A Rare Case of Resistant Pigmentation

Abstract

Introduction: Familial glucocorticoid deficiency (FGD) is characterised by ACTH resistance & isolated glucocorticoid deficiency, with typical biochemical findings of low serum cortisol & high plasma ACTH. Patients present with hyperpigmentation (due to stimulation of MC1R by POMC products) & hypoglycemia. Clinical presentation includes failure to thrive & susceptibility to infections. Case Report: A 14 year old girl presented to us with generalised hyperpigmentation of the skin and oral mucosa- it started when she was 4 years of age. There was history of recurrent respiratory infections around the same time the hyperpigmentation appeared - the patient required multiple hospitalisations for the same (she was admitted 3 times in 6 months). Her random serum cortisol was measured – it came out to be 8.27nmol/L. Her serum Na+ was 140 mEq/L & K+ was 3.5 mEq/L. She was also diagnosed with subclinical hypothyroidism at that time (TSH- 7.3 mIU/L, anti TPO antibodies positive). There was no history of alacrimia or achalasia. Her 17-OHP was 2.20 nmol/L. A probable diagnosis of autoimmune polyendocrine syndrome was made & oral hydrocortisone (@ 12 mg/m2) & levothyroxine (@25 mcg) was started. The patient was compliant with the treatment, but the mother complained that her hyperpigmentation improved only by 20–30 % despite continued treatment. There was no history of salt wasting crises or hospitalisations after the initiation of treatment. Her serum ACTH values were checked 2 times (2011 & 2015) and were > 2000 pg/ml on both the occasions. The hydrocortisone dose was increased to 20mg/m2 for 1 year in between, without any improvement in hyperpigmentation. Patient presented to us with persistent hyperpigmentation in 2019. She was a product of consanguineous marriage. Non-compliance was ruled out. She had attained menarche at the age of 12 years. There was history of delayed pubarche (started @ age of 13 years) & axillary hair was absent. Again, her serum ACTH was > 2000 pg/ml and electrolytes and BP were normal. In view of normal electrolytes with low cortisol at the time of diagnosis & persistent hyperpigmentation even on supraphysiological doses of hydrocortisone, Familial Glucocorticoid Deficiency was considered. Genetic analysis showed mutation in Thioredoxin Reductase (TXNRD2) Gene. This gene mutation has recently been reported in FGD. (Prasad R et al, JCEM Aug 2014.) Conclusion: In cases of primary adrenal insufficiency with normal electrolytes & resistant hyperpigmentation, familial glucocorticoid deficiency should be thought of. Treatment with standard glucocorticoid therapy should be given. Serum ACTH values should not be chased. The hyperpigmentation may not resolve completely. TXNRD2 deficiency leads to impaired redox homeostasis, highlights the important redox pathway in addition to defective ACTH signaling, giving us new insights in regard to steroidogenesis.