Endocrine Abstracts

Introduction: FGD is a rare autosomal recessive disorder, characterised by isolated glucocorticoid deficiency. Loss-of-function mutations in MC2R (ACTH receptor) cause FGD type-1 (FGD1) and mutations in Melancortin-2-receptor accessory protein (MRAP) cause FGD type-2 (FGD2). Here, we describe characteristics of FGD1 and FGD2.

Methods: Retrospective analysis of our FGD international database. Statistical analysis performed on SPSS-Version-29. Significance defined as P < 0.05.

Results and discussion: Our database includes 70 patients with FGD1 (F=29, M=40, unknown n = 1) and 56 with FGD2 (F=17, M=27, unknown n = 12). Mean age of presentation for FGD1 was 2.21 +/- 3.13 yr (range 0.003-10.0 yr) compared to 1.90 +/- 4.01 y (range 0.003-18 yr) for FGD2, P = 0.347. There was no statistically significant difference in height, weight or BMI Z-scores between FGD1 and FGD2. Comparing FGD1 to FGD2, mean baseline serum cortisol and ACTH levels were similar (cortisol 25.0 vs 27.70 nmol/l, ACTH 238.45 vs 203.12 pmol/l). Hydrocortisone replacement was 15.2 +/- 4.0 vs 13.0 +/- 6 mg/m²/day, higher than recommended dosages for primary adrenal insufficiency. Our database includes 26 different MC2R and 18 MRAP mutations. S74I is the commonest mutation for FGD1 (40%, n = 28) and M1I for FGD2 (21.2%, n = 11). MC2R missense mutations account for 78.6%, n = 55 of FGD1, whereas MRAP nonsense mutations (involving initiating methionine or causing truncating non-functional protein) account for 86.5%, n = 45 of FGD2. MRAP nonsense mutations present significantly earlier compared to missense MRAP mutations (mean age 0.538 +/- 0.914 yr, range 0.003-4.0 yr vs 7.528 +/- 7.142 yr, range 1.5 – 18.0 y), P < 0.001, and all MC2R mutations, P = 0.006.

Conclusions: MRAP nonsense mutations present clinically earlier compared to MRAP missense and MC2R mutations. There is no difference in anthropomorphic or biochemical markers between FGD1 and FGD2. Hydrocortisone replacement is higher compared to recommended dosages. Long-term follow-up data would help determine associated co-morbidities in FGD1 and 2.