MON-LB68 Dual Pathologic Mutations in SLC12A1 and GALNT3 Lead to Impaired Mineral Homeostasis

Abstract

BackgroundLoss-of-function mutations in SLC12A and GALNT3 individually have effects on calcium and phosphorus metabolism but the combined effect has not been described.Case: A 1-week-old female infant presented with hyponatremia (129 mmol/L), hypokalemia (3.1 mmol/L) and metabolic alkalosis (29 mmol/L). Pregnancy was complicated by polyhydramnios requiring several amnioreduction procedures and parental consanguinity. Urine studies showed sodium, potassium, and chloride loss with hyperreninemia (490 ng/ml/h) and hyperaldosteronism (210 ng/dL). Genetic testing revealed a homozygous mutation in SLC12A1 leading to a diagnosis of severe antenatal Bartter syndrome. The patient was started on sodium and potassium supplements with improvement in electrolytes. A few weeks later, she was found to have mild hypercalcemia (11.1 mg/dL) with elevated PTH (102 pg/mL) and high 1,25(OH)2D levels (224 pg/mL) suggestive of primary hyperparathyroidism. While hypercalcemia and hyperparathyroidism have been described in Bartter syndrome, the infant was also noted to have hyperphosphatemia (8.5 mg/dL), which was not expected. Further review of her chromosomal microarray showed a homozygous mutation in GALNT3, an enzyme that normally protects fibroblast growth factor 23 (FGF23) from proteolytic cleavage through glycosylation. Low FGF23 would subsequently result in hyperphosphatemia as well as elevated 1,25(OH)2D, and could contribute to elevated PTH. She was started on Calcilo formula and sevelamer with improvements in her hypercalcemia and hyperphosphatemia. Conclusions: To our knowledge, this is the first patient known to have mutations in both SLC12A1 and GALNT3 leading to derangements in mineral homeostasis. Patients with Bartter syndrome typically have hypercalciuria and increased risk of nephrocalcinosis, variable serum calcium levels, and possibly decreased serum phosphate with decreased urine phosphate reabsorption. In contrast, GALNT3 mutations result in hyperphosphatemia and reduced phosphaturia. By approximately 1 month of age, our patient developed hypercalcemia, hyperphosphatemia and elevated PTH. While hypercalcemic, hypercalciuric hyperparathyroidism has been described in Bartter syndrome and could be the driver of increased PTH in our patient, the GALNT3 mutation leading to low FGF23 must also be considered. Thus, patients with dual mutations in SLC12A1 and GALNT3 require close monitoring as symptomatic electrolyte imbalances may present at variable times.