromes such as Poland syn-

drome, acrocephalopolysyndactyly type IV, preaxial polydactyly,

Hunter–Macdonald syndrome, Weaver syndrome, etc. However,

the concurrence of camptodactyly and clinodactyly as cardinal

clinical presentation in a single family is rare. Here we report on

a large Pakistani family with a unique combination of digit mal-

formations, that is, camptodactyly, clinodactyly, syndactyly, and

bifid toes. Pedigree analysis is strongly suggestive of an autosomal

dominant mode of inheritance.

SUBJECTS AND METHODS

The family originates from a suburb of Islamabad. A detailed

pedigree comprising five generations was constructed with the help

of the elders and the original pedigree drawn �25 years ago was

revised and authenticated [Wahab, 1986]. Since 1986, the kindred

has expanded and at least 28 additional family members have been

born including 6 affected, permitting disease transmission in two

further generations and a phenotype analysis of the mutant allele.

Additional supporting information may be found in the online version of

this article.

Grant sponsor: Pakistan Science Foundation; Grant sponsor: Quaid-i-

Azam University Research Fund.

*Correspondence to:

Dr. Sajid Malik, Human Genetics Program, Department of Animal

Sciences, Quaid-i-Azam University Islamabad, 45320 Islamabad, Pakistan.

E-mail: malik@qau.edu.pk

Published online 3 August 2010 in Wiley Online Library

(wileyonlinelibrary.com).

DOI 10.1002/ajmg.a.33552

How to Cite this Article:Malik S, Afzal M, Gul S, Wahab A, Ahmad M.

2010. Autosomal dominant syndrome of

camptodactyly, clinodactyly, syndactyly, and

bifid toes.

Am J Med Genet Part A 152A:2313–2317.

� 2010 Wiley-Liss, Inc. 2313

Forty-one subjects (18 affected, 23 normal) volunteered for a

physical examination, including 15 subjects available for follow-

up from the original pedigree [Wahab, 1986]. All together, the

photographs of 25 (18A, 7N) and roentgenograms of 9 subjects (8A,

1N) were obtained. All information was collected after informed

consent according to the Helsinki II declaration.

CLINICAL REPORT

Twenty-six subjects (12M, 14F) were affected in 7 sibships (Fig. 1).

The malformation was confined to the autopods and in general was

bilateral and symmetrical. There was no history of any associated

defect of joints or muscles. The following phenotypic variants were

observed in the affected subjects (Table I).

Camptodactyly of 5th FingersCamptodactyly was observed in six affected subjects being more

common in males (5M, 1F). Contracture of 5th fingers was non-

progressive and restricted to the PIP joint, resulting in an inward

bending of finger at �50� with limited extension (Fig. 2A,B) and

symphalangism of the interphalangeal (DIP) joint. The roentgeno-

grams of III-3 showed osseous fusion and reduced joint spaces at the

PIP and DIP joints, respectively.

Clinodactyly of 5th FingersClinodactyly of 5th fingers was observed in five subjects (1M, 4F). In

IV-9, the 5th metacarpals and middle phalanges were short with

hypoplastic PIP joints and radially deviated terminal phalanx

(Fig. 2E,F).

Ulnar Deviation of 3rd FingersUlnar deviation of 3rd fingers was a common finding (6/21), more

prominent in females (1M, 5F). The affected finger showed a valgus

deviation at the PIP joint. Ulnar deviation/camptodactyly of 3rd

fingers was most prominent in subject V-14 (Fig. 2O).

Mesoaxial Camptodactyly of ToesCamptodactyly of toes (2nd, 2/3, or 2/3/4) at the PIP joints was

common (9/21). The affected toes were found to be adducted in a

slanting fashion (Fig. 2B). In the roentgenograms of III-3, there was

dysplasia of middle/distal phalangeal bones particularly visible in

the 2/3/4 toes (Fig. 2C,D). In addition, he had a hallux valgus with

exostosis arising from the 2nd metacarpal.

Severe Syndactyly/Synpolydactyly of Handsand FeetThis represents the most severe phenotypic manifestation evident

in three subjects (IV-5, IV-7, V-4) in two sibships (Fig. 1). This is

characterized by complete syndactyly with preaxial polydactyly.

Hands were short and disfigured, giving a spade like appearance.

The thumbs were small, hypoplastic and abducted. Fingers 2/3/4/5

showed complete fusion with malformed and fused nails.

Feet were short with complete fusion of all toes with an additional

toe in the web. For instance, IV-7 had short and crippled

hands with rudimentary thumbs and index fingers (Fig. 2G).

IV-5 and V-4 had similar presentation (Fig. 2M,K, respectively).

