Alternative titles; symbols
ORPHA: 361; DO: 0080621;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 18p11.21 | Glucocorticoid deficiency, due to ACTH unresponsiveness | 202200 | Autosomal recessive | 3 | MC2R | 607397 |
A number sign (#) is used with this entry because glucocorticoid deficiency-1 (GCCD1), or familial glucocorticoid deficiency (FGD1), is caused by homozygous or compound heterozygous mutation in the gene encoding melanocortin-2 receptor (MC2R; 607397), which is also referred to as adrenocorticotropin receptor (ACTHR), on chromosome 18p11.
Familial glucocorticoid deficiency is an autosomal recessive disorder resulting from defects in the action of adrenocorticotropic hormone (ACTH) to stimulate glucocorticoid synthesis in the adrenal. Production of mineralocorticoids by the adrenal is normal. Patients present in early life with low or undetectable cortisol and, because of the failure of the negative feedback loop to the pituitary and hypothalamus, grossly elevated ACTH levels (summary by Clark et al., 2009).
Genetic Heterogeneity of Familial Glucocorticoid Deficiency
Familial glucocorticoid deficiency-2 (GCCD2; 607398) is caused by mutation in the MRAP gene (609196) on chromosome 21q22. GCCD3 (609197) has been mapped to chromosome 8q11.2-q13.2. GCCD4 with or without mineralocorticoid deficiency (614736) is caused by mutation in the NNT gene (607878) on chromosome 5p12. GCCD5 (617825) is caused by mutation in the TXNRD2 gene (606448) on chromosome 22q11.
Migeon et al. (1968) described an entity of adrenal unresponsiveness to ACTH characterized by hypoglycemia, hyperpigmentation, feeding problems in infancy, low urinary 17-OHCS, normal tolerance to salt deprivation, and no elevation of 17-OHCS excretion or plasma cortisol concentration with administration of ACTH. Two of their patients were brothers. Sibs of 2 other patients were probably affected. Affected male and female sibs were reported by Shepard et al. (1959).
Franks and Nance (1970) observed the condition in 2 sisters and a brother, offspring of first-cousin parents, and reviewed 8 other familial cases. An excess of males and a deficiency of consanguinity suggested the existence of both autosomal and X-linked recessive forms. Plasma ACTH levels were greatly elevated. Kelch et al. (1972) reported 3 families. They pointed out that variable adrenal pathology from family to family and the possibility of both autosomal and X-linked forms suggest heterogeneity in this condition.
Thistlethwaite et al. (1975) described affected brothers who had intermittent hypoglycemia precipitated by the 'stress' of infection. Both were tall and hyperpigmented. Failure of adrenocortical response to ACTH was progressive in the elder boy. Electrolyte balance was normal, even on low sodium diet. Levels of ACTH and deoxycorticosterone in the blood were high.
Moshang et al. (1973) studied 5 affected sibs. Because of progression of manifestations, they concluded that a primary unresponsiveness to ACTH is not the lesion, but rather that the disorder is an inherited degenerative process. On the other hand, Spark and Etzkorn (1977) favored a defect at the ACTH receptor or a postreceptor site.
ACTH receptors in mononuclear leukocytes have been reported to be similar to those in the adrenal cortex in affinity, immunogenicity, and the coupling to effectors. Smith et al. (1987) reported that a patient with familial ACTH unresponsiveness had a significantly decreased number of high-affinity ACTH receptors in circulating monocytes.
Allen et al. (1989) described 2 fatal cases in brothers with a clinical presentation resembling Reye syndrome at ages 3 years and 9 months and 5.5 years. In both boys the findings in the adrenal were consistent with the diagnosis of unresponsiveness to ACTH: the adrenocortical cells were arranged in a pseudoglandular pattern that resembled zona glomerulosa. Neither fasciculata nor reticularis cells could be identified.
Yamaoka et al. (1992) described a form of ACTH unresponsiveness in which the defect appeared to reside distal to the receptor (202355); they described 2 cousins with ACTH unresponsiveness and normal ACTH receptors in monocytes.
Yamamoto et al. (1995) described ACTH insensitivity in 2 sibs, a 9-year-old boy and his 4-year-old sister. They were referred to a hospital because of cutaneous hyperpigmentation. Peripheral blood mononuclear leukocytes obtained from the patients showed no generation of adenylate cyclase when treated in vitro with ACTH. A lack of high-affinity ACTH binding was observed in the patients. A mutation search in these patients failed to reveal the causative mutation.
The transmission pattern of GCCD1 in the family reported by Clark et al. (1993) was consistent with autosomal recessive inheritance.
Isolated glucocorticoid deficiency was shown by Clark et al. (1993) and Tsigos et al. (1993) to be caused by homozygous or compound heterozygous mutation in the MC2R gene (see 607397.0001-607397.0003). Nephrogenic diabetes insipidus (304800) had previously been shown to be due to a defect in a G protein-coupled receptor.
