Infantile hypercalcemia is a rare phosphocalcic metabolism disorder caused by pathogenic variants in CYP24A1 or SLC34A1. CYP24A1 loss of function impairs degradation of active vitamin D metabolites, while SLC34A1 loss of function causes renal phosphate wasting that drives inappropriate 1,25-dihydroxyvitamin D3 generation. Both mechanisms converge on PTH-independent hypercalcemia, hypercalciuria, nephrocalcinosis, failure to thrive, vomiting, dehydration, polyuria, constipation, hypotonia, and a risk of chronic kidney disease in survivors.
Ask a research question about Infantile Hypercalcemia. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).
Do not include personal health information in your question. Questions and results are cached in your browser's local storage.
name: Infantile Hypercalcemia
category: Mendelian
creation_date: '2026-05-03T00:00:00Z'
updated_date: '2026-05-20T11:03:06Z'
synonyms:
- Autosomal recessive infantile hypercalcemia
- Familial infantile hypercalcemia with suppressed intact parathyroid hormone
- Idiopathic infantile hypercalcemia
- Idiopathic infantile hypercalcaemia
- Infantile hypercalcaemia
- Hypersensitivity to vitamin D3
- Infantile hypercalcemia type 1
- Infantile hypercalcemia type 2
- IIH
- IIH type 1
- IIH type 2
- HCINF1
description: >
Infantile hypercalcemia is a rare phosphocalcic metabolism disorder caused by
pathogenic variants in CYP24A1 or SLC34A1. CYP24A1 loss of function impairs
degradation of active vitamin D metabolites, while SLC34A1 loss of function
causes renal phosphate wasting that drives inappropriate 1,25-dihydroxyvitamin
D3 generation. Both mechanisms converge on PTH-independent hypercalcemia,
hypercalciuria, nephrocalcinosis, failure to thrive, vomiting, dehydration,
polyuria, constipation, hypotonia, and a risk of chronic kidney disease in
survivors.
disease_term:
preferred_term: hypercalcemia, infantile
term:
id: MONDO:0000212
label: hypercalcemia, infantile
parents:
- Inborn Error of Metabolism
- Phosphocalcic Metabolism Disorder
- Renal Tubulopathy
inheritance:
- name: Autosomal recessive
description: >
Orphanet describes autosomal recessive inheritance for infantile
hypercalcemia, and the original CYP24A1 and SLC34A1 reports identified
recessive disease-causing variants. Later cohorts also report some
monoallelic variants in clinically compatible patients, suggesting a broader
susceptibility spectrum.
evidence:
- reference: ORPHA:300547
supports: SUPPORT
snippet: "Autosomal recessive"
explanation: Orphanet reports autosomal recessive inheritance.
- reference: PMID:21675912
reference_title: "Mutations in CYP24A1 and idiopathic infantile hypercalcemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "revealed recessive mutations in six affected children."
explanation: The original CYP24A1 study identified recessive variants in affected children.
- reference: PMID:26047794
reference_title: "Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "cotransporter 2A (NaPi-IIa), revealed autosomal-recessive mutations in the four"
explanation: The original SLC34A1 study identified autosomal-recessive mutations in index cases.
- reference: PMID:38504242
reference_title: "Biallelic and monoallelic pathogenic variants in CYP24A1 and SLC34A1 genes cause idiopathic infantile hypercalcemia."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: "A monoallelic variant of CYP24A1 or SLC34A1 gene contributes to"
explanation: A recent series supports monoallelic CYP24A1 or SLC34A1 variants as contributors in some clinically compatible patients.
prevalence:
- population: Worldwide
percentage: Less than 1 per 1,000,000
notes: >
Orphanet reports cases/families worldwide and a point prevalence below one
per million.
evidence:
- reference: ORPHA:300547
supports: SUPPORT
snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | ORPHANET"
explanation: Orphanet provides a worldwide point prevalence estimate below one per million.
- population: Polish births
percentage: 1 in 32,465 births
notes: >
A historical Polish IIH study estimated incidence from the recurrent CYP24A1
p.R396W allele frequency; this population-specific estimate may not
generalize globally.
evidence:
- reference: PMID:28470390
reference_title: "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."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "1:32,465 births."
explanation: The study estimated Polish incidence from recurrent CYP24A1 allele frequency.
progression:
- phase: Neonatal and infantile presentation
notes: >
The disorder typically begins in infancy or the neonatal period with
symptomatic hypercalcemia. Episodes may be triggered or worsened by vitamin
D prophylaxis, and acute symptoms improve when serum calcium normalizes.
evidence:
- reference: ORPHA:300547
supports: SUPPORT
snippet: "Age of onset: Infancy"
explanation: Orphanet records infancy as an age of onset.
- reference: ORPHA:300547
supports: SUPPORT
snippet: "Age of onset: Neonatal"
explanation: Orphanet records neonatal onset for part of the clinical spectrum.
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "clinical symptoms of hypercalcaemia disappear after normalization of serum calcium levels"
explanation: Long-term cohort review notes that acute hypercalcemia symptoms resolve after calcium normalization.
- phase: Long-term renal sequelae in survivors
notes: >
Survivors can retain nephrocalcinosis, subclinical abnormalities of calcium
and vitamin D metabolism, reduced GFR, chronic kidney disease, and rarely
end-stage renal disease requiring transplantation.
evidence:
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "subjects who suffered from IH may develop progressive chronic kidney disease and have a greater risk of end-stage renal disease."
explanation: Long-term follow-up identifies CKD and ESRD risk after infantile hypercalcemia.
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Two patients with a CYP24A1 mutation developed\nESRD and underwent renal transplantation."
explanation: The cohort included CYP24A1-associated survivors who developed ESRD and underwent renal transplantation.
has_subtypes:
- name: CYP24A1-associated infantile hypercalcemia
display_name: Infantile hypercalcemia type 1
description: >
Type 1 infantile hypercalcemia results from CYP24A1 loss of function, which
reduces 24-hydroxylase-mediated degradation of 25-hydroxyvitamin D3 and
1,25-dihydroxyvitamin D3 and increases sensitivity to vitamin D exposure.
evidence:
- reference: PMID:21675912
reference_title: "Mutations in CYP24A1 and idiopathic infantile hypercalcemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "24-hydroxylase, the key enzyme of 1,25-dihydroxyvitamin D(3) degradation,"
explanation: The CYP24A1 discovery paper establishes deficient vitamin D catabolism as the type 1 mechanism.
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "leads to IH Subtype 1 (143880)"
explanation: Long-term outcome paper links CYP24A1 variants to IH subtype 1.
- name: SLC34A1-associated infantile hypercalcemia
display_name: Infantile hypercalcemia type 2
description: >
Type 2 infantile hypercalcemia results from SLC34A1-associated NaPi-IIa
dysfunction, causing proximal-tubule phosphate wasting, hypophosphatemia,
and inappropriate 1,25-dihydroxyvitamin D3 generation.
evidence:
- reference: PMID:26047794
reference_title: "Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SLC34A1 encoding renal sodium-phosphate"
explanation: The SLC34A1 discovery paper identifies the NaPi-IIa phosphate transporter gene as the type 2 locus.
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This form of IH is currently termed type 2."
explanation: Long-term outcome paper links SLC34A1 variants to IH subtype 2.
pathophysiology:
- name: CYP24A1 vitamin D catabolism defect
description: >
CYP24A1 encodes 25-hydroxyvitamin D 24-hydroxylase, the enzyme responsible
for catabolism of active vitamin D metabolites. Loss-of-function variants
reduce degradation of 1,25-dihydroxyvitamin D3, increasing sensitivity to
vitamin D and predisposing to PTH-independent hypercalcemia.
genes:
- preferred_term: CYP24A1
term:
id: hgnc:2602
label: CYP24A1
biological_processes:
- preferred_term: vitamin D metabolic process
term:
id: GO:0042359
label: vitamin D metabolic process
chemical_entities:
- preferred_term: calcitriol
term:
id: CHEBI:17823
label: calcitriol
modifier: INCREASED
evidence:
- reference: ORPHA:300547
supports: SUPPORT
snippet: "CYP24A1 | cytochrome P450 family 24 subfamily A member 1 | hgnc:2602 | Disease-causing germline mutation(s) (loss of function) in"
explanation: Orphanet lists CYP24A1 loss-of-function variants as disease-causing.
- reference: PMID:21675912
reference_title: "Mutations in CYP24A1 and idiopathic infantile hypercalcemia."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "characterization revealed a complete loss of function in all CYP24A1 mutations."
explanation: Functional characterization showed complete loss of function for reported CYP24A1 mutations.
- reference: PMID:21675912
reference_title: "Mutations in CYP24A1 and idiopathic infantile hypercalcemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "CYP24A1 mutations explains the increased"
explanation: CYP24A1 loss explains vitamin D hypersensitivity in the disorder.
downstream:
- target: Active vitamin D excess and PTH-independent hypercalcemia
description: Impaired vitamin D catabolism increases active vitamin D exposure and calcium absorption/signaling.
causal_link_type: DIRECT
evidence:
- reference: PMID:21675912
reference_title: "Mutations in CYP24A1 and idiopathic infantile hypercalcemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The presence of CYP24A1 mutations explains the increased sensitivity to vitamin D"
explanation: The discovery paper links CYP24A1 pathogenic variants to vitamin D hypersensitivity and symptomatic hypercalcemia.
