Making Haste in Magnesium Waste: A Case for Genetic Testing

Introduction: Hypomagnesemia is estimated to affect between 2-15% of the general population. While the most common etiologies of hypomagnesemia are acquired, genetic causes need to be considered and can be associated with additional complications. Our case describes a patient found to have an HNF1B gene mutation. Case Description: A 22-year-old female with multiple sclerosis and borderline primary hyperparathyroidism was found to have hypomagnesemia during work up for chronic headaches and fatigue. Despite discontinuation of a PPI, the patient had persistent hypomagnesemia requiring intermittent IV repletion. Laboratory testing showed isolated hypomagnesemia as low as 1.0mg/dL, with normal serum potassium and other electrolytes, high-normal calcium, and creatinine of 0.7mg/dl. Renal ultrasound was unremarkable. Her initial FeMg at 2% was borderline and non-diagnostic for renal wasting. A 24-hour urine magnesium was done, with results suggestive of renal wasting at 155mg in the presence of hypomagnesemia (normal < 30mg/24 hours). Of note, the patient was still receiving IV magnesium repletion, which may confound 24-hour urinary testing. Ultimately, genetic testing was pursued given diagnostic uncertainty, and it revealed a heterozygous mutation in HNF1B. Discussion: Unlike most patients with HNF1B mutations who have renal cystic disease or hypoplasia, our patient’s kidneys were anatomically normal. Her only clinical manifestation was hypomagnesemia, which occurs in up to 50% of patients. Of its many roles, HNF1B regulates the transcription of a subunit of Na/K-ATPase in the kidney and is involved in distal convoluted tubule magnesium reabsorption. The HNF1B mutation may also explain this patient’s hyperparathyroidism, as mutations can cause loss of PTH transcription repression. Absent clear indicators for the etiology of hypomagnesemia, genetic testing was imperative. Providers may now screen for associated complications of HNF1B mutations, such as early-onset diabetes, chromophobe renal cell carcinoma, CKD, and abnormal liver function. HNF1B is only one of many genetic causes of hypomagnesemia and has variable phenotypic manifestations. Genetic testing should be considered in the evaluation of hypomagnesemia because diagnosis can allow for early identification and prevention of comorbidities, as well as referrals to genetic counseling.