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

Lin Lin,Peter C Hindmarsh,Maryam Al‐Ali,Mahmoud Alzyoud,Adrian J L Clark,Louise A Metherell,Caroline E Brain,John C Achermann,Mehul T Dattani

doi:10.1111/j.1365-2265.2006.02709.x

Abstract

ObjectiveFamilial 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.DesignMutational analysis of MC2R by direct sequencing.PatientsChildren (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).ResultsMC2R 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.ConclusionsMC2R 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.

Highlights

Familial glucocorticoid deficiency type 1 (FGD1) (MIM: 202200) is an autosomal recessive ACTH–resistance syndrome resulting from mutations in the ACTH receptor.[1,2]
The molecular basis of this condition was first described in 1993 and, to date, approximately 20 different MC2R mutations have been reported in around 40 individuals or families with FGD1·3–11 The majority of MC2R mutations are homozygous or compound heterozygous missense mutations that impair the function of this G-protein coupled receptor to varying degrees.[10,11]
Following Institutional Board Approval and with informed consent, genomic DNA was extracted from peripheral blood lymphocytes and the entire coding region of MC2R was amplified using variations on conditions reported previously.[3]

Summary

Introduction

Children with FGD1 typically present with symptoms and signs of glucocorticoid deficiency, such as prolonged jaundice, hypoglycaemia or hypoglycaemic convulsions, failure to thrive, hyperpigmentation and sepsis.[1,2] Tall stature has been reported in a subset of individuals with FGD1, especially prior to glucocorticoid treatment, but the pathogenic basis of this feature is not clear.[6,12] Disturbances in the renin-angiotensin system, mineralocorticoid synthesis or sodium homeostasis are not a well-established feature of this condition, and patients with classic FGD1 do not receive mineralocorticoid replacement. The MC2R is expressed in the zona glomerulosa of the adrenal gland, and acute administration of ACTH(1–24) results in aldosterone release in normal human volunteers.[13,14,15] a facilitative role for ACTH in supporting mineralocorticoid synthesis may be physiologically important, perhaps during stress or in early life – a time of relative mineralocorticoid insensitivity.[16,17,18,19] children with cortisol

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