Although mutations in the ACTHR gene were demonstrated in some families (e.g., 607397.0001), no mutation was found in the gene in other families. Genetic heterogeneity was confirmed by the demonstration that a highly polymorphic CA repeat marker (D18S40), closely linked to the ACTHR locus, was not linked to the clinical phenotype in these families (Weber and Clark, 1994). The markers segregated with the syndrome in 4 families and independently of the syndrome in 3 families. In an eighth family, the D18S40 genotype neither excluded nor confirmed linkage to the locus, but no mutations in the ACTHR gene were found. Thus, half of affected families probably have a cause other than mutation in the ACTHR gene.
Naville et al. (1998) investigated 11 families in which members presented with the clinical features of familial glucocorticoid deficiency but lacked mutations in the coding exon of the MC2R gene. The authors carried out linkage analysis to determine whether mutations outside the coding region of the MC2R gene were involved in familial glucocorticoid deficiency in these families. Using 3 markers flanking the MC2R gene on chromosome 18, they excluded linkage in a 12-cM region around the gene. Naville et al. (1998) concluded that familial glucocorticoid deficiency is genetically heterogeneous and that defects in gene(s) other than the MC2R gene are implicated in this syndrome.
Genin et al. (2002) found evidence of linkage to chromosome 8q in 3 of 14 families with glucocorticoid deficiency and no mutations in the MC2R gene. These 3 families were consanguineous, and the locus (GCCD3; 609197) could be mapped by homozygosity between markers D8S285 and D8S1718 in an 8.8-cM region spanning 8q11.2-q13.2. Linkage to chromosome 8q could be excluded in 5 of the remaining families, suggesting that at least a third gene is involved in glucocorticoid deficiency.
In 2 consanguineous families with glucocorticoid deficiency whose disease did not segregate with either MC2R or the 8q12.1-q21.2 region, Metherell et al. (2005) identified a candidate region of 2.2 Mbp in chromosome 21q22.1 (FGD2; 609196). They identified homozygous mutations in the melanocortin-2 receptor accessory protein gene (MRAP; 609196), encoding a 19-kD single transmembrane domain protein that interacts with MC2R and may have a role in the trafficking of MC2R from the endoplasmic reticulum to the cell surface.
O'Riordan et al. (2008) studied the clinical features and assessed the prevalence of familial glucocorticoid deficiency (FGD) among Irish Travellers in the Republic of Ireland and described their phenotype. They identified 21 cases of FGD in the Irish population, generating an overall prevalence of 1 in 201,898. They reported 9 Irish Travellers (5 females) with FGD related to a novel gene, negative for MC2R and MRAP mutations. Of a total population of 22,557 Travellers, this yielded a disease prevalence of 1 in 2,506 with a carrier frequency of 1 in 25 in this group, and represented a prevalence of 1 in 665 and a carrier frequency of 1 in 13 in the 4- to 15-year Traveller age group. O'Riordan et al. (2008) stated that this was the highest recorded prevalence for FGD quoted worldwide. Among these 9 children initial biochemical testing was normal, which delayed the diagnosis of FGD. Later biochemical analysis was typical of cases presenting with FGD types 1 or 2 (607398).
Allen, D. B., Hendricks, S. A., Perloff, W. H., Chandra, S., Gibert, E. F. Clinico-pathological conference: the simultaneous presentation of a Reye-like syndrome in two male sibs. Am. J. Med. Genet. 32: 52-59, 1989. [PubMed: 2539720] [Full Text: https://doi.org/10.1002/ajmg.1320320112]
Clark, A. J. L., Chan, L. F., Chung, T.-T., Metherell, L. A. The genetics of familial glucocorticoid deficiency. Best Pract. Res. Clin. Endocr. Metab. 23: 159-165, 2009. [PubMed: 19500760] [Full Text: https://doi.org/10.1016/j.beem.2008.09.006]
Clark, A. J. L., McLoughlin, L., Grossman, A. Familial glucocorticoid deficiency associated with point mutation in the adrenocorticotropin receptor. Lancet 341: 461-462, 1993. [PubMed: 8094489] [Full Text: https://doi.org/10.1016/0140-6736(93)90208-x]
Franks, R. C., Nance, W. E. Hereditary adrenocortical unresponsiveness to ACTH. Pediatrics 45: 43-48, 1970. [PubMed: 4312011]
