Absent Aldosterone Response to ACTH in Familial Glucocorticoid Deficiency

Spark, Richard F.; Etzkorn, James R.

doi:10.1056/nejm197710272971707

Cited by 32 publications

(13 citation statements)

References 17 publications

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“…Only one of these seven patients had decreased mineralocorticoid production [7] which was found in some patients with this syndrome without achalasia [11]. Table 1 Table 2.…”

Section: Discussionmentioning

confidence: 96%

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Selective ACTH insensitivity associated with autonomic nervous system disorders and sensory polyneuropathy

et al. 1987

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A 10-year-old boy is described with a syndrome of adrenal insufficiency due to selective ACTH insensitivity associated with autonomic nervous system disorders. In addition to insufficient production of glucocorticoids and adrenal androgens, achalasia, defective lacrimation, anisocoria and hyperkeratosis of palms and soles we also found defective sweating, permanent cutis anserina and sensory polyneuropathy, which have not been reported previously in this rare syndrome.

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“…Only one of these seven patients had decreased mineralocorticoid production [7] which was found in some patients with this syndrome without achalasia [11]. Table 1 Table 2.…”

Section: Discussionmentioning

confidence: 96%

“…A syndrome of familial primary glucocorticoid insufficiency due to ACTH unresponsiveness with normal or subnormal mineralocorticoid activity has been described in a number of patients [6,8,[10][11][12]. The association with autonomic nervous system disorders was found only in seven patients [1,3,4,7].…”

Section: Discussionmentioning

confidence: 99%

Selective ACTH insensitivity associated with autonomic nervous system disorders and sensory polyneuropathy

et al. 1987

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“…Firstly, there is evidence that ACTH directly activates the production of aldosterone in the zona glomerulosa (ZG). It has been found that MC2R mRNA localizes to the ZG and administration of synthetic ACTH to normal human subjects results in a rise in plasma aldosterone levels [5,24,25,26,27]. The physiological importance of ACTH-dependent regulation of aldosterone in normal physiology and disease is undetermined.…”

Section: Clinical and Biochemical Features Of Fgdmentioning

confidence: 99%

“…The report of two siblings with what was called ‘familial Addison’s disease’ prompted subsequent papers describing patients with isolated glucocorticoid deficiency [3,4,5]. It took a further 30 years before the identification of the first inactivating ACTH receptor mutation in a patient with FGD [6].…”

Section: Introductionmentioning

confidence: 99%

Familial Glucocorticoid Deficiency: Advances in the Molecular Understanding of ACTH Action

Chan¹,

Clark²,

Metherell³

2007

Horm Res Paediatr

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Familial glucocorticoid deficiency (FGD), otherwise known as hereditary unresponsiveness to ACTH, is a rare autosomal recessive disease characterized by glucocorticoid deficiency in the absence of mineralocorticoid deficiency. Mutations of the ACTH receptor, also known as the melanocortin-2 receptor (MC2R), account for approximately 25% of FGD cases. More recently a second gene, MRAP (melanocortin-2 receptor accessory protein), was identified and found to account for a further 15–20%. MRAP encodes a small single transmembrane domain protein, which is essential in the trafficking of the MC2R to the cell surface. In this review, we will firstly summarize the clinical presentation and genetic aetiology of this condition. Secondly, we will discuss how the discovery of MRAP has enhanced our understanding of the mechanisms of ACTH/MC2R action. Finally, we will explore future developments in this field.

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“…The disorder is occasionally associated with alacrima and achalasia of the esophagus, suggesting potential heterogeneity in its etiology (4,5). Affected individuals have no cortisol or aldosterone responses to exogenous ACTH but retain a normal aldosterone response to activation of the renin-angiotensin axis by salt restriction, orthostasis, and furosemide-induced diuresis (6)(7)(8). In keeping with the biochemical studies, in these patients the angiotensin II-dependent zonae fasciculata and reticularis are extremely atrophic, reduced to a narrow band of fibrous tissue, while the zona glomerulosa is relatively well preserved ( 1,2,6).…”

Section: Introductionmentioning

confidence: 99%

Hereditary isolated glucocorticoid deficiency is associated with abnormalities of the adrenocorticotropin receptor gene.

Tsigos

Arai²,

Hung³

et al. 1993

J. Clin. Invest.

174

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Isolated glucocorticoid deficiency (IGD) is an autosomal recessive disorder characterized by progressive primary adrenal insufficiency, without mineralocorticoid deficiency. The cDNA and gene of the human ACTH receptor were recently cloned. The gene encodes a 297-amino acid protein that belongs to the G protein-coupled superfamily of membrane receptors. We hypothesized that the ACIH receptor gene might be defective in IGD. To examine this, we studied its genomic structure by PCR and direct sequencing in a 5-yr-old proband with the disease, his parents, and grandparents. The proband was a compound heterozygote for two different point mutations, one in each allele: (a) a substitution (C --T), also found in one allele of the mother and maternal grandmother, which introduced a premature stop codon (TGA) at position 201 of the protein; this mutant receptor lacks its entire carboxy-terminal third and, if expressed, should be unable to transduce the signal; and (b) a substitution (C -G), also found in one of the paternal alleles, which changed neutral serine " in the apolar third transmembrane domain of the receptor to a positively charged arginine, probably disrupting the ligand-binding site. Standard ovine corticotropin releasing hormone (oCRH) test in the heterozygote parents and maternal grandmother revealed exaggerated and prolonged ACTH responses, suggestive of subclinical resistance to ACTH. We conclude that IGD in this family appears to be due to defects of the ACTH receptor gene. The oCRH test appears to be useful in ascertaining heterozygosity in this syndrome. (J. Clin. Invest. 1993Invest. .92:2458Invest. -2461

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Absent Aldosterone Response to ACTH in Familial Glucocorticoid Deficiency

Cited by 32 publications

References 17 publications

Selective ACTH insensitivity associated with autonomic nervous system disorders and sensory polyneuropathy

Selective ACTH insensitivity associated with autonomic nervous system disorders and sensory polyneuropathy

Familial Glucocorticoid Deficiency: Advances in the Molecular Understanding of ACTH Action

Hereditary isolated glucocorticoid deficiency is associated with abnormalities of the adrenocorticotropin receptor gene.

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