Endo Annual 2022

Expanding the Phenotype of Familial Hypocalciuric Hypercalcemia Type 3

Merav Fraenkel 1 Lior Baraf 1 Lior Karmon 2 Auryan Szalat 3 Noa Shefer Averbuch 5,6 Rivka Sukenik Halevy 4,7
1Endocrinology, Soroka University Medical Center, Ben-Gurion University of the Negev
2Pediatrics Endocrinology, Soroka University Medical Center, Ben-Gurion University of the Negev
3Internal Medicine, Hadassah Medical Center
4Genetics Institute, Meir Medical Center
5Genetic Institute, Rabin Medical Center–Beilinson Hospital
6Endocrinology and Diabetes, Schneider Children's Medical Center
7Sackler Faculty of Medicine, Tel Aviv University

Introduction:
Familial hypocalciuric hypercalcemia (FHH) is a rare mostly asymptomatic genetic disorder affecting the calcium sensing receptor (CaSR) and its associated proteins with autosomal dominant inheritance. Mutation in AP2S1 gene is responsible for FHH3.

Aim:
Expand the phenotype of FHH type 3.

Methods:
Clinical and biochemical characterization of a patient with de-novo FHH3 mutation.

Results:
S.Z, A 30-year-old man was hospitalized for recurrent pancreatitis. His medical history included chronic hypercalcemia in the range of 11.7-13.3 mg/dl attributed to his prior clinical diagnosis of FHH. Abdominal imaging and lipid profile were unremarkable. The working diagnosis was of hypercalcemia-related acute pancreatitis. He was treated conservatively with resolution of symptoms and normalization of serum amylase and lipase. A multi-gene panel that was performed (INVITAE) revealed a heterozygous mutation in the AP2S1 gene- p.Arg15Leu. His parents and two siblings were normocalcemic. A second genetic panel for pancreatitis related genes was negative.

DXA bone mineral density revealed Z score of -2.3 at LS and -2.9 at FN and TH - a typical finding in FHH3 patients. Cinacalcet at a dose of 120mg daily was well tolerated and normalized calcium levels with no episodes of pancreatitis within 26 months of follow-up. His three-year-old son is followed for speech delay and was found to be hypercalcemic; he carries the same AP2S1 mutation.

Conclusions:
We describe a family with a de novo mutation in the AP2S1 gene presenting with recurrent pancreatitis, low bone mass and speech delay thus expanding the phenotype of FHH3.