What is FHH: Causes, Symptoms, and Treatments?
Caused by the mutation of the calcium-sensing receptor gene (CASR). It causes an increase in the plasma calcium levels in the body, low urinary calcium excretion, and slightly higher plasma parathyroid hormone (PTH). FHH is very rare, affecting 1 in 78,000 people. It is usually a benign condition that is inherited.
Since it is asymptomatic, there is rarely a need for treatment. That said, pregnant women with familial hypocalciuric hypercalcemia (FHH) should be identified as the fetus has a high risk of developing hypocalcemia immediately after birth. It is always best to know FHH, its causes, symptoms, and treatments. It can help prevent the condition from being transferred to the patient’s offspring.
What is FHH?
It is a hereditary condition that results in extremely high levels of calcium in the blood, known as hypercalcemia. It also causes low to moderate calcium levels in the urine, called hypocalciuric. It occurs when there are mutations in specific genes in the body.
While most cases are asymptomatic, few patients have been known to report fatigue, weakness, lack of concentration, and polydipsia. Few patients may experience premature vascular calcification, relapsing pancreatitis, and chondrocalcinosis.
The disease is almost always diagnosed by chance during routine blood work. Patients with Primary Hyperparathyroidism (PHPT) are usually misdiagnosed for FHH as both conditions result in hypercalcemia.
FHH is caused due to the mutation of calcium-sensing genes and other genes that function in tandem with it. The mutation can occur on the CASR gene, GNA11, or AP2S1 gene. Therefore, the condition is classified into type 1, 2, and 3 based on the gene mutation causing it.
Accounting for about 65% of all FHH cases, type 1 is caused by the mutation of the calcium-sensing receptor gene (CASR). This gene is responsible for calcium-sensing, and the loss of its function due to mutations can cause a reduction in the sensitivity to calcium levels. Therefore, the body perceives hypercalcemia as usual.
The GAN11 gene produces the G11 protein, which works with other proteins to regulate the level of calcium in the blood. When this gene mutates, it cannot detect and control the calcium levels in the blood. Mutations in the GNA11 gene cause Type 2 FHH.
Changes in the Adaptor Related Protein Complex 2 Subunit Sigma 1 (AP2S1) gene results in Type 3 FHH. The mutation in this gene causes a loss of interaction with the C-terminal of the CASR and does not allow the gene to monitor and regulate blood calcium levels. It helps transport protein via transport vesicles to various membrane pathways.
While no outward symptoms indicate the condition, hypercalcemia and hypocalciuria are always present. The patient will have high calcium levels in their blood due to hypercalcemia and low to moderate levels of calcium in the urine due to hypocalciuria. These symptoms are similar to PHPT, and therefore, they should be ruled out first.
Other less common symptoms are parathormone-independent increased renal tubular calcium reabsorption, reduced renal calcium clearance to creatinine clearance ratio, chondrocalcinosis, episodic abdominal pain, fatigue, headaches, hypermagnesemia, hypomagnesemia, nausea and vomiting, peptic ulcer, infantile hypercalcemia, osteomalacia, and renal hypophosphatemia.
Some of the rate symptoms include autoimmunity, hypocalcemic seizures, lipoma, nephrolithiasis, and pancreatitis. The single exclusion criteria of FHH is nephrocalcinosis.
Diagnosing FHH requires advanced genetic testing. While hypercalcemia and hypocalciuria are indicators, they are also symptoms of PHPT. The treatment protocol is different for both conditions, and therefore, a confirmed diagnosis is essential.
Since blood reports can give limited information, advanced genetic testing is required to diagnose FHH. These tests can be costly and unreliable as they provide information such as “high probability of FHH” or “moderate probability of FHH.” The patient’s DNA needs to be examined for the mutations mentioned above.
FHH patients live with high calcium levels all their life, and therefore, it is normal for them. Since most patients do not display any outward symptoms, they don’t need treatment. However, a clear distinction is required in diagnosing FHH and PHPT, as both have similar symptoms. While there is no treatment for FHH, PHPT needs surgery.
FHH does not cause much harm without treatment, but PHPT can be devastating if left untreated. Those who have minor issues such as headaches, fatigue, and abdominal pain can be given medication to relieve the symptoms.Familial hypocalciuric hypercalcemia (FHH) is a rare genetic condition that results in high calcium levels in the blood and low to moderate levels in urine. These do not affect the patient as they are used to living with these increased calcium levels. The concern is misdiagnosing FHH for PHPT, which can be catastrophic for the patient.