Metaphyseal Chondrodysplasia, Jansen Type

Mendelian MONDO:0007982 Pathograph 20 Show in embeddings browser Skeletal Dysplasia Metaphyseal Chondrodysplasia Disorder of Calcium Homeostasis

Jansen metaphyseal chondrodysplasia is an ultra-rare autosomal dominant skeletal dysplasia caused by heterozygous activating missense variants in PTH1R, the PTH/PTHrP receptor. The mutant receptor signals constitutively through Gs-alpha in the complete absence of ligand, and that one lesion accounts for both halves of the disease. In the growth plate, PTH1R signalling normally holds chondrocytes in proliferation and delays hypertrophy; locked on, it delays hypertrophy pathologically, producing metaphyseal widening, bowed limbs and severe short stature. In kidney and bone, the same constitutive signal produces hypercalcaemia and hypercalciuria with low or suppressed PTH — a PTH-independent hypercalcaemia that is close to unique among skeletal dysplasias and is the diagnostic signature. Two features make this entry mechanistically unusual. The severity tracks the intrinsic constitutive activity of the specific allele rather than being uniform, so genotype predicts phenotype in a way most dominant dysplasias do not. And the downstream transcriptional route is now identified: constitutive PTH1R inhibits salt-inducible kinases SIK2 and SIK3, de-repressing class IIa histone deacetylases, and combined Sik2/Sik3 deletion phenocopies the constitutively active receptor. There is no approved disease-specific therapy; PTH1R inverse-agonist peptides that suppress basal signalling are the leading mechanism-directed strategy.

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1
Definitions
1
Inheritance
9
Pathophys.
14
Phenotypes
2
Gaps
20
Pathograph
1
Genes
2
Variants
5
Medical Actions
2
Differentials
4
Models
3
References
1
Deep Research
📘

Definitions

1
PTH1R-JMC diagnostic criteria
Established in a proband with characteristic clinical and radiographic findings plus a heterozygous pathogenic PTH1R variant. Hypercalcaemia with low-normal or suppressed PTH is the biochemical signature, but it is not reliably present at every age — which is the diagnostic trap this entry records.
CASE_DEFINITION Disease-level ascertainment.
Show evidence (1 reference)
PMID:40638774 SUPPORT Human Clinical
"The diagnosis of PTH1R-JMC is established in a proband with characteristic clinical and radiographic findings and a heterozygous pathogenic variant in PTH1R identified by molecular genetic testing."
GeneReviews states the diagnostic criteria.
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
Most cases are de novo; transmission from an affected heterozygous parent is documented, including a father and two sons carrying T410R.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:40638774 SUPPORT Human Clinical
"PTH1R-JMC is inherited in an autosomal dominant manner. Although some individuals diagnosed with PTH1R-JMC have the disorder as the result of a pathogenic variant inherited from a heterozygous parent manifesting the skeletal features of the disorder, most individuals have the disorder as the..."
GeneReviews states the mode of inheritance and the predominance of de novo variants.
PMID:40638774 SUPPORT Human Clinical
"Each child of an individual with PTH1R-JMC has a 50% chance of inheriting the PTH1R pathogenic variant."
Gives the transmission risk that follows from the dominant mode, which is what genetic counseling actually turns on.
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Discussions and Knowledge Gaps

