Homozygosity for a Mutation in the CYP11B2 Gene and GH Deficiency in a Child with Severe Growth Delay

Background: Isolated hypoaldosteronism is an autosomal recessive inherited disorder of terminal aldosterone synthesis, leading to selective aldosterone deficiency. Two different biochemical forms of this disease have been described, called aldosterone synthase deficiency or corticosterone methyl oxydase, types 1 and 2. In type 1, there is no aldosterone synthase activity and the 18 hydroxycorticosterone (18 OHB) level is low, whereas in type 2, a residual activity of aldosterone synthase persists and 18 OHB is overproduced. Objective and hypotheses: Isolated aldosterone synthase deficiency should be considered in neonates and infants with failure to thrive and salt wasting. Normal levels of plasma aldosterone compared with highly elevated levels of plasma renin indicate an impaired aldosterone biosynthesis and suggest the disorder. Case presentation: We report the case of an infant with severe neonatal hyponatremia, hyperpotassemia and growth failure. She was born at 38 weeks of gestational age, weight: 3650 g. At the age of 1 month she was admitted to a paediatric unit for severe dehydratation, vomiting and growth failure. She showed normal values of plasma aldosterone (85 pg/ml) associated with hyperreninemia (88.2 ng/ml per h), hyponatremia and hyperkalemia. Molecular genetic analysis supported the diagnosis revealing a homozygous mutation for a pathogenic c.554COT (p.T185I) mutation in exon 3 of the CYP11B2 Aldosterone synthase gene (8q22). Treatment with fludrocortisone and oral supplementation with sodium, resulted in correction of hyponatremia and hyperkalemia, and a transient catch-up growth. The unaffected mother was a heterozygous carrier of the T185I mutation as the sister, while the father was a heterozygous carrier of the same mutation with a severe clinical course at the neonatal period and a normal sodium balance without no further drug supplementation in adult age. However actually the girl is 1.7 years old and shows a severe failure to thrive (height: 70.3 cm; weight: 7.300 kg) with a low growth velocity (!K2 SDS). She shows a bone age delay (1 year) and low IGF1 levels (!K2 SDS for age). She underwent GH stimulation testing witch documented a GH deficiency after pharmacological induction (peak: 5.2 ng/ml). Conclusion: At our knowledge this is the first case report of a child with a CYP11B2 gene mutation associated with GH deficiency, a further support to growth failure.