TXNRD2 – Familial Glucocorticoid Deficiency

Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder characterized by isolated cortisol deficiency with preserved mineralocorticoid function, presenting in infancy or childhood with hyperpigmentation, hypoglycemia and elevated ACTH despite low cortisol levels. Exome sequencing studies identified biallelic loss-of-function variants in TXNRD2, encoding mitochondrial thioredoxin reductase 2, in FGD patients negative for MC2R, MRAP and STAR mutations (PMID:30817990).

In a consanguineous Kashmiri kindred, whole-exome sequencing and Sanger confirmation revealed a homozygous stop-gain variant c.1341T>G (p.Tyr447Ter) in TXNRD2 that segregated with disease in seven family members, six of whom were affected with FGD (autosomal recessive; 6 affected relatives) (PMID:24601690). RT-PCR and Western blotting demonstrated complete absence of TXNRD2 protein in homozygotes, establishing genotype-phenotype concordance.

An independent patient with primary adrenal insufficiency and glucocorticoid deficiency was found to carry a homozygous splice-site variant c.1348-1G>T in TXNRD2. Patient-derived induced adrenal-like cells showed loss of cortisol production and elevated mitochondrial reactive oxygen species, confirming functional impact in steroidogenesis and redox homeostasis (PMID:39097530).

To date, at least two distinct biallelic TXNRD2 variants—one nonsense and one splice—have been reported in FGD, consistent with an autosomal recessive inheritance pattern. All variants are predicted loss-of-function, implicating TXNRD2 haploinsufficiency and impaired mitochondrial antioxidant defense as the pathogenic mechanism.

Functional studies in an H295R adrenocortical cell line with TXNRD2 knockdown recapitulate impaired redox balance, supporting a critical role for mitochondrial thioredoxin reductase in cortisol biosynthesis. Patient-derived iALCs further corroborate deficient steroidogenesis and excessive reactive oxygen species formation, linking molecular defect to endocrine phenotype.

No conflicting reports have been published disputing the TXNRD2–FGD association. Additional rare missense alleles and animal models address broader roles of TXNRD2 but remain outside the core FGD evidence. Key take-home: Biallelic loss-of-function variants in TXNRD2 cause autosomal recessive familial glucocorticoid deficiency and should be included in FGD gene panels for early molecular diagnosis and management.

References

• The Journal of clinical endocrinology and metabolism • 2014 • Thioredoxin Reductase 2 (TXNRD2) mutation associated with familial glucocorticoid deficiency (FGD). PMID:24601690
• European journal of endocrinology • 2024 • Insight into the role of TXNRD2 in steroidogenesis through a novel homozygous TXNRD2 splice variant. PMID:39097530
• The Journal of steroid biochemistry and molecular biology • 2019 • Isolated glucocorticoid deficiency: Genetic causes and animal models. PMID:30817990

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