Gordon's syndrome I15.80

Pseudohypoaldosteronism type 2 belongs to the group of monogenetically inherited forms of hypertension. It is characterized by hyperkalemia, hyperchloremic metabolic acidosis, normal or elevated aldosterone, low renin, and normal renal function.

Prevalence: Unknown; about 180 families have been described so far.

Autosomal dominant mutations in the WNK1 gene (12p13), classified as PHA2C, and WNK4 (17q21- regulators of the Na-Cl and Na-K-Cl co-transporters (NCC and NKCC2) and the potassium channel ROMK in distal q22), classified as PHA2B The genes code for the lysine-free kinases WNK1 and WNK4. Additional genetic heterogeneity was revealed by the detection of a further locus (PHA2A) on chromosome 1, resulting in increased salt absorption in the distal renal convolute due to an increase in the function of the luminal sodium chloride cotransporter (NCC). At the same time, a reduced aldosterone-dependent potassium excretion is observed. The abundant intake of liquorice can also lead to inhibition of 11-beta-hydroxysteroid hydrogenase via its ingredient glycyrrhetinic acid and thus cause a similar phenotype.

All age groups

Patients < 20 years of age usually have normal blood pressure; hypertension only in adulthood. In adolescence: hyperkalemia, mild hyperchloremic acidosis and low renin. Possible retardation of growth. Normal renal function. The Spitzer-Weinstein syndrome (synonym: adolescent hyperkalemia syndrome) is considered an early manifestation of PHA2, with hypertension associated with other clinical symptoms (dwarfism, muscular weakness, periodic paralysis).

The differential diagnosis includes other causes of hyperkalemia, especially chronic kidney disease. When GFR is normal, differential diagnoses include hyperkalemic renal tubular acidosis as seen in PHA1, hypoaldosteronism, primary adrenal insufficiency, and drug-induced hyperkalemia (e.g., potassium-sparing diuretics, nonsteroidal anti-inflammatory drugs, angiotensin inhibitors, trimethoprim). These forms of hyperkalemic RTA are typically associated with hypovolemia and low blood pressure. An acquired form of PHA2 may be seen with calcineurin inhibitors, particularly tacrolimus.

Low-dose thiazide diuretics correct high blood pressure, hyperkalemia and hypercalciuria. Patients with WNK4 mutations respond better to thiazide diuretics than patients with WNK1<7I> mutations. Type 2 pseudohypoaldosteronism does not respond to exogenous mineralocorticoids. Patients must follow a low-sodium diet.

The inheritance pattern for PHA2 is typically autosomal dominant.

However, PHA2 due to KLHL3 mutations can be inherited in an autosomal recessive or dominant manner.

The risk for offspring to inherit the mutation from an affected parent is 50% in the autosomal dominant form. Offspring of an individual with autosomal recessive PHA2 are obligate carriers and typically asymptomatic. Pathogenetic variants arising de novo are possible. PHA2 due to the CUL3 gene is typically the most severe form. The phenotype of PHA type II due to WNK1 is typically less severe than PHA2 due to WNK4 or a dominant or recessive mutation in the KLHL3 gene.

17-year-old patient who had been under regular pediatric nephrological care since the second month of life due to renal-tubular acidosis with hyperkalemia (type IV). Laboratory tests revealed hyperchlorinemic metabolic acidosis and hyperkalemia with borderline low serum renin and normal serum aldosterone levels. The transtubular potassium gradient (TTKG) consistently showed values below 5. At the age of 16 years, clear arterial hypertension with systolic blood pressure peaks of up to 240 mmHg was observed for the first time. The constellation of findings of arterial hypertension in combination with the laboratory values mentioned was groundbreaking for the diagnosis of Gordon's syndrome.

The patient clearly benefited from antihypertensive medication with hydrochlorothiazide (2mg/kg/d) and showed a drop in blood pressure values to the normal range for the age of the patient. At the same time, the substitution dose for bicarbonate was reduced.

1. Gopal-Kothandapani JS et al. (2019) Phenotypic diversity and correlation with the genotypes of pseudohypoaldosteronism type 1. J Pediatr Endocrinol Metab 32:959-967.
2. Riepe FG (2013) Pseudohypoaldosteronism. Endocr Dev 24:86-95.
3. Yakubov R et al. (2019) One-month-old girl presenting with pseudohypoaldosteronism leading to the diagnosis of CDK13-related disorder: a case report and review of the literature. J Med Case Rep 13:386.