MC2R Loss in Salt-losing Adrenal Hypoplasia

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Familial glucocorticoid deficiency type I (FGD1) is a rare form of primary adrenal insufficiency resulting from mutations in the ACTH receptor ( MC2R ). These children typically have severe neonatal symptoms and signs of cortisol deficiency. The issue of mineralocorticoid deficiency is not well documented in this group and it is widely accepted that classic cases do not require mineralocorticoid replacement. However, hyponatremia has been observed in some patients, not related to hypocortisolism.

Lin et al considered the possibility of alterations in mineralocorticoid control since the MC2R is also expressed in the aldosterone producing zona glomerulosa in the adrenal gland. Twenty-two children diagnosed with salt-losing forms of primary adrenal hypoplasia (19 isolated cases, 3 familial) were investigated. All children were negative for the 2 mutations known to be involved in adrenal hypoplasia: DAX1 and SF1. All subjects were investigated for MC2R mutations, after amplifying the entire coding region (exon 2).

The MC2R mutations were found in 3 kindreds, involving 9 patients; age at presentation ranged from 1 day to 19 months. The initial symptoms were pigmentation, hypoglycemia, jaundice, and failure to thrive. The mutational changes in all 3 families represented disruptive loss-of-function in the G-protein coupled receptor, including the first reported homozygous frameshift mutations. In kindred 1, the patient was diagnosed at 3 months: electrolytes were normal, but aldosterone was low for age with elevated plasma rennin activity (PRA) that improved with prolonged fludrocortisone treatment. Two cases were later diagnosed in family 2. One presented with elevation of PRA, the other siblling had low aldosterone and developed hyponatremia during a severe viral illness. Kindred 3 presented early symptoms. The first child required fludrocortisone because of early salt-losing syndrome. The 2 subsequent siblings were treated before overt sodium imbalance.

Salt-losing forms of adrenal insufficiency are generally clear and occur in well defined conditions. However, if biochemical findings are subtle, the exact biochemical nature of the condition can be difficult to assess. MC2R mutations should be considered in patients with apparent mild disturbances in rennin-sodium homeostasis. These children could be misdiagnosed for primary salt-losing adrenal hypoplasia. The genetic finding has important implications for treatment, counselling and long-term prognosis.

Lin L, Hindmarsh PC, Metherell LA, et al. Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia. Clin Endocrinol. 2007;66:205-10.

Editor’s Comment

The authors described important clinical and pathophysiological issues in a rare but often confusing disorder. The diagnosis of isolated cortisol deficiency is suggested by the clinical presentation. Assessment of the mineralocorticoid function in the affected neonate may be difficult. If aldosterone deficiency is partial, as it appears to be in these cases, repeated coupled evaluation of plasma aldosterone and PRA is necessary. Furthermore, severe inactivation of the ACTH receptor may have an impact on the control of aldosterone secretion and suggests a risk of a salt-losing condition. Therefore, it is necessary to identify the genetic defect in these patients, assessing the most severe end of the spectrum of FGD1. These patients paradoxically may require fludrocortisone therapy at critical periods of severe illness. As the authors suggested, these mutations may be found in a significant proportion of children with primary adrenal insufficiency who sometimes have minimal signs of salt loss.

In addition, these data confirm the supportive role for ACTH in mineralocorticoid synthesis and secretion, especially in a time of stress. It is possible that, as observed in pseudohypoaldosteronism type 1 due to mineralocorticoid receptor defect, the need for mineralocorticoid replacement weans off during childhood. This requires careful follow-up, as the risk of salt loss may persist at times of stress or potential volume depletion. An ongoing clinical vigilance is necessary.

Raphaël Rappaport, MD

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Last Updated: 04/30/2008