Familial Hypocalciuric Hypercalcemia

Introduction:

Familial hypocalciuric hypercalcemia is an inherited disorder characterized by high serum calcium levels and low to moderate urine calcium levels. Patients with this condition are usually asymptomatic and are diagnosed by chance. In some cases, they may present with considerable symptoms that need immediate management. The age of onset at which the symptoms start to appear varies from person to person.

What Is Familial Hypocalciuric Hypercalcemia?

Familial hypocalciuric hypercalcemia is an autosomal dominant condition caused due to a mutation in the calcium-sensing receptor gene (CaSR). This, in turn, decreases the receptor activity resulting in abnormally increased serum calcium levels (hypercalcemia).

What Is Autosomal Dominant Inheritance Pattern?

The autosomal dominant inheritance pattern is when only a single copy of a mutated gene is present in any one of the parents or as a result of a new mutation in the affected individual. The chance of transmitting the disease from one generation to another in each pregnancy is 50 %.

What Is the Epidemiology of Familial Hypocalciuric Hypercalcemia?

Familial hypocalciuric hypercalcemia is a rare disorder with a prevalence of one in 78,000 worldwide. There is no suggested gender predilection.

What Are the Types of Familial Hypocalciuric Hypercalcemia?

There are three types of familial hypocalciuric hypercalcemia based on the type of mutation; it is as follows:

• Familial Hypocalciuric Hypercalcemia Type 1 - Mutation in CaSR (calcium-sensing receptor) gene.

• Familial Hypocalciuric Hypercalcemia Type 2 - Mutation in GNA11 gene (Guanine nucleotide-binding protein subunit alpha-11).

• Familial Hypocalciuric Hypercalcemia Type 3 - Mutation in AP2S1 gene (adaptor-related protein complex two subunit sigma 1).

What Is the Etiology of Familial Hypocalciuric Hypercalcemia?

• The primary etiology of familial hypocalciuric hypercalcemia is the loss of function mutation in the calcium-sensing receptor genes in 85 % of cases. The CaSR gene is located in the long arm of chromosome three. It shows a benign clinical course in patients with a heterozygous mutation with mild hypercalcemia, whereas, in patients with a homozygous mutation, there is a severe increase in serum calcium levels with dominant features of hyperparathyroidism.

• The genes responsible for familial hypocalciuric hypercalcemia type 2 and type 3 are located in chromosome 19q13, which is called the Oklahoma variant.

• A few percent of cases occur due to autoimmune reactions, where autoantibodies are directed against the calcium-sensing receptors, thus affecting them.

What Are Calcium Sensing Receptors?

The CaSR gene provides instructions for making a protein called the calcium-sensing receptor. These receptors are mainly expressed in the kidney and the parathyroid glands. Calcium molecules attach to this receptor and control and monitor the calcium levels in the blood. The functions of CaSR include regulating parathyroid hormone secretion and mediating renal tubular calcium reabsorption.

What Is the Pathophysiology of Familial Hypocalciuric Hypercalcemia?

Calcium sensing receptors are expressed in the kidneys, parathyroid gland, thyroid C cells, intestine, and bone. It is essential for regulating serum calcium levels. The mutations in the calcium-sensing receptor gene would reduce the receptor's calcium sensitivity, thereby reducing the receptor stimulation. The parathyroid glands become less sensitive to calcium receptors, thus increasing the serum calcium levels. In the kidneys, it would result in excessive tubular reabsorption of calcium and magnesium. These changes would result in hypercalcemia, hypocalciuria, and hypermagnesemia.

What Are the Symptoms of Familial Hypocalciuric Hypercalcemia?

Familial hypocalciuric hypercalcemia symptoms include:

• Weakness.

• Headache.

• Fatigue.

• Constipation.

• Polyuria (increased urine production).

• Polydipsia (increased thirst).

• Renal insufficiency.

• Mental disturbances.

• Confusion.

• Chondrocalcinosis (a type of arthritis).

• Pancreatitis (inflammation of the pancreas).

• Intraductal calcifications.

