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Hypercalcemia, infantile, 2(HCINF2)

MedGen UID:: 934441
•Concept ID:: C4310473
•: Disease or Syndrome

Synonym:	HCINF2

Gene (location): Gene(s) directly associated with this condition or phenotype.	SLC34A1 (5q35.3)

Monarch Initiative:	MONDO:0014851
OMIM®:	616963

Definition

Infantile hypercalcemia is characterized by severe hypercalcemia with failure to thrive, vomiting, dehydration, and nephrocalcinosis (summary by Schlingmann et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of infantile hypercalcemia, see HCINF1 (143880). [from OMIM]

Clinical features

From HPO

Hypercalciuria

MedGen UID:: 43775
•Concept ID:: C0020438
•: Finding

Abnormally high level of calcium in the urine.

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Nephrocalcinosis

MedGen UID:: 10222
•Concept ID:: C0027709
•: Disease or Syndrome

Nephrocalcinosis is the deposition of calcium salts in renal parenchyma.

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Polyuria

MedGen UID:: 19404
•Concept ID:: C0032617
•: Sign or Symptom

An increased rate of urine production.

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Medullary nephrocalcinosis

MedGen UID:: 588418
•Concept ID:: C0403477
•: Disease or Syndrome

The deposition of calcium salts in the parenchyma of the renal medulla (innermost part of the kidney).

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Renal phosphate wasting

MedGen UID:: 335116
•Concept ID:: C1845169
•: Finding

High urine phosphate in the presence of hypophosphatemia.

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Failure to thrive

MedGen UID:: 746019
•Concept ID:: C2315100
•: Disease or Syndrome

Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.

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Hypotonia

MedGen UID:: 10133
•Concept ID:: C0026827
•: Finding

Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.

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Hypercalcemia

MedGen UID:: 5686
•Concept ID:: C0020437
•: Disease or Syndrome

An abnormally increased calcium concentration in the blood.

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Hypophosphatemia

MedGen UID:: 39327
•Concept ID:: C0085682
•: Disease or Syndrome

An abnormally decreased phosphate concentration in the blood.

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Abnormality of metabolism/homeostasis
- Hypercalcemia
- Hypophosphatemia
Abnormality of the genitourinary system
Abnormality of the musculoskeletal system
- Hypotonia
Growth abnormality
- Failure to thrive

Professional guidelines

PubMed

Bisphosphonates for treatment of severe idiopathic infantile hypercalcemia.

Hooman N
Iran J Kidney Dis 2013 Mar;7(2):79-81. PMID: 23485530

Infantile hypercalcemia and hypercalciuria: new insights into a vitamin D-dependent mechanism and response to ketoconazole treatment.

Nguyen M, Boutignon H, Mallet E, Linglart A, Guillozo H, Jehan F, Garabedian M
J Pediatr 2010 Aug;157(2):296-302. Epub 2010 Apr 14 doi: 10.1016/j.jpeds.2010.02.025. PMID: 20394945

Williams syndrome: from genotype through to the cognitive phenotype.

Donnai D, Karmiloff-Smith A
Am J Med Genet 2000 Summer;97(2):164-71. doi: 10.1002/1096-8628(200022)97:2<164::aid-ajmg8>3.0.co;2-f. PMID: 11180224

See all (4)

Recent clinical studies

Etiology

When to suspect infantile hypercalcemia-1?

Brancatella A, Cappellani D, Pierotti L, Dinoi E, Sardella C, Borsari S, Piaggi P, Baldinotti F, Caligo MA, Marcocci C, Cetani F
J Endocrinol Invest 2024 Sep;47(9):2305-2312. Epub 2024 Feb 8 doi: 10.1007/s40618-024-02312-7. PMID: 38329607

Idiopathic infantile hypercalcemia in children with chronic kidney disease due to kidney hypodysplasia.

Gurevich E, Borovitz Y, Levi S, Perlman S, Landau D
Pediatr Nephrol 2023 Apr;38(4):1067-1073. Epub 2022 Sep 26 doi: 10.1007/s00467-022-05740-w. PMID: 36156733

Hypercalcemia due to CYP24A1 mutations: a systematic descriptive review.

Cappellani D, Brancatella A, Morganti R, Borsari S, Baldinotti F, Caligo MA, Kaufmann M, Jones G, Marcocci C, Cetani F
Eur J Endocrinol 2021 Dec 10;186(2):137-149. doi: 10.1530/EJE-21-0713. PMID: 34735369

Mild Idiopathic Infantile Hypercalcemia-Part 2: A Longitudinal Observational Study.

Lenherr-Taube N, Furman M, Assor E, Elia Y, Collins C, Thummel K, Levine MA, Sochett E
J Clin Endocrinol Metab 2021 Sep 27;106(10):2938-2948. doi: 10.1210/clinem/dgab432. PMID: 34139759 Free PMC Article

Renal phosphate handling and inherited disorders of phosphate reabsorption: an update.

Wagner CA, Rubio-Aliaga I, Hernando N
Pediatr Nephrol 2019 Apr;34(4):549-559. Epub 2017 Dec 23 doi: 10.1007/s00467-017-3873-3. PMID: 29275531

See all (25)

Diagnosis

When to suspect infantile hypercalcemia-1?

Genetic causes of neonatal and infantile hypercalcaemia.

