RESEARCH LETTER 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 Eva Barroso, 1,2 Julia Berges-Soria, 1 Sara Benito-Sanz, 1,2 Carlos Ivan Rivera-Pedroza, 1 Marı ´a Juliana Ballesta-Martı ´nez, 2,3 Vanesa Lo ´pez-Gonza ´lez, 2,3 Encarna Guillen-Navarro, 2,3,4 and Karen E Heath 1,2* 1 Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Auto ´noma de Madrid, IdiPAZ, Madrid, Spain 2 Centro de Investigacio ´n Biome ´dica en Enfermedades Raras (CIBERER), Instituto Carlos, Madrid, Spain 3 Medical Genetics Unit, Dept. of Pediatrics, Hospital Clı ´nico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain 4 Ca ´tedra de Gene ´tica Me ´dica., UCAM-Universidad Cato ´lica San Antonio de Murcia, Spain Manuscript Received: 22 July 2014; Manuscript Accepted: 15 September 2014 TO THE EDITOR: Craniosynostosis, caused by the premature fusion of one or more of the 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 malformations of the digits, including craniosynostosis Philadelphia type (CP), a rare form of syndromic craniosynostosis with sagital craniosynostosis and syndactyly of the fingers and toes, with a relatively normal facial appearance [Robin et al., 1996]. Syndactyly is one of the most common abnormalities of the extremities, and occurs either as an isolated malformation or as part of a malformation syndrome. Syndactyly type 1 (SD1, OMIM 185900) is the most common type, with a prevalence of 2–3 in 10,000 newborns [Castilla et al., 1980]. Generally, SD1 involves complete or partial webbing between the third and fourth fingers and/or second and third toes, but other digits are occasionally involved. Bony fusion of the distal phalanges occurs in some cases. The syndactyly is not always bilateral or symmetrical, sometimes only affecting the hands or feet and incomplete penetrance is observed. Two multi-generation families with SD1 narrowed the candidate gene region to chromosome 2q34–36 [Bosse et al., 2000; Ghadami et al., 2001]. In 2008, linkage analysis delimited the implicated locus of CP to chromosome 2q25, suggesting that CP and SD1 shared a common gene defect [Jain et al., 2008]. Indeed, this was true, with the identification of variable sized duplications upstream of Indian hedgehog gene (IHH), localized on chromosome 2q35 in the three previously described families [Klopocki et al., 2011]. The two entities now share the OMIM code 185900. Subsequently, they identified and functionally characterized, using mouse models, three long-range enhancer elements of IHH, specifically regulating IHH expression during endochondral bone formation. IHH encodes a member of the Hedgehog family of secreted signalling proteins, essential regulators of a variety of developmen- tal processes including growth, patterning and morphogenesis How to Cite this Article: Barroso E, Berges-Soria J, Benito-Sanz S, Rivera-Pedroza CI, Ballesta-Martı´nez MJ, Lo ´ pez-Gonza ´lez V, Guillen-Navarro E, Heath KE. 2014. 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. Am J Med Genet Part A 9999:1–5. Conflict of interest: None. Grant sponsor: Ministerio de Innovacio ´ n y Ciencia; Grant number: SAF2012-30871.  Correspondence to: Karen Heath, Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, P˚ Castellana 261, Madrid 28046, Spain E-mail: karen.heath@salud.madrid.org Article first published online in Wiley Online Library (wileyonlinelibrary.com): 00 Month 2014 DOI 10.1002/ajmg.a.36811 Ó 2014 Wiley Periodicals, Inc. 1