A Neonate with Autosomal Dominant Pseudohypoaldosteronism Type 1 Due to a Novel Microdeletion of the NR3C2 Gene at 4q31.23

Abstract

Dehydration with hyponatremia can occur from a variety of causes and can be potentially fatal to infants. Pseudohypoaldosteronism type 1 (PHA1) is a rare disease that can cause severe dehydration along with hyponatremia and hyperkalemia because of renal tubular unresponsiveness to mineralocorticoids. Autosomal dominant PHA1 (ADPHA1, OMIM #177735) is caused by inactivating mutations in the NR3C2 gene, which encodes the mineralocorticoid receptor, and it can lead to renal salt-wasting, dehydration, and failure to thrive during infancy. Here, we report a case of a 20-day-old female neonate who presented as severe dehydration with hyponatremia and polyuria. We suspected that her diagnosis might be PHA1 based on markedly elevated plasma renin activity and serum aldosterone levels. For the genetic diagnosis of PHA1, we performed targeted exome sequencing of all causative genes of PHA1, but the result was negative. We confirmed by chromosomal microarray that a novel heterozygous microdeletion was found in the 4q31.23 region spanning exons 7–9 of the NR3C2 gene, and the patient was diagnosed with ADPHA1. In conclusion, our patient is a case of ADPHA1 that developed into a salt-wasting crisis in the neonatal period due to a microdeletion of the 4q31.23 region inherited from her father.

Clinical Manifestations of Pseudohypoaldosteronism with Genotype-phenotype Correlation. A Single Center Experience, A Retrospective Cohort Study.

“…Furthermore, many factors can affect sodium reabsorption in the distal tubule, such as prematurity, infection, and unknown gene function [4]. PHA1b occurs in the rst week of life and manifests with electrolyte imbalances such as hyperkalaemia and metabolic acidosis alongside nausea, vomiting, and hypotension with salt-wasting episodes after birth [3,7].…”

“…Renal ultrasonography revealed mild hydronephrosis in the right kidney. Accordingly, the patient received IV uid and 60 ml of 3% sodium chloride [4]. Hanukoglu et al reported in a family study spanning 40 years that even families with the same mutation had different clinical manifestations and renin/aldosterone levels [4].…”

“…Accordingly, the patient received IV uid and 60 ml of 3% sodium chloride [4]. Hanukoglu et al reported in a family study spanning 40 years that even families with the same mutation had different clinical manifestations and renin/aldosterone levels [4]. Alshaikh reported that two Omani siblings presented in the rst week with complaints of nausea and vomiting missense mutation in SCNNA1 (Ser243Pro) encoding α-ENaC of a preterm baby whose sodium requirements decreased rapidly with age.…”

“…Renal PHA 1 (PHA1a) is an autosomal dominant inherited disorder with a heterogeneous NR3C2 gene mutation characterized by an inactivating mutation [2,4]. This gene encodes for mineralocorticoid receptors that can result in the absence of binding the aldosterone to the receptor with a phenotypic expression restricted to the kidney [3,5].…”

Neonatal Pseudohypoaldosteronism Type-1 in Japan

“…Pseudohypoaldosteronism type 1 (PHA-1) is a disorder caused by renal tubular resistance to aldosterone and is characterized by hyperkalemia, hyponatremia, metabolic acidosis, and high renin and aldosterone concentrations [ 1 ]. In clinical settings, PHA-1 is a significant cause of neonatal hyperkalemia [ 2 ], and there are reports of life-threatening cases of excessive hyponatremia (113.3 mEq/L) associated with hyperkalemia (8.8 mEq/L) [ 3 ], and cardiac arrest due to excessive hyperkalemia [ 4 ]. PHA-1 is typically divided into the following two forms based on cause: primary PHA-1, which is caused by genetic mutation of the NR3C2 gene encoding the mineralocorticoid receptor (MR) or of the epithelial sodium channel ( ENaC ) gene, and secondary PHA-1, which is associated with renal urinary tract abnormality.…”