- name: SLC34A1 renal phosphate transport defect
description: >
SLC34A1 encodes the renal sodium-phosphate cotransporter NaPi-IIa. Defective
NaPi-IIa trafficking or transport causes proximal-tubule phosphate wasting
and hypophosphatemia, which promotes inappropriate production of
1,25-dihydroxyvitamin D3 and symptomatic hypercalcemia.
genes:
- preferred_term: SLC34A1
term:
id: hgnc:11019
label: SLC34A1
biological_processes:
- preferred_term: phosphate ion transport
term:
id: GO:0006817
label: phosphate ion transport
- preferred_term: phosphate ion homeostasis
term:
id: GO:0055062
label: phosphate ion homeostasis
chemical_entities:
- preferred_term: phosphate
term:
id: CHEBI:26020
label: phosphate
modifier: DECREASED
- preferred_term: calcitriol
term:
id: CHEBI:17823
label: calcitriol
modifier: INCREASED
cell_types:
- preferred_term: epithelial cell of proximal tubule
term:
id: CL:0002306
label: epithelial cell of proximal tubule
locations:
- preferred_term: kidney
term:
id: UBERON:0002113
label: kidney
evidence:
- reference: ORPHA:300547
supports: SUPPORT
snippet: "SLC34A1 | solute carrier family 34 member 1 | hgnc:11019 | Disease-causing germline mutation(s) (loss of function) in"
explanation: Orphanet lists SLC34A1 loss-of-function variants as disease-causing.
- reference: PMID:26047794
reference_title: "Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "loss of phosphate transport activity."
explanation: Functional studies showed mutant NaPi-IIa loss of phosphate transport.
- reference: PMID:26047794
reference_title: "Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Analysis of calcium and phosphate metabolism in Slc34a1-knockout mice\nhighlighted the effect of phosphate depletion and fibroblast growth factor-23\nsuppression on the development"
explanation: Slc34a1-knockout mice support phosphate depletion as an upstream mechanism in the IIH phenotype.
downstream:
- target: Active vitamin D excess and PTH-independent hypercalcemia
description: Renal phosphate wasting stimulates inappropriate 1,25-dihydroxyvitamin D3 generation.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- Proximal tubular phosphate wasting.
- Increased 1,25-dihydroxyvitamin D3 generation.
evidence:
- reference: PMID:26047794
reference_title: "Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "renal phosphate wasting and symptomatic hypercalcemia"
explanation: The SLC34A1 discovery paper links renal phosphate wasting to symptomatic hypercalcemia.
- target: Hypophosphatemia
description: SLC34A1 loss reduces renal phosphate reabsorption, producing serum phosphate depletion.
causal_link_type: DIRECT
evidence:
- reference: PMID:32866123
reference_title: "Idiopathic infantile hypercalcemia: mutations in SLC34A1 and CYP24A1 in two siblings and fathers."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both of them also had hypophosphatemia and decreased tubular phosphate reabsorption."
explanation: Human family report supports hypophosphatemia from renal phosphate wasting in the IIH spectrum.
- name: Active vitamin D excess and PTH-independent hypercalcemia
description: >
CYP24A1-associated impaired catabolism or SLC34A1-associated excessive
generation of active vitamin D metabolites increases active vitamin D
signaling. The resulting PTH-independent hypercalcemia includes
hypercalciuria, suppressed intact PTH, hypophosphatemia in phosphate-wasting
cases, and nephrocalcinosis.
biological_processes:
- preferred_term: vitamin D metabolic process
term:
id: GO:0042359
label: vitamin D metabolic process
- preferred_term: calcium ion homeostasis
term:
id: GO:0055074
label: calcium ion homeostasis
chemical_entities:
- preferred_term: calcitriol
term:
id: CHEBI:17823
label: calcitriol
modifier: INCREASED
- preferred_term: calcium ion
term:
id: CHEBI:29108
label: calcium(2+)
modifier: INCREASED
- preferred_term: phosphate
term:
id: CHEBI:26020
label: phosphate
modifier: DECREASED
evidence:
- reference: ORPHA:300547
supports: SUPPORT
snippet: "A rare, genetic, phosphocalcic metabolism disorder characterized by early-onset hypercalcemia, hypophosphatemia, hypercalciuria, decreased intact parathyroid hormone serum levels and medullary nephrocalcinosis"
explanation: Orphanet summarizes the biochemical and renal phenotype of infantile hypercalcemia.
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "catabolism disorders (CYP24A1 mutations) or"
explanation: Long-term outcome paper distinguishes impaired catabolism in CYP24A1-associated disease.
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "excessive generation of 1,25-dihydroxyvitamin D3"
explanation: Long-term outcome paper describes excessive active vitamin D generation in SLC34A1-associated disease.
- reference: PMID:33516786
reference_title: "Analysis of vitamin D(3) metabolites in survivors of infantile idiopathic hypercalcemia caused by CYP24A1 mutation or SLC34A1 mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "disturbed catabolism of 25(OH)D3 and 125(OH)2D3 or"
explanation: Vitamin D metabolite profiling supports the two convergent biochemical mechanisms.
downstream:
- target: Nephrocalcinosis and chronic kidney injury
description: Persistent calcium and vitamin D abnormalities promote renal calcium deposition and kidney injury.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- PTH-independent hypercalcemia.
- Hypercalciuria and renal calcium deposition.
evidence:
- reference: ORPHA:300547
supports: SUPPORT
snippet: "early-onset hypercalcemia, hypophosphatemia, hypercalciuria, decreased intact parathyroid hormone serum levels and medullary nephrocalcinosis"
explanation: Orphanet's defining biochemical pattern links hypercalcemia and hypercalciuria with nephrocalcinosis.
- target: Hypercalcemia
description: Active vitamin D excess drives the defining PTH-independent hypercalcemia phenotype.
causal_link_type: DIRECT
evidence:
- reference: ORPHA:300547
supports: SUPPORT
snippet: "early-onset hypercalcemia"
explanation: Orphanet defines infantile hypercalcemia by early-onset hypercalcemia.
- target: Hypercalciuria
description: Vitamin D-driven calcium excess is accompanied by urinary calcium wasting.
causal_link_type: DIRECT
evidence:
- reference: ORPHA:300547
supports: SUPPORT
snippet: "hypercalciuria"
explanation: Orphanet lists hypercalciuria in the characteristic biochemical phenotype.
- target: Failure to thrive
description: Symptomatic infantile hypercalcemia manifests with failure to thrive.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:21675912
reference_title: "Mutations in CYP24A1 and idiopathic infantile hypercalcemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hypercalcemia, failure to thrive, vomiting, dehydration, and nephrocalcinosis."
explanation: The CYP24A1 discovery paper lists failure to thrive in the symptomatic hypercalcemia presentation.
- target: Vomiting
description: Hypercalcemia causes gastrointestinal symptoms including vomiting or emesis.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:21675912
reference_title: "Mutations in CYP24A1 and idiopathic infantile hypercalcemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hypercalcemia, failure to thrive, vomiting, dehydration, and nephrocalcinosis."
explanation: The discovery paper lists vomiting in the hypercalcemic infantile presentation.
- target: Dehydration
description: Vomiting and polyuria during symptomatic hypercalcemia contribute to dehydration.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- Emesis.
- Polyuria from calcium-mediated renal concentrating impairment.
evidence:
- reference: PMID:21675912
reference_title: "Mutations in CYP24A1 and idiopathic infantile hypercalcemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "vomiting, dehydration, and nephrocalcinosis."
explanation: The discovery paper lists dehydration among hypercalcemic infant symptoms.
- target: Constipation
description: Symptomatic hypercalcemia includes gastrointestinal dysmotility with constipation.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "polyuria, dehydration, constipation, generalized hypotonia"
explanation: The long-term cohort background lists constipation among symptomatic hypercalcemia features.
- target: Polyuria
description: Hypercalcemia can impair renal concentrating function and produce polyuria.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "symptomatic hypercalcaemia, including emesis, anorexia, polyuria"
explanation: The long-term cohort background lists polyuria among symptomatic hypercalcemia features.
- target: Hypotonia
description: Infantile symptomatic hypercalcemia may include generalized hypotonia.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "dehydration, constipation, generalized hypotonia"
explanation: The long-term cohort background lists generalized hypotonia among symptomatic hypercalcemia features.
- target: Hypertension
description: Symptomatic hypercalcemia descriptions include arterial hypertension in the IIH spectrum.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "generalized hypotonia, arterial hypertension"
explanation: The long-term cohort background lists arterial hypertension among symptomatic hypercalcemia features.
- name: Nephrocalcinosis and chronic kidney injury
description: >
Hypercalcemia and hypercalciuria drive renal calcium deposition, medullary
nephrocalcinosis, and tubulointerstitial injury. Long-term survivors can
have persistent nephrocalcinosis, reduced GFR, CKD, and rarely ESRD.
locations:
- preferred_term: kidney
term:
id: UBERON:0002113
label: kidney
chemical_entities:
- preferred_term: calcium ion
term:
id: CHEBI:29108
label: calcium(2+)
modifier: INCREASED
evidence:
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "nephrocalcinosis in 16 of 18 (88%) patients"
explanation: Long-term cohort found persistent nephrocalcinosis in most molecularly confirmed survivors.
