Abstract
ContextFamilial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder as a result of mutation in genes encoding either the ACTH receptor [melanocortin 2 receptor (MC2R)] or its accessory protein [melanocortin 2 receptor accessory protein (MRAP)[. The disorder is known as FGD type 1 and 2, respectively.ObjectiveThe aim of the study was to compare the phenotype/genotype relationships between FGD 1 and 2.Design and patientsForty patients with missense MC2R mutations and 22 patients with MRAP mutations were included. Forty-four of these patients had been referred for genetic screening and 18 were patients published by other authors.ResultsThe median age at presentation for FGD type 1 was variable at 2·0 years; range 0·02–16 years, and this was associated with unusually tall stature, mean height SDS + 1·75 ± 1·53 (mean ± SD). In contrast, FGD type 2 presented at a much earlier median age (0·08 years; range at birth to 1·6 years) (P < 0·01) and patients were of normal height SDS + 0·12 ± 1·35 (P < 0·001). No differences in baseline cortisol or ACTH levels were seen between FGD types 1 and 2.ConclusionFGD type 2 appears to present earlier. This may reflect the functional significance of the underlying mutations in that all MRAP mutations are nonsense or splice site mutations that result in abolition of a functional protein, whereas most of the MC2R mutations are missense mutations and give rise to proteins with some residual function. Tall stature is associated with mutations in MC2R but not in MRAP. There were no other significant clinical distinctions between the two.
Highlights
Familial glucocorticoid deficiency (FGD) or hereditary unresponsiveness to ACTH is characterized by isolated glucocorticoid deficiency
The first inactivating melanocortin 2 receptor (MC2R) mutations in FGD were described in 1993.5,6 Since multiple mutations have been identified throughout the receptor, the majority of which are homozygous or compound heterozygous missense mutations; FGD resulting from MC2R mutations accounts for 25% of all FGD and is known as FGD type 1 (OMIM#202200)
FGD type 2 (OMIM*609196) describes a group of patients with normal MC2R but with mutation in the melanocortin 2 receptor accessory protein (MRAP) which is required for MC2R trafficking and function[7] and this accounts for 20% of FGD and is known as FGD type 2.8
Summary
Familial glucocorticoid deficiency (FGD) or hereditary unresponsiveness to ACTH is characterized by isolated glucocorticoid deficiency. It is an autosomal recessive disorder resulting from ACTH resistance, typically presenting between the neonatal period and late childhood; with hyperpigmentation, hypoglycaemia and seizure.[1,2,3,4] The first inactivating melanocortin 2 receptor (MC2R) mutations in FGD were described in 1993.5,6 Since multiple mutations have been identified throughout the receptor, the majority of which are homozygous or compound heterozygous missense mutations; FGD resulting from MC2R mutations accounts for 25% of all FGD and is known as FGD type 1 (OMIM#202200). Nine mutations of MRAP in FGD type 2 have been reported to date, all of which are splice site or nonsense mutations and are predicted to produce proteins lacking the transmembrane domain essential for interaction with MC2R.7,9–11
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