ESPE Abstracts

Introduction: The molecular aetiology of familial glucocorticoid deficiency (FGD) is very heterogeneous. A recent report of a genetic variant in TXNRD2, the gene encoding thioredoxin reductase Type 2, in a South Asian kindred with FGD suggests that the maintenance of redox balance may be critical for adrenocortical function. We present the second report of an individual from another south Asian family harbouring a different pathological variant in TXNRD2.

Case description: The index case presented with a right undescended testis and micropenis at birth. The family were of South Asian origin and parents were first cousins. His two sisters were healthy and one older brother had been diagnosed with mild dysplastic pulmonary valve without any obstructive symptoms. Endocrine investigations at 1.9 yrs showed serum AMH of 872 pmol/l (ref 300-1700), post-hCG serum testosterone and dihydrotestosterone of 9.9 nmol/l and 1.31 nmol/l, respectively and a post-LHRH LH and FSH of 12.0 U/l and 5.2 IU/l, respectively. Urinary steroid analysis by GCMS did not reveal any abnormalities. At the age of 10.3 years, he re-presented with a history of fatigue and hyperpigmentation and investigations revealed a plasma ACTH of 1070 mU/l, undetectable cortisol post ACTH stimulation and a plasma renin concentration of 26.5 mIU/l (ref <125). Adrenal autoantibodies were negative. Following 5 months of replacement, his plasma ACTH had reduced to 265 mU/L. Targeted genetic analysis using XY DSD panel and congenital adrenal hypoplasia panel revealed a variant of uncertain significance in CYP11B1. Exome analysis revealed an autosomal recessive homozygous missense variant (c.1081G>A; p.(Val361Met)) in TXNRD2 which was absent from gnomAD. In silico analysis provided equivocal evidence of the variant’s pathogenicity. However, functional studies on peripheral blood mononuclear cells showed decreased mRNA expression on quantitative RT-PCR of TXNRD2 (1.6 fold, P=0.0007), decreased TNXRD2 protein (1.3 fold, P<0.0001) on immunoblotting studies and decreased glutathione:oxidized glutathione ratio (6.7 fold, P<0.0001) in the index case compared to the heterozygote parents and controls. Other than atypical genitalia and adrenal insufficiency, he had no other health issues and his echocardiogram was normal.

Discussion: This second report of isolated glucocorticoid deficiency with a homozygous missense variant in TXNRD2 strengthens the role of this protein in adrenocortical redox homeostasis. In addition to isolated glucocorticoid deficiency, our case had micropenis and undescended testis, which have not been reported in the previous kindred with TXNRD2 variants, thus extending the associated phenotype.