Fingers 3/4/5 were fused in a single mass with fused nails. In the

roentgenograms, carpals and metacarpals were short and broad,

demonstrating crowding with sings of hypoplasia and decalcifica-

tion (Fig. 2H,K). Phalanges did not originate from their normal

sites and were misaligned. Total cutaneous webbing was evident in

the toes. There was crowding of tarsal and metatarsal bones (IV-7;

Fig. 2I,J). Metatarsals 4/5 were drastically reduced in size with a

supernumerary digit emerging between toes 1 and 2. The phalanges

were short and dysplastic, the terminal phalanx being rudimentary.

There was evidence of ankylosis of tarso-metatarsus joint (Fig. 2I,J).

FIG. 1. Pedigree of the Pakistani family with campto-clino-syndactyly. Horizontal bars represent the subjects who were examined (41; 18A, 23N). The

symbols with (?) represent the subjects whose phenotype could not be ascertained.

2314 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

V-4 additionally showed broad halluces with anonychia and

marked valgus deviation (Fig. 2L).

Bifid ToesSubject III-5 had bilateral bifid halluces with broad fused nails,

the right hallux demonstrating valgus abduction (Fig. 2N). In IV-29

there were bifid 5th toes. However, she is not related to this

family and therefore, postaxial polydactyly is not be the part of

deformity.

Pedigree Analysis and InheritancePedigree analysis shows a pattern of normal and affected subjects

consistent with autosomal dominant inheritance. Every affected

subject has an affected parent. Sons and daughters of affected

subjects are equally affected (12M, 14F; c2¼ 0.154, P< 0.1). In

the offspring of the affected subjects the proportion of normal and

affected individuals is equally varied among both sexes (12 affected

sons, 16 normal sons, 11 affected daughters, 13 normal daughters

(c2¼ 1.077; P> 0.1)). There is father-to-son transmission on four

occasions. There are five normal daughters of affected fathers in

three parenthoods. One likely case of incomplete penetrance is a

reportedly unaffected subject III-10 who mothered an affected

daughter (IV-16).

Differential DiagnosisThe unique combination of digit anomalies makes the differential

diagnosis of this malformation easy (see supporting information

Table II which may be found in the online version of this article).

Type II syndactyly or synpolydactyly (SPD) is the only entity which

shows noticeable phenotypic overlap with the malformation ob-

served in the present family. The cardinal features of type II

syndactyly are fusion of fingers 3/4 and toes 2/3 with additional

digits in the web, which are absent in the present family. SPD may

show clinodactyly and/or camptodactyly of 5th finger as minor

clinical variants in different families, which appear as major phe-

notypes in the present family. However, both camptodactyly and/or

clinodactyly are not considered as the diagnostic criteria for SPD

[Malik et al., 2006, 2007; reviewed in Malik and Grzeschik, 2008].

Camptodactyly of mesoaxial toes, ulnar deviation of 3rd fingers and

bifid hallux are also not the characteristics of SPD but are promi-

nent in this kindred. However, the severe syndactyly typical of

homozygous SPD appears in three subjects in the present family

(IV-5, IV-7, and V-4) [Goodman et al., 1997]. Considering this

severe phenotype there is remote possibility that the limb anomaly

in the present family and SPD are allelic. If this were the case then the

affected subjects IV-5, IV-7, and V-4 should be homozygous for the

mutant allele by the virtue of segregation from both parents.

However, the status of V-4 with a phenotypically unaffected father,

IV-1 could not be explained. This scenario further implicates that

the clinical categories observed in the present family (i.e., campto-

dactyly of toes, ulnar deviation of 3rd fingers, bifid toes), are an

expression of SPD. The present family is unique as the cardinal SPD

finding (i.e., fusion of fingers 3/4 and toes 2/3) is absent while the

milder variants appear as paramount traits. However, this hypoth-

esis awaits molecular elucidation.

DISCUSSION

The combination of camptodactyly, clinodactyly, and syndactyly in

well-established limb syndromes is rare. In the present kindred

parents with camptodactyly have offspring with clinodactyly and

ulnar deviation of 3rd fingers. Similarly, parents with clinodactyly

have offspring showing clinodactyly and camptodactyly. Therefore,

the phenotypes are not mutually exclusive and the possibility of a

mixture of phenotypes segregating independently is rather remote.

Camptodactyly and syndactyly type I segregated in a family

(kindred 5) described by Temtamy and McKusick [1978]. In that

family, the propositus had soft tissue syndactyly between fingers 3/4

and toes 2/3. He also had a right epicanthic fold with functional

heart murmur. His mother, a maternal aunt, and the maternal

grandmother had camptodactyly of the 5th fingers with normal feet.

