Familial Glucocorticoid Deficiency Type 1
A male infant born to consanguineous Kurdish parents presented with persistent hypoglycaemia from birth. Despite normal APGAR scores and a healthy gestational period, initial investigations revealed severe hypoglycaemia (<1.1mmol/L) unresponsive to treatment. Examination showed normal male genitalia and no dysmorphic features. Blood pressure was within normal ranges. Initial biochemistry indicated undetectable cortisol levels and elevated ACTH (>275pmol/L).
Further endocrinological investigations confirmed primary adrenal insufficiency with a failed cortisol response to ACTH stimulation. Genetic analysis identified a homozygous 560delT mutation in the MC2R gene, diagnosing Familial Glucocorticoid Deficiency (FGD) Type 1, characterized by ACTH resistance, resulting in inadequate cortisol production while typically sparing aldosterone synthesis.
Treatment with weight-based hydrocortisone and fludrocortisone showed initial improvement. In subsequent follow-ups, the patient exhibited tall stature, a hallmark of FGD Type 1, likely due to ACTH's extra-pituitary effects. Bone age assessment at 17 years showed delayed skeletal maturation. Additionally, his mineralocorticoid requirements and concomitant hypothyroidism presented management difficulties due to the unknown nature of this condition and its heterogeneous manifestations.
Discussion:
FGD Type 1 is an autosomal recessive ACTH resistance disorder, primarily affecting cortisol synthesis due to MC2R gene mutations. (1) Worldwide prevalence is unknown, with roughly 42 case reports. (2) While mineralocorticoid function often remains intact, cases like this exhibit variability, making management of mineralocorticoid requirements uncertain. Our patient’s 560delT mutation is thought to represent a more severe phenotype, possibly associated with salt-wasting forms requiring mineralocorticoid replacement. (3, 4) Patients with FGD often have thyroid dysfunction, with no consensus on management. (5) Although our patient did not have significant issues with adrenarche and bone health, these are potential concerns in this rare condition.
This case underscores the heterogeneity of FGD Type 1 and the necessity for tailored therapeutic strategies to manage complications.