Genin, E., Huebner, A., Jaillard, C., Faure, A., Halaby, G., Saka, N., Clark, A. J. L., Durand, P., Begeot, M., Naville, D. Linkage of one gene for familial glucocorticoid deficiency type 2 (FGD2) to chromosome 8q and further evidence of heterogeneity. Hum. Genet. 111: 428-434, 2002. [PubMed: 12384787] [Full Text: https://doi.org/10.1007/s00439-002-0806-3]
Kelch, R. P., Kaplan, S. L., Biglieri, E. G., Daniels, G. H., Epstein, C. J., Grumbach, M. M. Hereditary adrenocortical unresponsiveness to adrenocorticotropic hormone. J. Pediat. 81: 726-736, 1972. [PubMed: 4342294] [Full Text: https://doi.org/10.1016/s0022-3476(72)80093-3]
Metherell, L. A., Chapple, J. P., Cooray, S., David, A., Becker, C., Ruschendorf, F., Naville, D., Begeot, M., Khoo, B., Nurnberg, P., Huebner, A., Cheetham, M. E., Clark, A. J. L. Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2. Nature Genet. 37: 166-170, 2005. [PubMed: 15654338] [Full Text: https://doi.org/10.1038/ng1501]
Migeon, C. J., Kenny, F. M., Kowarski, A. A., Snipes, C. A., Spaulding, J. S., Finkelstein, J. W., Blizzard, R. M. The syndrome of congenital adrenocortical unresponsiveness to ACTH. Report of six cases. Pediat. Res. 2: 501-513, 1968. [PubMed: 4302512] [Full Text: https://doi.org/10.1203/00006450-196811000-00008]
Moshang, T., Jr., Rosenfield, R. L., Bongiovanni, A. M., Parks, J. S., Amrhein, J. A. Familial glucocorticoid insufficiency. J. Pediat. 82: 821-826, 1973. [PubMed: 4349230] [Full Text: https://doi.org/10.1016/s0022-3476(73)80073-3]
Naville, D., Weber, A., Genin, E., Durand, P., Clark, A. J. L., Begeot, M. Exclusion of the adrenocorticotropin (ACTH) receptor (MC2R) locus in some families with ACTH resistance but no mutations of the MC2R coding sequence (familial glucocorticoid deficiency type 2). J. Clin. Endocr. Metab. 83: 3592-3596, 1998. [PubMed: 9768670] [Full Text: https://doi.org/10.1210/jcem.83.10.5166]
O'Riordan, S. M. P., Lynch, S. A., Hindmarsh, P. C., Chan, L. F., Clark, A. J. L., Costigan, C. A novel variant of familial glucocorticoid deficiency prevalent among the Irish Traveler Population. J. Clin. Endocr. Metab. 93: 2896-2899, 2008. [PubMed: 18430777] [Full Text: https://doi.org/10.1210/jc.2008-0034]
Shepard, T. H., Landing, B. H., Mason, D. G. Familial Addison's disease. Case reports of two sisters with corticoid deficiency unassociated with hypoaldosteronism. Am. J. Dis. Child. 97: 154-162, 1959. [PubMed: 13616862]
Smith, E. M., Brosnan, P., Meyer, W. J., Blalock, J. E. An ACTH receptor on human mononuclear leukocytes: relation to adrenal ACTH-receptor activity. New Eng. J. Med. 317: 1266-1269, 1987. [PubMed: 2823138] [Full Text: https://doi.org/10.1056/NEJM198711123172006]
Spark, R. F., Etzkorn, J. R. Absent aldosterone response to ACTH in familial glucocorticoid deficiency. New Eng. J. Med. 297: 917-920, 1977. [PubMed: 198655] [Full Text: https://doi.org/10.1056/NEJM197710272971707]
Stempfel, R. S., Jr., Engel, F. L. A congenital, familial syndrome of adrenocortical insufficiency without hypoaldosteronism. J. Pediat. 57: 443-451, 1960.
Thistlethwaite, D., Darling, J. A. B., Fraser, R., Mason, D. A., Rees, L. H., Harkness, R. A. Familial glucocorticoid deficiency: studies of diagnosis and pathogenesis. Arch. Dis. Child. 50: 291-297, 1975. [PubMed: 238474] [Full Text: https://doi.org/10.1136/adc.50.4.291]
Tsigos, C., Arai, K., Hung, W., Chrousos, G. P. Hereditary isolated glucocorticoid deficiency is associated with abnormalities of the adrenocorticotropin receptor gene. J. Clin. Invest. 92: 2458-2461, 1993. [PubMed: 8227361] [Full Text: https://doi.org/10.1172/JCI116853]
Weber, A., Clark, A. J. L. Mutations of the ACTH receptor gene are only one cause of familial glucocorticoid deficiency. Hum. Molec. Genet. 3: 585-588, 1994. [PubMed: 8069303] [Full Text: https://doi.org/10.1093/hmg/3.4.585]
Werder, E. A., Haller, R., Vetter, W., Zachmann, M., Siebenmann, R. Isolated glucocorticoid insufficiency. Helv. Paediat. Acta 30: 175-183, 1975. [PubMed: 1150481]
Yamamoto, Y., Kawada, Y., Noda, M., Yamagishi, M., Ishida, O., Fujihira, T., Shirakawa, F., Morimoto, I. Siblings with ACTH insensitivity due to lack of ACTH binding to the receptor. Endocr. J. 42: 171-177, 1995. [PubMed: 7627261] [Full Text: https://doi.org/10.1507/endocrj.42.171]
Yamaoka, T., Kudo, T., Takuwa, Y., Kawakami, Y., Itakura, M., Yamashita, K. Hereditary adrenocortical unresponsiveness to adrenocorticotropin with a postreceptor defect. J. Clin. Endocr. Metab. 75: 270-274, 1992. [PubMed: 1320052] [Full Text: https://doi.org/10.1210/jcem.75.1.1320052]