Idiopathic infantile hypercalcemia

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 (failure to thrive). 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, failure to thrive, 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.

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

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.

Genetic Testing Information

• Genetic Testing Registry: Autosomal recessive infantile hypercalcemia

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Clinical Trials

• ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

• HYPERCALCEMIA, INFANTILE, 1; HCINF1
• HYPERCALCEMIA, INFANTILE, 2; HCINF2

Scientific Articles on PubMed

• PubMed

• Carpenter TO. CYP24A1 loss of function: Clinical phenotype of monoallelic and biallelic mutations. J Steroid Biochem Mol Biol. 2017 Oct;173:337-340. doi: 10.1016/j.jsbmb.2017.01.006. Epub 2017 Jan 16. Citation on PubMed
• Cools M, Goemaere S, Baetens D, Raes A, Desloovere A, Kaufman JM, De Schepper J, Jans I, Vanderschueren D, Billen J, De Baere E, Fiers T, Bouillon R. Calcium and bone homeostasis in heterozygous carriers of CYP24A1 mutations: A cross-sectional study. Bone. 2015 Dec;81:89-96. doi: 10.1016/j.bone.2015.06.018. Epub 2015 Jun 25. Citation on PubMed
• Figueres ML, Linglart A, Bienaime F, Allain-Launay E, Roussey-Kessler G, Ryckewaert A, Kottler ML, Hourmant M. Kidney function and influence of sunlight exposure in patients with impaired 24-hydroxylation of vitamin D due to CYP24A1 mutations. Am J Kidney Dis. 2015 Jan;65(1):122-6. doi: 10.1053/j.ajkd.2014.06.037. Epub 2014 Nov 4. Citation on PubMed
• Pronicka E, Ciara E, Halat P, Janiec A, Wojcik M, Rowinska E, Rokicki D, Pludowski P, Wojciechowska E, Wierzbicka A, Ksiazyk JB, Jacoszek A, Konrad M, Schlingmann KP, Litwin M. Biallelic mutations in CYP24A1 or SLC34A1 as a cause of infantile idiopathic hypercalcemia (IIH) with vitamin D hypersensitivity: molecular study of 11 historical IIH cases. J Appl Genet. 2017 Aug;58(3):349-353. doi: 10.1007/s13353-017-0397-2. Epub 2017 May 3. Citation on PubMed or Free article on PubMed Central
• Schlingmann KP, Kaufmann M, Weber S, Irwin A, Goos C, John U, Misselwitz J, Klaus G, Kuwertz-Broking E, Fehrenbach H, Wingen AM, Guran T, Hoenderop JG, Bindels RJ, Prosser DE, Jones G, Konrad M. Mutations in CYP24A1 and idiopathic infantile hypercalcemia. N Engl J Med. 2011 Aug 4;365(5):410-21. doi: 10.1056/NEJMoa1103864. Epub 2011 Jun 15. Citation on PubMed
• Schlingmann KP, Ruminska J, Kaufmann M, Dursun I, Patti M, Kranz B, Pronicka E, Ciara E, Akcay T, Bulus D, Cornelissen EA, Gawlik A, Sikora P, Patzer L, Galiano M, Boyadzhiev V, Dumic M, Vivante A, Kleta R, Dekel B, Levtchenko E, Bindels RJ, Rust S, Forster IC, Hernando N, Jones G, Wagner CA, Konrad M. Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia. J Am Soc Nephrol. 2016 Feb;27(2):604-14. doi: 10.1681/ASN.2014101025. Epub 2015 Jun 5. Citation on PubMed or Free article on PubMed Central