Case report and literature review: novel TXNRD2 compound heterozygous variants in familial glucocorticoid deficiency type 5

TL;DR

This paper reports a new case of a rare adrenal disorder caused by mutations in the TXNRD2 gene, expanding our understanding of its genetic and clinical features.

Contribution

The study identifies novel compound heterozygous TXNRD2 variants and links them to FGD5 and electrocardiographic abnormalities.

Findings

The novel TXNRD2 variants reduce protein levels in a heterologous expression system.

This case expands the genetic spectrum of FGD5 and highlights a potential link to heart-related abnormalities.

TXNRD2 is shown to play a key role in adrenal redox homeostasis.

Abstract

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by isolated glucocorticoid deficiency. Mutations of MC2R, MRAP, STAR, NNT, and TXNRD2 have been implicated in FGD pathogenesis. To date, only four families with TXNRD2-associated familial Glucocorticoid Deficiency Type 5 (FGD5) have been reported worldwide. We report a patient with clinical features consistent with FGD5, increasing the total number of reported cases. Including this case, 11 probands across five independent kindreds have now been identified globally. Functional studies demonstrated that the novel compound heterozygous variants (c.1391A > G; p.H464R and c.1141C > T; p.R381W) reduce TXNRD2 protein levels in a heterologous expression system. This case expands the genetic spectrum of FGD5 and suggests a potential association between TXNRD2 variants and electrocardiographic abnormalities. Our findings underscore the importance of TXNRD2 in adrenal redox homeostasis and provide new insights for FGD5 diagnosis.

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