Familial glucocorticoid deficiency due to a novel TXNRD2 variant: expanding the spectrum of a rare genetic cause.

PMID 42290847 | PMCID PMC13253293 | DOI 10.3389/fendo.2026.1834727 · Frontiers in endocrinology · 2026

BACKGROUND: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by isolated cortisol deficiency and elevated adrenocorticotropic hormone (ACTH) levels. Variants in TXNRD2, which encodes mitochondrial thioredoxin reductase 2, have recently been implicated in FGD; however, the phenotypic and mutational spectrum remain extremely limited. METHODS: Whole-genome sequencing (WGS) was performed in a proband from a Saudi family who presented in early childhood with clinical and biochemical features consistent with FGD (Low basal and stimulated cortisol of < 5 nmol/l and extremely elevated ACTH levels of > 2500 pg/ml) and seizure disorder requiring medical treatment and with basal ganglia changes noted on brain MRI at presentation. WGS identified a novel likely pathogenic TXNRD2 variant with no other potential variant in FGD-associated genes. Population frequency, segregation analysis, evolutionary conservation, and in silico pathogenicity predictions were assessed for the identified variant. RESULTS: WGS identified a novel missense homozygous TXNRD2 (NM_001282512) variant (c.575C>T (p.Pro192Leu) in the proband, and in the heterozygous state in both parents, supporting autosomal recessive inheritance. This variant has not been reported in a local population database of > 18000 exomes, is extremely rare in international population databases (minor allele frequency 0.00000479), and affects a highly conserved residue. The variant was consistently predicted by multiple in silico tools to have deleterious effects on protein structure and function. No pathogenic, likely pathogenic, or VUS was found in other genes involved in FGD, including MC2R, MRAP, STAR, CYP11A1, NNT, MCM4, or SGPL1. CONCLUSION: This report adds another patient with a novel variant to the few previously described patients and expands the genetic spectrum of the very rare TXNRD2-associated FGD, supporting the role of mitochondrial redox dysregulation in adrenal insufficiency.