Familial hypocalciuric hypercalcemia (FHH) is a rare genetic disorder of calcium regulation. FHH type 3 (FHH3), caused by pathogenic variants in AP2S1, may present with clinically significant complications. Data on the treatment of this rare disorder is limited. CASE DESCRIPTION: We report an 11-year-old girl with a de novo heterozygous pathogenic variant in AP2S1 (NM_004069.6): c.44G>T p.(Arg15Leu). At the age of seven, our patient presented with hypercalcemia, hypocalciuria, and elevated parathyroid hormone (PTH), which were accompanied by low bone mineral density and persistent neurodevelopmental difficulties. Primary hyperparathyroidism and causative variants in the CASR gene were excluded, and cinacalcet was initiated. After a dose titration and vitamin D3 dose adjustments, a normalization of serum calcium and PTH was achieved, and symptoms improved substantially, although lumbar bone mineral density declined further, and neurological symptoms remained. CONCLUSIONS: This case demonstrates cinacalcet as an effective and well-tolerated therapy in FHH3, with unresolved questions regarding skeletal and neurocognitive outcomes.

Background: Familial hypocalciuric hypercalcemia type 3 (FHH3) is a rare hereditary disorder caused by a heterozygous AP2S1 gene mutation, characterized by hypocalciuria and hypercalcemia due to impaired intracellular signal transduction of calcium (Ca)-sensing receptors (CaSRs). All affected patients harbored a heterozygous missense mutation at the Arg15 residue of the encoded AP2σ1. Case Presentation: A 21-year-old female was referred to our hospital with hypercalcemia and reduced bone mineral density (BMD) detected during a preoperative examination for scoliosis surgery. She had a developmental disorder and exhibited hypocalciuria on urinalysis. Genetic testing revealed a heterozygous AP2S1 gene mutation (p.Arg15Leu), and the patient was diagnosed with FHH3. In the present case, we investigated the effects of evocalcet, a newly approved CaSR agonist. Treatment with evocalcet gradually decreased and normalized the serum Ca level, and promoted improvements in bone metabolism, without serious adverse events. Conclusion: Evocalcet may be a promising therapeutic candidate for symptomatic FHH3.

To evaluate the prevalence and degree of any neurodevelopmental abnormalities in children with familial hypocalciuric hypercalcemia type 3 (FHH3). A formal neurodevelopmental assessment was performed in children diagnosed with FHH3. The Vineland Adaptive Behavior Scales, which is a standardized parent report assessment tool for adaptive behavior, was used to assess communication, social skills, and motor function and to generate a composite score. Six patients were diagnosed with hypercalcemia between 0.1 and 8 years of age. All had neurodevelopmental abnormalities in childhood consisting of either global developmental delay, motor delay, expressive speech disturbances, learning difficulties, hyperactivity, or autism spectrum disorder. Four out of the 6 probands had a composite Vineland Adaptive Behavior Scales SDS of < -2.0, indicating adaptive malfunctioning. Significant deficits were observed in the domains of communication (mean SDS: -2.0, P < .01), social skills (mean SDS: -1.3, P < .05), and motor skills (mean SDS: 2.6, P < .05). Individuals were equally affected across domains, with no clear genotype-phenotype correlation. All family members affected with FHH3 also described evidence of neurodevelopmental dysfunction, including mild-to-moderate learning difficulties, dyslexia, and hyperactivity. Neurodevelopmental abnormalities appear to be a highly penetrant and common feature of FHH3, and early detection is warranted to provide appropriate educational support. This case series also supports consideration of serum calcium measurement as part of the diagnostic work-up in any child presenting with unexplained neurodevelopmental abnormalities.

Familial hypocalciuric hypercalcemia (FHH) is a heterogeneous autosomal-dominant disorder of calcium hemostasis that may be difficult to distinguish clinically from mild primary hyperparathyroidism. Loss-of-function mutations mainly involving Arg15 residue of the adaptor-related protein complex 2, sigma subunit 1 (AP2S1) cause a rarer, more recently recognized form of FHH, FFH type-3. Recently, 18F-fluorocholine positron emission tomography/computed tomography (FCH-PET/CT) showed superior sensitivity to conventional imaging in localizing parathyroid adenomas. We report a new FFH type-3 patient who underwent unnecessary parathyroidectomy in association with misleading FCH-PET/CT imaging. A 29-year old woman was initially evaluated for parathyroid hormone (PTH)-dependent hypercalcemia in 2013. Medical history was positive only for chronic constipation and malaise with no personal or family history of hypercalcemia, kidney stones, or neck surgery. Over seven years, serum calcium level was 2.51-2.89 mmol/L with concomitant PTH level of 58.7-94.8 mmol/L. Serum phosphate levels were in the low/low normal range. Serum creatinine and magnesium levels were normal. 25-hydroxy vitamin D level was 13 nmol/L. 24-hour urine calcium level was 1.92 mmol/day but increased to 6.99 mmol/day after treatment with cholecalciferol 1000 IU daily. Bone mineral density and renal ultrasound were normal. Parathyroid ultrasound showed two hypoechoic nodules inferior to the left and right thyroid lobes; however, 99mtechnitium-sestamibi scans (2013, 2016, 2018) were negative. FCH-PET/CT (2019) showed focal uptake co-localizing with the nodule inferior to the left thyroid lobe. The patient underwent left inferior parathyroidectomy and pathology was consistent with parathyroid hyperplasia. However, postoperatively, serum calcium and PTH levels remained elevated and FCH-PET/CT and ultrasound showed persistence of the uptake/nodule. Whole exome sequencing showed Arg15Cys mutation in the AP2S1 gene characteristic of FHH type-3. In this new case of FHH type-3, FCH-PET/CT failed to localize to the hyperplastic parathyroid glands and localized instead to apparently a lymph node. This, together with increased urinary calcium after vitamin D supplementation, led to unnecessary parathyroidectomy. Given the increasingly lower cost of genetic testing and the cost of follow up and unnecessary surgery, it may prudent to include genetic testing for FHH early on in patients with mild PTH-dependent hypercalcemia.

Familial hypocalciuric hypercalcemia (FHH) is usually a benign condition divided into three types. FHH-3 occurs in about 20% of the cases and is caused due to missense mutations in AP2S1 (adaptor-related protein complex 2 subunit sigma 1) involving the codon Arg15 (p.R15). We report a case of FHH-3 with a heterozygous mutation in the AP2S1 gene on chr19_47349359 C>T, c.44G>A, p.Arg15His. There are a handful of reports describing the clinical features in patients diagnosed with FHH-3. Herein, we describe the laboratory and clinical features associated with a case of FHH-3 with mutation in the Arg15His codon of the AP2S1 gene.