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Generalized pseudohypoaldosteronism type 1
Generalized pseudohypoaldosteronism type 1 (generalized PHA1) is a severe form of primary mineralocorticoid resistance with systemic involvement and salt loss in multiple organs.
ORPHA:171876Classification level: Subtype of disorder
Prevalence is unknown.
Generalized PHA1 is characterised by salt wasting from the kidney, colon, and sweat and salivary glands. In addition to severe dehydration, vomiting and failure to thrive occurring in the first weeks of life, the clinical picture may be complicated by cardiac dysrhythmias, collapse, shock or cardiac arrest. Polyhydramnios has occasionally been reported. An increase in the volume of airway surface liquid leads to frequent respiratory tract manifestations, mimicking cystic fibrosis. Eczematoid skin rashes are frequent due to the severe salt loss from sweat glands. Generalized PHA1 is severe: no remission has been reported and patients suffer from recurrent life-threatening episodes of salt loss.
The disease is transmitted in an autosomal recessive manner and is caused by mutations in the genes coding for the subunits of the amiloride-sensitive sodium channel, ENaC: SCNN1A (12p13); SCNN1B (16p12.2-p12.1), and SCNN1G (16p12).
Diagnosis is based on the disease history and clinical examination, family history, genetic analysis, and biological findings (identical to those found in renal PHA1; see this term). The hyperkalemia is severe and when found in combination with high aldosterone and plasma renin levels confirms the diagnosis. A positive salivary or sweat test showing increased sweat and salivary sodium and chloride levels completes the diagnostic picture.
Differential diagnoses include renal PHA1, congenital adrenal hyperplasia (CAH) associated with 21-hydroxylase deficiency or 3-beta-hydroxysteroid dehydrogenase deficiency, hypoaldosteronism (HA) due to aldosterone deficiency, antenatal or infantile Bartter syndrome (in particular, type 2 Bartter syndrome caused by ROMK mutations) and transient PHA (see these terms).
Antenatal diagnosis may be indicated in families with affected children or when both parents are heterozygous carriers from affected families. Alternatively, neonatal genetic analysis of cord blood may allow rapid diagnosis and management in affected offspring from families with identified mutations.
Management and treatment
No evidence-based treatment has been described and therapeutic intervention is patient-specific consisting of salt and fluid replacement: high doses of sodium together with ion exchange resins and dietary manipulations to reduce potassium levels. Correction of hyperkalemia and acidosis are also required during the acute phase of the disease. As CAH and HA due to aldosterone deficiency are the major differential diagnoses, fludrocortisone and hydrocortisone replacement therapy may be initiated while confirming the diagnosis by hormonal measurements. Corticoid treatment and indomethacin may be beneficial in some patients. The respiratory tract manifestations and skin phenotype require symptomatic treatment.
Although patients require life-long salt supplementation, the clinical course improves with age with a significant decrease in the frequency and severity of salt-wasting episodes and respiratory tract infections requiring hospitalization.