ESPE Abstracts (2014) 82 P-D-3-2-891

A Novel Mutation in the NR3C2 Gene Causing Pseudohypoaldosteronism Type 1

Amalia Sertedaki, Christina Kanaka-Gantenbein & George P Chrousos


Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, University of Athens Medical School, Athens, Greece


Background: Pseudohypoaldosteronism type 1 (PHA1) is a rare inherited disease characterized by mineralocorticoid resistance with subsequent salt wasting, hyperkalemia, metabolic acidosis, and elevated plasma renin and aldosterone levels.

Patients and methods: We report a male newborn that presented with failure to thrive and sustained hyponatremia during his early postnatal period. He was conceived after IVF (twin pregnancy) and prematurely born by cesarean section at the 34th gestational week. His birth weight was 1920 g, length 45 cm and head circumference 31 cm. His Apgar score was 5 at 1 min and 7 at 5 min. His twin brother had a birth weight of 2140 g. The patient presented with poor weight gain soon after birth; from the seventh day onwards he had significant hyponatremia (124–127 mEq/l) and hyperkalemia (5.6–6.2 mEq/l). Laboratory investigations revealed normal circulating ACTH, 17-OH-progesterone and cortisol levels and significantly high plasma renin and aldosterone concentrations. With the diagnosis of pseudohypoaldosteronism, substitution of NaCl was initiated. The boy responded with a significant weight gain and normal psychomotor development on NaCl substitution. NaCl was gradually discontinued after the age of 22 months. Genomic DNA was isolated from peripheral blood lymphocytes of the patient and his mother and the coding region of NR3C2 gene was PCR-amplified and sequenced.

Results: A heterozygous four nucleotide duplication was detected in exon 7 of the NR3C2 gene in the patient and his mother, namely c.2525_2526insATCA; p.A844Vfs*5. This mutation changes codon 844 from alanine to valine, causes a frameshift and a premature stop codon five amino acids downstream. Thus, a receptor protein 137 amino acids shorter than the WT and lacking the C-terminal ligand-binding domain of the receptor might be produced.

Conclusions: We report a new mutation, p.A844Vfs*5, of the NR3C2 gene causing autosomal dominant PAH1 detected in a neonate and his mother.

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