What Are the Laboratory Signs of Familial Hypocalciuric Hypercalcemia?

The laboratory signs include the following:

• Hypercalcemia - Increase in serum calcium levels.

• Hypocalciuria - Decreased excretion of calcium in the urine.

• Hypermagnesemia - Increased serum magnesium levels.

• Hyperparathyroidism - Increased serum parathyroid hormone levels.

How Is Familial Hypocalciuric Hypercalcemia Diagnosed?

History:

A thorough medical and family history should be collected from the patient. Symptoms of the disease, along with laboratory findings, would help in framing the diagnosis of the condition. Family history would also identify the genetic link in families.

Physical Examination:

Physical examination of the patient for vital signs and to confirm the symptomatic history, such as mental disturbances, weakness, etc., would help in further planning.

Blood Test:

• Serum Calcium Levels - This would indicate increased serum calcium levels (hypercalcemia).

• Serum Magnesium Levels - This would indicate increased serum magnesium levels (hypermagnesemia).

• Serum Parathyroid Hormone Levels - This would indicate an increase in serum parathyroid hormone levels (hyperparathyroidism).

• Vitamin D Levels - Vitamin D levels might be decreased in patients with PTH-dependent hypocalciuric hypercalcemia.

Urine Test:

• Urinary Calcium - Decreased excretion of calcium in the urine (hypocalciuria).

• 24-Hour Urinary Calcium Excretion - This would reveal the 24-hour urinary excretion values of less than 100 mg/24 hours.

• Calcium-Creatinine Clearance Ratio (CCCR) - It would indicate values less than 0. 01 in 80 % of cases with this condition.

GeneticTest:

Genetic studies would help identify the type of gene mutated in the condition and tell us the type of familial hypocalciuric hypercalcemia.

What Are the Differential Diagnosis of Familial Hypocalciuric Hypercalcemia?

• Adrenal Insufficiency - This occurs as a result of insufficient adrenal hormone secretion, which exhibits similar symptoms as that of familial hypocalciuric hypercalcemia.

• Granulomatous Disease - This is characterized by the inability of the white blood cells to exhibit defensive activity.

• Osteolytic Metastasis - This is characterized by the breakdown or weakening of the bone.

• Primary Hyperparathyroidism - This is characterized by the increased parathyroid hormone in the blood.

What Distinguishes Primary Hyperparathyroidism (PHPT) From Familial Hypocalciuric Hypercalcemia (FHH)?

It is possible to misdiagnose FHH as PHPT because both conditions can cause hypercalcemia.

Parathyroid hormone levels are normal or elevated in FHH, but in PHPT, they are above average.

Patients with FHH have GNA11 (G protein subunit alpha 11), AP2S1 (adaptor-related protein complex 2 subunit sigma 1), or CaSR (calcium-sensing receptor) gene mutations.

How Is Familial Hypocalciuric Hypercalcemia Managed?

• Patients with familial hypocalciuric hypercalcemia usually do not need any treatment as they do not develop complications from this disorder.

• Treatment measures are indicated in patients developing pancreatitis as a result of this condition. In those cases, total parathyroidectomy is advised to reduce further episodes of pancreatitis.

• CaSR antagonists, such as calcimimetics and calcilytics, are used to improve the sensitivity of the calcium-sensing receptors.

What Are the Complications of FHH?

Complications include severe hyperparathyroidism in newborns, polyuria (increased urination), abnormalities in bone causing fractures, and hypotonia (reduction of muscle tone). Occasionally, adults may endure challenges that arise due to hypercalcemia (increased calcium level in blood).

What Is the Prognosis?

Like other hypercalcemia syndromes, FHH has a favorable prognosis without any permanent complications.

Conclusion:

Familial hypocalciuric hypercalcemia is a rare autosomal dominant condition. It is a benign condition that usually does not develop complications. The patients and their family members should be properly educated and reassured about the benign nature of the condition as it avoids unnecessary surgical interventions and mental pressure. It should be differentiated from other conditions with similar symptoms and laboratory findings. The prognosis of this condition is reported to be good if the calcium levels are stable.