In the roentgenograms, the mother had an exostosis on the ventral

surface of the 2nd and 5th metatarsals. Each toe had two phalanges

only. Malhotra and Ripe [1963] reported a person with 2/3 toe

syndactyly who had 16 affected decedents in three generations of

whom 9 had clinodactyly with 2/3 toe syndactyly and 5 with

clinodactyly and syndactyly. However, the authors concluded

that the simultaneous appearance of these two conditions was

probably coincidence. Tsai et al. [2009] has recently reported a

three-generation family in which three affected subjects were

TABLE I. Clinical Variability of Limb Malformation Segregating in the Pakistani Family

Phenotypic variant

Subjects

III-2, V-14 III-3, IV-26a, IV-31a III-8 IV-28 IV-33a IV-16 III-4, IV-9 III-7 III-9 IV-2, IV-3 IV-30 IV-5, IV-7, V-4 III-5

Camptodactyly of 5th fingers þ þ þClinodactyly of 5th fingers þ þ þUlnar deviation of 3rd fingers þ þ þ b þCamptodactyly (2nd, 2/3, or 2/3/4 toes) 2/3/4 2/3 2/3/4 2/3, L 2nd 2/3 2/3

Severe syndactyly / synpolydactyly þBifid hallux þ

L, left foot only.aSubjects not physically examined.bRadial deviation of index finger, reportedly secondary to arthritis.

MALIK ET AL. 2315

observed to have clinodactyly and bifid toes. However, the index

person also had developmental delay and psychomotor retardation.

This condition was shown to be segregating with a microdeletion at

chromosome 2q31.1–31.2.

In summary, we report a family in which camptodactyly and

clinodactyly of 5th fingers, mesoaxial camptodactyly of toes, ulnar

deviation of 3rd fingers, and bifid toes segregate as possibly

heterozygous phenotypes, and severe syndactyly/SPD as likely

homozygous phenotype.

ACKNOWLEDGMENTS

The authors highlyacknowledge the participation of the family in this

research. We are indebted to Prof. Karl-Heinz Grzeschik and anony-

mous reviewers for their helpful comments on the manuscript.

REFERENCES

Brites MM, Moreno A, Salgado M, Poiares-Baptista A. 1998. Familialcamptodactyly. Eur J Dermatol 8:355–356.

FIG. 2. The phenotypic manifestation of the malformation. Camptodactyly of 5th fingers (A,B, subject III-3); clinodactyly of 5th fingers (E,F,

subject IV-9); ulnar deviation of 3rd fingers (O, subject V-14); mesoaxial camptodactyly of toes (C,D, subject III-3); severe syndactyly (G–J, subject

IV-7; K,L, subject V-4; M, subject IV-5); and bifid toes (N, subject III-5). [Color figure can be viewed in the online issue, which is available at

wileyonlinelibrary.com.]

2316 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

Goodman FR, Mundlos S, Muragaki Y, Donnai D, Giovannucci-UzielliML, Lapi E, Majewski F, McGaughran J, McKeown C, Reardon W, UptonJ, Winter RM, Olsen BR, Scambler PJ. 1997. Synpolydactyly phenotypescorrelate with size of expansions in HOXD13 polyalanine tract. Proc NatlAcad Sci 94:7458–7463.

Malhotra KC, Ripe DC. 1963. Syndactyly and clinodactyly within a Indiankindred. J Hered 54:219–220.

Malik S, Grzeschik K-H. 2008. Synpolydactyly: Clinical and molecularadvances. Clin Genet 73:113–120.

Malik S, Schott J, Ali SW, Oeffner F, Amin-ud-Din M, Ahmad W,Grzeschik K-H, Koch MC. 2005. Evidence for clinical and geneticheterogeneity of syndactyly type I: The phenotype of second and thirdtoe syndactyly maps to chromosome 3p21.31. Eur J Hum Genet 13:1268–1274.

Malik S, Abbasi A, Ansar M, Ahmad W, Koch M, Grzeschik KH.2006. Genetic heterogeneity of synpolydactyly: A novel locusSPD3 maps to chromosome 14q11.2-q12. Clin Genet 69:518–524.

Malik S, Girisha KM, Wajid M, Roy AK, Phadke SR, Haque S, Ahmad W,Koch MC, Grzeschik KH. 2007. Synpolydactyly and HOXD13 poly-alanine repeat: Addition of 2 alanine residues is without clinical con-sequences. BMC Med Genet 8:78.

Malik S, Schott J, Schiller J, Junge A, Baum E, Koch MC. 2008. Fifth fingercamptodactyly maps to chromosome 3q11.2–q13.12 in a large Germankindred. Eur J Hum Genet 16:265–269.

Temtamy SA, McKusick VA. 1978. The genetics of hand malformations.New York: Alan R. Liss.

Tsai L-P, Liao H-M, Chen Y-J, Fang J-S, Chen C-H. 2009. A novelmicrodeletion at chromosome 2q31.1-31.2 in a three-generation familypresenting duplication of great toes with clinodactyly. Clin Genet 75:449–456.

Wahab A. 1986. Certain aspects of human genetics in Pakistan. MPhilThesis. Department of Biological Sciences Quaid-i-Azam UniversityIslamabad, Pakistan.

Welch JP, Temtamy SA. 1966. Hereditary contractures of the fingers(camptodactyly). J Med Genet 3:104–113.

MALIK ET AL. 2317