Gordon syndrome caused by a CUL3 mutation in a patient with short stature in Korea: a case report

Objectives: Gordon syndrome (GS), also known as pseudohypoaldosteronism type II, is a rare tubular disease characterized by hypertension, hyperkalemia, and metabolic acidosis. Its causative genes are CUL3, KLHL3, WNK1, and WNK4, and they are associated with varying severity of the disease. Herein, we report the first case of GS caused by a CUL3 mutation in a patient with short stature in Korea.Case presentation: A 7-year-old boy had hypertension, metabolic acidosis, and persistent hyperkalemia, which were initially detected during the evaluation of short stature. He was born small for gestational age at late preterm gestation. Laboratory test findings showed hyperkalemia with low trans-tubular potassium gradient, hyperchloremic metabolic acidosis with a normal anion gap, and low plasma renin levels. Genetic analysis revealed a heterozygous de novo mutation in the CUL3 gene (c.1377+1G > C in intron 9). Thus, a diagnosis of GS was made. The results of the endocrine function test (including growth hormone stimulation tests) were normal. After thiazide treatment, the patient’s electrolyte levels were normalized. However, he presented with persistent hypertension and short stature.Conclusions: GS should be considered in children with short stature, hypertension, and hyperkalemia, and early treatment may reduce complications.

A case report of pseudohypoaldosteronism type II with a homozygous KLHL3 variant accompanied by hyperthyroidism

Background Pseudohypoaldosteronism type II (PHAII), also called Gordon syndrome, is a rare hereditary disease caused by variants in the WNK1, WNK4, KLHL3 and CUL3 genes. The combination of PHAII with hyperthyroidism and secondary hyperparathyroidism has not been reported previously. Case presentation A 54-year-old female with recently diagnosed Graves’ disease presented hyperkalemia, hypertension, hypercalciuria, elevated levels of parathyroid hormone (PTH) and normal renal function. PHAII was established based on the finding of a homozygous variant (c.328 A > G, T110A) in the KLHL3 gene. Low-dose thiazide diuretics normalized her potassium, calcium and PTH. Conclusions PHAII caused by a KLHL3 variant can affect adults later in life. This diagnosis should be considered in patients with hypertension, consistent hyperkalemia, and normal eGFR and can be corrected by thiazides. The patient also had hyperthyroidism and secondary hyperparathyroidism. The latter was also corrected by thiazide treatment. The hyperthyroidism was assumed to be unrelated to PHAII.

A Rare Case of Pseudohypoaldosteronism Type II or Gordon Syndrome

Introduction: Pseudohypoaldosteronism type II (PHA II) or Gordon Syndrome is a rare, autosomally inherited disease with unknown prevalence. It is caused by mutations in the WNK1, WNK4, CUL3, or KLHL3 gene. It is characterized by hypertension, hyperkalemia, hyperchloremic metabolic acidosis and low plasma aldosterone levels, but otherwise normal kidney function. The age of onset of PHA2 is variable, ranging from infancy or childhood to adolescence and adultdood. The electrolyte and blood pressure abnormalities of PHA II is often managed with salt restriction and hydrochlorthiazide (HCTZ). Here we report a rare case of Pseudohypoaldosteronism type II in an adolescent patient. Case Presentation: A 16-yo female with past medical history of asthma and anemia presented to the emergency department with acute severe abdominal/suprapubic pain, associated with diaphoresis, non bloody diarrhea and non bilious non bloody vomiting. The patient also reported daily headaches relieved with Tylenol. In the ED, she was found to be hypertensive at 190/118 mmHg. Blood count showed mild anemia but normal white count and platelets. Comprehensive metabolic panel showed sodium 140, potassium 6.6, chloride 115, bicarbonate 16, creatinine 0.5, and normal liver enzymes. Urine electrolytes were as follows: sodium 189, potassium 20.8 and chloride 140. Arterial Blood Gas ahowed pH of 7.32. Plasma renin activity was low normal at 0.34 and aldosterone level was 2. CT scan of abdomen and pelvis was unremarkable. The blood work was consistent with pseudohypoaldosteronism type II or Gordon syndrome. The patient was adopted so there was no family history. She was started on hydrochlorothiazide. Later, she developed severe itching reaction with hydrochlorthiazide. She is currently being treated with Indapamide, with well controlled blood pressure and normal electrolytes. Conclusion: Pseudohypoaldosteronism type II or Gordon’s Syndrome is a rare disease, with usually autosomal dominant inheritance, with no specific diagnostic criteria for diagnosis. It should be suspected in adolescent or adult patients with hyperkalemia with normal glomerular filtartion, accompanied by hypertension (can be absent), metabolic acidosis, hyperchloremia, decreased plasma renin, relatively suppressed aldosteronism and family history of similar findings.

