Pseudohypoaldosteronism type 1 (ORPHA:756)
A rare, primary form of mineralocorticoid resistance characterized by mild to profound salt wasting either restricted to the kidney (renal pseudohypoaldosteronism type 1), or generalized affecting many organs (generalized pseudohypoaldosteronism type 1). Clinical presentation is in the neonatal period with failure to thrive, vomiting and dehydration with biochemical findings of hyperkalaemia, metabolic acidosis and, elevated plasma aldosterone and renin concentration.
Epidemiology
The overall prevalence at birth in the United Kingdom is estimated at 1/47,000, with prevalence at birth for renal pseudohypoaldosteronism type 1 (renal PHA1) and generalized pseudohypoaldosteronism type 1 (generalized PHA1), estimated at of 1/66,000 and 1/166,000, respectively. Epidemiological data is limited elsewhere.
Clinical description
The two different forms can be distinguished at the clinical and genetic level: i) renal PHA1 is the most frequent form and presents with mild mineralocorticoid resistance that is restricted to the kidneys and that usually improves in early childhood; ii) generalized PHA1 is a more severe form with salt wasting from multiple organs (including lung, kidney, colon, sweat and salivary glands) and persistence into adulthood. In both forms, presentation is in the neonatal period with a salt-losing syndrome, failure to thrive, vomiting and dehydration. Biological findings include hyponatremia, hyperkaliemia, metabolic acidosis and inappropriately high urinary sodium excretion. The generalized form may present with respiratory involvement (including persistent rhinorrhea, infections, tachypnea, recurrent coughing and wheezing, and, less frequently, respiratory distress syndrome), and cutaneous lesions (caused by inflammation of eccrine structures). The clinical course may be complicated by cardiac dysrhythmias and cardiac arrest in generalized PHA1.
Etiology
Renal PHA1 is caused by mutations or exon deletions in the gene encoding the mineralocorticoid receptor, NR3C2 (4q31.23). Generalized PHA1 is caused by mutations in the genes coding for one of the subunits of the amiloride-sensitive sodium channel including SCNN1A (12p13.31), SCNN1B (16p12.2) and SCNN1G (16p12.2).
Diagnostic methods
Diagnosis is confirmed by the presence of high plasma and urinary aldosterone and high plasma renin levels. Neonatal genetic diagnosis on cord blood may allow rapid diagnosis and management of the condition in affected offspring from families with identified mutations of PHA1.
Differential diagnosis
The main differential diagnoses include congenital adrenal hyperplasia (21-hydroxylase deficiency, 3b-hydroxysteroid dehydrogenase deficiency), aldosterone synthase deficiency (familial hyperreninemic hypoaldosteronism type I and II) and transient pseudohypoaldosteronism (in infants with urinary tract malformations). Occasionally, antenatal or early postnatal hyperkalemia may complicate antenatal Bartter syndrome and erroneously suggest the diagnosis of PHA1.
Antenatal diagnosis
In families with a history of generalized PHA1 (autosomal recessive), prenatal genetic testing may be requested.
Genetic counseling
Renal PHA1 is transmitted in an autosomal dominant manner or occurs sporadically. Generalized PHA1 is transmitted in an autosomal recessive manner. Genetic counselling should be offered to affected families, corresponding to the form of PHA1.
Management and treatment
Treatment consists in salt supplementation and rehydration and, where indicated, correction of hyperkalemia and acidosis. Salt supplementation is administered in accordance with disease severity. Mineralocorticoid replacement therapy with fludrocortisone and hydrocortisone may be undertaken while proceeding through differential diagnosis. Symptomatic treatment is necessary for the respiratory tract illness and to correct the skin phenotype.
Prognosis
Renal PHA1 improves with age and treatment can be discontinued after a variable period of time in most patients, generally around age 18-24 months. With age, patients compensate for the distal salt loss by up-regulating the mineralocorticoid receptor axis. Early diagnosis within the first week of life is critical to survival in patients with generalized PHA1. In this form, no remission has been reported and patients are prone to life-threatening episodes of salt loss into adulthood.

                            Last update: 
                            September 2021


                            - Expert reviewer(s): 
                            Dr Maria-Christina ZENNARO