A Novel Homozygous Mutation of the Calcium-Sensing Receptor Gene Associated with Apparent Autosomal Recessive Inheritance of Familial Hypocalciuric Hypercalcemia
Familial hypocalciuric hypercalcemia (FHH) is a group of rare hereditary disorders characterized by lifelong hypercalcemia, typically asymptomatic, and inappropriately low urinary calcium excretion. FHH is genetically heterogeneous, with the majority of cases classified as FHH1, caused by inactivating mutations in the calcium-sensing receptor (CASR) gene located on chromosome 3. FHH2 and FHH3 result from inactivating mutations in the G protein subunit alpha 11 gene and the adaptor-related protein complex 2 subunit sigma 1 gene, respectively. The CASR gene encodes a G-protein coupled receptor that plays a crucial role in regulating parathyroid hormone (PTH) secretion and calcium homeostasis. Over 200 loss-of-function CASR mutations have been identified, leading to hypercalcemia disorders such as FHH and neonatal severe hyperparathyroidism (NSHPT). The severity of these conditions depends on the degree of CASR function impairment, with severe mutations causing NSHPT and milder mutations resulting in FHH. However, the genotype-phenotype correlation remains poorly understood.
This case report presents a 12-year-old boy with FHH1 caused by a novel homozygous mutation in the CASR gene, highlighting the challenges in diagnosing and managing this condition. The patient initially presented with acute pancreatitis, accompanied by hypercalcemia (4.70 mmol/L; reference range: 2.09–2.54 mmol/L) and inappropriately normal PTH levels (26 pg/mL; reference range: 12–88 pg/mL). After symptomatic treatment, his pancreatitis resolved, but hypercalcemia persisted. Further evaluation revealed a hypermetabolic nodule beneath the thyroid gland, likely of parathyroid origin. The patient reported a 12-month history of fatigue and bilateral heel pain but denied other symptoms such as headache, polydipsia, polyuria, constipation, or kidney stones. His medical history included a diagnosis of cerebral palsy at 14 months old, attributed to delayed motor development, and hyperbaric oxygen therapy until age 3. Physical examination showed normal vital signs and anthropometric measurements, with a weight of 68 kg (>97th percentile) and height of 164 cm (>90th percentile). X-ray and ultrasound examinations revealed no fractures or bone lesions, and the kidneys appeared normal.
Biochemical tests confirmed persistent hypercalcemia (4.00 mmol/L) and inappropriately normal PTH levels (49.19 pg/mL; reference range: 15.00–65.00 pg/mL). Fractional excretion of calcium was consistently low (1.07%, 0.05%, and 0.09% on three separate tests). Genetic sequencing identified a homozygous mutation in exon 2 of the CASR gene (c.178T>G), resulting in the substitution of cysteine (TGT) to glycine (GGT) at codon 60 (p.C60G). This mutation was predicted to impair CASR protein function using online tools MutationT@sting and Polyphen. The patient’s parents were heterozygous for the same mutation, with normal but elevated serum calcium levels (2.42 and 2.47 mmol/L) and low fractional excretion of calcium (0.78% and 1.08%).
FHH1 is typically inherited in an autosomal dominant pattern, with heterozygous CASR mutations causing mild hypercalcemia. Homozygous inactivating CASR mutations usually lead to NSHPT, characterized by severe symptomatic hypercalcemia in infancy and high mortality. However, this case demonstrates an FHH1-like phenotype with homozygous CASR mutation, suggesting an autosomal recessive inheritance pattern. This finding aligns with previous reports of six families with autosomal recessive FHH1 due to homozygous CASR mutations, including P39A, Q27R, L13P, Q459R, and E671D. Functional studies indicate that the location of the mutation within the CASR protein significantly impacts its function and clinical phenotype. For example, P39A, Q27R, and L13P mutations exhibit greater impairment and higher serum calcium levels (3.50–4.20 mmol/L) compared to Q459R and E671D mutations (2.90–3.25 mmol/L). The p.C60G mutation in this case affects the extracellular domain of the CASR protein, which is critical for dimerization and signal transduction. Although C60G is a novel mutation, other codon 60 mutations (C60F and C60R) have been associated with FHH1.
Management of FHH is challenging due to its benign but persistent nature. Subtotal parathyroidectomy is ineffective, and total parathyroidectomy is reserved for severe cases due to the risk of lifelong hypoparathyroidism. Calcimimetic drugs like cinacalcet, which act as allosteric agonists at CASR, are approved for adults with primary hyperparathyroidism but lack established safety and efficacy in children. Additionally, the high cost of cinacalcet limits its long-term use. Bisphosphonates, such as alendronate, can reduce serum calcium and prevent recurrent pancreatitis in FHH1 patients. However, PTH levels may increase significantly when serum calcium normalizes, necessitating careful dosage adjustment. In this case, the patient was treated with alendronate, and his serum calcium remained below 3.50 mmol/L during a two-month follow-up, with no recurrence of pancreatitis.
This study highlights the heterogeneity of biochemical phenotypes associated with CASR mutations and provides evidence for autosomal recessive inheritance of FHH1. The efficacy and safety of long-term bisphosphonate treatment in FHH1 warrant further investigation. The novel p.C60G mutation expands the spectrum of CASR mutations and underscores the importance of genetic testing in diagnosing and managing calcium homeostasis disorders.
doi.org/10.1097/CM9.0000000000001568
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