Glucocorticoid resistance syndrome (GRS) is a rare genetic disorder caused by inactivating mutations of the NR3C1 gene encoding the glucocorticoid receptor. The phenotypic spectrum is broad but typically includes symptoms of adrenal insufficiency, mineralocorticoid excess and hyperandrogenism. So far, about 20 different mutations in NR3C1 presenting with the GRS phenotype have been reported.
We report a 13-year-old girl that presented with severe hirsutism and clitoromegaly. No suppression of cortisol following short overnight dexamethasone test, repeated elevated urinary free cortisol (UFC) and elevated ACTH indicated a diagnosis of Cushing syndrome. Imaging evaluation by brain and abdominal MRI revealed normal pituitary and adrenal glands. Based on the contradiction between the phenotype, with absence of manifestations of Cushing syndrome, and the laboratory findings that indicated Cushing syndrome, GRS was suspected.
Sanger sequencing of NR3C1 identified a previously reported heterozygous mutation, c.1759_1762dupTTAC; p.His588Leufs*5, which results in a frameshift and stop codon 5 amino acids forward, in the proband and in her father. Other family members were negative for the identified mutation. The father was asymptomatic but had elevated 24-h UFC. Treatment with a low dose of dexamethasone improved the hirsutism and her well-being, but follow-up is needed.
The reported case demonstrates the unique phenotype of GRS andhighlighted raises awareness of this rare condition. Glucocorticoid receptor sequencing is recommended in cases with discrepancies between laboratory findings that suggest Cushing syndrome and clinical manifestations of hyperandrogenism and mineralocorticoid excess with no symptoms of glucocorticoid excess.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology