A Novel NR3C1 Frameshift Variant Associated With Familial Glucocorticoid Resistance Syndrome: An Integrated Analysis of Steroid Profiling and Structural Modeling.
Sufang Yun, Zhifeng Zhu, Fengye Zhou et al.
✦ AI-curated · Sources linked
Case in brief
A man and his father, affected across successive generations, had refractory hypertension without Cushingoid features. Steroid profiling showed mild hypercortisolemia with elevated ACTH, markedly increased 11-deoxycorticosterone and 11-deoxycortisol, suppressed renin, and low-to-normal aldosterone, consistent with ACTH-driven mineralocorticoid precursor accumulation. Sequencing identified the NR3C1 frameshift variant c.923dupG (p.Ala309Serfs*6), which co-segregated with the familial phenotype and was classified as pathogenic. Structural prediction supported premature termination in the N-terminal transactivation domain, with loss of downstream domains. The findings supported familial glucocorticoid resistance syndrome.
What made this case unusual
The combination of resistant hypertension without Cushingoid features and a steroid profile showing marked mineralocorticoid precursor accumulation pointed to glucocorticoid resistance rather than a more familiar cause of hypertension.
Diagnostic / clinical pearl
In resistant hypertension, elevated ACTH with increased 11-deoxycorticosterone and 11-deoxycortisol, suppressed renin, and low-to-normal aldosterone should prompt consideration of NR3C1-related glucocorticoid resistance, even without Cushingoid features.