Identification of the fourth duplication of upstream IHH regulatory elements, in a family with craniosynostosis Philadelphia type, helps to define the phenotypic characterization of these regulatory elements.

Craniosynosto sis, caused by the premature fusion of one or more ofthe cranial sutures, can be classified into nonsyndromic or syn-dromic and by which sutures are affected. It affects one in 2,000–2,500 children [Boulet et al., 2008]. Several craniosynostosis syn-dromes are associated with malformation s of the digits, includingcraniosynostosis Philadelphia type (CP), a rare form of syndromiccraniosynostosis with sagital craniosynosto sis and syndactyly of thefingers and toes, with a relatively normal facial appearance [Robinet al., 1996]. Syndactyly is one of the most common abnormaliti es ofthe extremities , and occurs either as an isolated malformation or aspart of a malformation syndrome. Syndactyly type 1 (SD1, OMIM185900) is the most common type, with a prevalence of 2–3 in10,000 newborns [Castilla et al., 1980]. Generally, SD1 involvescomplete or partial webbing between the third and fourth fingersand/or second and third toes, but other digits are occasionallyinvolved. Bony fusion of the distal phalanges occurs in some cases.The syndactyly is not always bilateral or symmetrical, sometime sonly affecting the hands or feet and incomplete penetrance isobserved.Two multi-gener ation families with SD1 narrowed the candidategene region to chromosome 2q34–36 [Bosse et al., 2000; Ghadamiet al., 2001]. In 2008, linkage analysis delimited the implicated locusof CP to chromosom e 2q25, suggesting that CP and SD1 shared acommon gene defect [Jain et al., 2008]. Indeed, this was true, withthe identification of variable sized duplications upstream of Indianhedgehog gene (