Familial Hypocalciuric Hypocalcemia: Pitfalls and Implications for the Parathyroid Surgeon

Abstract

Objectives:

Modifications to the Guidelines for the Management of Asymptomatic Primary Hyperparathyroidism (2008) eliminated the recommendation for routine 24-hour urine calcium collection. Surgeons are now seeing an increasing number of referrals for surgical evaluation of hyperparathyroidism without this test that can help differentiate between primary hyperparathyroidism (PHPT), a surgical disease and familial hypocalciuric hypercalcemia (FHH), a medical disease. We will review the characteristics of our cohort of FHH patients and describe findings that should raise suspicion for this diagnosis.

Methods:

Subjects were evaluated at Oregon Health and Science University from 2011 to 2013. Retrospective chart review was performed of a cohort of 11 patients with FHH confirmed by calcium-creatinine clearance ratio (CCCR) and/or CASR gene mutation.

Results:

All patients had CCCR of <0.015, In 8 patients imaging studies could not localize an adenoma, and 6 patients reported a family history of hypercalcemia.

Conclusions:

FHH is a benign, autosomal dominantly inherited disorder from heterozygous mutations in the calcium sensing receptor gene, resulting in lifelong hypercalcemia and relative hypocalciuria. Suspicion for FHH is raised with the presence of long-term hypercalcemia, a positive family history of hypercalcemia, and inability to localize an adenoma on imaging studies. Further evaluation is indicated including a 24-hour urine calculation of the calcium creatinine clearance ratio (CCCR). Significant clinical overlap with PHPT presents certain diagnostic challenges. Additionally, we report novel CASR mutations clinically associated with FHH, highlighting the broad spectrum of this disorder. Heightened awareness of the diagnostic criteria for FHH should decrease the incidence of unnecessary surgeries performed.