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "nephrocalcinosis and CKD developed in a large group of subjects."
explanation: Long-term follow-up links the disorder to nephrocalcinosis and CKD.
downstream:
- target: Nephrocalcinosis
description: Renal calcium deposition manifests as nephrocalcinosis on ultrasound.
causal_link_type: DIRECT
evidence:
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "nephrocalcinosis in 16 of 18 (88%) patients"
explanation: Follow-up renal ultrasound detected nephrocalcinosis in most molecularly confirmed survivors.
- target: Chronic kidney disease
description: Persistent nephrocalcinosis and tubulointerstitial injury can progress to chronic kidney disease.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- Nephrocalcinosis.
- Tubulointerstitial inflammation and fibrosis.
evidence:
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "nephrocalcinosis and tubulointerstitial injury resulting in CKD"
explanation: The cohort discussion links nephrocalcinosis and tubulointerstitial injury to CKD.
- target: Nephrolithiasis
description: The same calcium/vitamin D metabolism disturbance can produce nephrolithiasis as well as nephrocalcinosis.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- Hypercalcemia and hypercalciuria.
- Renal calcium crystal deposition.
evidence:
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Nephrocalcinosis and/or nephrolithiasis is a typical consequence of IH as well as CYP24A1 and SLC34A1 mutations"
explanation: The long-term outcome review explicitly identifies nephrolithiasis as a typical renal consequence.
phenotypes:
- name: Hypercalcemia
description: Severe early-onset PTH-independent hypercalcemia is the defining clinical feature.
phenotype_term:
preferred_term: Hypercalcemia
term:
id: HP:0003072
label: Hypercalcemia
evidence:
- reference: ORPHA:300547
supports: SUPPORT
snippet: "early-onset hypercalcemia"
explanation: Orphanet defines the disorder by early-onset hypercalcemia.
- reference: PMID:21675912
reference_title: "Mutations in CYP24A1 and idiopathic infantile hypercalcemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hypercalcemia, failure to thrive, vomiting, dehydration, and nephrocalcinosis."
explanation: CYP24A1 discovery paper lists hypercalcemia among the defining manifestations.
- name: Hypercalciuria
description: Hypercalciuria accompanies the hypercalcemic phenotype and contributes to renal calcification risk.
phenotype_term:
preferred_term: Hypercalciuria
term:
id: HP:0002150
label: Hypercalciuria
evidence:
- reference: ORPHA:300547
supports: SUPPORT
snippet: "hypercalciuria"
explanation: Orphanet lists hypercalciuria as a characteristic feature.
- reference: PMID:38504242
reference_title: "Biallelic and monoallelic pathogenic variants in CYP24A1 and SLC34A1 genes cause idiopathic infantile hypercalcemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hypercalcemia, hypercalciuria and nephrocalcinosis."
explanation: A recent case series describes hypercalciuria with hypercalcemia and nephrocalcinosis.
- name: Hypophosphatemia
description: Hypophosphatemia is especially prominent in SLC34A1-associated renal phosphate wasting.
phenotype_term:
preferred_term: Hypophosphatemia
term:
id: HP:0002148
label: Hypophosphatemia
evidence:
- reference: ORPHA:300547
supports: SUPPORT
snippet: "hypophosphatemia"
explanation: Orphanet lists hypophosphatemia as a characteristic feature.
- reference: PMID:26047794
reference_title: "Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "renal phosphate wasting and symptomatic hypercalcemia"
explanation: SLC34A1-associated disease presents with renal phosphate wasting and hypercalcemia.
- name: Nephrocalcinosis
frequency: VERY_FREQUENT
description: Medullary nephrocalcinosis is a frequent renal manifestation and can persist into long-term follow-up.
phenotype_term:
preferred_term: Nephrocalcinosis
term:
id: HP:0000121
label: Nephrocalcinosis
evidence:
- reference: ORPHA:300547
supports: SUPPORT
snippet: "medullary nephrocalcinosis"
explanation: Orphanet lists medullary nephrocalcinosis as a characteristic feature.
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A renal ultrasound revealed\nnephrocalcinosis in 16 of 18 (88%) patients"
explanation: Long-term outcome cohort assessed renal ultrasound and found persistent nephrocalcinosis in most survivors.
- name: Failure to thrive
description: Failure to thrive is a typical infant presentation of symptomatic hypercalcemia.
phenotype_term:
preferred_term: Failure to thrive
term:
id: HP:0001508
label: Failure to thrive
evidence:
- reference: ORPHA:300547
supports: SUPPORT
snippet: "failure to thrive"
explanation: Orphanet lists failure to thrive among typical manifestations.
- reference: PMID:26047794
reference_title: "Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hypercalcemia with failure to thrive, vomiting, dehydration, and"
explanation: SLC34A1 discovery paper lists failure to thrive among typical features.
- name: Vomiting
description: Vomiting reflects symptomatic hypercalcemia in affected infants.
phenotype_term:
preferred_term: Vomiting
term:
id: HP:0002013
label: Vomiting
evidence:
- reference: ORPHA:300547
supports: SUPPORT
snippet: "vomiting"
explanation: Orphanet lists vomiting among typical manifestations.
- reference: PMID:28470390
reference_title: "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."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "severe hypercalcemia, failure to thrive, vomiting, dehydration,"
explanation: Historical molecular study lists vomiting in the typical IIH presentation.
- name: Dehydration
description: Dehydration is part of the acute symptomatic hypercalcemia presentation.
phenotype_term:
preferred_term: Dehydration
term:
id: HP:0001944
label: Dehydration
evidence:
- reference: PMID:21675912
reference_title: "Mutations in CYP24A1 and idiopathic infantile hypercalcemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "vomiting, dehydration, and nephrocalcinosis."
explanation: CYP24A1 discovery paper lists dehydration among typical symptoms.
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "polyuria, dehydration, constipation, generalized hypotonia"
explanation: Long-term cohort background lists dehydration among symptomatic hypercalcemia features.
- name: Hypotonia
description: Generalized hypotonia may occur during symptomatic infantile hypercalcemia.
phenotype_term:
preferred_term: Hypotonia
term:
id: HP:0001252
label: Hypotonia
evidence:
- reference: ORPHA:300547
supports: SUPPORT
snippet: "hypotonia"
explanation: Orphanet lists hypotonia among typical manifestations.
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "generalized hypotonia, arterial hypertension"
explanation: Long-term cohort background lists generalized hypotonia among symptomatic hypercalcemia features.
- name: Constipation
description: Constipation is a gastrointestinal manifestation of symptomatic hypercalcemia.
phenotype_term:
preferred_term: Constipation
term:
id: HP:0002019
label: Constipation
evidence:
- reference: ORPHA:300547
supports: SUPPORT
snippet: "constipation"
explanation: Orphanet lists constipation among typical manifestations.
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "dehydration, constipation, generalized hypotonia"
explanation: Long-term cohort background lists constipation among symptomatic hypercalcemia features.
- name: Polyuria
description: Polyuria is a urinary manifestation of hypercalcemia in infancy.
phenotype_term:
preferred_term: Polyuria
term:
id: HP:0000103
label: Polyuria
evidence:
- reference: ORPHA:300547
supports: SUPPORT
snippet: "polyuria"
explanation: Orphanet lists polyuria among typical manifestations.
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "emesis, anorexia, polyuria"
explanation: Long-term cohort background lists polyuria among symptomatic hypercalcemia features.
- name: Chronic kidney disease
description: Long-term survivors may develop reduced GFR and chronic kidney disease.
phenotype_term:
preferred_term: Chronic kidney disease
term:
id: HP:0012622
label: Chronic kidney disease
evidence:
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "14 of 18 (77%) subjects had GFR <90"
explanation: Long-term outcome cohort documented reduced GFR in most molecularly confirmed survivors.
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "progressive CKD with interstitial fibrosis."
explanation: The cohort discussion links initial kidney injury and tubulointerstitial fibrosis to progressive CKD.
- name: Nephrolithiasis
description: >
Nephrolithiasis can occur in older children, adults, and monoallelic
carriers with the infantile hypercalcemia biochemical spectrum.
phenotype_term:
preferred_term: Nephrolithiasis
term:
id: HP:0000787
label: Nephrolithiasis
evidence:
- reference: DOI:10.1186/s13023-024-03135-8
reference_title: Biallelic and monoallelic pathogenic variants in CYP24A1 and SLC34A1 genes cause idiopathic infantile hypercalcemia
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "IIH should be considered in patients with nephrolithiasis either in older children or adults."
explanation: Recent genotype-expansion series highlights nephrolithiasis as a later presentation of IIH.
- reference: DOI:10.1530/eje-21-0713
reference_title: "Hypercalcemia due to CYP24A1 mutations: a systematic descriptive review"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Monoallelic carriers displayed significant rates of nephrolithiasis (19.4%), nephrocalcinosis (4.9%), and symptomatic hypercalcemia (5.6%)."
explanation: Systematic review documents nephrolithiasis among monoallelic CYP24A1 carriers.
