Clinical characteristics and treatment requirements of children with autosomal recessive pseudohypoaldosteronism

Abstract

Introduction: Autosomal recessive forms of pseudohypoaldosteronism are caused by genetic defects in the epithelial sodium channel. Little is known about the long-term outcome and medication needs during childhood and adolescence. Objective: This study reports a single centre experience of children affected with this ultra-rare condition over a 37 year period. Methods: We report the clinical presentation, growth, neuro-development, associated conditions, mortality and medication dosing and administration for 12 affected children from 8 families. Results: All children presented within the first 2 weeks of life with life threatening, severe hyperkalaemia and hyponatraemia. All parents were consanguineous and of South Asian, Middle Eastern or African ethnic origin. Eight children had homozygous mutations in the SCNN1A and SCNN1G genes encoding the epithelial sodium channel subunits alpha and gamma, respectively, including one novel mutation. Three children died (25%) and two (16%) have severe neurological impairment post cardiac arrest secondary to hyperkalaemia. One affected female had a successful pregnancy at the age of 28 years. Conclusion: Despite high mortality and morbidity in this condition, survival with normal physical and neurological outcome is possible, justifying intensive management to prevent electrolyte imbalance.

Autosomal Recessive Pseudo Hypoaldosteronism- Type 1 in Four Patients from Mixteco-Speaking Families from Coastal California

“…Mutations in the SCNN1A, SCNN1B, or SCNN1G genes cause arPHA1 (Table 1). Each of these genes provides instructions for making one of the pieces (subunits) of a protein complex called the epithelial sodium channel (ENaC) [8,10,11].…”

“…Affected children present very early in life and typically require extremely high doses of sodium to compensate for their severe multiorgan salt wasting. Spontaneous remission has not been described [10]. Due to the epithelial sodium channel mutations, some patients are also prone to develop atopic dermatitis rash and respiratory infections.…”

“…Many patients have feeding difficulties and growth failure and need gastrostomy tube placement for adequate nutrition and medication administration. [10,11,15].…”

The Epithelial Sodium Channel—An Underestimated Drug Target

“…PHA-1B usually manifests itself in the neonatal period and can be fatal in cases where severe electrolyte imbalance leads to cardiac failure or other complications [146]. Because of the multi-organ phenotypic consequences of PHA-1B and varying degrees of severity of symptoms, diagnosis is challenging [147][148][149][150]. Misdiagnosis is common, particularly as congenital adrenal hyperplasia (CAH) [151] or CF [148,152].…”

“…Misdiagnosis is common, particularly as congenital adrenal hyperplasia (CAH) [151] or CF [148,152]. Although PHA-1B can be life-threatening, survival with normal physical and neurological outcome is possible when correct management prevents electrolyte imbalance [147]. A correlation between severity of phenotype and genotype has not been possible so far for PHA-1B owing to the small number of cases reported, the rarity of the disease and the heterogeneity of symptoms.…”