From the Guidelines
The most likely cause of hypercalcemia in a patient with low PTH levels and a family history of hypercalcemia is a genetic disorder, and genetic testing for Multiple Endocrine Neoplasia Type 1 (MEN1) or Familial Hypocalciuric Hypercalcemia (FHH) should be considered. Given the family history of hypercalcemia, it is essential to investigate the possibility of a hereditary condition. The patient's low PTH levels suggest that the hypercalcemia is not due to primary hyperparathyroidism (PHPT) [ 1 ]. The clinical features of MEN1, including primary hyperparathyroidism, pancreatic islet tumors, and anterior pituitary neuroendocrine tumors, can present with hypercalcemia [ 1 ]. However, the low PTH levels in this patient make PHPT less likely, and other causes of hypercalcemia should be explored. Some key points to consider in the diagnosis and management of this patient include:
- Genetic testing for MEN1 or FHH to determine the underlying cause of hypercalcemia [ 1 ]
- Evaluation for other clinical features of MEN1, such as pancreatic islet tumors or pituitary neuroendocrine tumors [ 1 ]
- Monitoring of calcium levels and consideration of parathyroid imaging studies if genetic testing is negative [ 1 ] It is crucial to prioritize the patient's morbidity, mortality, and quality of life when determining the best course of action. In this case, genetic testing and evaluation for hereditary conditions are essential to provide an accurate diagnosis and guide management decisions [ 1 ].
From the Research
Causes of Hypercalcemia
The cause of hypercalcemia in a patient with low PTH levels and a family history of hypercalcemia can be attributed to several factors, including:
- Familial hypocalciuric hypercalcemia (FHH), a rare, benign syndrome that affects the regulation of calcium metabolism 2, 3, 4
- Primary hyperparathyroidism (PHPT), a common endocrine disorder characterized by autonomous hypersecretion of parathyroid hormone (PTH) 2, 5
- Other genetic syndromes, such as multiple endocrine neoplasia type 1 (MEN1) and MEN2A 5, 6
Familial Hypocalciuric Hypercalcemia (FHH)
FHH is an autosomal-dominant genetic disease with high penetrance, caused by an inactivating variant in the CASR gene encoding the calcium-sensing receptor (CaSR) 2, 4. It is characterized by:
- Hypercalcemia with low calcium levels in the urine
- Normal longevity and lack of symptoms in most cases
- Family history of asymptomatic hypercalcemia
Differentiation from Primary Hyperparathyroidism (PHPT)
It is essential to differentiate FHH from PHPT to prevent unnecessary parathyroidectomy 2, 3, 4. The clinical features of FHH and PHPT can overlap, but FHH is typically characterized by:
- Low calcium-creatinine clearance ratio
- Normal or low PTH levels
- Family history of hypercalcemia
- Lack of response to parathyroidectomy
Genetic Syndromes
Other genetic syndromes, such as MEN1 and MEN2A, can also cause hypercalcemia and should be considered in the differential diagnosis 5, 6. However, these syndromes are typically associated with other endocrinopathies and are managed differently than FHH.