OR11-6 ARNT2 Deficiency Causes a Multisystem Disorder with Hypothalamic Insufficiency

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR11-Pediatric Endocrinology
Saturday, June 15, 2013: 11:30 AM-1:00 PM
Presentation Start Time: 12:45 PM
Room 104 (Moscone Center)
Daniel Kelberman*1, Emma Webb1, Angham N Almutair2, Chiara Bacchelli1, Estelle Chanudet1, Francesco Lescai1, Cynthia Lilian Andoniadou3, Abdul Hameed Al Banyan2, Abdulrahman Al Swaid2, Mohammad Alrifai2, Mohammed AlBalwi2, Neda Mousavy-Gharavy1, Biljana Lukovic4, Derek Burke5, Simon Heales4, Mark J McCabe1, Tessa Kasia1, Robert Kleta6, Elia Stupka7, Philip L Beales1, Dorothy A Thompson4, Kling W Chong4, Fowzan Alkuraya8, Juan Pedro Martinez-Barbera3, Jane C Sowden1 and Mehul Tulsidas Dattani1
1UCL Institute of Child Health, London, United Kingdom, 2King Abdulaziz Med City, Riyadh, Saudi Arabia, 3UCL, London, United Kingdom, 4Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom, 5Great Ormond Street Hospital for Children NHS Foundation Trust, London`, United Kingdom, 6UCL Centre for Nephrology, London, United Kingdom, 7San Raffaele Scientific Institute, Milan, Italy, 8King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Introduction Mutations affecting hypothalamic development in humans have been identified in genes that affect isolated domains of hypothalamic function leading to restricted phenotypes, such as obesity or hypogonadotrophic hypogonadism. We describe the first human cases of diabetes insipidus and combined pituitary hormone deficiency due to a mutation in a gene regulating hypothalamic development.

Results Six affected individuals from a highly consanguineous pedigree presented with cortisol deficiency and central diabetes insipidus. Four also presented with or developed central hypothyroidism and three showed an abnormal growth curve, with maintenance of linear growth in conjunction with obesity. Despite initial cerebral sparing, progressive microcephaly was present in all patients in association with global developmental delay and seizures (onset 5 days to 2.5 years) as well as  hydronephrosis, vesicoureteric reflux and a neurogenic bladder. Using a combination of whole genome homozygosity mapping coupled with exome sequencing we have identified a single novel homozygous variant, c.1373_1374insTC, segregating between affected family members. This mutation resides in a transcription factor essential for normal hypothalamic development and is predicted to result in a frameshift and consequent loss of function. Moreover, levels of the mutant transcript were significantly reduced in patient fibroblasts compared to controls. We demonstrate high levels of expression in the hypothalamus, telencephalon and renal tract in the developing human embryo identical to that previously observed in the mouse.

Conclusion We describe a mutation in a transcription factor known to regulate development of the paraventricular, supraoptic and anterior periventricular nuclei in mice. The affected patients display several features of hypothalamic insufficiency, including obesity, diabetes insipidus, ACTH and TSH deficiency. Oxytocin and somatostatin are also likely to be deficient. The growth pattern of three of these children, the first human cases of probable somatostatin deficiency, is significantly abnormal with increased weight appearing to be the main driver of linear growth.

Nothing to Disclose: DK, EW, ANA, CB, EC, FL, CLA, AHA, AA, MA, MA, NM, BL, DB, SH, MJM, TK, RK, ES, PLB, DAT, KWC, FA, JPM, JCS, MTD

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

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