Gorvin CM
Pediatr Nephrol 2022 Feb;37(2):289-301. Epub 2021 May 14 doi: 10.1007/s00467-021-05082-z. PMID: 33990852 Free PMC Article

Presymptomatic diagnosis of CYP24A1-related infantile idiopathic hypercalcemia: A case report.

Mirea AM, Pop RM, Căinap SS, Trifa AP
Eur J Med Genet 2020 Dec;63(12):104100. Epub 2020 Nov 10 doi: 10.1016/j.ejmg.2020.104100. PMID: 33186763

Genetic Diseases of Vitamin D Metabolizing Enzymes.

Jones G, Kottler ML, Schlingmann KP
Endocrinol Metab Clin North Am 2017 Dec;46(4):1095-1117. Epub 2017 Oct 5 doi: 10.1016/j.ecl.2017.07.011. PMID: 29080636

Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia.

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
J Am Soc Nephrol 2016 Feb;27(2):604-14. Epub 2015 Jun 5 doi: 10.1681/ASN.2014101025. PMID: 26047794 Free PMC Article

See all (42)

Therapy

Antenatal presentation and early postnatal treatment of infantile hypercalcemia type 2.

Verjans M, Hindryckx A, Rosier K, Devriendt K, Mekahli D, Bockenhauer D
Pediatr Nephrol 2024 Oct;39(10):2911-2913. Epub 2024 May 16 doi: 10.1007/s00467-024-06403-8. PMID: 38753084

Rifampin monotherapy for children with idiopathic infantile hypercalcemia.

Lenherr-Taube N, Furman M, Assor E, Thummel K, Levine MA, Sochett E
J Steroid Biochem Mol Biol 2023 Jul;231:106301. Epub 2023 Mar 27 doi: 10.1016/j.jsbmb.2023.106301. PMID: 36990163 Free PMC Article

Mild Idiopathic Infantile Hypercalcemia-Part 2: A Longitudinal Observational Study.

Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects.

Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G
Physiol Rev 2016 Jan;96(1):365-408. doi: 10.1152/physrev.00014.2015. PMID: 26681795 Free PMC Article

Infantile hypercalcemia and hypercalciuria: new insights into a vitamin D-dependent mechanism and response to ketoconazole treatment.

Nguyen M, Boutignon H, Mallet E, Linglart A, Guillozo H, Jehan F, Garabedian M
J Pediatr 2010 Aug;157(2):296-302. Epub 2010 Apr 14 doi: 10.1016/j.jpeds.2010.02.025. PMID: 20394945

See all (30)

Prognosis

Antenatal presentation and early postnatal treatment of infantile hypercalcemia type 2.

Verjans M, Hindryckx A, Rosier K, Devriendt K, Mekahli D, Bockenhauer D
Pediatr Nephrol 2024 Oct;39(10):2911-2913. Epub 2024 May 16 doi: 10.1007/s00467-024-06403-8. PMID: 38753084

Early vs late initiation of sodium glycerophosphate: Impact on hypophosphatemia in preterm infants <32 weeks.

Ozer Bekmez B, Oguz SS
Clin Nutr 2022 Feb;41(2):415-423. Epub 2021 Dec 10 doi: 10.1016/j.clnu.2021.12.011. PMID: 35007810

Renal phosphate handling and inherited disorders of phosphate reabsorption: an update.

Wagner CA, Rubio-Aliaga I, Hernando N
Pediatr Nephrol 2019 Apr;34(4):549-559. Epub 2017 Dec 23 doi: 10.1007/s00467-017-3873-3. PMID: 29275531

Childhood Sustained Hypercalcemia: A Diagnostic Challenge.

Çullas İlarslan NE, Şıklar Z, Berberoğlu M
J Clin Res Pediatr Endocrinol 2017 Dec 15;9(4):315-322. Epub 2017 Apr 26 doi: 10.4274/jcrpe.4247. PMID: 28443817 Free PMC Article

Mild infantile hypercalcemia: diagnostic tests and outcomes.

Koltin D, Rachmiel M, Wong BY, Cole DE, Harvey E, Sochett E
J Pediatr 2011 Aug;159(2):215-21.e1. Epub 2011 Mar 17 doi: 10.1016/j.jpeds.2011.01.035. PMID: 21414629

See all (19)

Clinical prediction guides

Idiopathic infantile hypercalcemia in children with chronic kidney disease due to kidney hypodysplasia.

Gurevich E, Borovitz Y, Levi S, Perlman S, Landau D
Pediatr Nephrol 2023 Apr;38(4):1067-1073. Epub 2022 Sep 26 doi: 10.1007/s00467-022-05740-w. PMID: 36156733

Mild Idiopathic Infantile Hypercalcemia-Part 2: A Longitudinal Observational Study.

Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects.

Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G
Physiol Rev 2016 Jan;96(1):365-408. doi: 10.1152/physrev.00014.2015. PMID: 26681795 Free PMC Article

Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia.

Williams syndrome: from genotype through to the cognitive phenotype.

Donnai D, Karmiloff-Smith A
Am J Med Genet 2000 Summer;97(2):164-71. doi: 10.1002/1096-8628(200022)97:2<164::aid-ajmg8>3.0.co;2-f. PMID: 11180224

See all (20)