IllnessPseudohypoaldosteronism type I and II, differential diagnosis

NGS +

Pseudohypoaldosteronism type 1 (PHA1) leads to impaired renal regulation of the amount of sodium ions in the organism and to hypertension. In PHA1, pseudo-low aldosterone levels are mimicked, but PHA1 patients have high aldosterone concentrations. In autosomal dominant PHA1, there is excessive renal sodium loss. Symptoms are relatively mild and often improve in early childhood. In autosomal recessive generalized PHA1, renal sodium loss is accompanied by parallel excretions to the colon, sweat and salivary glands. The latter form of PHA1 is more severe and does not improve with age. Early signs of PHA1 usually include failure to thrive and dehydration in infancy. Characteristic laboratory parameters include hyponatremia, hyperkalemia and metabolic acidosis, eventually causing nausea, vomiting, fatigue and muscle weakness. In autosomal recessive PHA1 in addition cardiac arrhythmias or shock may occur with frequent pulmonary infections or skin lesions. Mutations in the NR3C2 gene cause autosomal dominant PHA1; mutations in the SCNN1A, SCNN1B, or SCNN1G genes cause autosomal recessive PHA1.

PHA2 is caused by renal-triggered problems that affect the amount of sodium and potassium in the body. PHA2 patients have hypertension, hyperkalemia and hyperchloremic metabolic acidosis despite normal renal function. Initial PHA2 symptoms occur at different ages, initially hyperkalemia, later hypertension. In addition to nonspecific symptoms as in PHA1, PHA2 patients may also present with hypercalciuria. The proteins encoded by the WNK1 and WNK4 genes control the extent of sodium and potassium transport into and out of renal cells. Hypertension and hyperkalemia result from impaired control of the channels. Proteins produced by the CUL3 and KLHL3 genes control the amount of WNK1 and WNK4 proteins available. While the diagnostic yield for PHA1 is unknown, it can reach nearly 90% for PHA2. Nevertheless, a negative DNA test result cannot exclude the clinical diagnosis of PHA.

References: https://www.ncbi.nlm.nih.gov/books/NBK65707/

https://www.ncbi.nlm.nih.gov/books/NBK1496/

• Better alias - preferred designation for PHA: Familial hyperkalemic hypertension
• Alias: Gordon's syndrome
• Alias: Pseudohyperaldosteronism type I + II
• Allelic: Bronchiectasis with/-out elevated sweat chloride 1 (SCNN1B)
• Allelic: Bronchiectasis with/-out elevated sweat chloride 2 (SCNN1A)
• Allelic: Bronchiectasis with/-out elevated sweat chloride 3 (SCNN1G)
• Allelic: Hypertension, early-onset, AD, with exacerbation in pregnancy (NR3C2)
• Allelic: Liddle syndrome 1 (SCNN1B)
• Allelic: Liddle syndrome 2 (SCNN1G)
• Allelic: Liddle syndrome 3 (SCNN1A)
• Allelic: Long QT syndrome 13 (KCNJ5)
• Allelic: Neuropathy, hereditary sensory + autonomic, type II (WNK1)
• Apparent mineralocorticoid excess (HSD11B2)
• Hyperaldosteronism, familial, type III (KCNJ5)
• Pseudohypoaldosteronism type I, AD (NR3C2)
• Pseudohypoaldosteronism, type I (SCNN1A, SCNN1B, SCNN1G)
• Pseudohypoaldosteronism, type IIB (WNK4)
• Pseudohypoaldosteronism, type IIC (WNK1)
• Pseudohypoaldosteronism, type IID (KLHL3)
• Pseudohypoaldosteronism, type IIE (CUL3)