2
Does the intrinsic constitutive activity of each PTH1R allele quantitatively predict clinical severity, and if so can it be used prospectively?
KNOWLEDGE GAP allele_specific_constitutive_activity_sets_severity
Attached to
pathophysiology#Constitutively Active PTH1R
The ingredients for a dose-response account are present and the account has not been made. Five mutants show varying degrees of constitutive cAMP signalling in reporter cells; separately, adult height was below the third centile in every patient except the T410R carriers. Those two observations are consistent with severity tracking basal activity, but they have not been fitted against each other, and with 24 patients across five alleles — 18 of them a single allele — the series cannot support it. Two things would need separating: whether basal activity predicts severity at all, and whether it predicts the skeletal and renal arms to the same degree, which is not obvious given that they act through different tissues. Until that is done, genotype cannot be used prospectively to counsel a newly diagnosed infant.
Show evidence (2 references)
PMID:29788189 SUPPORT In Vitro
"The five PTHR1 mutants showed varying degrees of constitutive and PTH-stimulated cAMP signaling activity when expressed in HEK293 reporter cells."
The in vitro half of the proposed relationship.
PMID:29788189 SUPPORT Human Clinical
"Adult heights were well below the 3rd percentile for all patients, except for those with the T410R mutation."
The clinical half, and the single data point that suggests the two are related.
PTH1R inverse agonists suppress basal signalling of every JMC mutant in vitro. What would a clinical trial in an ultra-rare disease with an age-dependent biochemical endpoint and an irreversible skeletal one actually measure?
KNOWLEDGE GAP inverse_agonist_translation
Attached to
pathophysiology#Ligand-Independent Gs-alpha and cAMP Signaling
This is the one mechanism-directed strategy for JMC and the pharmacology is encouraging: the inverse agonist reduced basal cAMP signalling for each of the five mutant receptors, so it acts on the lesion rather than a consequence. The difficulty is on the trial side, and it is structural rather than pharmacological. Serum calcium, the obvious biomarker, is normal in most infants and normalises in adults, so it is only informative in a window; urinary calcium/creatinine is elevated in both children and adults and is the better candidate. Adult height is a decisive endpoint but takes two decades and is unavailable to anyone diagnosed late. And nephrocalcinosis, the complication that accumulates, is what a trial would most want to prevent and is the slowest to read out. An endpoint strategy is a prerequisite here, not an afterthought.
Show evidence (2 references)
PMID:29788189 SUPPORT In Vitro
"reduced basal cAMP signaling for each PTHR1 mutant"
Establishes that the strategy works against every reported allele in vitro, which is what makes the translational question the live one.
PMID:29788189 SUPPORT Human Clinical
"Urinary calcium/creatinine (mg/mg) were consistently elevated (children, 0.80 ± 0.40; adults, 0.28 ± 0.19)."
The one mineral-ion measure that is abnormal across all ages, and therefore the most usable candidate endpoint.
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Pathophysiology

