Idiopathic infantile hypercalcemia

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Idiopathic infantile hypercalcemia is a condition characterized by high levels of calcium in the blood (hypercalcemia). Two types of idiopathic infantile hypercalcemia have been identified and are distinguished by their genetic causes: infantile hypercalcemia 1 and infantile hypercalcemia 2. In infants with either type, hypercalcemia can cause vomiting, increased urine production (polyuria), dehydration, constipation, poor feeding, weight loss, and an inability to grow and gain weight as expected (faltering weight). As they age, affected babies usually have delayed development of mental and movement abilities (psychomotor delay). Individuals with infantile hypercalcemia 1 or 2 may also have high levels of calcium in their urine (hypercalciuria) and deposits of calcium in their kidneys (nephrocalcinosis).

With treatment, the outward symptoms of hypercalcemia, such as vomiting, dehydration, faltering weight, and psychomotor delay, usually improve in childhood. However, affected children still tend to have higher-than-normal amounts of calcium in their blood and urine and calcium deposits in their kidneys. By adulthood, long-term hypercalcemia and hypercalciuria can lead to the formation of kidney stones (nephrolithiasis) and may damage the kidneys and impair their function. Affected adults may also develop calcium deposits in the joints or in the clear outer covering of the eye (the cornea), and some have low bone mineral density (osteoporosis).

In rare cases, affected individuals do not have symptoms of hypercalcemia in infancy, and the condition begins in later childhood or adulthood. These individuals usually develop hypercalciuria, nephrocalcinosis, and nephrolithiasis, although the features may not cause any obvious health problems.

Although most signs and symptoms are similar between the two known types of idiopathic infantile hypercalcemia, individuals with infantile hypercalcemia 2 have low levels of a mineral called phosphate in the blood (hypophosphatemia), while phosphate levels are typically normal in people with infantile hypercalcemia 1.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

The two known types of idiopathic infantile hypercalcemia are caused by mutations in different genes. Infantile hypercalcemia 1 is caused by CYP24A1 gene mutations, and infantile hypercalcemia 2 is caused by SLC34A1 gene mutations. Both genes help maintain the proper balance of calcium or phosphate in the body, a process that can involve vitamin D. When turned on (active), this vitamin stimulates the absorption of both phosphate and calcium from the intestines into the bloodstream. Vitamin D can be acquired from foods in the diet or made in the body with help from sunlight exposure.

The enzyme produced from the CYP24A1 gene helps control the amount of active vitamin D in the body. This enzyme, called 24-hydroxylase, helps break down active vitamin D when it is no longer needed, for example when the proper balance of calcium or phosphate in the body is reached. Mutations in the CYP24A1 gene reduce or eliminate the activity of the 24-hydroxylase enzyme, which impairs the breakdown of active vitamin D.

The amount of phosphate in the body can also be maintained through reabsorption of the mineral in the kidneys so that it is not removed in urine. Reabsorption occurs by transport of the mineral through special channels formed from a protein called sodium-dependent phosphate transporter 2A (NaPi-IIa), which is produced from the SLC34A1 gene. Mutations in the SLC34A1 gene prevent the NaPi-IIa channels from transporting phosphate, reducing the amount of phosphate in the body. To increase phosphate levels, vitamin D is activated.

Mutations in either the CYP24A1 or SLC34A1 gene result in too much active vitamin D in the body. This excess increases calcium absorption into the bloodstream, causing hypercalcemia. The abnormal balance of calcium leads to high levels of the mineral in urine and can result in deposition of calcium in the kidneys and the formation of kidney stones.

It is thought that other factors, such as the amount of calcium in the diet, vitamin D supplementation, or prolonged sunlight exposure can influence the development and severity of signs and symptoms in affected individuals.

Some people with idiopathic infantile hypercalcemia do not have mutations in the CYP24A1 or SLC34A1 gene. The cause of the condition in these cases is unknown. Other genes that have not been identified may be involved in development of the condition.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Infantile hypercalcemia types 1 and 2 are thought to be inherited in an autosomal recessive pattern, which means both copies of the respective gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. In some instances, individuals with one copy of the mutated gene have higher-than-normal levels of calcium in their blood or urine and may be more likely to develop kidney stones, but they do not typically have early, severe symptoms of infantile hypercalcemia 1 or 2. Nongenetic factors, such as the amount of calcium in the diet, vitamin D supplementation, or prolonged sunlight exposure, may influence whether signs and symptoms develop in individuals with one altered copy of the gene.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Infantile hypercalcemia 1 and 2 are thought to be rare conditions, although their prevalence is unknown.

Which doctor should you see?

The suggested department for discussing Idiopathic infantile hypercalcemia 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

Where the source describes treatments, these are an overview of possible care, not a prescription for an individual. Ask which option applies to the confirmed diagnosis, what benefit is expected, what adverse effects to watch for and how progress will be assessed. Availability, approvals and local practice can differ from the country described in the source.

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.