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A Hypocalcemic Child with a Novel Activating Mutation of the Calcium-Sensing Receptor Gene: Successful Treatment with Recombinant Human Parathyroid Hormone

Division of Endocrinology, Diabetes, and Metabolism (S.D.M., L.B., M.E.G.), Childrens Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, California 90027; Departments of Medicine, Physiology, and Human Genetics (G.N.H., L.C., I.M.), McGill University, and Calcium Research Laboratory and Hormones and Cancer Research Unit, Royal Victoria Hospital, Montreal, Quebec, Canada H3A 1A1; Department of Pediatrics (R.A.F.), Kaiser Permanente, Los Angeles, California 90027; Departments of Laboratory Medicine and Pathobiology, Medicine, and Pediatrics (Genetics) (D.E.C.C.), University of Toronto, Toronto, Ontario, Canada M5G 1L5; and The Saban Research Institute of Childrens Hospital Los Angeles (M.E.G.), Los Angeles, California 90027

Address all correspondence and requests for reprints to: Steven D. Mittelman, M.D., Ph.D., Division of Endocrinology, Diabetes, and Metabolism, Childrens Hospital Los Angeles, 4650 Sunset Boulevard, Mail Stop Number 61, Los Angeles, California 90027. E-mail: smittelman{at}chla.usc.edu.

Context: Persistent hypercalciuria, with the attendant risk of nephrocalcinosis and eventual renal failure, is common in hypoparathyroid patients, especially those with activating mutations of the calcium-sensing receptor (CASR) gene, being treated with oral calcium and calcitriol. Treatment with replacement PTH may be warranted, although this has yet to be evaluated in children.

Objectives: The objectives of this study were to identify the cause of the disorder in a young hypocalcemic patient and to assess the efficacy of treatment of the patient with recombinant human PTH(1–34).

Subject: An infant presenting with hypocalcemia at 3 wk of age was studied.

Methods: CASR gene mutation analysis was performed on genomic DNA of the proband and family members. The patient was treated with twice-daily administration of recombinant human PTH(1–34) over a 17-month period.

Results: The proband was heterozygous for a de novo novel missense mutation (L727Q), on the border between transmembrane helix 4 and intracellular loop 2 of the CASR. When transiently expressed in a human embryonic kidney 293 cell line, the mutant receptor demonstrated a significant leftward shift in the extracellular calcium/intracellular signaling dose-response curve vs. that for the wild-type receptor [EC₅₀; mutant, 2.59 ± 0.11 mM (mean ± SE) vs. wild-type, 3.78 ± 0.12 mM, P < 0.001]. During treatment with PTH(1–34), the patient had no further serious hypocalcemic episodes, and his urinary calcium excretion declined remarkably.

Conclusion: PTH should be evaluated further as a treatment of autosomal dominant hypocalcemia in young patients.

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