- name: Hypertension
description: >
Arterial hypertension has been reported in later-presenting patients and in
symptomatic hypercalcemia descriptions.
phenotype_term:
preferred_term: Hypertension
term:
id: HP:0000822
label: Hypertension
evidence:
- reference: DOI:10.1186/s13023-024-03135-8
reference_title: Biallelic and monoallelic pathogenic variants in CYP24A1 and SLC34A1 genes cause idiopathic infantile hypercalcemia
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "arterial hypertension, hypercalciuria and nephrocalcinosis"
explanation: Recent series reports arterial hypertension in an older patient with the IIH spectrum.
biochemical:
- name: Elevated serum calcium
presence: INCREASED
context: Hypercalcemia is the central biochemical abnormality and is independent of PTH.
biomarker_term:
preferred_term: calcium ion
term:
id: CHEBI:29108
label: calcium(2+)
readouts:
- target: Active vitamin D excess and PTH-independent hypercalcemia
relationship: READOUT_OF
direction: POSITIVE
endpoint_context: DIAGNOSTIC
interpretation: Elevated serum calcium is the central diagnostic readout of vitamin D-driven PTH-independent hypercalcemia.
evidence:
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "serum calcium levels >2.6"
explanation: The long-term cohort used elevated serum calcium as a biochemical marker in molecularly confirmed survivors.
evidence:
- reference: ORPHA:300547
supports: SUPPORT
snippet: "early-onset hypercalcemia"
explanation: Orphanet defines the disorder by early-onset hypercalcemia.
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "serum calcium levels >2.6"
explanation: Long-term outcome cohort used elevated serum calcium as a biochemical readout.
- name: Increased urinary calcium
presence: INCREASED
context: Hypercalciuria accompanies hypercalcemia and contributes to nephrocalcinosis risk.
biomarker_term:
preferred_term: calcium ion
term:
id: CHEBI:29108
label: calcium(2+)
readouts:
- target: Active vitamin D excess and PTH-independent hypercalcemia
relationship: READOUT_OF
direction: POSITIVE
endpoint_context: DIAGNOSTIC
interpretation: Increased urinary calcium reports downstream calcium excess and renal calcium wasting.
evidence:
- reference: ORPHA:300547
supports: SUPPORT
snippet: "hypercalciuria"
explanation: Orphanet lists hypercalciuria as part of the characteristic infantile hypercalcemia biochemical phenotype.
evidence:
- reference: ORPHA:300547
supports: SUPPORT
snippet: "hypercalciuria"
explanation: Orphanet lists hypercalciuria as a characteristic abnormality.
- name: Decreased serum phosphate
presence: DECREASED
context: Hypophosphatemia is part of the Orphanet definition and is mechanistically central in SLC34A1-associated disease.
biomarker_term:
preferred_term: phosphate
term:
id: CHEBI:26020
label: phosphate
readouts:
- target: SLC34A1 renal phosphate transport defect
relationship: READOUT_OF
direction: NEGATIVE
endpoint_context: DIAGNOSTIC
interpretation: Low serum phosphate is a diagnostic readout of renal phosphate wasting in SLC34A1-associated disease.
evidence:
- reference: PMID:32866123
reference_title: "Idiopathic infantile hypercalcemia: mutations in SLC34A1 and CYP24A1 in two siblings and fathers."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both of them also had hypophosphatemia and decreased tubular phosphate reabsorption."
explanation: Human family report connects hypophosphatemia with decreased tubular phosphate reabsorption.
evidence:
- reference: ORPHA:300547
supports: SUPPORT
snippet: "hypophosphatemia"
explanation: Orphanet lists hypophosphatemia as a characteristic abnormality.
- reference: PMID:32866123
reference_title: "Idiopathic infantile hypercalcemia: mutations in SLC34A1 and CYP24A1 in two siblings and fathers."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both of them also had hypophosphatemia"
explanation: Case report of combined CYP24A1/SLC34A1 variation documents hypophosphatemia in affected siblings.
- name: Suppressed intact parathyroid hormone
presence: DECREASED
context: Low intact PTH distinguishes the PTH-independent hypercalcemia state.
readouts:
- target: Active vitamin D excess and PTH-independent hypercalcemia
relationship: READOUT_OF
direction: NEGATIVE
endpoint_context: DIAGNOSTIC
interpretation: Suppressed intact PTH distinguishes the vitamin D-driven hypercalcemia from PTH-mediated hypercalcemia.
evidence:
- reference: ORPHA:300547
supports: SUPPORT
snippet: "decreased intact parathyroid hormone serum levels"
explanation: Orphanet includes decreased intact PTH in the characteristic biochemical pattern.
evidence:
- reference: ORPHA:300547
supports: SUPPORT
snippet: "decreased intact parathyroid hormone serum levels"
explanation: Orphanet lists decreased intact PTH as a characteristic abnormality.
- name: Increased active vitamin D exposure
presence: INCREASED
context: >
CYP24A1 variants disturb active vitamin D catabolism, while SLC34A1 variants
increase 1,25-dihydroxyvitamin D3 generation downstream of phosphate
wasting.
biomarker_term:
preferred_term: calcitriol
term:
id: CHEBI:17823
label: calcitriol
readouts:
- target: Active vitamin D excess and PTH-independent hypercalcemia
relationship: READOUT_OF
direction: POSITIVE
endpoint_context: DIAGNOSTIC
interpretation: Elevated or inappropriately high active vitamin D metabolites read out the convergent biochemical mechanism.
evidence:
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hypercalcaemia with elevated 1,25(OH)2D3 levels"
explanation: The cohort background links high vitamin D metabolite exposure to symptomatic hypercalcemia.
evidence:
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hypercalcaemia with elevated 1,25(OH)2D3 levels"
explanation: Long-term outcome paper links high vitamin D metabolite exposure to symptomatic hypercalcemia.
- reference: PMID:33516786
reference_title: "Analysis of vitamin D(3) metabolites in survivors of infantile idiopathic hypercalcemia caused by CYP24A1 mutation or SLC34A1 mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "increased generation of 125(OH)2D3."
explanation: Vitamin D metabolite profiling supports increased active vitamin D generation in part of the disease spectrum.
- name: Increased 25(OH)D3 to 24,25(OH)2D3 ratio
presence: INCREASED
context: A high 25(OH)D3/24,25(OH)2D3 ratio is a biochemical marker of CYP24A1-associated disease.
readouts:
- target: CYP24A1 vitamin D catabolism defect
relationship: READOUT_OF
direction: POSITIVE
endpoint_context: DIAGNOSTIC
interpretation: A high 25(OH)D3/24,25(OH)2D3 ratio reports impaired CYP24A1-dependent 24-hydroxylation.
evidence:
- reference: PMID:33516786
reference_title: "Analysis of vitamin D(3) metabolites in survivors of infantile idiopathic hypercalcemia caused by CYP24A1 mutation or SLC34A1 mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "extremely high 25(OH)D3/2425(OH)2D3 ratio values."
explanation: Vitamin D metabolite profiling found very high ratios in CYP24A1-associated survivors.
evidence:
- reference: PMID:33516786
reference_title: "Analysis of vitamin D(3) metabolites in survivors of infantile idiopathic hypercalcemia caused by CYP24A1 mutation or SLC34A1 mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "extremely high 25(OH)D3/2425(OH)2D3 ratio values."
explanation: Vitamin D metabolite profiling found persistently high ratios in CYP24A1-associated survivors.
diagnosis:
- name: Biochemical Hypercalcemia Workup
description: >
Laboratory evaluation includes serum and urinary calcium, serum phosphate,
creatinine or kidney-function markers, intact PTH, and vitamin D metabolites
to establish PTH-independent hypercalcemia and distinguish CYP24A1 from
SLC34A1-associated patterns.
diagnosis_term:
preferred_term: diagnostic procedure
term:
id: MAXO:0000003
label: diagnostic procedure
evidence:
- reference: DOI:10.3390/children10101701
reference_title: Phenotype of Idiopathic Infantile Hypercalcemia Associated with the Heterozygous Pathogenic Variant of SLC34A1 and CYP24A1
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hypercalcemia, hypercalciuria, suppressed intact parathormone levels (PTH), nephrocalcinosis, elevated levels of serum 1,25 (OH)2-vitamin D3 or inappropriately normal levels, and kidney phosphate wasting."
explanation: Recent clinical series summarizes the diagnostic biochemical constellation.
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Laboratory tests involved serum creatinine, cystatin C, 25(OH)D3, 1,25(OH)2D3, PTH, urinary calcium and creatinine in spot urine samples"
explanation: Long-term cohort describes the laboratory panel used to reassess survivors.
- name: Renal Ultrasonography
description: >
Renal ultrasound is used to identify medullary nephrocalcinosis and to
monitor persistent renal calcification in survivors.
diagnosis_term:
preferred_term: diagnostic procedure
term:
id: MAXO:0000003
label: diagnostic procedure
evidence:
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In all subjects, renal ultrasound and laboratory tests were carried out."
explanation: Long-term cohort used renal ultrasound in follow-up assessment.
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A renal ultrasound revealed\nnephrocalcinosis in 16 of 18 (88%) patients"
explanation: Ultrasound detected nephrocalcinosis in most molecularly confirmed survivors.
