Cargando…

Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia

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 insufficienc...

Descripción completa

Detalles Bibliográficos
Autores principales: Lin, Lin, Hindmarsh, Peter C, Metherell, Louise A, Alzyoud, Mahmoud, Al-Ali, Maryam, Brain, Caroline E, Clark, Adrian J L, Dattani, Mehul T, Achermann, John C
Formato: Texto
Lenguaje:English
Publicado: Blackwell Publishing Ltd 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1859977/
https://www.ncbi.nlm.nih.gov/pubmed/17223989
http://dx.doi.org/10.1111/j.1365-2265.2006.02709.x
_version_ 1782133182882119680
author Lin, Lin
Hindmarsh, Peter C
Metherell, Louise A
Alzyoud, Mahmoud
Al-Ali, Maryam
Brain, Caroline E
Clark, Adrian J L
Dattani, Mehul T
Achermann, John C
author_facet Lin, Lin
Hindmarsh, Peter C
Metherell, Louise A
Alzyoud, Mahmoud
Al-Ali, Maryam
Brain, Caroline E
Clark, Adrian J L
Dattani, Mehul T
Achermann, John C
author_sort Lin, Lin
collection PubMed
description 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.
format Text
id pubmed-1859977
institution National Center for Biotechnology Information
language English
publishDate 2007
publisher Blackwell Publishing Ltd
record_format MEDLINE/PubMed
spelling pubmed-18599772007-05-03 Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia Lin, Lin Hindmarsh, Peter C Metherell, Louise A Alzyoud, Mahmoud Al-Ali, Maryam Brain, Caroline E Clark, Adrian J L Dattani, Mehul T Achermann, John C Clin Endocrinol (Oxf) Original Article 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. Blackwell Publishing Ltd 2007-02-01 /pmc/articles/PMC1859977/ /pubmed/17223989 http://dx.doi.org/10.1111/j.1365-2265.2006.02709.x Text en © 2006 The Authors Journal compilation © 2006 Blackwell Publishing Ltd https://creativecommons.org/licenses/by/2.5/ Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.
spellingShingle Original Article
Lin, Lin
Hindmarsh, Peter C
Metherell, Louise A
Alzyoud, Mahmoud
Al-Ali, Maryam
Brain, Caroline E
Clark, Adrian J L
Dattani, Mehul T
Achermann, John C
Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia
title Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia
title_full Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia
title_fullStr Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia
title_full_unstemmed Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia
title_short Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia
title_sort severe loss-of-function mutations in the adrenocorticotropin receptor (acthr, mc2r) can be found in patients diagnosed with salt-losing adrenal hypoplasia
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1859977/
https://www.ncbi.nlm.nih.gov/pubmed/17223989
http://dx.doi.org/10.1111/j.1365-2265.2006.02709.x
work_keys_str_mv AT linlin severelossoffunctionmutationsintheadrenocorticotropinreceptoracthrmc2rcanbefoundinpatientsdiagnosedwithsaltlosingadrenalhypoplasia
AT hindmarshpeterc severelossoffunctionmutationsintheadrenocorticotropinreceptoracthrmc2rcanbefoundinpatientsdiagnosedwithsaltlosingadrenalhypoplasia
AT metherelllouisea severelossoffunctionmutationsintheadrenocorticotropinreceptoracthrmc2rcanbefoundinpatientsdiagnosedwithsaltlosingadrenalhypoplasia
AT alzyoudmahmoud severelossoffunctionmutationsintheadrenocorticotropinreceptoracthrmc2rcanbefoundinpatientsdiagnosedwithsaltlosingadrenalhypoplasia
AT alalimaryam severelossoffunctionmutationsintheadrenocorticotropinreceptoracthrmc2rcanbefoundinpatientsdiagnosedwithsaltlosingadrenalhypoplasia
AT braincarolinee severelossoffunctionmutationsintheadrenocorticotropinreceptoracthrmc2rcanbefoundinpatientsdiagnosedwithsaltlosingadrenalhypoplasia
AT clarkadrianjl severelossoffunctionmutationsintheadrenocorticotropinreceptoracthrmc2rcanbefoundinpatientsdiagnosedwithsaltlosingadrenalhypoplasia
AT dattanimehult severelossoffunctionmutationsintheadrenocorticotropinreceptoracthrmc2rcanbefoundinpatientsdiagnosedwithsaltlosingadrenalhypoplasia
AT achermannjohnc severelossoffunctionmutationsintheadrenocorticotropinreceptoracthrmc2rcanbefoundinpatientsdiagnosedwithsaltlosingadrenalhypoplasia