Pure Gitelman-like syndrome secondary to SLC26A4 (pendrin) mutation

The article by Lemoine et al.1 Lemoine S. Eladari D. Juillard L. et al. The case | hypokalemia and severe renal loss of sodium. Kidney Int. 2020; 97: 1305-1306 Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar confirms that pendrin plays an important role in human by controlling salt reabsorption 2 Sinning A. Radionov N. Trepiccione F. et al. Double knockout of the Na+-driven Cl-/HCO3- exchanger and Na+/Cl- cotransporter induces hypokalemia and volume depletion. J Am Soc Nephrol. 2017; 28: 130-139 Crossref PubMed Scopus (41) Google Scholar and blood pressure 3 Trepiccione F. Soukaseum C. Baudrie V. et al. Acute genetic ablation of pendrin lowers blood pressure in mice. Nephrol Dial Transplant. 2017; 32: 1137-1145 PubMed Google Scholar and that inactivating mutations of pendrin can cause a complex phenotype with a mix of features from Gitelman and from Pendred syndromes. Herein, we further extend this concept by identifying a patient with SLC26A4 mutations causing Gitelman-like but not Pendred syndrome. A 41-year-old woman presented with chronic renal hypokalemia (2.8 mM before KCl supplements) and metabolic alkalosis associated with renal salt-losing phenotype; she was nonhypercalciuric and normomagnesemic (Table 1). In her history, she underwent partial parathyroidectomy for primary hyperparathyroidism. The patient also exhibited chronic kidney disease with nephrocalcinosis. Whole exome sequence revealed the presence of 2 rare heterozygous variants (p.Ala110Thr and p.Thr508Asn) of SLC26A4 gene, excluding the involvement of known causative genes for hypokalemic salt-losing tubulopathies. According to the American College of Medical Genetics and Genomics classification, Ala110Thr variant was assigned as “uncertain significance,” whereas Thr508Asn was assigned as “likely pathogenic.” The patient did not present hypothyroidism, goiter, or deafness, which are typical of Pendred syndrome. In silico modeling of pendrin (Figure 11 Lemoine S. Eladari D. Juillard L. et al. The case | hypokalemia and severe renal loss of sodium. Kidney Int. 2020; 97: 1305-1306 Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar ) allowed us to test the putative effects of the mutations and suggested that p.Ala110Thr might impair the interaction of chloride to its binding site, whereas p.Thr508Asn is predicted to affect pendrin homodimerization because of its position close to the dimer interface and to the sulfate transporter and anti-sigma factor antagonist (STAS) domain of the protein, in agreement with the recent report by de Filippis et al.4 de Filippis T. Gelmini G. Paraboschi E. et al. A frequent oligogenic involvement in congenital hypothyroidism. Hum Mol Genet. 2017; 26: 2507-2514 Crossref PubMed Scopus (86) Google Scholar In summary, our observation extends the spectrum of the phenotypic abnormalities observed with pendrin’s mutation by showing that pendrin’s inactivating mutations can be associated with Gitelman-like syndrome even in the absence of thyroid or inner ear impairments. Table 1Physical, blood, and urine parameters during KCl and salt supplementation Parameter Value ABG pH 7.47 HCO3–, mM 34.9 PCO2, mm Hg 47.4 Na+, mM 142 Cl–, mM 97 K+, mM 3.4 iCa2+, mM 1.16 Mg2+, mM 1.1 PO4–, mM 1.09 Body weight, kg 52 Urine volume, L/24 h 3.3 SBP, mm Hg 90 DBP, mm Hg 60 Fe Na+, % 4.33 Fe Cl–, % 4.24 Ca2+ × urine volume, mg/24 h 204 ABG, arterial blood gas; Ca2+, calcium; Cl–, chloride ion; DBP, diastolic blood pressure; Fe Cl–, fractional excretion of Cl; Fe Na+, fractional excretion of Na+; HCO3–, bicarbonate ion; iCa2+, ionized calcium; K+, potassium; Mg2+, magnesium ion; NA+, sodium ion; PCO2, partial pressure of carbon dioxide; PO4–, phosphate; SBP, systolic blood pressure. Open table in a new tab ABG, arterial blood gas; Ca2+, calcium; Cl–, chloride ion; DBP, diastolic blood pressure; Fe Cl–, fractional excretion of Cl; Fe Na+, fractional excretion of Na+; HCO3–, bicarbonate ion; iCa2+, ionized calcium; K+, potassium; Mg2+, magnesium ion; NA+, sodium ion; PCO2, partial pressure of carbon dioxide; PO4–, phosphate; SBP, systolic blood pressure. The Case | Hypokalemia and severe renal loss of sodiumKidney InternationalVol. 97Issue 6PreviewA 32-year-old woman was referred to our nephrology department because of chronic hypokalemia with blood K+ concentration ∼2.1 mM. She had a history of Pendred syndrome (MIM #274600) diagnosed at adolescence because of deafness and compressive goiter requiring thyroidectomy. No history of diarrhea, vomiting, or diuretic or laxative abuse was found. The patient had consanguineous parents; she had 4 healthy living sisters and 1 brother who died at birth. Her blood pressure was in the lower normal range (93/64 mm Hg) with frequent tachycardia, and she exhibited craving for salt. Full-Text PDF