A 11-year 10-month boy born of non-consanguineous marriage presented with recurrent oral and respiratory tract infections and failure to thrive from the age of one year. He was born at term with a birth weight of 3.5 kg with an uneventful perinatal period. The parents noticed recurrent oral infections with the whitish curd-like layer deposited over the oral mucosa. They also complained of gradual skin darkening, easy fatiguability, and growth failure over the last three years. On examination, he was short (height 125 cm;-3.06 SDS), and lean (29.3 kg,-1.23 SDS, BMI 18.7 kg/m2, 0.8 SDS). He had stage 1 pubic hair with a stretched penile length of 4.5 cm and a testicular volume of 1 ml. He had generalized pigmentation with oral candidiasis. Blood pressure was 90/70 mmHg measured in the right arm. The diagnostic work-up showed hyponatremia (serum sodium level of 121 mmol/l; 135-145 mmol/l), and normal potassium (4.2 mmol/L, 3.5-4.5 mmol/l). Cortisol levels were low for the level of hyponatremia (115 nmol/L). Further work-up showed elevated ACTH 379 pg/ml and plasma renin (74.29 pg/ml). A diagnosis of isolated glucocorticoid deficiency due to Familial glucocorticoid deficiency was considered in view of hyponatremia, normal potassium, low cortisol, and high ACTH levels. The boy was started on oral hydrocortisone and a low dose of fludrocortisone. Clinical exome sequencing showed a heterozygous, stop gain mutation in TXNRD2 (c.1341T>G; (p.Tyr447Ter) within exon 15, and compound heterozygous variants were found in the ATP7B gene in exon 2 (c.174dup; (p.Thr59HisfsTer19) and exon 18 (c.3741C>G; (p.His1247Gln).TXNRD2 is a dimeric NADPH-dependent flavin adenine dinucleotide-containing enzyme that catalyzes the reduction of the active disulfide of thioredoxin 2 and other substrates.TXRD2 protects the cell from oxidative stress. The higher production of cortisol, explains the susceptibility of the zona fasciculata to oxidative stress; hence, individuals with TXNRD2 and NNT mutations primarily develop glucocorticoid deficiency. Absence of TXNRD2 in humans leads to glucocorticoid deficiency. Reaching a specific diagnosis can have implications for management and for monitoring associated features, as well as for counselling families about recurrence risk in siblings and relatives.
08 Nov 2023 - 10 Nov 2023