RESEARCH ARTICLE Potocki–Shaffer Deletion Encompassing ALX4 in a Patient With Frontonasal Dysplasia Phenotype Alessandra Ferrarini, #1 Muriel Gaillard, #2 Frederic Guerry, 2 Gianpaolo Ramelli, 1 Fodstad Heidi, 2 Caroline Verley Keddache, 2 Ilse Wieland, 3 Jacques S. Beckmann, 2,4 Se ´bastien Jaquemont, 2 and Danielle Martinet 2 * 1 Division of Pediatrics, San Giovanni Hospital, Bellinzona, Switzerland 2 Service of Medical Genetics, CHUV, Lausanne, Switzerland 3 Institut fu ¨r Humangenetik, Otto-von-Guericke-Universita ¨t, Magdeburg, Germany 4 Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland Manuscript Received: 24 May 2013; Manuscript Accepted: 21 June 2013 Frontonasal dysplasia (FND) is a genetically heterogeneous malformation spectrum with marked hypertelorism, broad nasal tip and bifid nose. Only a small number of genes have been associated with FND phenotypes until now, the first gene being EFNB1, related to craniofrontonasal syndrome (CFNS) with craniosynostosis in addition, and more recently the aristaless- like homeobox genes ALX3, ALX4, and ALX1, which have been related with distinct phenotypes named FND1, FND2, and FND3 respectively. We here report on a female patient presenting with severe FND features along with partial alopecia, hypogonadism and intellectual disability. While molecular investigations did not reveal mutations in any of the known genes, ALX4, ALX3, ALX1 and EFNB1, comparative genomic hybridization (array CGH) techniques showed a large heterozygous de novo deletion at 11p11.12p12, encompassing the ALX4 gene. Deletions in this region have been described in patients with Potocki–Shaffer syndrome (PSS), characterized by biparietal foramina, multiple exostoses, and intellectual disability. Although the patient reported herein manifests some overlapping features of FND and PPS, it is likely that the observed phenotype maybe due to a second unidentified mutation in the ALX4 gene. The phenotype will be discussed in view of the deleted region encompassing the ALX4 gene. Ó 2013 Wiley Periodicals, Inc. Key words: fronto-nasal dysplasia; ALX4; 11p11p12; Potocki– Shaffer syndrome INTRODUCTION Frontonasal dysplasia (FND) is a heterogeneous disorder associated with hypertelorism, abnormal nasal configuration and oral, palatal, or facial clefting. In addition to isolated FND, Wu et al. [2007] have classified FND patients into different subtypes based on associated malformations: OAFNS (oculoauriculovertebral syndrome), acromelic, cardiac or neuronal migration anomalies, and Poland syndrome. Most cases of FND are sporadic and the genetic etiology of FND is identified in a small number of cases. Mutations in the gene encoding ephrin-B1 (EFNB1), a ligand to ephrin receptor tyrosine kinases, have been associated with FND and craniosynos- tosis phenotype named as craniofrontonasal syndrome (CFNS, OMIM#304110) [Twigg et al., 2004; Wieland et al., 2004, 2007]. CFNS is an X-linked disorder characterized by a more severe phenotype in heterozygous females than in hemizygous males. While heterozygous females present the full blown phenotype for CFNS, hemizygous males show no features or are mildly affected as having hypertelorism, cleft lip and palate. Twigg et al. have reported homozygous loss-of-function mutations in the aristaless- like homeobox 3 (ALX3) gene in 11 patients from seven consan- guineous families. These patients presented a distinctive facial appearance with hypertelorism, wide nasal bridge, short nasal ridge, bifid nasal tip, broad columella, widely separated slit-like nares, long philtrum and a midline notch in the upper lip and alveolus. How to Cite this Article: Ferrarini A, Gaillard M, Guerry F, Ramelli G, Heidi F, Keddache CV, Wieland I, Beckmann JS, Jaquemont S, Martinet D. 2014. Potocki–Shaffer deletion encompassing ALX4 in a patient with frontonasal dysplasia phenotype. Am J Med Genet Part A 164A:346–352. # Alessandra Ferrarini and Muriel Gaillard contributed equally to this work. Ã Correspondence to: Danielle Martinet, Service of Medical Genetics, CHUV, 1011 Lausanne, Switzerland. E-mail: danielle.martinet@chuv.ch Article first published online in Wiley Online Library (wileyonlinelibrary.com): 13 December 2013 DOI 10.1002/ajmg.a.36140 Ó 2013 Wiley Periodicals, Inc. 346