Session: OR11-Pediatric Endocrinology
Room 104 (Moscone Center)
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
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