- name: CYP24A1 and SLC34A1 Genetic Testing
description: >
Molecular testing of CYP24A1 and SLC34A1 confirms the genetic subtype,
supports treatment selection, and informs long-term prognosis and family
counseling.
diagnosis_term:
preferred_term: genetic testing
term:
id: MAXO:0000127
label: genetic testing
evidence:
- reference: DOI:10.3390/children10101701
reference_title: Phenotype of Idiopathic Infantile Hypercalcemia Associated with the Heterozygous Pathogenic Variant of SLC34A1 and CYP24A1
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The genetic diagnosis is of paramount importance for proper treatment and the prediction of long-term outcomes."
explanation: Recent clinical series emphasizes genetic diagnosis for treatment and prognosis.
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In all patients, a genetic analysis of possible IH mutations was conducted"
explanation: Long-term outcome cohort performed genetic analysis to define molecularly confirmed IH.
genetic:
- name: CYP24A1 variants
gene_term:
preferred_term: CYP24A1
term:
id: hgnc:2602
label: CYP24A1
inheritance:
- name: Autosomal recessive
evidence:
- reference: PMID:21675912
reference_title: "Mutations in CYP24A1 and idiopathic infantile hypercalcemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "revealed recessive mutations in six affected children."
explanation: Discovery paper identified recessive CYP24A1 variants in affected children.
variants:
- name: Loss-of-function CYP24A1 variants
description: >
CYP24A1 variants impair or abolish 24-hydroxylase function, reducing
degradation of active vitamin D metabolites and causing vitamin D
hypersensitivity.
evidence:
- reference: PMID:21675912
reference_title: "Mutations in CYP24A1 and idiopathic infantile hypercalcemia."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "complete loss of function in all CYP24A1 mutations."
explanation: Functional testing showed complete loss of function for reported CYP24A1 variants.
- reference: PMID:28470390
reference_title: "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."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All persons were found to carry mutations in"
explanation: Historical molecular study found CYP24A1 or SLC34A1 variants in prior IIH cases.
features: >
CYP24A1 encodes 25-hydroxyvitamin D 24-hydroxylase and corresponds to
infantile hypercalcemia type 1.
evidence:
- reference: ORPHA:300547
supports: SUPPORT
snippet: "CYP24A1 | cytochrome P450 family 24 subfamily A member 1 | hgnc:2602 | Disease-causing germline mutation(s) (loss of function) in"
explanation: Orphanet lists CYP24A1 as a loss-of-function disease gene.
- reference: ORPHA:300547
supports: SUPPORT
snippet: "MONDO:0000212 | Exact"
explanation: Orphanet provides a direct exact MONDO mapping for the curated disorder.
- name: SLC34A1 variants
gene_term:
preferred_term: SLC34A1
term:
id: hgnc:11019
label: SLC34A1
inheritance:
- name: Autosomal recessive
evidence:
- reference: PMID:26047794
reference_title: "Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "revealed autosomal-recessive mutations in the four"
explanation: Discovery paper identified recessive SLC34A1 variants in index cases.
variants:
- name: Loss-of-function SLC34A1 variants
description: >
SLC34A1 variants impair NaPi-IIa phosphate transport, causing renal
phosphate wasting and inappropriate active vitamin D generation.
evidence:
- reference: PMID:26047794
reference_title: "Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "loss of phosphate transport activity."
explanation: Functional studies showed loss of phosphate transport by mutant NaPi-IIa.
- reference: PMID:28470390
reference_title: "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."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SLC34A1 defect (which impairs renal phosphate transport)."
explanation: Historical molecular study distinguishes SLC34A1 disease by phosphate-transport impairment.
features: >
SLC34A1 encodes the renal sodium-phosphate cotransporter NaPi-IIa and
corresponds to infantile hypercalcemia type 2.
evidence:
- reference: ORPHA:300547
supports: SUPPORT
snippet: "SLC34A1 | solute carrier family 34 member 1 | hgnc:11019 | Disease-causing germline mutation(s) (loss of function) in"
explanation: Orphanet lists SLC34A1 as a loss-of-function disease gene.
treatments:
- name: Vitamin D and calcium exposure reduction
description: >
Avoiding vitamin D supplements, high calcium intake, and excessive sun
exposure reduces the metabolic trigger for CYP24A1-associated disease and
helps prevent recurrent hypercalcemia.
treatment_term:
preferred_term: dietary intervention
term:
id: MAXO:0000088
label: dietary intervention
target_mechanisms:
- target: CYP24A1 vitamin D catabolism defect
treatment_effect: MODULATES
description: Reduces substrate and environmental load on impaired vitamin D catabolism.
- target: Active vitamin D excess and PTH-independent hypercalcemia
treatment_effect: MODULATES
description: Limits vitamin D-driven calcium absorption and active metabolite exposure.
target_phenotypes:
- preferred_term: Hypercalcemia
term:
id: HP:0003072
label: Hypercalcemia
- preferred_term: Hypercalciuria
term:
id: HP:0002150
label: Hypercalciuria
- preferred_term: Nephrocalcinosis
term:
id: HP:0000121
label: Nephrocalcinosis
evidence:
- reference: PMID:28470390
reference_title: "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."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "vit. D restriction is a first indication for CYP24A1"
explanation: Historical molecular study identifies vitamin D restriction as first-line prevention for CYP24A1 defects.
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "avoid sun exposure, vitamin D and calcium supplements and to drink large amounts of fluids."
explanation: Long-term cohort describes standard preventive advice for survivors.
- name: Phosphate supplementation for SLC34A1-associated disease
description: >
Phosphate supplementation targets the SLC34A1 mechanism by correcting renal
phosphate wasting, which can rapidly reduce inappropriate active vitamin D
production and hypercalcemia.
treatment_term:
preferred_term: nutritional supplementation
term:
id: MAXO:0000106
label: nutritional supplementation
target_mechanisms:
- target: SLC34A1 renal phosphate transport defect
treatment_effect: MODULATES
description: Replaces phosphate lost through defective renal reabsorption.
- target: Active vitamin D excess and PTH-independent hypercalcemia
treatment_effect: MODULATES
description: Correcting phosphate depletion reduces inappropriate 1,25-dihydroxyvitamin D3 generation.
target_phenotypes:
- preferred_term: Hypophosphatemia
term:
id: HP:0002148
label: Hypophosphatemia
- preferred_term: Hypercalcemia
term:
id: HP:0003072
label: Hypercalcemia
evidence:
- reference: PMID:26047794
reference_title: "Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "rapidly respond to phosphate\nsupplementation."
explanation: SLC34A1 discovery paper reports rapid response to phosphate supplementation.
- reference: PMID:28470390
reference_title: "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."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "phosphate supplementation for\nSLC34A1 defect (which impairs renal phosphate transport)."
explanation: Historical molecular study identifies phosphate supplementation as the SLC34A1-directed approach.
- name: Acute hypercalcemia management
description: >
Acute symptomatic hypercalcemia can require intensive hydration, loop
diuretic therapy, and phosphate replacement to lower calcium and stabilize
the infant during the hypercalcemic episode.
treatment_term:
preferred_term: supportive care
term:
id: MAXO:0000950
label: supportive care
target_mechanisms:
- target: Active vitamin D excess and PTH-independent hypercalcemia
treatment_effect: MODULATES
description: Hydration and calciuretic/supportive measures reduce acute hypercalcemia burden.
- target: SLC34A1 renal phosphate transport defect
treatment_effect: MODULATES
description: Phosphate replacement addresses hypophosphatemia in phosphate-wasting presentations.
target_phenotypes:
- preferred_term: Hypercalcemia
term:
id: HP:0003072
label: Hypercalcemia
- preferred_term: Dehydration
term:
id: HP:0001944
label: Dehydration
- preferred_term: Vomiting
term:
id: HP:0002013
label: Vomiting
evidence:
- reference: PMID:32866123
reference_title: "Idiopathic infantile hypercalcemia: mutations in SLC34A1 and CYP24A1 in two siblings and fathers."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Intensive hydration, furosemide and oral phosphorus\ntreatment were given."
explanation: Case report documents acute hypercalcemia management with hydration, furosemide, and oral phosphorus.
- name: Renal monitoring and supportive care
description: >
Survivors require ongoing nephrology follow-up, renal imaging, calcium and
vitamin D metabolite monitoring, hydration counseling, and early preventive
measures because CKD and nephrocalcinosis may progress after the acute
infantile episode.
treatment_term:
preferred_term: supportive care
term:
id: MAXO:0000950
label: supportive care
target_mechanisms:
- target: Nephrocalcinosis and chronic kidney injury
treatment_effect: MODULATES
description: Monitoring and supportive care aim to detect and limit chronic renal sequelae.
target_phenotypes:
- preferred_term: Nephrocalcinosis
term:
id: HP:0000121
label: Nephrocalcinosis
- preferred_term: Chronic kidney disease
term:
id: HP:0012622
label: Chronic kidney disease
- preferred_term: Nephrolithiasis
term:
id: HP:0000787
label: Nephrolithiasis
evidence:
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "of IH should be closely monitored"
explanation: Long-term outcome cohort concludes that all survivors require close monitoring.
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "all survivors of IIH should be under constant renal care."
explanation: Discussion recommends constant renal care for IIH survivors.