Sequence and structural variations determining the recruitment of WNK kinases to the KLHL3 E3 ligase

The BTB-Kelch protein KLHL3 is a Cullin3-dependent E3 ligase that mediates the ubiquitin-dependent degradation of kinases WNK1-4 to control blood pressure and cell volume. A crystal structure of KLHL3 has defined its binding to an acidic degron motif containing a PXXP sequence that is strictly conserved in WNK1, WNK2 and WNK4. Mutations in the second proline abrograte the interaction causing the hypertension syndrome pseudohypoaldosteronism type II. WNK3 shows a diverged degron motif containing 4 amino acid substitutions that remove the PXXP motif raising questions as to the mechanism of its binding. To understand this atypical interaction, we determined the crystal structure of the KLHL3 Kelch domain in complex with a WNK3 peptide. The electron density enabled the complete 11-mer WNK-family degron motif to be traced for the first time revealing several conserved features not captured in previous work, including additional salt bridge and hydrogen bond interactions. Overall, the WNK3 peptide adopted a conserved binding pose except for a subtle shift to accommodate bulkier amino acid substitutions at the binding interface. At the centre, the second proline was substituted by WNK3 Thr541, providing a unique phosphorylatable residue among the WNK-family degrons. Fluorescence polarisation and structural modelling experiments revealed that its phosphorylation would abrogate the KLHL3 interaction similarly to hypertension-causing mutations. Together, these data reveal how the KLHL3 Kelch domain can accommodate the binding of multiple WNK isoforms and highlight a potential regulatory mechanism for the recruitment of WNK3.

WNK4 kinase is a physiological intracellular chloride sensor

With-no-lysine (WNK) kinases regulate renal sodium-chloride cotransporter (NCC) to maintain body sodium and potassium homeostasis. Gain-of-function mutations of WNK1 and WNK4 in humans lead to a Mendelian hypertensive and hyperkalemic disease pseudohypoaldosteronism type II (PHAII). X-ray crystal structure and in vitro studies reveal chloride ion (Cl−) binds to a hydrophobic pocket within the kinase domain of WNKs to inhibit its activity. The mechanism is thought to be important for physiological regulation of NCC by extracellular potassium. To test the hypothesis that WNK4 senses the intracellular concentration of Cl−physiologically, we generated knockin mice carrying Cl−-insensitive mutant WNK4. These mice displayed hypertension, hyperkalemia, hyperactive NCC, and other features fully recapitulating human and mouse models of PHAII caused by gain-of-function WNK4. Lowering plasma potassium levels by dietary potassium restriction increased NCC activity in wild-type, but not in knockin, mice. NCC activity in knockin mice can be further enhanced by the administration of norepinephrine, a known activator of NCC. Raising plasma potassium by oral gavage of potassium inactivated NCC within 1 hour in wild-type mice, but had no effect in knockin mice. The results provide compelling support for the notion that WNK4 is a bona fide physiological intracellular Cl−sensor and that Cl−regulation of WNK4 underlies the mechanism of regulation of NCC by extracellular potassium.