A Novel Homozygous Mutation of the Calcium-Sensing Receptor Gene Associated with Apparent Autosomal Recessive Inheritance of Familial Hypocalciuric Hypercalcemia

Authors: Nan Li1,2, Xiang Li3, Xiao-Lin Ni3, Xiu-Ying Li1,4, Wei-Bo Xia3, Guo-Qing Yang1, Yu Pei1

Affiliations:

1. Department of Endocrinology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China;
2. Department of Endocrinology, The Second Medical Center, Chinese PLA General Hospital, Beijing 100853, China;
3. Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing 100730, China;
4. Department of Endocrinology, Liangxiang Teaching Hospital, Capital Medical University, Beijing 102401, China.

Introduction

Calcium homeostasis is crucial for the proper functioning of our bodies. Familial hypocalciuric hypercalcemia (FHH) is a rare hereditary disorder that disrupts this balance. It is characterized by lifelong hypercalcemia (high calcium levels in the blood), usually without obvious symptoms, and inappropriately low urinary calcium excretion. FHH is genetically heterogeneous, with most cases being FHH1 due to inactivating mutations in the calcium-sensing receptor (CASR) gene on chromosome 3. CASR is like a key sensor for extracellular calcium, playing a vital role in regulating parathyroid hormone (PTH) secretion and how the body handles calcium. More than 200 loss-of-function CASR mutations have been identified so far. Inactivating mutations in this gene can lead to hypercalcemia disorders like FHH and neonatal severe hyperparathyroidism (NSHPT). The genotype-phenotype correlation, however, is not always clear. In this article, we present a case of FHH1 that started with acute pancreatitis and was caused by a homozygous mutation in the CASR gene.

Case Presentation

Patient Information

A 12-year-old boy was admitted to the emergency department with abdominal pain and vomiting. He was diagnosed with acute pancreatitis. Laboratory tests showed hypercalcemia (4.70 mmol/L, normal range 2.09 – 2.54 mmol/L) and inappropriately normal PTH (26 pg/mL, normal range 12 – 88 pg/mL). After treatment for pancreatitis (feeding restriction, fluid infusion, acid suppression, etc.), his pancreatitis was cured, but the hypercalcemia persisted. Further tests showed a hypermetabolic nodule beneath the thyroid and in front of the trachea, and he was transferred to the endocrinology department.

Symptoms and Medical History

During the endocrinology evaluation, he reported fatigue for 12 months and bone pain in the bilateral heel. He had no headache, polydipsia (excessive thirst), polyuria (excessive urination), constipation, or history of kidney stones. His past medical and surgical histories were unremarkable. He was born by cesarean section due to intra-uterine distress and was diagnosed with “cerebral palsy” at 14 months as he had delayed motor development (couldn’t sit alone until 12 months and couldn’t walk at 14 months). He received hyperbaric oxygen therapy until 3 years old. He could speak some words at 2 years and walk independently at 2.5 years. His deciduous teeth eruption and replacement time was similar to peers, and there was no specific family history.

Physical Examination

On physical examination, his pulse rate was 76 beats/min, blood pressure 116/78 mmHg (50th percentile for both systolic and diastolic), weight 68 kg (>97th percentile), height 164 cm (>90th percentile). He had a rolling gait without deformities. X-ray examinations of bilateral limbs, skull, spine, and hip showed no fractures, periarticular erosions, or other bone lesions. Kidney ultrasound showed normal kidneys. Neck ultrasound showed a moderately echogenic nodule beneath the thyroid gland (likely parathyroid gland origin).

Biochemical Tests

Further biochemical tests confirmed hypercalcemia (4.00 mmol/L), inappropriate normal PTH (49.19 pg/mL), and low urinary calcium excretion (fractional excretion of calcium were 1.07%, 0.05%, and 0.09% on three separate tests).

Genetic Analysis

CASR gene sequencing showed a homozygous mutation in exon 2 (c.178T>G), which led to a substitution of the amino acid cysteine (TGT) to glycine (GGT) at codon 60 (p.C60G). Using online protein prediction programs (Mutation T@sting and Polyphen), it was predicted that this substitution would affect the protein’s function. Pedigree investigation showed his parents were heterozygous for the same CASR gene mutation. His parents’ serum calcium levels were normal but on the upper side (2.42 and 2.47 mmol/L for father and mother), PTH was normal, and fractional excretion of calcium was 0.78% and 1.08%.

Discussion

Inheritance Pattern

FHH1 is usually a heterozygous condition with an autosomal dominant pattern of inheritance. However, homozygous inactivating CASR mutations usually cause NSHPT. In this case, the proband had severe hypercalcemia with inappropriately normal PTH and hypocalciuria, which was similar to the FHH1-like clinical phenotype. Although FHH1 is generally considered autosomal dominant, autosomal recessive inheritance with both mutated CASR alleles has been reported in six families. Our proband’s parents were heterozygous, and with the current information, we can’t rule out an autosomal recessive manner in this family as other family members’ genotypes and phenotypes are unknown.

Mutation Impact

Functionally, different CASR mutations have different impacts. For example, P39A, Q27R, and L13P mutations show greater impairment. Patients with homozygous P39A, Q27R, and L13P mutations have higher serum calcium levels compared to those with homozygous Q459R and E671D. The CASR protein has three domains, and residue 60 is in the extracellular domain (ECD). Mutants of cysteine at codon 60 (like in this case) can affect protein expression and dimer formation (important for signal transduction). Although C60G was not reported before, mutants at codon 60 (like C60F and C60R) have been associated with FHH1.

Treatment

FHH was once thought to have a benign course. Subtotal parathyroidectomy is not recommended as it often leads to persistent hypercalcemia. Total parathyroidectomy is only for some severe cases due to the risk of hypoparathyroidism. Calcimimetic drugs (like cinacalcet) are approved for adults with certain hyperparathyroidism conditions, but their safety and efficacy in children under 18 are not established, and cost is a factor. Bisphosphonates can be used in FHH1 patients to reduce blood calcium and prevent recurrent pancreatitis. In this case, the family couldn’t afford cinacalcet, so alendronate was prescribed. During a 2-month follow-up, the patient’s serum calcium was sustained under 3.50 mmol/L without pancreatitis recurrence.

Conclusion

This study further shows the heterogeneity of biochemical phenotypes associated with CASR mutations and provides evidence for FHH1 inheritance as an autosomal recessive pattern. The long-term efficacy and safety of bisphosphonates treatment in FHH1 need further study.

References:

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doi: 10.1097/CM9.0000000000001568 (https://doi.org/10.1097/CM9.0000000000001568)

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