- name: Active Vitamin D Metabolite Suppression
description: >
Pharmacologic inhibition of active vitamin D metabolite synthesis or
induction of metabolite degradation has been proposed for survivors with
ongoing metabolic risk, but long-term safety data remain limited.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: ketoconazole
term:
id: CHEBI:47519
label: ketoconazole
- preferred_term: rifampicin
term:
id: CHEBI:28077
label: rifampicin
target_mechanisms:
- target: Active vitamin D excess and PTH-independent hypercalcemia
treatment_effect: MODULATES
description: Suppresses production or promotes degradation of active vitamin D metabolites that drive hypercalcemia.
- target: Nephrocalcinosis and chronic kidney injury
treatment_effect: MODULATES
description: Aims to reduce persistent metabolic exposure that contributes to renal calcification and CKD.
target_phenotypes:
- preferred_term: Hypercalcemia
term:
id: HP:0003072
label: Hypercalcemia
- preferred_term: Hypercalciuria
term:
id: HP:0002150
label: Hypercalciuria
- preferred_term: Nephrocalcinosis
term:
id: HP:0000121
label: Nephrocalcinosis
- preferred_term: Chronic kidney disease
term:
id: HP:0012622
label: Chronic kidney disease
evidence:
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: "early implementation of inhibitors of 25(OH)D3 and 1,25(OH)2D3 synthesis or inductor degradation—should be considered in all survivors of IIH"
explanation: Long-term cohort proposes active vitamin D metabolite suppression as a preventive strategy, while noting that long-term safety remains insufficiently studied.
- reference: PMID:33099630
reference_title: "Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: "long-term use and safety of both imidazole derivative and rifampicin in patients with CYP24A1 mutations have not been studied."
explanation: Discussion identifies imidazole-derivative and rifampicin approaches while emphasizing limited long-term safety data.
references:
- reference: ORPHA:300547
title: Autosomal recessive infantile hypercalcemia
found_in:
- Infantile_Hypercalcemia-deep-research-falcon.md
- reference: PMID:21675912
title: Mutations in CYP24A1 and idiopathic infantile hypercalcemia.
found_in:
- Infantile_Hypercalcemia-deep-research-falcon.md
- reference: PMID:26047794
title: Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia.
found_in:
- Infantile_Hypercalcemia-deep-research-falcon.md
- reference: PMID:28470390
title: '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.'
found_in:
- Infantile_Hypercalcemia-deep-research-falcon.md
- reference: PMID:32866123
title: 'Idiopathic infantile hypercalcemia: mutations in SLC34A1 and CYP24A1 in two siblings and fathers.'
found_in:
- Infantile_Hypercalcemia-deep-research-falcon.md
- reference: PMID:33099630
title: Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations.
found_in:
- Infantile_Hypercalcemia-deep-research-falcon.md
- reference: PMID:33516786
title: Analysis of vitamin D(3) metabolites in survivors of infantile idiopathic hypercalcemia caused by CYP24A1 mutation or SLC34A1 mutation.
found_in:
- Infantile_Hypercalcemia-deep-research-falcon.md
- reference: PMID:38504242
title: Biallelic and monoallelic pathogenic variants in CYP24A1 and SLC34A1 genes cause idiopathic infantile hypercalcemia.
found_in:
- Infantile_Hypercalcemia-deep-research-falcon.md
- reference: DOI:10.1007/s00467-022-05740-w
title: Idiopathic infantile hypercalcemia in children with chronic kidney disease due to kidney hypodysplasia
found_in:
- Infantile_Hypercalcemia-deep-research-falcon.md
- reference: DOI:10.1007/s00467-024-06403-8
title: Antenatal presentation and early postnatal treatment of infantile hypercalcemia type 2
found_in:
- Infantile_Hypercalcemia-deep-research-falcon.md
- reference: DOI:10.1093/ndt/gfaa178
title: Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations
found_in:
- Infantile_Hypercalcemia-deep-research-falcon.md
- reference: DOI:10.1186/s13023-024-03135-8
title: Biallelic and monoallelic pathogenic variants in CYP24A1 and SLC34A1 genes cause idiopathic infantile hypercalcemia
found_in:
- Infantile_Hypercalcemia-deep-research-falcon.md
- reference: DOI:10.1530/eje-21-0713
title: "Hypercalcemia due to CYP24A1 mutations: a systematic descriptive review"
found_in:
- Infantile_Hypercalcemia-deep-research-falcon.md
- reference: DOI:10.2139/ssrn.4257523
title: CYP24A1 and SLC34A1 Mutations in Five Cases with Idiopathic Infantile Hypercalcemia
found_in:
- Infantile_Hypercalcemia-deep-research-falcon.md
- reference: DOI:10.3390/children10101701
title: Phenotype of Idiopathic Infantile Hypercalcemia Associated with the Heterozygous Pathogenic Variant of SLC34A1 and CYP24A1
found_in:
- Infantile_Hypercalcemia-deep-research-falcon.md
- reference: DOI:10.7759/cureus.42811
title: "A Case of Delayed Diagnosis of Idiopathic Infantile Hypercalcemia Due to CYP24A1 Mutation: A 10-Year Journey"
found_in:
- Infantile_Hypercalcemia-deep-research-falcon.md
Infantile hypercalcemia (also called idiopathic infantile hypercalcemia, IIH) is a rare genetic disorder classically presenting in infancy with parathyroid hormone (PTH)-independent hypercalcemia, hypercalciuria, and nephrocalcinosis; it is most often caused by defects in vitamin D catabolism (CYP24A1; “infantile hypercalcemia type 1”) or renal phosphate handling (SLC34A1; “infantile hypercalcemia type 2”). (wang2024biallelicandmonoallelic pages 1-2, bizereamoga2023phenotypeofidiopathic pages 1-2)
Recent (2023–2024) literature emphasizes: (i) broader genotype–phenotype spectra including symptomatic monoallelic carriers; (ii) the utility of next-generation sequencing (NGS) for diagnosis; (iii) antenatal presentations in SLC34A1-related disease; and (iv) the need for long-term renal surveillance because chronic kidney disease (CKD) can develop in survivors. (wang2024biallelicandmonoallelic pages 1-2, khan2023acaseof pages 2-4, verjans2024antenatalpresentationand pages 6-9)
Idiopathic infantile hypercalcemia (IIH) is described as a “rare disorder of PTH-independent hypercalcemia.” (wang2024biallelicandmonoallelic pages 1-2)
A 2023 review/case series explicitly states: “Idiopathic infantile hypercalcemia (IIH) is a rare genetic disease, also called hypersensitivity to vitamin D3.” (bizereamoga2023phenotypeofidiopathic pages 1-2)
Clinically, IIH is classically characterized by hypercalcemia with suppressed PTH and associated renal and systemic manifestations such as hypercalciuria and nephrocalcinosis, often accompanied by nonspecific infant symptoms (poor feeding, vomiting, failure to thrive, dehydration). (bizereamoga2023phenotypeofidiopathic pages 1-2, khan2023acaseof pages 2-4)
Evidence source type: aggregated disease-level resources and case series/reviews, plus individual case reports and cohorts. (wang2024biallelicandmonoallelic pages 1-2, bizereamoga2023phenotypeofidiopathic pages 1-2, khan2023acaseof pages 2-4)
Synonyms/aliases used in recent literature include: infantile hypercalcemia / infantile hypercalcaemia, idiopathic infantile hypercalcemia (IIH), hypersensitivity to vitamin D3, infantile hypercalcemia type 1 / type 2, IIH type 1 / IIH type 2, and HCINF1 (for type 1). (bizereamoga2023phenotypeofidiopathic pages 1-2, janiec2021longtermoutcomeof pages 1-2)
OMIM identifiers (supported by primary literature): - Infantile hypercalcemia type 1 (CYP24A1-related): OMIM phenotype 143880; CYP24A1 OMIM gene *126065. (janiec2021longtermoutcomeof pages 1-2, cappellani2022hypercalcemiadueto pages 1-2) - Infantile hypercalcemia type 2 (SLC34A1-related): OMIM phenotype 616963; SLC34A1 OMIM gene *182309. (janiec2021longtermoutcomeof pages 1-2, bizereamoga2023phenotypeofidiopathic pages 6-7)
Orphanet / ICD-10/ICD-11 / MeSH / MONDO: these identifiers were not found in the retrieved full-text evidence set; therefore they cannot be stated with source-backed certainty here. (wang2024biallelicandmonoallelic pages 1-2, janiec2021longtermoutcomeof pages 1-2)
Artifact (identifiers & synonyms): | Entity | Synonyms/aliases | Gene(s) | OMIM phenotype ID | OMIM gene ID | Key notes | Key citation IDs | |---|---|---|---|---|---|---| | Infantile hypercalcemia | Infantile hypercalcaemia; idiopathic infantile hypercalcemia; idiopathic infantile hypercalcaemia; IIH; hypersensitivity to vitamin D3 | CYP24A1, SLC34A1 | General disease term used across subtype literature; specific phenotype IDs below | — | Rare genetic disorder of PTH-independent hypercalcemia; common features include hypercalcemia, hypercalciuria, nephrocalcinosis, suppressed PTH, and elevated/inappropriately normal 1,25(OH)2D3 | (wang2024biallelicandmonoallelic pages 1-2, bizereamoga2023phenotypeofidiopathic pages 1-2) | | Infantile hypercalcemia type 1 | IIH type 1; idiopathic infantile hypercalcemia type 1; infantile hypercalcaemia-1; HCINF1 | CYP24A1 | 143880 | CYP24A1 126065 | Caused by loss-of-function variants in CYP24A1 encoding vitamin D 24-hydroxylase; impaired vitamin D catabolism leads to increased active vitamin D and hypercalcemia | (wang2024biallelicandmonoallelic pages 1-2, janiec2021longtermoutcomeof pages 1-2) | | Infantile hypercalcemia type 2 | IIH type 2; idiopathic infantile hypercalcemia type 2; infantile hypercalcaemia-2; IH subtype 2 | SLC34A1 | 616963 | SLC34A1 182309 | Caused by variants in SLC34A1 encoding renal proximal tubular NaPi-IIa; phosphate wasting can drive increased 1,25(OH)2D3 and hypercalcemia/hypercalciuria | (bizereamoga2023phenotypeofidiopathic pages 6-7, janiec2021longtermoutcomeof pages 1-2) | | CYP24A1-related infantile hypercalcemia | 24-hydroxylase deficiency; vitamin D catabolism defect–related infantile hypercalcemia | CYP24A1 | 143880 | CYP24A1 126065 | CYP24A1 deficiency is the canonical molecular basis of IIH type 1; may also present later with nephrolithiasis/nephrocalcinosis | (khan2023acaseof pages 2-4, janiec2021longtermoutcomeof pages 1-2, cappellani2022hypercalcemiadueto pages 1-2) | | SLC34A1-related infantile hypercalcemia | NaPi-IIa deficiency–related infantile hypercalcemia; phosphate-wasting infantile hypercalcemia | SLC34A1 | 616963 | SLC34A1 182309 | SLC34A1-related disease overlaps with nephrocalcinosis/urolithiasis phenotypes and may respond to phosphate supplementation | (bizereamoga2023phenotypeofidiopathic pages 6-7, verjans2024antenatalpresentationand pages 6-9) | | SLC34A1 gene disease context | Fanconi renotubular syndrome 2; dominant hypophosphatemic nephrolithiasis/osteoporosis; infantile hypercalcemia 2 | SLC34A1 | 613388 (Fanconi renotubular syndrome 2); 612286 (dominant hypophosphatemic nephrolithiasis/osteoporosis); 616963 (infantile hypercalcemia 2) | SLC34A1 *182309 | Useful differential/allelic context for interpreting SLC34A1 findings in suspected IIH | (bizereamoga2023phenotypeofidiopathic pages 6-7) |
Table: This table summarizes the core naming conventions and OMIM mappings for infantile hypercalcemia and its major Mendelian subtypes. It is useful for harmonizing disease labels across literature and knowledge-base records.
