SAT-506 Identification of a Mutation in AP2S1 Causing Familial Hypocalciuric Hypercalcemia Type 3 in a Patient with Unknown Family History of the Disease

Abstract

Background: Calcium homeostasis is mediated by the CaSR on the parathyroid gland and kidney. Mutations in the CaSR or downstream signaling proteins can lead to dysregulation in serum calcium levels. It is estimated that AP2S1 missense mutations may be the underlying cause of 20% of cases of hypocalciuric hypercalcemia that are negative for mutations in the CaSR (1).Case: The patient is a 29 yo female with a past medical history of IBD who presented for evaluation of hypercalcemia. She had symptoms of joint and abdominal pain concerning for symptomatic hypercalcemia. Labs revealed a normal vitamin D level of 48 ng/ml (ref: 25 to 80), a calcium of 12.0 mg/dL (ref: 8.5-10.5), albumin of 4.2 g/dL (ref: 3.4-5.0), PTH of 54 pg/ml (ref: 16-77), and urinary calcium of < 28 mg/24h (ref: 100-300). Given her symptomatology, the patient had a thyroid US and sestamibi scan that were unremarkable for parathyroid adenoma. In lieu of these negative findings and a low 24h urinary calcium suggestive of FHH, the Patient was sent for genetic testing for over 130 mutations in the CaSR, a common cause of FHH. No mutation in the CaSR was identified. Initial lab results, imaging, and genetic analysis were unrevealing as to the cause of her hypercalcemia. Further consideration of neck exploration was considered given the severity of symptoms that were attributed to elevated serum calcium at the time. Additional genetic evaluation was undertaken prior to exposing the patient to the risk of surgery. The patient was found to have a rare cause of FHH, a heterozygous c.43C>T, Arg15Cys missense mutation in AP2S1 (rs.39751448). Surprisingly, the patient had never been evaluated for hypercalcemia nor has a known family history.Discussion: FHH is comprised of 3 genetically distinct causes: mutations in the CaSR (FHH1), mutations in G α11 that couples with the CaSR (FHH2), and mutations in AP2S1 involved in CaSR-mediated endocytosis (FHH3). To date, at least 3 kindreds have been identified with the AP2S1 mutation (1). The calcimimetic drug, cinacalcet, has been trialed for treatment of FHH3 with more than 20% reduction in serum calcium levels and improvement of symptoms (2).Conclusion: FHH3 is a rare cause of hypercalcemia. To avoid unnecessary neck exploration, it may be beneficial to broaden the initial gene panels to include all 3 genetic causes of FHH to identify Patients with FHH3 foremost. Moreover, screening of family members is also important to avoid unnecessary surgery in kin. Identifying overlapping symptomatology of hypercalcemia with comorbid conditions will prevent extraneous treatment and side effect exposure. When the patient’s IBD was controlled, her symptoms also improved abrogating the need for cinacalcet. 1. Nesbit et al. Nat. Genet. 2013 Jan;45(1):93-72. 2. Howles et al. N Engl J Med. 2016 Apr 7; 374(14):1