RESEARCH ARTICLE New Patients with Temple Syndrome Caused by 14q32 Deletion: Genotype-Phenotype Correlations and Risk of Thyroid Cancer Giulia Severi, 1 Laura Bernardini, 2 Silvana Briuglia, 3 Stefania Bigoni, 4 Barbara Buldrini, 4 Pamela Magini, 1 Maria L. Dentici, 5 Duccio M. Cordelli, 6 Teresa Arrigo, 3 Emilio Franzoni, 6 Sergio Fini, 4 Eleonora Italyankina, 4 Italia Loddo, 3 Antonio Novelli, 5 and Claudio Graziano 1 * 1 Medical Genetics Unit, Policlinico S. Orsola-Malpighi, University of Bologna, Bologna, Italy 2 IRCCS-Casa Sollievo della Sofferenza, Mendel Institute, Rome, Italy 3 Department of Pediatrics, University of Messina, Messina, Italy 4 Medical Genetics Unit, Ferrara University Hospital, Ferrara, Italy 5 Medical Genetics Unit, Bambino Ges u Children’s Hospital, IRCCS, Rome, Italy 6 Child Neurology Unit, University of Bologna, Bologna, Italy Manuscript Received: 30 May 2015; Manuscript Accepted: 12 August 2015 Temple syndrome (TS) is caused by abnormal expression of genes at the imprinted locus 14q32. A subset of TS patients carry 14q32 deletions of paternal origin. We aimed to define possible genotype-phenotype correlations and to highlight the preva- lence of thyroid dysfunction, which is a previously unreported feature of TS. We described four new patients who carry dele- tions of paternal origin at 14q32 detected by array-CGH and reviewed nine patients reported in the medical literature. We compared clinical features with respect to deletion size and position. Expression of DLK1 is altered in all the patients with TS, but intellectual disability (ID) is present only in patients with larger deletions extending proximally to the imprinted locus. This study led to the identification of an ID “critical region” containing four annotated genes including YY1 as the strongest candidate. Furthermore, we described three patients with thyroid dysfunction, which progressed to papillary carcinoma at a very young age in two of them. We conclude that DLK1 loss of function is likely to be responsible for the core features of TS, while haploinsufficiency of a gene outside the imprinted region causes ID. Thyroid cancer may be an unrec- ognized feature and monitoring for thyroid dysfunction should thus be considered in TS patients. Ó 2015 Wiley Periodicals, Inc. Key words: 14q32 deletion; DIO3; DLK1; Temple syndrome; thyroid cancer; YY1 INTRODUCTION Temple syndrome (TS) is a rare condition caused by an abnormal expression of genes at the imprinted locus 14q32, described for the first time in 1991 in a young male with chromosome 14 maternal uniparental disomy (UPD(14) mat) [Temple et al., 1991]. So far, more than 50 patients with TS have been reported in the literature, whose main clinical features include intrauterine growth retarda- tion (75% of cases), truncal hypotonia in early childhood (93%) and delayed motor milestones; 86% of patients underwent early puberty, with short adult stature and an increasing body weight (obesity is reported in about 50% of patients) starting from childhood; most of these patients have some non-specific dysmor- phic features such as almond-shaped eyes, broad nasal tip and tall forehead, but a striking characteristic is the small size of hands and Conflict of interest: none. Grant sponsor: European Commission’s FP7; Grant number: 223692. Ã Correspondence to: Claudio Graziano, U.O. Genetica Medica, Policlinico S. Orsola- Malpighi. Via Massarenti 9, 40138 Bologna, Italy. E-mail: claudio.graziano@unibo.it Article first published online in Wiley Online Library (wileyonlinelibrary.com): 3 September 2015 DOI 10.1002/ajmg.a.37346 How to Cite this Article: Severi G, Bernardini L, Briuglia S, Bigoni S, Buldrini B, Magini P, Dentici ML, Cordelli DM, Arrigo T, Franzoni E, Fini S, Italyankina E, Loddo I, Novelli A, Graziano C. 2016. New patients with temple syndrome caused by 14q32 deletion: Genotype-phenotype correlations and risk of thyroid cancer. Am J Med Genet Part A 170A:162–169. Ó 2015 Wiley Periodicals, Inc. 162