CASR Mutation Found as Cause of Patient’s Low Calcium Levels
A 13-year-old boy with autosomal dominant hypocalcemia (ADH) — a genetic form of hypoparathyroidism characterized by low calcium — who was unresponsive to conventional therapies was successfully treated with recombinant parathyroid hormone (rhPTH), according to a case report.
rhPTH is a synthetic parathyroid hormone that can help regulate calcium levels and may be “a potential treatment option” for patients whose hypoparathyroidism is not controlled by standard treatment, researchers said.
Further examination revealed that this patient had a mutation in the calcium-sensing receptor gene known as CASR.
The study, “A variant in the CASR gene (c.368T>C) causing hypocalcemia refractory to standard medical therapy,” was published in Endocrinology, Diabetes, and Metabolism: Case Reports.
Hypoparathyroidism is a rare endocrine or hormone disorder. It is characterized by low blood levels of parathyroid hormone, known as PTH — an important regulator of blood calcium levels — as well as low levels of calcium in the bloodstream and high levels of phosphate, a compound necessary for bone formation.
Up to 75% of the disease cases arise from injury to the parathyroid glands during neck surgery. The remaining cases are non-surgical — or may be related to genetic disorders.
One such genetic disorder is ADH caused by mutations in the CASR gene, which codes for the CASR protein that senses the body’s calcium level and regulates parathyroid hormone in response.
This case report looks at a teenager treated in the emergency department after fainting during physical activity, without any other signs or symptoms of an illness or other health problem. No evidence of seizures or other complaints were reported, and the patient’s prior medical history was unremarkable with no developmental delays.
His physical exam revealed some facial twitching, but no other obvious indications of any sort. The patient’s electrocardiogram, done to assess the heart’s electrical functioning, was normal, as were all other heart and kidney scans.
Blood work, however, revealed the boy had severely low blood calcium levels: 1.67 millimoles per liter (mmol/L) as compared with the normal range of 2.19-2.66.
The results of the blood work also showed low free calcium levels (0.80 mmol/L as compared with the normal range of 1.2–1.38), high phosphate levels (3.06 mmol/L, relative to the normal range of 0.95–1.75), low magnesium levels (0.62 mmol/L, in comparison with the normal range of 0.7–1.0), and low vitamin D levels (12.3 nanograms/mL as compared with the normal range of more than 30).
A CT scan of the brain showed multiple calcium deposits in various sections. Additionally, his electroencephalogram — a test for evaluating brain electrical activity — showed abnormal traces, suggesting brain impairment with some seizure or spasm activity.
The patient was then admitted to the pediatric department for stabilization, and started treatment with calcium and vitamin D. He remained without symptoms and was discharged after 16 days with a treatment plan that included daily doses of calcium carbonate (3000 miligrams/day) and active vitamin D (0.25 micrograms/day).
Following his hospital stay, the boy was referred to a pediatric endocrinology consultation for suspected hypoparathyroidism. At the patient’s first consultation, seven days after hospital discharge, he remained without any apparent symptoms.
However, further blood analysis again revealed low blood calcium levels (1.57 mmol/L), high phosphate blood levels (2.94 mmol/L), low levels of magnesium (0.59 mmol/L), excess calcium in the urine (9.23 mmol/24 h versus a normal range of 1.0–8.8), low vitamin D (8.7 nanograms/mL), and inappropriately low PTH (4.0 picograms/mL versus a normal range of 16.0–87.0).
The boy was then rehospitalized in an attempt to optimize his treatment.
His doses of oral calcium, active vitamin D, and magnesium were gradually increased. However, despite therapy optimization and adherence to his medications, the patient’s calcium levels remained low (1.60 mmol/L), and seemed resistant to the standard medical treatment.
The teen, now 14, then was given rhPTH to reduce long-term disease complications. His dose was 20 micrograms twice a day given as under-the-skin (subcutaneous) injections, which was increased to three times a day until an adequate calcium level was achieved (2.02 mmol/L).
According to the researchers, the patient has remained without symptoms since starting rhPTH, and experienced a 50% reduction in his daily calcium and vitamin D requirements. He was seen regularly at the endocrinology clinic until early adulthood and there were no further neurological concerns from his condition. However, a scan of his kidneys revealed some calcifications, requiring the patient to be re-educated with regard to the importance of a low-sodium diet and rhPTH therapy adherence.
While transitioning from pediatric to adult care, blood samples were collected to assess the cause of his low calcium levels. Genetic analysis revealed a mutation in the CASR gene [c.368T>C (p.Leu123Ser)], in which the DNA base thymine was substituted with a cytosine, causing the CASR protein to have a different amino acid (protein building block).
This mutation was predicted to be likely to cause disease. Indeed, it had previously been described in cases of ADH.
None of the patient’s family members had any medical history or symptoms associated with low calcium levels reported.
According to the team, the patient is currently 19 years old and is prescribed rhPTH 20 micrograms three times a day, and magnesium aspartate (1,229.6 mg/day) and active vitamin D (0.25 micrograms/day) once daily. He is on a low-sodium and low-phosphorus diet, and is followed up regularly by his care team.
Based on this case report, the researchers suggested that rhPTH “might be a potential treatment option for those individuals whose condition is not well controlled by the current standard therapy … in order to relieve their symptoms but also to minimize the risk of chronic hypocalcemia [low calcium levels] and hyperphosphatemia [high phosphate levels],” they wrote.
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