ABSTRACT
BACKGROUND: Type 1 pseudohypoaldosteronism (PHA1) is a salt-wasting syndrome caused by mineralocorticoid resistance. Autosomal recessive and dominant hereditary forms are caused by Epithelial Na Channel and Mineralocorticoid Receptor mutation respectively, while secondary PHA1 is usually associated with urological problems. METHODS: Ten patients were studied in four French pediatric units in order to characterize PHA1 spectrum in infants. Patients were selected by chart review. Genetic, clinical and biochemistry data were collected and analyzed. RESULTS: Autosomal recessive PHA1 (n = 3) was diagnosed at 6 and 7 days of life in three patients presenting with severe hyperkalaemia and weight loss. After 8 months, 3 and 5 years on follow-up, neurological development and longitudinal growth was normal with high sodium supplementation. Autosomal dominant PHA1 (n = 4) was revealed at 15, 19, 22 and 30 days of life because of failure to thrive. At 8 months, 3 and 21 years of age, longitudinal growth was normal in three patients who were given salt supplementation; no significant catch-up growth was obtained in the last patient at 20 months of age. Secondary PHA1 (n = 3) was diagnosed at 11, 26 days and 5 months of life concomitantly with acute pyelonephritis in three children with either renal hypoplasia, urinary duplication or bilateral megaureter. The outcome was favourable and salt supplementation was discontinued after 3, 11 and 13 months. CONCLUSIONS: PHA1 should be suspected in case of severe hyperkalemia and weight loss in infants and need careful management. Pathogenesis of secondary PHA1 is still challenging and further studies are mandatory to highlight the link between infection, developing urinary tract and pseudohypoaldosteronism.
Subject(s)
Pseudohypoaldosteronism/diagnosis , Epithelial Sodium Channels/chemistry , Epithelial Sodium Channels/genetics , Female , Genes, Dominant , Genes, Recessive , Humans , Infant , Infant, Newborn , Male , Models, Molecular , Mutation , Pseudohypoaldosteronism/classification , Pseudohypoaldosteronism/etiology , Pseudohypoaldosteronism/genetics , Pyelonephritis/complications , Receptors, Mineralocorticoid/genetics , Retrospective Studies , Urinary Tract/abnormalitiesABSTRACT
Aldosterone plays a key role in electrolyte balance and blood pressure regulation. Type 1 pseudohypoaldosteronism (PHA1) is a primary form of mineralocorticoid resistance characterized in the newborn by salt wasting, hyperkalemia, and failure to thrive. Inactivating mutations of the mineralocorticoid receptor (MR; NR3C2) are responsible for autosomal dominant and some sporadic cases of PHA1. The question as to whether other genes may be involved in the disease is of major importance because of the potential life-threatening character of the disease, the potential cardiovascular effects of compensatory aldosterone excess, and the role of the mineralocorticoid system in human hypertension. We present the first comprehensive study seeking nucleotide substitutions in coding regions, intron-exon junctions, and untranslated exons, as well as for large deletions. A total of 22 MR gene abnormalities were found in 33 patients. We demonstrate that MR mutations are extremely frequent in PHA1 patients classified according to aldosterone and potassium levels and give indications for accurate clinical and biological investigation. In our study the possibility of a genocopy exists in three PHA1 kindreds. The other patients without MR mutations might have different diseases resembling to PHA1 in the neonatal period, which could be identified by extensive clinical and functional exploration.
