American Journal of Medical Genetics 126A:61–67 (2004) A Novel Type of Autosomal Recessive Syndactyly: Clinical and Molecular Studies in a Family of 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 Grzeschik 1 1 Zentrum fu ¨r Humangenetik, Philipps-Universita ¨ t Marburg, Marburg, Germany 2 Department of Biological Sciences, Quaid-I-Azam University, Islamabad, Pakistan 3 Department of Biology, Government College, DG Khan, Pakistan 4 Institut fu ¨ r Medizinische Biometrie und Epidemiologie, Philipps-Universita ¨ t Marburg, Marburg, Germany Non-syndromic syndactylies have been clas- sified into five major types (I – V), all showing autosomal dominant mode of inheritance. Later, the classification was extended and three additional variants (VI–VIII) were defined. Type VII, the Cenani–Lenz syndac- tyly, is the only non-syndromic, autosomal recessive type. It is characterized by fusion of 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 syndactyly manifesting a unique combination of clinical features. In both hands, reduction of certain phalanges is evident. Radiological examina- tion shows synostosis of third and fourth metacarpals bearing single phalanges. The first three toes are webbed, with hypoplas- tic terminal phalanx in all the toes. Besides Cenani–Lenz syndactyly, the phenotype segregating in our family is the second well-documented autosomal recessive, non- syndromic syndactyly. A phenotype similar to our family was described in a Turkish kindred but was considered to be a homo- zygous expression of type I syndactyly. Since the 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 of this phenotype with any of the known loci for these respective types. We show that the phenotype in our family is not linked to chromosomal regions 2q34-q36, 2q31, and 6q22-q23 encompassing loci for syndactyly types I, II, and III. ß 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/or toes. The malformation can be unilateral or bilateral, and the fusion within the web may be cutaneous or bony. Castilla et al. [1986] reported a prevalence of 3 per 10,000 births in a Latin-American study. Temtamy and McKusick [1978] reviewed the reported cases and identified five major variants (type I–V), depending upon different combinations of involved fingers and toes. All variants were reported to exhibit autosomal dominant inheritance with variable expression and incomplete penetrance. Fifteen years later, Winter and Tickle [1993] proposed an alternative classifica- tion based on normal or abnormal patterning of the limb during development. Goldstein et al. [1994] re- viewed and extended the Temtamy and McKusick classification and defined three additional variants (type VI–VIII). Type VII of the Goldstein classification is a total syndactyly with metacarpal synostosis, named Cenani – Lenz syndactyly [MIM 212780]. This type, to the best of our knowledge, hitherto is the only well-documented non-syndromic, autosomal recessive form (Table I). Here we present a family from Pakistan with another non-syndromic, autosomal recessive syndactyly. Since Grant sponsor: Deutsche Forschungsgemeinschaft; Grant number: GRK 767; Grant sponsor: Higher Education Commission, Islamabad Pakistan (to WA). *Correspondence to: Sajid Malik, Zentrum fu ¨ r Humangenetik, Philipps-Universita ¨t 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 ß 2003 Wiley-Liss, Inc.