Ann Pediatr Endocrinol Metab.  2015 Dec;20(4):230-234. 10.6065/apem.2015.20.4.230.

Pseudohypoaldosteronism in a newborn male with functional polymorphisms in the mineralocorticoid receptor genes

• Jeong HA
• Park YK
• Jung YS
• Nam MH
• Nam HK
• Lee KH
• Rhie YJ

• KMID: 2354701
• DOI: http://doi.org/10.6065/apem.2015.20.4.230

Abstract

Hyponatremia and hyperkalemia in infancy can be attributed to various causes, originating from a variety of renal and genetic disorders. Pseudohypoaldosteronism type 1 (PHA1) is one of these disorders, causing mineralocorticoid resistance that results in urinary salt wasting, failure to thrive, metabolic acidosis, and dehydration. PHA1 is heterogeneous in etiology. Inactivating mutations in the NR3C2 gene (4q31.1), which encodes the mineralocorticoid receptor, causes a less severe autosomal dominant form that is restricted to the kidney, while mutations in the amiloride-sensitive epithelial sodium channel gene (alpha subunit=SCNN1A, 12p13; beta subunit=SCNN1b, 16p12.2-p12.1; gamma subunit=SCNN1G, 16p12) causes a more severe autosomal recessive form, which has systemic effects. Here we report a neonatal case of kidney restricted PHA1 (renal type of PHA1) who first showed laboratory abnormalities before obvious PHA1 manifestations, with two functional polymorphisms in the NR3C2 gene. This is the second genetically confirmed case in Korea and the first to show functional polymorphisms that have previously been reported in the literature.

Keyword

Pseudohypoaldosteronism; NR3C2 gene; Mineralocorticoid receptors; Hyponatremia; Hyperkalemia

MeSH Terms

Acidosis
Dehydration
Epithelial Sodium Channels
Failure to Thrive
Humans
Hyperkalemia
Hyponatremia
Infant, Newborn*
Kidney
Korea
Male*
Pseudohypoaldosteronism*
Receptors, Mineralocorticoid*
Epithelial Sodium Channels
Receptors, Mineralocorticoid

Figure

• 

  Fig. 1 Serum sodium and potassium levels. The patient initially showed normal electrolyte levels immediately after birth. On the 10th day after birth, serum sodium was 128.0 mmol/L, and potassium levels increased to 9.0 mmol/L. Treatment to lower the patient's potassium level was initiated simultaneously and was continued until electrolyte levels normalized*, and sodium supplementation was started†.

• 

  Fig. 2 Partial gene sequencing of the patient's NR3C2 gene. (A) The patient also showed a heterozygous c.-2C>G substitution in the 5'-UT region of the NR3C2 gene, 2 nucleotides upstream of the first translation start site. (B) The patient had a heterozygous c.538G>A substitution in exon 2, which results in an isoleucine changing to valine. G, guanine; A, adenine; C, cytosine; UT, untranslated.

Reference

1. Cheek DB, Perry JW. A salt wasting syndrome in infancy. Arch Dis Child. 1958; 33:252–256. PMID: 13545877.

2. Zennaro MC. Mineralocorticoid resistance. Steroids. 1996; 61:189–192. PMID: 8732998.

3. Geller DS, Rodriguez-Soriano J, Vallo Boado A, Schifter S, Bayer M, Chang SS, et al. Mutations in the mineralocorticoid receptor gene cause autosomal dominant pseudohypoaldosteronism type I. Nat Genet. 1998; 19:279–281. PMID: 9662404.

4. Chang SS, Grunder S, Hanukoglu A, Rosler A, Mathew PM, Hanukoglu I, et al. Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1. Nat Genet. 1996; 12:248–253. PMID: 8589714.

5. Kwon YS, Shin HG, Ahn MS, Kim HB. A case of pseudohypoaldosteronism. J Korean Pediatr Soc. 1992; 35:984–988.

6. Lee JE, Seo JW, Lee SJ. Two cases of pseudohypoaldosteronism type I. J Korean Pediatr Soc. 1994; 37:122–128.

7. Lee R, Kim SY, Choi SD, Chung SY, Kang JH, Lee BC. Two male siblings with pseudohypoaldosteronism type I. J Korean Pediatr Soc. 1994; 37:262–268.

8. Kang IN, Lee JW, Bang JG, Lee DB. A case of pseudohypoaldosteronism. J Korean Pediatr Soc. 1995; 38:1160–1163.

9. Kim SJ, Lim PJ, Ban SH, Lee DH, Jin DK, Song SM, et al. Two cases with pseudohypoaldosteronism. J Korean Soc Pediatr Endocrinol. 2000; 5:215–219.

10. Choi J, Hahn H, Park YS, You HW. A case of transient pseudohypoaldosteronism secondary to ureteropelvic junction obstruction. J Korean Soc Pediatr Nephrol. 2004; 8:91–95.

11. Han SB, Lim CH, Lee KY, Kim JS, Kim WH, Uhm M. A case of pseudohypoaldosteronism type l diagnosed after Infancy. J Korean Soc Pediatr Endocrinol. 2007; 12:82–86.

12. Ahn SY, Shin SM, Kim KA, Lee YK, Ko SY. Pseudohypoaldosteronism in a premature neonate with severe polyhydramnios in utero. Korean J Pediatr. 2009; 52:376–379.

13. Lee SE, Jung YH, Han KH, Lee HK, Kang HG, Ha IS, et al. A case of pseudohypoaldosteronism type 1 with a mutation in the mineralocorticoid receptor gene. Korean J Pediatr. 2011; 54:90–93. PMID: 21503203.

14. Ahn HS. Hong Chang Yee textbook of pediatrics. 10th ed. Seoul: Mirae N Co.;2012. p. 1240.

15. Riepe FG. Pseudohypoaldosteronism. Endocr Dev. 2013; 24:86–95. PMID: 23392097.

16. Amin N, Alvi NS, Barth JH, Field HP, Finlay E, Tyerman K, et al. Pseudohypoaldosteronism type 1: clinical features and management in infancy. Endocrinol Diabetes Metab Case Rep. 2013; 2013:130010. PMID: 24616761.

17. Geller DS. Mineralocorticoid resistance. Clin Endocrinol (Oxf). 2005; 62:513–520. PMID: 15853818.

18. Arai K, Nakagomi Y, Iketani M, Shimura Y, Amemiya S, Ohyama K, et al. Functional polymorphisms in the mineralocorticoid receptor and amirolide-sensitive sodium channel genes in a patient with sporadic pseudohypoaldosteronism. Hum Genet. 2003; 112:91–97. PMID: 12483305.

19. van Leeuwen N, Caprio M, Blaya C, Fumeron F, Sartorato P, Ronconi V, et al. The functional c.-2G>C variant of the mineralocorticoid receptor modulates blood pressure, renin, and aldosterone levels. Hypertension. 2010; 56:995–1002. PMID: 20855654.

20. Geller DS, Zhang J, Zennaro MC, Vallo-Boado A, Rodriguez-Soriano J, Furu L, et al. Autosomal dominant pseudohypoaldosteronism type 1: mechanisms, evidence for neonatal lethality, and phenotypic expression in adults. J Am Soc Nephrol. 2006; 17:1429–1436. PMID: 16611713.