9
Constitutively Active PTH1R
Genetic context PTH1R hgnc:9608 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns PTH1R (hgnc:9608). hgnc:9608 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: DE_NOVO zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION
Heterozygous activating missense variants at H223, T410 or I458 stabilise the active receptor conformation. Most arise de novo; inherited cases are documented.
constitutively active PTH/PTHrP receptor activity GO:0004991 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves constitutively active PTH/PTHrP receptor activity, annotated with parathyroid hormone receptor activity (GO:0004991), qualified as gain of function. GO:0004991 is a molecular function from the Gene Ontology. ⇑ GAIN OF FUNCTION
Downstream
Ligand-Independent Gs-alpha and cAMP Signaling The stabilised active receptor drives basal Gs-alpha coupling and cAMP accumulation with no hormone present.
Show evidence (1 reference)
PMID:7701349 SUPPORT In Vitro
"Constitutive, ligand-independent adenosine 3',5'-monophosphate accumulation was observed in COS-7 cells expressing the mutant PTH-PTHrP receptor but not in cells expressing the wild-type receptor."
Direct demonstration of ligand-independent activity, with the wild-type control that makes it a gain of function rather than a measurement artefact.
Ligand-Independent Gs-alpha and cAMP Signaling
Basal Gs-alpha activation with elevated cAMP. Gs-alpha is the critical mediator of PTH1R action in growth-plate chondrocytes: chondrocyte-specific Gs-alpha knockout accelerates hypertrophy, the mirror image of what constitutive receptor activity does.
adenylate cyclase-activating G protein-coupled receptor signaling pathway GO:0007189 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), qualified as gain of function. GO:0007189 is a biological process from the Gene Ontology. ⇑ GAIN OF FUNCTION
Downstream
SIK2/SIK3 Inhibition and Class IIa HDAC De-repression cAMP-dependent signalling inhibits salt-inducible kinases, which are the kinases that transduce PTH1R's skeletal actions.
Renal and Skeletal Calcium Mobilization The same constitutive signal in kidney and bone drives calcium reabsorption and release, producing hypercalcaemia without PTH.
Show evidence (1 reference)
PMID:15765186 SUPPORT Model Organism
"These results show that G(s)alpha negatively regulates chondrocyte differentiation and is the critical signaling mediator of the PTH/PTH-rP receptor in growth plate chondrocytes."
Establishes Gs-alpha as the mediator through which the receptor acts on chondrocyte differentiation.
SIK2/SIK3 Inhibition and Class IIa HDAC De-repression
The transcriptional route from receptor to skeletal phenotype. SIK inhibition de-represses class IIa histone deacetylases, and the genetic evidence for this being the operative path is unusually strong: combined Sik2/Sik3 deletion in osteoblasts and osteocytes produces a skeletal and molecular phenotype closely resembling that of the constitutively active PTH1R that causes JMC. That is a phenocopy in the direction that matters — removing the kinase reproduces the disease.
growth plate chondrocyte CL:1000217 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves growth plate chondrocyte, annotated with growth plate cartilage chondrocyte (CL:1000217). CL:1000217 is a cell type from the Cell Ontology. osteocyte CL:0000137 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteocyte (CL:0000137). CL:0000137 is a cell type from the Cell Ontology.
Animal models
Humanized T410R-PTH1R knock-in mouse Mouse recapitulates This model supplies the decisive in vivo test of the SIK-HDAC route: genetic ablation of Hdac4 rescues the growth plate abnormalities, which is an epistasis result rather than a correlation.
Sik2/Sik3 double-knockout mouse Mouse recapitulates Combined Sik2/Sik3 deletion produces a skeletal and molecular phenotype closely resembling that of the constitutively active PTH1R.
Downstream
Delayed Growth Plate Chondrocyte Hypertrophy The de-repressed transcriptional program holds chondrocytes in proliferation and delays their differentiation into hypertrophic cells.
Show evidence (2 references)
PMID:31430259 SUPPORT Model Organism
"Combined deletion of Sik2 and Sik3 in osteoblasts and osteocytes led to a dramatic increase in bone mass that closely resembled the skeletal and molecular phenotypes observed when these bone cells express a constitutively active PTH1R that causes Jansen's metaphyseal chondrodysplasia."
The phenocopy result placing SIK inhibition on the causal path.
PMID:31430259 SUPPORT Model Organism
"genetic evidence demonstrated that class IIa histone deacetylases were key PTH1R-regulated SIK substrates in both chondrocytes and osteocytes"
Identifies the downstream substrate in both affected cell types.
Delayed Growth Plate Chondrocyte Hypertrophy
Chondrocytes fail to progress to hypertrophy on schedule, disorganising the growth plate and producing the metaphyseal widening and irregularity that name the disease. In the normal PTHrP-Indian hedgehog feedback loop this delay is a regulated, transient signal; here it is permanent.
growth plate chondrocyte CL:1000217 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves growth plate chondrocyte, annotated with growth plate cartilage chondrocyte (CL:1000217). CL:1000217 is a cell type from the Cell Ontology. hypertrophic chondrocyte CL:0000743 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hypertrophic chondrocyte (CL:0000743). CL:0000743 is a cell type from the Cell Ontology.
growth plate cartilage chondrocyte differentiation GO:0003418 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased growth plate cartilage chondrocyte differentiation (GO:0003418). GO:0003418 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Humanized H223R-PTH1R knock-in mouse Mouse recapitulates Growth plates show markedly expanded proliferating and prehypertrophic zones with progressive loss of type X collagen-positive hypertrophic chondrocytes - the delayed-maturation lesion, seen directly.
Jansen H223R-PTH1R transgenic mouse Mouse recapitulates Expressing the human JMC allele in growth-plate chondrocytes reproduces the delayed-hypertrophy phenotype and rescues receptor-null mice.
Downstream
Short-Limbed Short Stature and Skeletal Deformity Disordered endochondral bone formation produces metaphyseal widening, bowed long bones, scoliosis and severe short stature.
Show evidence (1 reference)
PMID:16831900 SUPPORT Other
"PTHrP action keeps chondrocytes proliferating and delays their further differentiation."
Names the effect of the signalling pathway on chondrocyte maturation.
Renal and Skeletal Calcium Mobilization
Constitutive PTH1R signalling in kidney and bone raises serum calcium and lowers phosphate with low or suppressed PTH. Bone histomorphometry in two H223R patients shows what this looks like in tissue: increased osteoid with prolonged maturation, intense cortical osteoclast activity, marrow fibrosis, osteoid buildup within osteocyte lacunae, a shortened and sparser canalicular network, enhanced FGF23 and diminished sclerostin staining.
osteocyte CL:0000137 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteocyte (CL:0000137). CL:0000137 is a cell type from the Cell Ontology. osteoblast CL:0000062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoblast (CL:0000062). CL:0000062 is a cell type from the Cell Ontology.
Animal models
Humanized T410R-PTH1R knock-in mouse Mouse recapitulates Serum calcium is elevated and endogenous PTH suppressed, reproducing the PTH-independent hypercalcaemia that defines the human disease.
Downstream
Hypercalciuria Sustained hypercalcaemia raises the filtered calcium load and produces persistent hypercalciuria.
Show evidence (2 references)
PMID:39950977 SUPPORT Human Clinical
"Both patients with JMC displayed irregular bone architecture, increased osteoid, and a prolonged osteoid maturation process."
Direct histomorphometric observation in patient bone.
PMID:39950977 SUPPORT Human Clinical
"Remarkably, osteocytes in samples from patients with JMC had osteoid buildup within their lacunae and canaliculi that were both shorter and less abundant."
The osteocyte-level lesion, which is where the constitutive receptor signal is being read out.
Short-Limbed Short Stature and Skeletal Deformity
The skeletal endpoint: short-limb short stature with joint swelling, bowed lower limbs, scoliosis, and characteristic craniofacial and dental features. Intelligence is normal.
Show evidence (1 reference)
PMID:40638774 SUPPORT Human Clinical
"PTH1R-related Jansen metaphyseal chondrodysplasia (PTH1R-JMC) is characterized by short-limb short stature with swelling of the joints in the extremities, bowing of the lower extremities, mild-to-severe scoliosis, hypercalcemia with low-normal or suppressed parathyroid hormone, and kidney stones."
GeneReviews' summary of the clinical phenotype.
Hypercalciuria
The filtered calcium load rises with the serum calcium. Unlike serum calcium, urinary calcium/creatinine is consistently elevated in both children and adults, which is what makes it the durable marker of disease activity.
Downstream
Nephrocalcinosis Sustained calcium excretion deposits calcium in the renal parenchyma.
Show evidence (1 reference)
PMID:29788189 SUPPORT Human Clinical
"Urinary calcium/creatinine (mg/mg) were consistently elevated (children, 0.80 ± 0.40; adults, 0.28 ± 0.19)."
Documents persistent hypercalciuria across both age groups.
Nephrocalcinosis
Calcium deposition in the renal parenchyma, present in most patients in the largest cohort. This is the lesion that accumulates: serum calcium normalises in adults, and nephrocalcinosis does not.
Downstream
Chronic Kidney Disease Accumulated nephrocalcinosis progresses over years to impaired renal function.
Show evidence (1 reference)
PMID:29788189 SUPPORT Human Clinical
"Most patients with JMC had undergone orthopedic surgical procedures, most had nephrocalcinosis, and two had advanced chronic kidney disease."
Gives the frequency of nephrocalcinosis in the largest cohort.
Chronic Kidney Disease
Advanced chronic kidney disease occurred in two of the 24 patients in the largest cohort. It is the least reversible consequence of the disease and the main argument for lifelong calcium and renal surveillance.
Show evidence (1 reference)
PMID:29788189 SUPPORT Human Clinical
"most had nephrocalcinosis, and two had advanced chronic kidney disease"
Gives the observed frequency of advanced renal disease.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Metaphyseal Chondrodysplasia, Jansen Type Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

