Familial isolated hyperparathyroidism

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Familial isolated hyperparathyroidism is an inherited condition that is characterized by overactive parathyroid glands (hyperparathyroidism). The four parathyroid glands are located in the neck. They release a hormone called parathyroid hormone that regulates the amount of calcium in the blood.

In people with familial isolated hyperparathyroidism, too much parathyroid hormone is produced, and levels of calcium in the blood become elevated (hypercalcemia). Hypercalcemia causes many of the common signs and symptoms of familial isolated hyperparathyroidism, such as kidney stones, nausea, vomiting, high blood pressure (hypertension), thinning of the bones (osteoporosis), weakness, and fatigue.

Many people with familial isolated hyperparathyroidism have one or more noncancerous (benign) tumors called adenomas. Typically, only one of the four parathyroid glands is affected, but sometimes more than one gland has an adenoma. Rarely, the tumor can become cancerous; this is called parathyroid carcinoma.

In some cases, familial isolated hyperparathyroidism may not be diagnosed until adulthood. Often, the first indication of the condition is elevated calcium levels that are identified during a routine blood test, even though the affected individual may not yet have signs or symptoms of hyperparathyroidism or hypercalcemia.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Familial isolated hyperparathyroidism can be caused by variants (also called mutations) in the MEN1, CDC73, or CASR gene. Certain variants in the GCM2 gene may increase the risk of developing familial isolated hyperparathyroidism.

The MEN1 and CDC73 genes provide instructions for making proteins that act as tumor suppressors. Tumor suppressors keep cells from growing and dividing (proliferating) too fast or in an uncontrolled way. In people with familial isolated hyperparathyroidism, variants in either of these genes lead to the production of an altered protein that cannot effectively control cell growth and division. The resulting increase in cell proliferation can cause one or more of the parathyroid glands to become enlarged (hyperplasia) or to develop an adenoma.

The adenomas or enlarged parathyroid glands stimulate the overproduction of parathyroid hormone, which triggers the release of too much calcium into the blood. This excess calcium causes the characteristic features of familial isolated hyperparathyroidism.

The CASR gene provides instructions for producing a protein called the calcium-sensing receptor (CaSR), which helps regulate the amount of calcium in the blood. In parathyroid gland cells, when calcium binds to the CaSR protein, the CaSR protein sends a signal that blocks the production and release of parathyroid hormone. Without parathyroid hormone, calcium is not released into the blood. The CASR gene variants that are associated with familial isolated hyperparathyroidism cause cells to produce a version of the CaSR protein that requires higher levels of calcium to trigger the signaling that blocks hormone production. As a result, parathyroid hormone is produced even when calcium levels are elevated, which leads to hyperparathyroidism, hypercalcemia, and the other features seen in people with familial isolated hyperparathyroidism.

The GCM2 gene provides instruction for making a protein that helps regulate the amount of parathyroid hormone that is produced. Certain variants in this gene cause cells to produce a version of the GCM2 protein that allows more parathyroid hormone to be produced. As a result, more calcium could be released into the blood, causing people to have an increased risk of developing the signs and symptoms of familial isolated hyperparathyroidism.

Many individuals with the signs and symptoms of familial isolated hyperparathyroidism do not have an identified variant in the associated genes, indicating that other genes may be involved in the development of this condition. The genetic cause in these cases is unknown.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

The prevalence of familial isolated hyperparathyroidism is unknown. The condition accounts for 1 percent of all cases where the parathyroid glands produce too much parathyroid hormone (primary hyperparathyroidism).

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Chondrocalcinosis · Very frequent (99-80%)

Radiographic evidence of articular calcification that represent calcium pyrophosphate depositions in soft tissue surrounding joints and at the insertions of tendons near joints (Entheses/Sharpey fibers) .

Elevated circulating parathyroid hormone level · Very frequent (99-80%)

An abnormal increased concentration of parathyroid hormone.

Hypercalcemia · Very frequent (99-80%)

The concentration of calcium in the blood circulation is above the upper limit of normal.

Hyperphosphaturia · Very frequent (99-80%)

An increased excretion of phosphates in the urine.

Hypophosphatemia · Very frequent (99-80%)

The concentration of phosphate ion in the blood circulation is below the lower limit of normal.

Nephrocalcinosis · Very frequent (99-80%)

Nephrocalcinosis is the deposition of calcium salts in renal parenchyma.

Osteopenia · Very frequent (99-80%)

Osteopenia is a term to define bone density that is not normal but also not as low as osteoporosis. By definition from the World Health Organization osteopenia is defined by bone densitometry as a T score -1 to -2.5.

Parathyroid adenoma · Very frequent (99-80%)

A benign tumor of the parathyroid gland that can cause hyperparathyroidism.

Other findings in the same source

From: Orphanet

Additional reported features include Primary hyperparathyroidism (Very frequent (99-80%)); Generalized osteoporosis (Very frequent (99-80%)); Hypercalciuria (Very frequent (99-80%)); Abdominal symptom (Occasional (29-5%)); Renal insufficiency (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Familial isolated hyperparathyroidism is Endocrinology, with a endocrinologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which hormone or metabolic finding is important in this case?
• How should test timing and current medicines be taken into account?
• What follow-up would show whether the care plan is working?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Familial isolated hyperparathyroidism. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.