Novel sonic hedgehog gene variant in a patient with hyponatremia, microsomia, and midline defects; phenotype description in association with a variant of unknown significance [c.755_757del p.(Phe252del)] and an approach to salt-wasting in SHH-related adrenal disorders

Abstract

Objective To contribute a novel sonic hedgehog (SHH) gene variant in association with a novel-meagerly described phenotype and discuss SHH signaling pathway pathology. Case presentation We present a 5-year-old boy with excessive hyponatremia and natriuresis, microform holoprosencephaly and microsomia, with morphologically intact hypothalamic–pituitary–adrenal (HPA) axis, and hypoaldosteronism, yet without hyperreninemia, hyperkalemia, dehydration episodes, or glucocorticoid insufficiency. Extensive workup excluded common causes of salt-wasting and revealed a novel variant of unknown significance on the sonic hedgehog (SHH) gene; NM_000193.4:c.755_757del (p.Phe252del), in heterozygosity. Conclusions Salt-wasting in children is predominantly caused by central nervous system lesions, renal tubular dysfunction, or adrenal insufficiency. The SHH protein is a signaling molecule, essential in embryogenesis-including HPA axis differentiation. Inactivating SHH variants disrupt the signaling pathway, leading to dysplasia or dysfunction of target organs. What’s new: • We analyze the patient's phenotype in the light of this novel variant • Patient’s isolated aldosterone deficiency possibly implies a selective signaling defect affecting the development of adrenal zona glomerulosa • Unexplained hyporeninemia and hypokalemia in the context of hypoaldosteronism raise questions on SHH signaling pathophysiology.