Catch-up growth and discontinuation of fludrocortisone treatment in aldosterone synthase deficiency

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:0.4-8.1). The most common symptom was poor weight gain (56.3%).Median age of onset of fludrocortisone treatment was 3.6 months (0.9-8.3). Catch-up growth was achieved at median 2 months (0.5-14.5) after treatment. Fludrocortisone could be stopped in five patients at a median age of 6.0 years (2.2-7.6). Plasma steroid profiles revealed reduced aldosterone synthase activity both at diagnosis and after discontinuation of treatment compared to age-matched controls.We identified six novel (p.Y195H, c.1200 + 1G>A, p.F130L, p.E198del, c.1122-18G>A, p.I339_E343del) and four previously described CYP11B2 variants. The most common variant was p.T185I (40%). 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.

Diagnosis of Hypoaldosteronism in Infancy

Hypoaldosteronism is associated with either insufficient aldosterone production or lack of responsiveness to aldosterone and can be isolated or in the context of primary adrenal failure. Τhe severity of clinical manifestations is inversely correlated to age, with the neonatal period being the most vulnerable time for a patient to present with mineralocorticoid insufficiency. Salt-wasting forms of congenital adrenal hyperplasia (CAH), adrenal hypoplasia congenita (AHC), aldosterone synthase deficiency (ASD) and pseudohypoaldosteronism (PHA) are all causes of hypoaldosteronism in infancy. Affected infants present with salt wasting, failure to thrive and potentially fatal hyperkalemia and shock. Α blood sample for the essential hormonal investigations should be collected before any steroid treatment is given, in order to confirm aldosterone insufficiency and to determine the underlying cause. Renal ultrasonography and urine culture are also useful for exclusion of secondary causes of aldosterone resistance. Initial management requires treatment of electrolyte imbalances and restoration of intravascular fluid volume. In case of a salt-wasting crisis, affected infants are usually treated initially with both hydrocortisone and fludrocortisone, pending the results of investigations. Interpretation of the hormonal profile will guide further therapy and molecular analysis of candidate genes.

Molecular Analysis of the CYP11B2 Gene in 62 Patients with Hypoaldosteronism Due to Aldosterone Synthase Deficiency

Context Isolated congenital hypoaldosteronism presents in early infancy with symptoms including vomiting, severe dehydration, salt wasting, and failure to thrive. The main causes of this rare autosomal recessive disorder is pathogenic variants of the CYP11B2 gene leading to aldosterone synthase deficiency. Objective To investigate the presence of CYP11B2 pathogenic variants in a cohort of patients with a clinical, biochemical, and hormonal profile suggestive of aldosterone synthase deficiency. Design Clinical and molecular study. Setting Tertiary academic Children’s Hospital, Center for Rare Pediatric Endocrine Diseases. Patients and Methods Sixty-two patients (56 unrelated patients and 6 siblings), with hypoaldosteronism and their parents, underwent CYP11B2 gene sequencing after its selective amplification against the highly homologous CYP11B1 gene. In silico analysis of the identified novel variants was carried out to evaluate protein stability and potential pathogenicity. Results CYP11B2 gene sequencing revealed that 62 patients carried a total of 12 different pathogenic CYP11B2 gene variants, 6 of which are novel. Importantly, 96% of the 56 patients carried the previously reported p.T185I variant either in homozygosity or in compound heterozygosity with another variant. The 6 novel variants detected were: p.M1I, p.V129M, p.R141Q, p.A165T, p.R448C, and the donor splice site variant of intron 8, c.1398 + 1G > A. Conclusion Molecular diagnosis was achieved in 62 patients with aldosterone synthase deficiency, the largest cohort thus far reported. Six novel genetic variants were identified as possibly pathogenic, extending the spectrum of reported molecular defects of the CYP11B2 gene.

Aldosterone synthase deficiency type II: an unusual presentation of the first Greek case reported with confirmed genetic analysis

Objective. Aldosterone synthase deficiency (ASD) is a rare, autosomal recessive inherited disease with an overall clinical phenotype of failure to thrive, vomiting, severe dehydration, hyperkalemia, and hyponatremia. Mutations in the CYP11B2 gene encoding aldosterone synthase are responsible for the occurrence of ASD. Defects in CYP11B2 gene have only been reported in a limited number of cases worldwide. Due to this potential life-threatening risk, comprehensive hormonal investigation followed by genetic confirmation is essential for the clinical management of offsprings.Case presentation. We herein describe an unusual case of ASD type II in a neonate with faltering growth as a single presenting symptom. To our knowledge, this is the first Greek case of ASD type II reported with confirmed genetic analysis. Next generation sequencing of her DNA revealed the homozygous mutation p.T185I (ACC-ATC) (c.554C>T) (g.7757C>T) in exon 3 of the CYP11B2 gene in the neonate, inherited from both parents who were heterozygotes for the mutation.Conclusions. Physicians handling neonates with faltering growth, particularly in the initial six weeks of life, should be suspicious of mineralocorticoid insufficiency either as isolated hypoaldosteronism or in the context of congenital adrenal hyperplasia. Essential investigations should be performed and appropriate treatment should be administered promptly without awaiting for the hormonal profile results. Interpretation of the clinical picture and the hormonal profile will guide the analysis of candidate genes. Primary selective hypoaldosteronism is a rare, life threatening disease, but still with an unknown overall population impact. Thus, reporting cases with confirmed gene mutations is of major importance.