Conditions: Familial Hypocalciuric Hypercalcemia (FHH)

Familial hypocalciuric hypercalcemia (FHH) is an inherited condition in which blood calcium runs mildly high for life while urine calcium stays low. It is usually harmless, but it can look like primary hyperparathyroidism on blood tests.

What is familial hypocalciuric hypercalcemia?

Familial hypocalciuric hypercalcemia, usually shortened to FHH, is an inherited condition in which the level of calcium in the blood runs mildly higher than normal for a person's whole life, while the amount of calcium passed in the urine is lower than expected. The long name simply describes these two features: "hypercalcemia" means high blood calcium, "hypocalciuric" means low urine calcium, and "familial" means it runs in families.

The most important thing to understand up front is that FHH is generally a benign, stable condition. The vast majority of people who have it feel completely well, never develop symptoms, and never need treatment. It is sometimes even called "familial benign hypercalcemia." It does not progress or worsen over time, which is why doctors describe it as "lifelong non-progressive."

Why does it happen? The body's calcium thermostat

Calcium in the blood is kept within a narrow range by a tightly controlled system. A key part of that system is a molecular sensor called the calcium-sensing receptor (CaSR), which sits on the surface of cells in the parathyroid glands (four small glands in the neck) and the kidneys. Think of this receptor as the body's calcium thermostat. It constantly measures the calcium level and signals the parathyroid glands to release more or less parathyroid hormone (PTH), the hormone that raises blood calcium, and tells the kidneys how much calcium to hold onto or release into the urine.

In FHH, a change (a genetic variant, or mutation) makes this thermostat slightly less sensitive to calcium. As a result, the body behaves as though the normal calcium level is "too low" and settles at a new, slightly higher set point. The parathyroid glands keep releasing a normal or near-normal amount of PTH even though calcium is already a bit high, and the kidneys hold onto extra calcium rather than spilling it into the urine. This explains the condition's two signature features at the same time: higher blood calcium and lower urine calcium. Magnesium in the blood may also run on the higher side for the same reason.

There are three closely related forms, caused by variants in three different genes that all affect this same calcium-sensing pathway:

• FHH type 1 is caused by changes in the CASR gene (the gene for the calcium-sensing receptor itself). This is by far the most common form, accounting for roughly 85% of cases.

• FHH type 2 is caused by changes in the GNA11 gene. This is the rarest form.

• FHH type 3 is caused by changes in the AP2S1 gene. This form can sometimes produce a somewhat more pronounced picture, with higher calcium levels.

How is FHH inherited?

FHH follows what is called an autosomal dominant pattern. In practical terms, this means:

• A person needs only one copy of the altered gene (inherited from one parent) to have the condition.

• Each child of an affected parent has about a 50% chance of inheriting the variant.

• It affects men and women equally, and the condition is often found in multiple generations of the same family.

Because of this inheritance pattern, when one person is diagnosed, their close blood relatives often turn out to have the same mildly high calcium, sometimes discovered only after the first person in the family is identified.

One special situation involves newborns. The combination of genes inherited from both parents matters: a baby who inherits the variant from an affected father while the mother is unaffected may have more noticeable high calcium in the newborn period, and in the rare case where a baby inherits an altered gene from both parents, a much more serious infant condition can occur. Although these situations are uncommon, they are the reason family and pregnancy planning are often part of the conversation once FHH is diagnosed.

How is FHH usually discovered?

Most people with FHH have no symptoms at all, so it is very often found by accident. A routine blood test, perhaps done for an unrelated reason, shows a calcium level that is a little high, and the investigation that follows eventually points to FHH. Because the high calcium is mild and stable, many people have had it for years without knowing.

When symptoms do occur, they are uncommon and tend to arise only in the minority of people whose calcium is at the higher end. These can include increased thirst and urination, tiredness, and, rarely, problems such as inflammation of the pancreas (pancreatitis) or calcium deposits in cartilage. Again, these are the exception rather than the rule. The typical experience of FHH is to feel entirely normal.

Why getting the right diagnosis matters

The single most important reason FHH is worth identifying correctly is that its blood picture can look very similar to a far more common condition called primary hyperparathyroidism (PHPT). Both conditions show high blood calcium with a normal or elevated PTH level, which makes FHH one of several conditions that can mimic hyperparathyroidism. The crucial difference is that PHPT is often treated with surgery to remove an overactive parathyroid gland, whereas in FHH surgery does not fix the high calcium and is generally the wrong approach. Correctly telling the two apart prevents an unnecessary operation.

Doctors use several tools to distinguish them:

• Urine calcium testing. The hallmark of FHH is low calcium in the urine, usually measured with a 24-hour urine calcium test. This is often expressed as the calcium-to-creatinine clearance ratio (CCCR), a calculation that compares calcium and creatinine in the blood and urine. A ratio below 0.01 points toward FHH, while a ratio above 0.02 points toward primary hyperparathyroidism; values in between fall into a "gray zone" that is harder to interpret. This test is not perfect (about 1 in 5 people with FHH can have a ratio above 0.01), so it is used as a guide rather than a final answer.

• A careful family history, since FHH frequently appears in relatives.

• Genetic testing of the CASR, AP2S1, and GNA11 genes, which can confirm the diagnosis when the blood and urine results are not clear-cut. Confirming the diagnosis genetically can spare a person from an operation that would not help.

It is worth noting that some everyday factors, including certain medications (such as thiazide-type water pills or lithium) and vitamin D status, can also affect calcium levels and test results, so clinicians take these into account when interpreting the numbers. Physicians can find the diagnostic criteria, including how FHH is ruled out, on the hyperparathyroidism workup page.

How common is FHH?

FHH is considered rare, though it is probably underdiagnosed because so many people have no symptoms. Traditional estimates range from roughly 1 in 10,000 to 1 in 100,000 people, but studies that screen large populations by their genes suggest it may be considerably more common than those older figures imply.

The bottom line

FHH is a lifelong but generally harmless genetic condition in which a slightly "recalibrated" calcium thermostat keeps blood calcium mildly high and urine calcium low. It runs in families, affects both sexes, and most often causes no symptoms. Its greatest practical importance is making sure it is not mistaken for primary hyperparathyroidism, so that unnecessary surgery can be avoided. Most people with FHH require no treatment at all; monitoring and the uncommon situations that might call for treatment are separate topics.