CYP24A1 gene mutations cause hypercalcemia in man with low PTH

Researchers urge genetic analysis when PTH is suppressed, vitamin D is normal

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Mutations in the CYP24A1 gene were identified as a cause of a 43-year-old man’s idiopathic infantile hypercalcemia (IIH), a condition marked by higher than normal blood calcium levels.

The man also had low levels of parathyroid hormone (PTH), a sign of hypoparathyroidism, and normal vitamin D —  unusual for hypercalcemia patients — the study’s researchers noted in “Case report: Two heterozygous pathogenic variants of CYP24A1: A novel cause of hypercalcemia and nephrocalcinosis in adulthood,” which was published in Frontiers in Medicine.

“Genetic analysis of CYP24A1 should be considered in patients with hypercalcemia and suppressed PTH,” they wrote, noting such mutations may be the underlying cause of disease even when vitamin D levels are normal.

Hypoparathyroidism is marked by deficiencies in PTH, which is important for regulating calcium and phosphorous’s balance in the blood. As a result, patients typically have lower than normal blood calcium levels (hypocalcemia).

If blood calcium levels are too high, however, a negative feedback loop can develop that suppresses PTH activity. As such, low PTH can also emerge as a symptom of hypercalcemia.

This is the case with IIH, for which mutations in the CYP24A1 gene are a possible cause. CYP24A1 encodes part of an enzyme that controls the amount of vitamin D by breaking down its active version into a less active or inactive metabolite.

IIH patients typically have a deficiency in this enzyme, leading to too much vitamin D in the bloodstream. Since vitamin D increases the efficiency of calcium absorption, this also drives high calcium levels and low PTH.

Symptoms of this rare condition can be severe in infancy and include failure to thrive, dehydration, vomiting, and calcium deposition in the kidneys, or milder in adulthood.

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Searching for cause of hypercalcemia

The report concerned a 43-year-old man with symptoms resembling Marfan syndrome, a genetic connective tissue disease, including a tall frame and long extremities. He’d been treated for high blood pressure since 2013.

Medical findings included calcium deposits in his kidney (nephrocalcinosis) and his arteries (artherosclerosis) of the heart and abdomen, as well as blood clots attached to blood vessel walls.

Marfan syndrome was ruled out by a geneticist, but a mutation called factor V Leiden was identified that’s associated with blood clots. The man was started on aspirin and atorvastatin.

A nephrologist found the man to have slightly reduced kidney function and excess calcium excretion in the urine, or hypercalciuria. He was started on hydrochlorothiazide, which stimulates urine production.

Because he had low PTH, he was referred to an endocrinologist in 2019 with possible hypoparathyroidism.

The man didn’t have a family history of kidney stones, deposits of minerals and salts (including calcium) that form in the kidneys, which can be an indicator of hypercalcemia.

Laboratory tests revealed hypoparathyroidism, normal blood calcium, and no bone abnormalities, which are common where calcium is impaired.

The man’s blood calcium levels progressively increased, reaching a peak by the summer of 2021, while measures of vitamin D and bone health were normal.

The man’s blood calcium levels were highest in the summer, corresponding with maximum sun exposure. Sunlight is the largest environmental source of vitamin D.

The next year, genetic testing revealed two mutations in the CYP24A1 gene, both of which were predicted to be pathogenic, or disease-causing. At the time of the report, the man’s family members hadn’t been tested.

The man was instructed to increase his fluid intake and avoid vitamin D — including sun exposure — and excess calcium intake. He was told to advise his family members, who could have the same mutation, to do the same. At follow-up, his calcium levels remained stable and slightly above normal.

Although rare, CYP24A1 mutations should be considered as a possible cause of hypercalcemia when nephrocalcinosis or kidney stones are observed, according to researchers, who noted the man’s normal vitamin D  “did not fit into the typical clinical picture,” but said high variability in this measurement is possible for patients with mild forms of infantile hypercalcemia and said genetic testing may be appropriate even when vitamin D isn’t elevated.