Inherited, not acquired, Gitelman syndrome in a patient with Sjögren’s syndrome: importance of genetic testing to distinguish the two forms

Abstract

Gitelman syndrome (GS) is an autosomal recessive, salt-losing renal tubulopathy caused by mutations in the SLC12A3 gene; however, it can also be acquired in patients with autoimmune disease, especially in those with Sjögren’s syndrome. Differentiating between the inherited and acquired forms of GS is clinically difficult. We report a case of inherited, not acquired, GS in a patient with Sjögren’s syndrome. A 41-year-old woman, who had been diagnosed with Sjögren’s syndrome at 27-years-old, had shown chronic hypokalemia (2.5–3.5 mmol/L). Laboratory tests showed hypokalemic alkalosis, hypomagnesemia, and hypocalciuria, corresponding to GS. Although acquired GS associated with Sjögren’s syndrome was initially suspected, a genetic test identified a novel homozygous mutation of c.1336-2A > T in the SLC12A3 gene, which resulted in aberrant splicing in the SLC12A3 transcript with the exclusion of exons 11 and 12. Thus, the GS was diagnosed as not the acquired but the inherited form. In the diagnosis of GS in patients with autoimmune disease, genetic testing of SLC12A3 is essential for differentiating the two forms.Electronic supplementary materialThe online version of this article (doi:10.1007/s13730-017-0271-4) contains supplementary material, which is available to authorized users.

Inherited salt-losing tubulopathies are associated with immunodeficiency due to impaired IL-17 responses

“…Moreover, an association between SLT and autoimmunity (e.g. autoimmune thyroid disease, Sjögren’s syndrome, autoimmune hepatitis, and vasculitis) is recognised 22 – 24 , 26 , 28 ; findings in our cohort confirm this association and our demonstration of dysregulated immunity provide an explanation for this link.…”

“…Disease controls are patients attending tubular disorders clinics with a diagnosis that is not associated with renal salt wasting (Supplemental Table 2). The median age of SLT patients is 35 (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43) years and 26 (55.3%) patients are female. Biochemical findings at the time of recruitment are typical of SLT, with hypokalaemic metabolic alkalosis and frequent hypomagnesaemia (Supplemental Table 3).…”

“…Together, these Salt-Losing Tubulopathies share a number of clinical and biochemical features including chronic salt depletion from renal salt wasting, in addition to hyperaldosteronism and hypokalaemic metabolic alkalosis, commonly associated with renal magnesium wasting and hypomagnesaemia. Patients often report a number of somewhat unexplained symptoms, including recurrent febrile episodes in childhood; a link to autoimmunity in both BS and GS has been described, but not fully explained [22][23][24][25][26][27][28] . Immune reactivity in SLT has not been previously explored.…”

Systemic lupus erythematosus complicated by a Gitelman-like syndrome in an 8-year-old girl

“…The occurrence of Gitelman syndrome in Sjogren syndrome and Systemic sclerosis has been attributed to antibodies against the sodium-chloride co-transporter (NCC) as exemplified by renal immunohistochemistry showing absent staining of the NCC in the distal tubules [15], heterozygous mutations involving the NCC [15] or even an incidentally co-inherited homozygous mutation involving the gene encoding the NCC (SLC12A3) [16]. Our case is negative for mutations in the SLC12A3 gene, hinting towards an acquired mechanism, possibly related to antibodies directed against the NCC.…”

HPRT-related hyperuricemia with a novel p.V35M mutation in HPRT1 presenting familial juvenile gout

“…The genetic test was performed in accordance with the ethical standards of Tohoku University Graduate School of Medicine and Tokyo Medical and Dental University. Isolation of genomic DNA and the creation of cDNA were performed as described previously [15][16][17].…”