• SOX3 duplication is associated with variable degrees of hypopituitarism and intellectual disability. • To date, a single family with 2 affected brothers has been reported with panhypopituitarism and a neural tube defect in association with Xq26-q27 duplication which encompasses SOX3. Novel Insights • We describe the smallest Xq27.1 duplication encompassing SOX3 associated with congenital hypopituitarism reported to date. • We describe two additional unrelated pedigrees with phenotypes of congenital hypopituitarism and a neural tube defect associated with SOX3 duplication, strengthening the link between SOX3 duplication and neural tube defects. • Identification of SOX3 duplication, readily assessed by array comparative genomic hybridization, should be sought in males with intellectual disability and congenital hypopituitarism with or without midline central nervous system defects.
The aryl hydrocarbon receptor interacting protein (AIP) founder mutation R304* (or p.R304*; NM_003977.3:c.910C>T, p.Arg304Ter) identified in Northern Ireland (NI) predisposes to acromegaly/gigantism; its population health impact remains unexplored. We measured R304* carrier frequency in 936 Mid Ulster, 1,000 Greater Belfast (both in NI) and 2,094 Republic of Ireland (ROI) volunteers and in 116 NI or ROI acromegaly/gigantism patients. Carrier frequencies were 0.0064 in Mid Ulster (95%CI = 0.0027–0.013; P = 0.0005 vs. ROI), 0.001 in Greater Belfast (0.00011–0.0047) and zero in ROI (0–0.0014). R304* prevalence was elevated in acromegaly/gigantism patients in NI (11/87, 12.6%, P < 0.05), but not in ROI (2/29, 6.8%) versus non‐Irish patients (0–2.41%). Haploblock conservation supported a common ancestor for all the 18 identified Irish pedigrees (81 carriers, 30 affected). Time to most recent common ancestor (tMRCA) was 2550 (1,275–5,000) years. tMRCA‐based simulations predicted 432 (90–5,175) current carriers, including 86 affected (18–1,035) for 20% penetrance. In conclusion, R304* is frequent in Mid Ulster, resulting in numerous acromegaly/gigantism cases. tMRCA is consistent with historical/folklore accounts of Irish giants. Forward simulations predict many undetected carriers; geographically targeted population screening improves asymptomatic carrier identification, complementing clinical testing of patients/relatives. We generated disease awareness locally, necessary for early diagnosis and improved outcomes of AIP‐related disease.
• HSD3B2 enzyme deficiency is one of the rarest forms of congenital adrenal hyperplasia associated with salt wasting due to hypoaldosteronism, hypoglycaemia due to glucocorticoid deficiency, and undervirilisation of the external genitalia in genotypic males due to androgen deficiency. • Bartter syndrome causes hypokalemic, hypochloraemic metabolic alkalosis by activation of the reninangiotensin system. Novel Insights • The coexistence of HSD3B2 enzyme deficiency and Bartter syndrome can result in a state of persistent hypokalemic alkalosis suggestive of high mineralocorticoid activity. • Identification of a rare homozygous mutation in an offspring of non-consanguineous parents should raise suspicion of uniparental isodisomy.
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