A Case of Gitelman Syndrome Complicated by Familial Chronic Intestinal Pseudo-Obstruction and Refractory Electrolyte Imbalance

Gitelman syndrome (GS) is an autosomal recessive salt-losing tubulopathy characterized by hypokalemia, hypomagnesemia, and metabolic alkalosis, caused by pathogenic variants in SLC12A3 mutations encoding the thiazide-sensitive Na-Cl cotransporter. Chronic intestinal pseudo-obstruction (CIPO) is a rare disorder of gastrointestinal dysmotility in the absence of mechanical obstruction, often accompanied by severe nutritional and metabolic derangements. Although GS and CIPO have distinct pathophysiologic bases, their coexistence has not been documented. We report a unique familial case of GS complicated by CIPO, resulting in refractory electrolyte disturbances.

A 47-year-old Japanese man presented with recurrent muscle stiffness and weakness. His parents were first cousins (consanguineous marriage). His brother underwent small-bowel transplantation at 27 for CIPO, and his sister was diagnosed with GS in childhood. Since childhood, he had experienced easy fatigability and intermittent hand cramps. GS was diagnosed in his twenties after persistent hypokalemia and hypomagnesemia were detected. He later developed abdominal distension and diarrhea, and CIPO was confirmed by endoscopy and small-intestinal manometry. 

Four years before admission, he was referred for refractory electrolyte disturbances. Despite high-dose oral potassium chloride (96 mEq/day), magnesium oxide, and eplerenone, serum potassium remained 2.5–3.0 mEq/L and magnesium 0.5–1.0 mEq/L. Oral magnesium and calcium supplementation were continued, but hypomagnesemia and hypocalcemia persisted.

As CIPO had been worsened and oral intake declined, he required multiple hospitalizations for worsening hypokalemia with weakness (2.4 mEq/L) and severe hypocalcemia (5.6 mg/dL) with muscle rigidity. Intravenous potassium, magnesium, and calcium

provided only transient correction. Because of recurrent hypokalemia driven by poor intake from CIPO-associated non-obstructive ileus, gastrointestinal decompression using a nasointestinal tube was instituted to facilitate oral intake. Laboratory evaluation also demonstrated vitamin D malabsorption, accounting for hypocalcemia and vitamin B12 deficiency, both of which are likely attributable to intestinal dysfunction.

Despite optimized therapy with an angiotensin II receptor blocker, a mineralocorticoid receptor antagonist, potassium chloride, and magnesium oxide, electrolyte abnormalities remained refractory. The combination of renal tubular salt wasting from GS and intestinal malabsorption from CIPO was difficult to control. Whole-genome sequencing of the proband and his siblings identified homozygous SLC12A3 mutations in the patient and her sister. Given that the proband and his brother were both diagnosed with CIPO, an additional genetic lesion may underlie the CIPO phenotype. Further analyses are required to identify the causal variant(s). To our knowledge, this is the first report of familial GS complicated by CIPO/intestinal failure. The kidney and the gut are central to systemic electrolyte homeostasis. Overlapping renal and intestinal defects led to persistent hypokalemia, hypomagnesemia, and hypocalcemia necessitating continuous intravenous replacement and coordinated multidisciplinary management.

This rare coexistence of Gitelman syndrome and chronic intestinal pseudo-obstruction resulted in a severe clinical course. Intestinal failure amplified the metabolic consequences of GS, rendering electrolyte control difficult and underscoring the need for multidisciplinary management in such complex hereditary disorders.