Severe loss‐of‐function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt‐losing adrenal hypoplasia
Open Access
- 20 November 2006
- journal article
- Published by Wiley in Clinical Endocrinology
- Vol. 66 (2), 205-210
- https://doi.org/10.1111/j.1365-2265.2006.02709.x
Abstract
Objective Familial glucocorticoid deficiency type I (FGD1) is a rare form of primary adrenal insufficiency resulting from recessive mutations in the ACTH receptor (MC2R, MC2R). Individuals with this condition typically present in infancy or childhood with signs and symptoms of cortisol insufficiency, but disturbances in the renin‐angiotensin system, aldosterone synthesis or sodium homeostasis are not a well‐documented association of FGD1. As ACTH stimulation has been shown to stimulate aldosterone release in normal controls, and other causes of hyponatraemia can occur in children with cortisol deficiency, we investigated whether MC2R changes might be identified in children with primary adrenal failure who were being treated for mineralocorticoid insufficiency. Design Mutational analysis of MC2R by direct sequencing. Patients Children (n = 22) who had been diagnosed with salt‐losing forms of adrenal hypoplasia (19 isolated cases, 3 familial), and who were negative for mutations in DAX1 (NR0B1) and SF1 (NR5A1). Results MC2R mutations were found in three individuals or kindred (I: homozygous S74I; II: novel compound heterozygous R146H/560delT; III: novel homozygous 579‐581delTGT). These changes represent severely disruptive loss‐of‐function mutations in this G‐protein coupled receptor, including the first reported homozygous frameshift mutation. The apparent disturbances in sodium homeostasis were mild, manifest at times of stress (e.g. infection, salt‐restriction, heat), and likely resolved with time. Conclusions MC2R mutations should be considered in children who have primary adrenal failure with apparent mild disturbances in renin‐sodium homeostasis. These children may have been misdiagnosed as having salt‐losing adrenal hypoplasia. Making this diagnosis has important implications for treatment, counselling and long‐term prognosis.Keywords
This publication has 36 references indexed in Scilit:
- Inherited ACTH insensitivity illuminates the mechanisms of ACTH actionTrends in Endocrinology & Metabolism, 2005
- Inherited adrenal hypoplasia: not just for kids!Clinical Endocrinology, 2004
- Functional Characterization of Naturally Occurring Mutations of the Human Adrenocorticotropin Receptor: Poor Correlation of Phenotype and GenotypeJournal of Clinical Endocrinology & Metabolism, 1999
- Adrenocorticotropin Insensitivity SyndromesEndocrine Reviews, 1998
- ACTH receptor mutation in a girl with familial glucocorticoid deficiencyClinical Genetics, 1998
- Localization of ACTH receptor mRNA by in situ hybridization in mouse adrenal glandCell and tissue research, 1996
- Adrenocorticotropin receptor gene mutations in familial glucocorticoid deficiency: relationships with clinical features in four familiesJournal of Clinical Endocrinology & Metabolism, 1995
- Molecular insights into inherited ACTH resistance syndromesTrends in Endocrinology & Metabolism, 1994
- GLOMERULOSA FAILURE IN CONGENITAL ADRENOCORTICAL UNRESPONSIVENESS TO ACTHClinical Endocrinology, 1984
- Absent Aldosterone Response to ACTH in Familial Glucocorticoid DeficiencyNew England Journal of Medicine, 1977