Familial glucocorticoid deficiency type 2 (FGD2) is a rare autosomal recessive disorder caused by pathogenic variants in the MRAP gene, typically characterized by isolated cortisol deficiency with markedly elevated ACTH levels. We report a term male neonate born to consanguineous parents who presented with striking scrotal hyperpigmentation at birth, despite an otherwise normal appearance and a normal newborn screening limited to classical congenital adrenal hyperplasia (CAH). Initial biochemical evaluations, including glucose and electrolytes, were unremarkable; however, due to severe hyperpigmentation, further endocrine workup was pursued. Laboratory findings revealed profoundly low serum cortisol and markedly elevated ACTH, supporting the diagnosis of primary adrenal insufficiency. Hydrocortisone therapy was initiated promptly, and during follow-up, transient hyperkalemia and low-normal aldosterone levels necessitated short-term fludrocortisone supplementation, suggesting partial mineralocorticoid involvement. Genetic analysis identified a homozygous MRAP in-frame deletion (c. 88₉0del; p. K30del), classified as likely pathogenic according to ACMG 2015 criteria and as a variant of uncertain significance according to the ClinGen SVI recommendations. Despite the dramatic initial presentation, the patient remained euglycemic and demonstrated normal neurodevelopment under appropriate hormone replacement, with gradual resolution of hyperpigmentation. This case highlights striking neonatal scrotal hyperpigmentation as a potential early clinical clue suggestive of familial glucocorticoid deficiency in a patient with a homozygous MRAP variant. Importantly, even when newborn screening for CAH is normal, marked hyperpigmentation should prompt evaluation for other causes of primary adrenal insufficiency to prevent life-threatening adrenal crises.
Gürpınar et al. (Wed,) studied this question.