ESPE Abstracts (2015) 84 FC14.3

ESPE2015 Free Communications Puberty (6 abstracts)

The New Syndrome of Hypogonadotropic Hypogonadism, Arrythmogenic Right Ventricular Dysplasia, Facial Dysmorphism and Absence of Corpus Callosum is Associated to TAX1 Binding Protein 3 Gene Mutation

Eli Hershkovitz a , Maram Arafat b , Zaid Afawi c , Neta Loewenthal a , Alon Haim a , Aviva Levitas d & Ruti Parvari b

aPediatric Endocrinology Unit, Soroka Medical Center and Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel; bShraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, and National Institute for Biotechnology in the Negev, Ben Gurion University of the Negev, Beer Sheva, Israel; cSourasky Medical Center, Tel Aviv, Israel; dPediatric Cardiology Unit, Soroka Medical Center and Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel

Background: A growing list of genes has been implicated in the pathogenesis of congenital hypogonadotropic hypogonadism (HH).

Objective and hypotheses: To identify the cause of a unique syndromic HH in a consanguineous Bedouin family.

Method: Medical records of the patients were reviewed. Genotyping of the brothers and their parents and whole exome sequencing (WES) were performed.

Results: Two brothers presented at 19 and 8 years of age. Both were normosmic, had facial dysmorphism with underdeveloped genitalia due to partial isolated HH. Brain MRI disclosed absence of corpus callosum in both patients. Renal US was normal. Recurrent pre-syncope events at 26 years of age lead to the diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVD) in the older patient and subsequently in his young brother who has recently died after heart transplantation. Genotyping done on the patients and their parents identified a total of 17.4 Mb of homozygosity larger than 5 cM. Assuming the disease is caused by homozygotisation of the causative mutation, WES identified only one variation segregating as expected in the family and not present in the public databases, Ile33Thr substitution in the Tax1 (human T-cell leukemia virus type I) binding protein 3 (TAX1BP3), The Ile at position 33 is evolutionary conserved, has the highest prediction to be deleterious by polyphene, additionaly the change is predicted to cause loss of the PDZ domain and affect the structure of all other domains.

Conclusion: A new clinical syndrome combining HH, ARVD absence of corpus callosum and peculiar facial dysmorphism has been found to be associated to TAX1BP3 gene mutation.

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