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      Homozygous nonsense and frameshift mutations of the ACTH receptor in children with familial glucocorticoid deficiency (FGD) are not associated with long-term mineralocorticoid deficiency

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          Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease characterized by isolated glucocorticoid deficiency with preserved mineralocorticoid secretion. Mutations in the ACTH receptor (MC2R) account for approximately 25% of all FGD cases, but since these are usually missense mutations, a degree of receptor function is frequently retained. A recent report, however, suggested that disturbances in the renin–aldosterone axis were seen in some patients with potentially more severe MC2R mutations. Furthermore, MC2R knock out mice have overt aldosterone deficiency and hyperkalaemia despite preservation of a normal zona glomerulosa. We wished to determine whether a group of patients with severe nonsense mutations of the MC2R exhibited evidence of mineralocorticoid deficiency, thereby challenging the conventional diagnostic feature of FGD which might result in diagnostic misclassification.


          Clinical review of patients with nonsense MC2R mutations.


          Between 1993 and 2008, 164 patients with FGD were screened for mutations in the MC2R. Totally 42 patients (34 families) were found to have mutations in the MC2R. Of these, 6 patients (4 families) were found to have homozygous nonsense or frameshift mutations.


          Mild disturbances in the renin–angiotensin–aldosterone axis were noted in four out of six patients, ranging from slightly elevated plasma renin levels to low aldosterone levels, although frank mineralocorticoid deficiency or electrolyte disturbance were not found. No patient required fludrocortisone replacement.


          Severe nonsense and frameshift MC2R mutations are not associated with clinically significant mineralocorticoid deficiency and are thus unlikely to require long-term mineralocorticoid replacement.

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          Most cited references 16

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          Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion.

          Consistent gene mutation nomenclature is essential for efficient and accurate reporting, testing, and curation of the growing number of disease mutations and useful polymorphisms being discovered in the human genome. While a codified mutation nomenclature system for simple DNA lesions has now been adopted broadly by the medical genetics community, it is inherently difficult to represent complex mutations in a unified manner. In this article, suggestions are presented for reporting just such complex mutations. Copyright 2000 Wiley-Liss, Inc.
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            Familial glucocorticoid deficiency associated with point mutation in the adrenocorticotropin receptor.

            Familial glucocorticoid deficiency is an uncommon disorder that appears to be due to congenital insensitivity or resistance to adrenocorticotropin (ACTH), and is usually inherited in an autosomal recessive pattern. We investigated the DNA base sequence in a family with this condition by polymerase chain reaction amplification of DNA with pairs of primers that span the ACTH-receptor domain. The affected male proband showed a single base mutation, ser74-->ile, in the sequence coding for the second transmembrane domain of the ACTH receptor. A similar defect was found in an affected sister, a normal sequence in an unaffected brother, and both alleles in each parent. This is only the second clinical disorder associated with a GTP-binding-protein-linked hormone-receptor mutation.
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              Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia

               Lou Metherell (corresponding) ,  Lin Lin Gao,  Peter C Hindmarsh (2007)
              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.

                Author and article information

                Clin Endocrinol (Oxf)
                Clinical Endocrinology
                Blackwell Publishing Ltd
                August 2009
                : 71
                : 2
                : 171-175
                [* ]Centre for Endocrinology, William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry London EC1M 6BQ, UK
                []Institute of Experimental Paediatric Endocrinology, Charite-University medicine Berlin, Germany
                []Department of Child Health, King's College Hospital Denmark Hill, London SE5 9RS, UK
                [§ ]Institute of Child Health, University College London London WC1N 1EH, UK
                []Our Lady's Children's Hospital and The National Centre for Medical Genetics Crumlin, Dublin, Ireland
                [** ]Department of Paediatrics, University of Verona Verona, Italy
                Author notes
                Correspondence: A. J. L. Clark, Centre for Endocrinology, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK. Tel.: +44 2078828284; Fax: +44 2078826197; E-mail: a.j.clark@ 123456qmul.ac.uk
                © 2009 Blackwell Publishing Ltd

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

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