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 ... 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 (699196) on chromosome 21q22. GCCD3 has been mapped to chromosome 8q11.2-q13.2. GCCD4 (614736) is caused by mutation in the NNT gene (607878) on chromosome 5p12.
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 ... 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.
Isolated glucocorticoid deficiency was shown by Clark et al. (1993) and Tsigos et al. (1993) to be produced by mutations in the MC2R gene. Nephrogenic diabetes insipidus (304800) had previously been shown to be due to a defect ... Isolated glucocorticoid deficiency was shown by Clark et al. (1993) and Tsigos et al. (1993) to be produced by mutations in the MC2R gene. Nephrogenic diabetes insipidus (304800) had previously been shown to be due to a defect in a G protein-coupled receptor.
O'Riordan et al. (2008) studied the clinical features and assessed the prevalence of familial glucocorticoid deficiency (FGD) among Irish Travelers in the Republic of Ireland and described their phenotype. They identified 21 cases of FGD in the Irish ... O'Riordan et al. (2008) studied the clinical features and assessed the prevalence of familial glucocorticoid deficiency (FGD) among Irish Travelers 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 Travelers (5 females) with FGD related to a novel gene, negative for MC2R and MRAP mutations. Of a total population of 22,557 Travelers, 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 Traveler 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).