FRI160 Pseudohypoaldosteronism Type 1- A Rare Mutation In The NR3C2 Gene

Abstract

Abstract Disclosure: J.A. Siddiqui: None. C. Mintz: None. R. Rapaport: None. Autosomal dominant pseudohypoaldosteronism type I is characterized by salt wasting resulting from renal unresponsiveness to mineralocorticoids. It is a rare condition that has been estimated to affect 1 in 80,000 newborns. A previously healthy 4-week-old female baby was hospitalized for poor weight gain. She was born to non-consanguineous parents following an uncomplicated pregnancy with a birth weight of 8 pounds 7 ounces and a birth length of 21 inches, both appropriate for age. She was exclusively breastfed since birth. Her initial laboratory results were concerning for hyponatremia, hypochloremia, and hyperkalemia. She was evaluated by pediatric endocrinology because of the initial concern for salt-wasting CAH. After clinical evaluation, she was noted to have an elevated aldosterone of 1333 ng/dL and renin level of 74515 ng/dL/hr. She was clinically diagnosed with pseudohypoaldosteronism and was started on sodium chloride supplementation which she continued until 4 years of age. Eventually, she was able to self-regulate her sodium levels and her aldosterone levels normalized. With her clinical diagnosis of pseudohypoaldosteronism, she was sent for genetic evaluation in 2021 and was found to have a likely pathogenic mutation in NR3C2, which is associated with autosomal dominant pseudohypoaldosteronism type 1. She was found to be heterozygous for c.2015-4_2015-2delATAinsG:IVS4-2delATAinsG in exon 5 in the NR3C2 gene. The particular variant identified in this patient is a canonical splice site variant which is expected to result in aberrant splicing, supporting the pathogenicity of this variant. To our knowledge, this specific variant has not been reported in other patients and is absent from large population databases. The patient was also tested for SCNNA1, SCNNA1B and SCNN1G, and the results were negative. After the genetic evaluation, multiple family members were tested for PHA1. Her brother and mother both were negative, but her father was found to be heterozygous for the genetic variant in NR3C2, giving him a molecular diagnosis of autosomal dominant PHA type 1. He was clinically undiagnosed until the genetic diagnosis of his daughter. Her father had a history of multiple episodes of dehydration in infancy and childhood along with slow growth. He was evaluated by an endocrinologist at age 57 and was found to have elevated aldosterone at 73.9 ng/dL(normal range- 7-30 ng/dL, which was consistent with PHA type 1. The patient’s paternal grandmother and paternal uncle also underwent targeted testing for the NR3C2 variant and the result was negative. This case report signifies the importance of clinical diagnosis and continued longitudinal follow-up. This led to genetic evaluation and the discovery of a previously unknown variant causing pseudohypoaldosteronism. In addition to the indexed case, the family was able to recognize a familial mutation that was previously undetected. Presentation Date: Friday, June 16, 2023