Catch-up Growth and Discontinuation of Fludrocortisone Treatment in Aldosterone Synthase Deficiency

Abstract

Background Aldosterone synthase deficiency (ASD) caused by mutations in the CYP11B2 gene is characterized by isolated mineralocorticoid deficiency. Data are scarce regarding clinical and biochemical outcomes of the disease in the follow-up. Objective Assessment of the growth and steroid profiles of patients with ASD at the time of diagnosis and after discontinuation of treatment. Design and method Children with clinical diagnosis of ASD were included in a multicenter study. Growth and treatment characteristics were recorded. Plasma adrenal steroids were measured using liquid chromatography-mass spectrometry. Genetic diagnosis was confirmed by CYP11B2 gene sequencing and in silico analyses. Results Sixteen patients from 12 families were included (8 females; median age at presentation: 3.1 months, range: 0.4 to 8.1). The most common symptom was poor weight gain (56.3%). Median age of onset of fludrocortisone treatment was 3.6 months (range: 0.9 to 8.3). Catch-up growth was achieved at median 2 months (range: 0.5 to 14.5) after treatment. Fludrocortisone could be stopped in 5 patients at a median age of 6.0 years (range: 2.2 to 7.6). Plasma steroid profiles revealed reduced aldosterone synthase activity both at diagnosis and after discontinuation of treatment compared to age-matched controls. We identified 6 novel (p.Y195H, c.1200 + 1G > A, p.F130L, p.E198del, c.1122-18G > A, p.I339_E343del) and 4 previously described CYP11B2 variants. The most common variant (40%) was p.T185I. Conclusions Fludrocortisone treatment is associated with a rapid catch-up growth and control of electrolyte imbalances in ASD. Decreased mineralocorticoid requirement over time can be explained by the development of physiological adaptation mechanisms rather than improved aldosterone synthase activity. As complete biochemical remission cannot be achieved, a long-term surveillance of these patients is required.

Congenital hyperreninemic hypoaldosteronism: A case report

“…Patients with this condition require mineralocorticoid replacement therapy and oral sodium supplementation with plasma renin follow-up. [1][2][3][4] Mineralocorticoid replacement was started in our patient and maintained within a year, with improved symptoms, resolution of electrolyte disturbances, and weight gain. 9 Among several studies, research has demonstrated the effects of hormone replacement in the biochemical variables implicated in hyperreninemic hypoaldosteronism, as well as in clinical variables such as height and weight.…”

“…Within the second category, hypoaldosteronism can result from all causes of primary adrenal insufficiency and primary hypoaldosteronism caused by ASD or as an acquired state secondary to infections, lesions, or autoimmune processes. [3][4][5] ASD is a rare genetic disorder inherited in an autosomal dominant or recessive manner with mixed penetrance. This condition is caused by impaired aldosterone synthase enzyme activity encoded by the CYP11B2 gene located on chromosome 8q24.3, leading to hyperreninemic hypoaldosteronism.…”

“…As mentioned before, ASD is subdivided into two types according to 18-hydroxycorticosterone levels, being mildly decreased in ASD I and significantly elevated in ASD II. [1][2][3][4] Clinical presentation includes frequent vomiting, dehydration, hypovolemia, electrolyte disturbances such as hyponatremia, hyperkalemia, metabolic acidosis, and failure to thrive. 1,3,6 These symptoms generally develop as early as 3 months of age, most commonly after the first 5 days of life.…”

“…9 Among several studies, research has demonstrated the effects of hormone replacement in the biochemical variables implicated in hyperreninemic hypoaldosteronism, as well as in clinical variables such as height and weight. 4 The Kayes-Wendover study includes five patients with clinical manifestations of hydro-saline crisis and failure to thrive associated with a marked elevation of PRA and low or inappropriately normal levels. 5 This study demonstrated how fludrocortisone replacement in a dose of 150 µg per day normalized electrolyte levels and PRA at the first months of life.…”

A Japanese girl with aldosterone synthase deficiency requiring fludrocortisone until 10 years of age

“…The symptoms of this disorder typically become milder or disappear by adulthood. The need for fludrocortisone therapy decreases with age and therapy can be discontinued in adulthood 4,5 . The reasons for these observations include increased sensitivity to mineralocorticoids and increased dietary intake of sodium with age.…”