Benign familial hypocalciuric hypercalcemia (BFHH) is a rare genetic condition due to mutations involving the calcium-sensing receptor gene (CaSR). It is a rare inherited condition that occurs among 1 in 78,000 people. In benign familial hypocalciuric hypercalcemia, the affected individuals may have high blood calcium levels (hypercalcemia) and moderate to low calcium levels in the urine (hypocalciuric). Usually, people with benign familial hypocalciuric hypercalcemia do not have any specific symptoms, and thus this condition is often diagnosed by chance during other routine blood tests. However, some people experience symptoms like fatigue, weakness, excessive thirst, and altered concentration.
What Is Hypercalcemia?
Hypercalcemia is commonly associated with overactive parathyroid glands, hereditary factors, severe dehydration, cancer, taking too much vitamin D and calcium supplements, certain medications, and more than 25 diseases. In hypercalcemia, the calcium level in the blood will be above normal. Abnormal calcium levels may cause bone loss, kidney stones, bone fractures, hypertension, and kidney failure. Complications such as bone fractures, kidney stones, hypertension, bradycardia, and kidney failure may occur in individuals with long-standing high calcium blood levels.
What Is Benign Familial Hypocalciuric Hypercalcemia?
Benign familial hypocalciuric hypercalcemia is an inherited condition that causes abnormally increased calcium in the blood and reduced calcium levels in the urine. It is divided into three types based on the genetic cause. They are:
Familial Hypocalciuric Hypercalcemia Type 1 - It is the most common type and is caused by alterations in the CaSR gene.
Familial Hypocalciuric Hypercalcemia Type 2 - This condition occurs due to changes in the GNA11 gene.
Familial Hypocalciuric Hypercalcemia Type 3 occurs due to alterations in the AP2S1 gene.
All three types of benign familial hypocalciuric hypercalcemia are inherited in an autosomal dominant manner. However, in rare cases, benign familial hypocalciuric hypercalcemia is caused when an individual's immune system mistakenly makes antibodies that damage the CaSR protein (autoimmune familial hypocalciuric hypercalcemia).
What Are the Causes of Benign Familial Hypocalciuric Hypercalcemia?
Most benign familial hypocalciuric hypercalcemia cases are associated with mutations involving the calcium-sensing receptor (CaSR) gene, which is expressed in the kidney and parathyroid tissues. Mutations in the calcium-sensing receptor (CaSR) gene decrease receptors' calcium sensitivity, causing reduced receptor stimulation even at normal calcium levels. As a result, the parathyroid hormone release is not inhibited until the serum calcium levels are very high. Parathyroid hormone is involved in the reabsorption of calcium from the bone and thus increases serum calcium levels. Individuals with benign familial hypocalciuric hypercalcemia have normal parathyroid hormone levels since normal calcium homeostasis is balanced due to a higher set point for calcium sensing.
What Are the Symptoms Associated With Benign Familial Hypocalciuric Hypercalcemia?
Most patients with benign familial hypocalciuric hypercalcemia usually have few symptoms or are asymptomatic. The symptoms usually seen are the following.
How Can We Diagnose Benign Familial Hypocalciuric Hypercalcemia?
In most cases with benign familial hypocalciuric hypercalcemia, there will not be any unique features; hence, it is less likely to make a diagnosis using the clinical features. Typically the diagnosis is made based on the evaluation of calcium levels in the blood and urine and parathyroid hormone levels. There will be elevated calcium levels in the blood with normal or slightly elevated parathyroid hormone levels. Commonly, in cases of hypercalcemia, the parathyroid hormone levels will be low. However, in benign familial hypocalciuric hypercalcemia, there will be decreased calcium sensitivity of the parathyroid leading to normal levels.
Urinary calcium levels can also be a diagnostic aid for benign familial hypocalciuric hypercalcemia. Usually, urinary calcium levels will also be high in patients with hypercalcemia. However, in benign familial hypocalciuric hypercalcemia, the urine calcium levels will be low.
What Are the Laboratory Signs of Benign Familial Hypocalciuric Hypercalcemia?
High blood calcium levels (more than 10.2 milligrams per deciliters).
High levels of magnesium in the blood (hypermagnesemia).
Low amount of calcium in the urine (excretion rate less than 0.02 millimoles per liter)
Normal to mildly elevated levels of parathyroid hormone.
What Are Treatment Options for Benign Familial Hypocalciuric Hypercalcemia?
Benign familial hypocalciuric hypercalcemia does not show aggressive clinical symptoms or complications. Thus, most patients do not require any specific treatment. Educating the patient about the condition and reassuring them is an important aspect of the initial treatment. However, in patients with severe complications, a surgical approach is indicated to reduce the risk of developing further attacks. Pharmacological agents like calcilytics and calcimimetics can improve defective calcium sensing in patients with benign familial hypocalciuric hypercalcemia.
How Can We Distinguish Between Hyperparathyroidism and Familial Hypocalciuric Hypercalcemia?
Benign familial hypocalciuric hypercalcemia (BFHH) and primary hyperparathyroidism (PHPT) are misdiagnosed. Both conditions manifest high calcium levels in the blood with normal or slightly elevated levels of parathyroid hormones. The calcium clearance ratio (CCCR) can be used as a biochemical test to differentiate between primary hyperparathyroidism and benign familial hypocalciuric hypercalcemia.
Benign familial hypocalciuric hypercalcemia is a rare autosomal dominant genetic condition characterized by lifelong hypocalciuria and hypercalcemia. It occurs due to mutations in the CaSR gene, resulting in alterations in the calcium-sensing receptor. Some people may show fatigue, weakness, excessive thirst, concentration issues, and pancreatitis.