IIH is primarily genetic and mechanistically related to disturbed vitamin D metabolism or renal phosphate transport.
CYP24A1 (Infantile hypercalcemia type 1): - CYP24A1 encodes vitamin D 24-hydroxylase, which inactivates 25(OH)D and 1,25(OH)2D; loss-of-function (LOF) variants reduce catabolism and drive vitamin D-dependent hypercalcemia. (wang2024biallelicandmonoallelic pages 1-2, khan2023acaseof pages 2-4)
SLC34A1 (Infantile hypercalcemia type 2): - SLC34A1 encodes the renal proximal tubule sodium–phosphate cotransporter NaPi-IIa; variants cause phosphate wasting that can increase 1,25(OH)2D and drive hypercalcemia/hypercalciuria. (wang2024biallelicandmonoallelic pages 1-2, bizereamoga2023phenotypeofidiopathic pages 6-7)
No robust genetic “protective variants” or environmental protective factors were identified in the retrieved evidence set for IIH specifically.
Across sources, common disease features include: - Laboratory abnormalities: hypercalcemia, suppressed PTH, hypercalciuria, and elevated or inappropriately normal 1,25(OH)2D3. (bizereamoga2023phenotypeofidiopathic pages 1-2, khan2023acaseof pages 2-4) - Kidney manifestations: nephrocalcinosis and/or nephrolithiasis; renal medullary nephrocalcinosis is frequently noted. (wang2024biallelicandmonoallelic pages 1-2, khan2023acaseof pages 2-4) - Infant symptoms/signs: failure to thrive, poor feeding, vomiting, dehydration, hypotonia, lethargy/irritability. A review of neonatal/infant hypercalcemia states hypercalcemia may present with “failure to thrive, poor feeding, constipation, polyuria, irritability, lethargy, seizures and hypotonia.” (gurevich2023idiopathicinfantilehypercalcemia pages 1-2)
The following Human Phenotype Ontology (HPO) terms are consistent with the phenotypes repeatedly described in the retrieved evidence: - Hypercalcemia (HP:0003072) - Hypercalciuria (HP:0002150) - Nephrocalcinosis (HP:0000121) - Nephrolithiasis (HP:0000787) - Suppressed PTH / Hypoparathyroidism (context: low PTH in setting of hypercalcemia; often represented by “Decreased circulating parathyroid hormone level” if available) - Failure to thrive (HP:0001508) - Vomiting (HP:0002013) - Dehydration (HP:0001944) - Hypotonia (HP:0001252)
(bizereamoga2023phenotypeofidiopathic pages 1-2, khan2023acaseof pages 2-4)
Quality of life impact: Not systematically quantified in the retrieved evidence. However, long-term renal morbidity (nephrocalcinosis/CKD) implies substantial chronic health impact. (janiec2021longtermoutcomeof pages 1-2)
No validated modifier genes or epigenetic signatures specific to IIH were identified in the retrieved evidence.
The dominant non-genetic contributors discussed are iatrogenic/environmental exposures that increase vitamin D signaling or calcium load, including vitamin D supplementation and dietary calcium intake; clinical management commonly includes stopping supplementation and reducing exogenous vitamin D and calcium during acute episodes. (wang2024biallelicandmonoallelic pages 4-7, wang2022cyp24a1andslc34a1 pages 4-6)
No specific toxins/pollution/infectious agents were identified as causal in the retrieved evidence.
Mechanistic description from 2024: CYP24A1 variants “impair catabolism of 25(OH)D3 and 1,25(OH)2D3, leading to accumulation of active vitamin D,” driving increased intestinal calcium absorption/bone resorption and causing hypercalcemia, hypercalciuria, nephrocalcinosis and suppressed PTH. (wang2024biallelicandmonoallelic pages 1-2)
A 2024 mechanistic summary states SLC34A1 mutations cause renal phosphate wasting and downstream hormonal changes that raise 1,25(OH)2D3, producing hypercalcemia and hypercalciuria. (wang2024biallelicandmonoallelic pages 1-2)
Across reports, the characteristic biochemical signature is PTH-independent hypercalcemia with inappropriate vitamin D metabolite patterns. For example, a 2023 report notes typical features including “raised serum calcium, suppressed PTH, mildly elevated levels of 1,25-dihydroxyvitamin D3, and hypercalciuria.” (khan2023acaseof pages 2-4)
Because the retrieved evidence is primarily clinical genetics, pathway annotations are inferred from the described biology: - GO Biological Process: vitamin D metabolic process; calcium ion homeostasis; phosphate ion homeostasis; regulation of renal tubular transport - Primary cell types (CL): renal proximal tubule epithelial cell (SLC34A1 context); intestinal epithelial cell/enterocyte (for calcium absorption as downstream physiology) - Key organs (UBERON): kidney (renal medulla/proximal tubule), small intestine
(wang2024biallelicandmonoallelic pages 1-2, khan2023acaseof pages 2-4)
Disease-level epidemiology is limited in the retrieved evidence. One 2024 report provides an incidence estimate: “an estimated incidence of 1:33,000 live births.” (wang2024biallelicandmonoallelic pages 1-2)
A separate 2023 cohort study in children with kidney hypodysplasia used biochemical criteria for IIH (PTH ≤14 pg/mL and 1,25(OH)2D ≥160 pmol/L) and found 16/139 (11.5%) met these criteria, suggesting a notable contribution of IIH-like physiology in this selected CKD population (without genetic confirmation). (gurevich2023idiopathicinfantilehypercalcemia pages 1-2)
Evidence supports variable expressivity and possible incomplete penetrance, including symptomatic monoallelic carriers. (cappellani2022hypercalcemiadueto pages 1-2, wang2024biallelicandmonoallelic pages 1-2)
The SLC34A1 Val91_Ala97del allele is discussed as common in European ancestry populations (~5.2% in gnomAD European reference), raising the possibility of hypomorphic alleles contributing to disease in trans with a pathogenic variant. (verjans2024antenatalpresentationand pages 6-9)
A comprehensive neonatal/infant hypercalcemia evaluation includes calcium and phosphate measurements, PTH, vitamin D metabolites, and urinary indices. A review states diagnosis requires “biochemical measurements, including total and ionised serum calcium, serum phosphate, creatinine and albumin, intact parathyroid hormone (PTH), vitamin D metabolites and urinary calcium, phosphate and creatinine.” (gurevich2023idiopathicinfantilehypercalcemia pages 1-2)
In IIH, a typical diagnostic signature includes hypercalcemia with suppressed PTH and hypercalciuria; 1,25(OH)2D may be elevated or inappropriately normal. (bizereamoga2023phenotypeofidiopathic pages 1-2, khan2023acaseof pages 2-4)
Renal ultrasonography is frequently used to identify nephrocalcinosis and to monitor renal status over time. Persistent nephrocalcinosis is common in long-term follow-up. (janiec2021longtermoutcomeof pages 1-2)
Because IIH can be difficult to diagnose clinically, multiple sources emphasize genetic testing. A 2023 case report notes IIH historically was a diagnosis of exclusion but “can now… be diagnosed using CYP24A1 genetic testing.” (khan2023acaseof pages 2-4)
Practical approach: targeted gene panel for hypercalcemia/nephrocalcinosis/nephrolithiasis (including CYP24A1 and SLC34A1) or exome/genome sequencing in complex/antenatal cases. (verjans2024antenatalpresentationand pages 6-9, khan2023acaseof pages 2-4)
Neonatal/infant hypercalcemia differentials include high-PTH disorders (e.g., neonatal severe hyperparathyroidism, familial hypocalciuric hypercalcemia) vs low-PTH disorders (including IIH and Williams-Beuren syndrome). (gurevich2023idiopathicinfantilehypercalcemia pages 1-2)
A 2021 long-term outcome study of genetically confirmed survivors (CYP24A1 or SLC34A1) found substantial CKD burden: - Mean GFR 72 mL/min/1.73m² (range 15–105) - GFR <90 mL/min/1.73m² in 77% - GFR <60 mL/min/1.73m² in 28% - Nephrocalcinosis in 88% - Two patients developed ESRD and underwent renal transplantation (CYP24A1). (janiec2021longtermoutcomeof pages 1-2)
Genotype (biallelic LOF) and degree/duration of hypercalcemia/hypercalciuria and nephrocalcinosis are plausible prognostic indicators, but robust prognostic models were not found in the retrieved evidence.
