Short report Identification of a novel causative mutation in the ROR2 gene in a Lebanese family with a mild form of recessive Robinow syndrome Cybel Mehawej a , Eliane Chouery a , Diane Maalouf a , Geneviève Baujat b , Martine Le Merrer b , Valérie Cormier-Daire b , André Mégarbané a, * a Unité de Génétique Médicale, Laboratoire de Biologie Moléculaire et Cytogénétique, Faculté de Médecine, Université Saint-Joseph, Beirut, Lebanon b Département de Génétique, Unité INSERM U781, Université Paris Descartes, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants Malades, Paris, France article info Article history: Received 11 October 2011 Accepted 20 November 2011 Available online 27 November 2011 Keywords: Autosomal recessive Gene Robinow syndrome ROR2 Bone dysplasia abstract Autosomal recessive Robinow syndrome (OMIM 268310) is a condition caused by mutations in the ROR2 gene, the receptor tyrosine kinase-like orphan receptor 2. The main characteristic features are: a face resembling that of a fetus, cleft lip and palate, mesomelic limb shortening, a micropenis in males, hydronephrosis or urinary tract infections, and skeletal and vertebral anomalies. This study reports two sisters from a consanguineous Lebanese family with an autosomal recessive Robinow syndrome. Both presented with short stature, dysmorphic facial features, and mild bone abnormalities. One of the affected girls had a malformation of her right hand: a mesoaxial polydactyly combined with a syndactyly of the 3rd and 4th fingers, and a short right 3rd metacarpal bone. Molecular analysis of the ROR2 gene revealed the presence of a previously undescribed missense mutation: p.R272C (c.814C>T), in the cysteine-rich domain of the protein. These patients are compared with other cases, and a phenotype egenotype correlation is discussed. Ó 2011 Elsevier Masson SAS. All rights reserved. 1. Introduction Robinow syndrome (RS) is a rare genetic disorder first described by Robinow et al. in 1969 [1]. It is characterized by a prominent forehead, hypertelorism, a small nose with anteverted nostrils, a wide mouth and gum hypertrophy, mesomelic limb shortening, a micropenis in males, hydronephrosis or urinary tract infections, cleft lip and palate, skeletal and vertebral anomalies. Autosomal dominant (ADRS; OMIM 180700) and autosomal recessive (ARRS; OMIM 268310) modes of inheritance have been reported. ADRS is caused by mutations in the WNT5A gene, member of the Wnt family [2], whereas ARRS is associated with mutations located on 9q22 in the ROR2 gene, a member of the receptor tyrosine kinase-like gene family that encodes an orphan membrane-bound tyrosine kinase [3,4]. ROR2 is expressed during embryogenesis and is thought to play a key role in cartilage and growth plate development [5]. In families with ARRS, significant vertebral anomalies, rib fusion, severe mesomelic shortening of the arms with abnormally modeled radii and ulnae, umbilical hernia, supernumerary teeth and increased mortality are present [6,7]. Here, we report a Lebanese family where two sisters present an ARRS with mild bone abnormalities. A previously undescribed missense mutation p.R272C (c.814C>T) in the ROR2 gene was found. Phenotypeegenotype correlations are discussed. 2. Materials and methods 2.1. Patients Members of this kindred originate from North Lebanon. The patients, two sisters, were born to healthy first-cousin Lebanese parents. Their two brothers are healthy (Fig. 1). Both affected siblings underwent an extensive work-up including thorough clinical evaluation, total body X-rays, routine blood tests (complete blood count, serum electrolytes, blood glucose levels, cholesterol, thyroid, and phosphate alkaline levels), and liver and renal function tests. 2.2. Molecular analysis After informed consent for genetic analyses was obtained from the parents, EDTA blood samples were collected from all members of the family for genetic studies. DNA was extracted from leuco- cytes by the standard salt-precipitation method. Genomic and * Corresponding author. Unité de Génétique Médicale, Faculté de Médecine, Université Saint-Joseph, 42, rue de Grenelle, 75007 Paris, France. Fax: þ33 961 1 421 021. E-mail address: megarbane@usj.edu.lb (A. Mégarbané). Contents lists available at SciVerse ScienceDirect European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg 1769-7212/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2011.11.003 European Journal of Medical Genetics 55 (2012) 103e108