Congenital adrenal hypoplasia

Gene: TXNRD2

Green List (high evidence)

Comment on phenotypes: OMIM phenotype updated 13th May 2026.

Created: 13 May 2026, 4:09 p.m. | Last Modified: 13 May 2026, 4:09 p.m.

Panel Version: 5.4

Comment on list classification: There are now more than 3 unrelated individuals reported with biallelic TXNRD2 variants and Glucocorticoid deficiency, evidenced by loss of cortisol production and severe elevation of ACTH. Hence, this gene should be promoted to Green at the next update.

Created: 13 May 2026, 4:08 p.m. | Last Modified: 13 May 2026, 4:08 p.m.

Panel Version: 5.2

PMID: 40726908 Wang et al., 2025
Report of a 7yo Chinese male patient, compound het for TXNRD2 c.1391A > G; p.H464R and c.1141C > T; p.R381W variants. He presented with acute gastroenteritis, generalized hyperpigmentation. Normal development. Cardiac features: prolonged QT interval and premature atrial contractions on echocardiogram. Pre-treatment, his cortisol was <22  (reference 138-690 nmol/L) and Adrenocorticotropic hormone was elevated to >278ng/L (ref 0-10).

PMID: 38011841 Patjamontri et al., 2024
Proband with selective glucocorticoid deficiency at 10 years of age. He had a history of a small penis and a right undescended testis, which subsequently required an orchidopexy. The parents were of Pakistani origin and first cousins. WGS detected variants p.Val361Met and p.Val361Met in TXNRD2. Compared to controls, he had lower TXNRD2 protein on immunoblotting, lower mRNA expression of TXNRD2, and a lower glutathione:oxidized glutathione ratio. Cortisol was undetectable, and plasma ACTH was 1,070 mU/L (ref <20 mU/L).

PMID: 39097530 Brachet et al., 2024
Patient had a complex phenotype of primary adrenal insufficiency (PAI), combined with genital, ophthalmological, and neurological features. He carried a homozygous splice variant c.1348-1G > T in TXNRD2 which leads to a shorter protein lacking the C-terminus. Patient derived cells showed loss of cortisol production with overall diminished adrenal steroidogenesis.

PMID: 30237576 Maddirevula et al., 2019
Large autozygome study. Patient 17-3959 had a homozygous truncating variant in TXNRD2 (c.1252C>T, p.R418X) had a syndromic manifestation characterized by low cortisol, intellectual disability, epilepsy, dysmorphic features, truncus arteriosus, and omphalocele.

Created: 13 May 2026, 4:07 p.m. | Last Modified: 13 May 2026, 4:07 p.m.

Panel Version: 5.1

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Glucocorticoid deficiency 5 , OMIM:617825; glucocorticoid deficiency 5, MONDO:0040502

Publications

• 24601690
• 30237576
• 38011841
• 39097530
• 40726908

Comment on list classification: Insufficient evidence to date but may be promoted in future.

Created: 11 Sep 2016, 9:03 a.m.

Red List (low evidence)

Associated with isolated glucocorticoid insufficiency in several children from a single Kashmiri kindred. Potential association with cardiac defects. No other families reported yet.

Created: 4 Feb 2016, 4:32 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 24601690