Across case series and reviews, acute therapy is consistent with general hypercalcemia management: - Hydration (saline loading) and loop diuretics (e.g., furosemide). (khan2023acaseof pages 2-4, wang2022cyp24a1andslc34a1 pages 4-6) - Escalation strategies include calcitonin, bisphosphonates, and hemodialysis in refractory/life-threatening cases. (wang2024biallelicandmonoallelic pages 4-7, wang2022cyp24a1andslc34a1 pages 4-6)
(wang2024biallelicandmonoallelic pages 4-7, khan2023acaseof pages 2-4, verjans2024antenatalpresentationand pages 6-9)
No IIH-specific interventional clinical trials were identified in the retrieved evidence set.
Because IIH is Mendelian, prevention is largely secondary/tertiary: - Avoidance of triggering exposures (particularly vitamin D and excess calcium) in genetically susceptible individuals. (wang2024biallelicandmonoallelic pages 4-7, bizereamoga2023phenotypeofidiopathic pages 1-2) - Genetic counseling for affected families is recommended in case series. (bizereamoga2023phenotypeofidiopathic pages 4-6) - Long-term surveillance with early preventive measures has been recommended due to CKD risk; the long-term outcome study emphasizes monitoring and “early implementation of preventive measures.” (janiec2021longtermoutcomeof pages 1-2)
No naturally occurring veterinary disease analogs were identified in the retrieved evidence set.
No model organism studies specific to IIH were included in the retrieved evidence set used for citation; therefore, this section cannot be populated with tool-supported primary evidence here.
References
(wang2024biallelicandmonoallelic pages 1-2): Qiao Wang, Jia-jia Chen, Li-ya Wei, Yuan Ding, Min Liu, Wen-jing Li, Chang Su, and Chun-xiu Gong. Biallelic and monoallelic pathogenic variants in cyp24a1 and slc34a1 genes cause idiopathic infantile hypercalcemia. Orphanet Journal of Rare Diseases, Mar 2024. URL: https://doi.org/10.1186/s13023-024-03135-8, doi:10.1186/s13023-024-03135-8. This article has 10 citations and is from a peer-reviewed journal.
(bizereamoga2023phenotypeofidiopathic pages 1-2): Teofana Otilia Bizerea-Moga, Flavia Chisavu, Cristina Ilies, Orsolya Olah, Otilia Marginean, Mihai Gafencu, Gabriela Doros, and Ramona Stroescu. Phenotype of idiopathic infantile hypercalcemia associated with the heterozygous pathogenic variant of slc34a1 and cyp24a1. Children, 10:1701, Oct 2023. URL: https://doi.org/10.3390/children10101701, doi:10.3390/children10101701. This article has 8 citations.
(khan2023acaseof pages 2-4): Zahid Khan, Gideon Mlawa, Yu-Hsuen Yang, and Bashir Mahamud. A case of delayed diagnosis of idiopathic infantile hypercalcemia due to cyp24a1 mutation: a 10-year journey. Cureus, Aug 2023. URL: https://doi.org/10.7759/cureus.42811, doi:10.7759/cureus.42811. This article has 2 citations.
(verjans2024antenatalpresentationand pages 6-9): Marcelien Verjans, An Hindryckx, Karen Rosier, Koen Devriendt, Djalila Mekahli, and Detlef Bockenhauer. Antenatal presentation and early postnatal treatment of infantile hypercalcemia type 2. Pediatric nephrology, 39:2911-2913, May 2024. URL: https://doi.org/10.1007/s00467-024-06403-8, doi:10.1007/s00467-024-06403-8. This article has 2 citations and is from a domain leading peer-reviewed journal.
(janiec2021longtermoutcomeof pages 1-2): Agnieszka Janiec, Paulina Halat-Wolska, Łukasz Obrycki, Elżbieta Ciara, Marek Wójcik, Paweł Płudowski, Aldona Wierzbicka, Ewa Kowalska, Janusz B Książyk, Zbigniew Kułaga, Ewa Pronicka, and Mieczysław Litwin. Long-term outcome of the survivors of infantile hypercalcaemia with cyp24a1 and slc34a1 mutations. Nephrology Dialysis Transplantation, 36:1484-1492, Oct 2021. URL: https://doi.org/10.1093/ndt/gfaa178, doi:10.1093/ndt/gfaa178. This article has 39 citations and is from a domain leading peer-reviewed journal.
(cappellani2022hypercalcemiadueto pages 1-2): Daniele Cappellani, Alessandro Brancatella, Riccardo Morganti, Simona Borsari, Fulvia Baldinotti, Maria Adelaide Caligo, Martin Kaufmann, Glenville Jones, Claudio Marcocci, and Filomena Cetani. Hypercalcemia due to cyp24a1 mutations: a systematic descriptive review. European Journal of Endocrinology, 186:137-149, Feb 2022. URL: https://doi.org/10.1530/eje-21-0713, doi:10.1530/eje-21-0713. This article has 55 citations and is from a highest quality peer-reviewed journal.
(bizereamoga2023phenotypeofidiopathic pages 6-7): Teofana Otilia Bizerea-Moga, Flavia Chisavu, Cristina Ilies, Orsolya Olah, Otilia Marginean, Mihai Gafencu, Gabriela Doros, and Ramona Stroescu. Phenotype of idiopathic infantile hypercalcemia associated with the heterozygous pathogenic variant of slc34a1 and cyp24a1. Children, 10:1701, Oct 2023. URL: https://doi.org/10.3390/children10101701, doi:10.3390/children10101701. This article has 8 citations.
(wang2024biallelicandmonoallelic pages 4-7): Qiao Wang, Jia-jia Chen, Li-ya Wei, Yuan Ding, Min Liu, Wen-jing Li, Chang Su, and Chun-xiu Gong. Biallelic and monoallelic pathogenic variants in cyp24a1 and slc34a1 genes cause idiopathic infantile hypercalcemia. Orphanet Journal of Rare Diseases, Mar 2024. URL: https://doi.org/10.1186/s13023-024-03135-8, doi:10.1186/s13023-024-03135-8. This article has 10 citations and is from a peer-reviewed journal.
(wang2022cyp24a1andslc34a1 pages 4-6): Qiao Wang, Jia-jia Chen, Li-ya Wei, Min Liu, Wen-jing Li, Chang Su, and Chunxiu Gong. Cyp24a1 and slc34a1 mutations in five cases with idiopathic infantile hypercalcemia. SSRN Electronic Journal, Oct 2022. URL: https://doi.org/10.2139/ssrn.4257523, doi:10.2139/ssrn.4257523. This article has 0 citations.
(gurevich2023idiopathicinfantilehypercalcemia pages 1-2): Evgenia Gurevich, Yael Borovitz, Shelli Levi, Sharon Perlman, and Daniel Landau. Idiopathic infantile hypercalcemia in children with chronic kidney disease due to kidney hypodysplasia. Pediatric Nephrology, 38:1067-1073, Sep 2023. URL: https://doi.org/10.1007/s00467-022-05740-w, doi:10.1007/s00467-022-05740-w. This article has 0 citations and is from a domain leading peer-reviewed journal.
(bizereamoga2023phenotypeofidiopathic pages 4-6): Teofana Otilia Bizerea-Moga, Flavia Chisavu, Cristina Ilies, Orsolya Olah, Otilia Marginean, Mihai Gafencu, Gabriela Doros, and Ramona Stroescu. Phenotype of idiopathic infantile hypercalcemia associated with the heterozygous pathogenic variant of slc34a1 and cyp24a1. Children, 10:1701, Oct 2023. URL: https://doi.org/10.3390/children10101701, doi:10.3390/children10101701. This article has 8 citations.