The ACTH insensitivity syndromes are rare disorders. In the majority of cases they are inherited but they can be acquired due to the development of auto-antibodies blocking the ACTH receptor. All patients with the ACTH insensitivity syndromes exhibit low or undetectable serum cortisol levels, high plasma ACTH, and absent or markedly impaired adrenal response to exogenous ACTH. The patients develop early primary adrenal insufficiency, which characteristically have no fluid and electrolyte disturbances, which are typically present in primary adrenal insufficiency of Addison’s syndrome. These disorders can be fatal if proper treatment is not given.

ACTH resistance consists of two distinct genetic syndromes that are both inherited as autosomal recessive traits: the isolated ACTH resistance and the Allgrove syndrome (triple-A syndrome i.e. alacrimia – achalasia - adrenal insufficiency plus neurologic disorders) (45). Inactivating mutations of the ACTH receptor usually cause isolated ACTH resistance now termed as Familial Glucocorticoid Deficiency (FGD). Introduction of stop codons within the coding region of the ACTH receptor, frameshift mutations and mutations that cause single amino acid substitutions and structural disruption of the ACTH receptor affecting the ligand-binding domain result in loss of the ligand-binding capability. On the other hand, mutations in the intracellular portion of the receptor may result in loss of the signal transduction properties of the receptor. Absence of a biological response to ACTH may thus be due to impaired binding of ACTH to its receptors or inability of the bound ACTH to initiate its post-receptor effects.

The Allgrove (triple A) syndrome is characterized by ACTH unresponsiveness and adrenal insufficiency as well as alacrimia, achalasia, and several neurological defects (46). There is a significant clinical variability between patients with the triple A syndrome (45). ACTH-R gene mutations have been identified in some families with the syndrome (47). However, it should be emphasized that most kindreds with the triple A syndrome have no ACTH-R mutations (45, 47, 48). It is possible that the disease is due to defects in molecules that affect the ACTH receptor signaling pathways, conditions that are now designated as FGD type 2.

Indeed, it now appears that FGD is associated with ACTHR mutations in approximately 25% of the cases while the remaining 75% are not. Recent work revealed a novel gene encoding a single transmembrane domain protein termed “melanocortin 2 receptor accessory protein” (MRAP) as one of the other genes underlying FGD type 2 (49). MRAP had previously been identified as a protein induced when NIH3T3-L1 cells differentiated into adipocytes. In the effort to identify additional genetic loci for FGD type 2, microarray-based SNP genotyping identified a further disease locus on chromosome 21. Fine mapping of this locus led to the identification of MRAP as a candidate for FGD type 2, and several mutations of MRAP were identified in FGD type 2 patients. These mutations cluster around the first coding exon (exon 3), especially at the splice donor site. The same mutation has been found in genetically unrelated individuals suggesting that this is a true ‘hot spot’ area for mutation. The other common site for missense mutations is in the initiator methionine. This mutation prevents translation of the full-length protein. The next in-frame methionine is at position 60 which, if translated, would result in a severely truncated protein (50).

Mutations in MRAP account for approximately 20% of all FGD cases (50, 51), implying that at least half of all FGD cases result from other genes yet to be identified. The identification of a novel genetic cause of this disorder allows one to ask whether there are any phenotypic features that associate particularly with MRAP mutations. However, based on current genotype–phenotype information there seem to be no clearly defined clinical entity. Features such as increased height are also seen in FGD type 2. Adrenal histology of FGD type 2 is typical of other cases of FGD resulting from MC2R defects, showing a relatively preserved glomerulosa cell layer with highly atrophic and disorganized fasciculata and reticularis cell layers. It, thus, remains to be evaluated whether mutations in additional GPCR accessory proteins are also associated with FGD.