14
Cardiovascular 1
Hypertension HP:0000822 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertension (HP:0000822). HP:0000822 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40638774 SUPPORT INDIRECT Human Clinical
"drugs targeting the angiotensin receptor pathway as needed for elevated blood pressure"
GeneReviews carries a disorder-specific treatment recommendation for elevated blood pressure, which is independent of the single case report and is what makes this more than a one-patient observation. Graded INDIRECT because the quote instructs clinicians to treat elevated blood pressure and the phenotype claim follows from that by one inference step, rather than being asserted outright.
PMID:31977144 SUPPORT INDIRECT Human Clinical
"We report on a patient presenting in the neonatal period with clinical signs of JMC in addition to severe hypertension. A pathogenic mutation in PTH1R was demonstrated, but investigations for hypertension yielded normal results."
A single neonate with molecularly confirmed JMC and severe hypertension whose secondary workup was negative. Graded INDIRECT because one case with a negative workup is consistent with, but does not establish, a causal link to the receptor defect.
Genitourinary 4
Hypercalciuria VERY_FREQUENT HP:0002150 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypercalciuria (HP:0002150). HP:0002150 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29788189 SUPPORT Human Clinical
"Urinary calcium/creatinine (mg/mg) were consistently elevated (children, 0.80 ± 0.40; adults, 0.28 ± 0.19)."
Reports consistent elevation across both age groups, unlike serum calcium.
Nephrocalcinosis FREQUENT HP:0000121 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nephrocalcinosis (HP:0000121). HP:0000121 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29788189 SUPPORT Human Clinical
"Most patients with JMC had undergone orthopedic surgical procedures, most had nephrocalcinosis, and two had advanced chronic kidney disease."
"Most" supports a FREQUENT band in the largest cohort.
Nephrolithiasis HP:0000787 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nephrolithiasis (HP:0000787). HP:0000787 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40638774 SUPPORT Human Clinical
"hypercalcemia with low-normal or suppressed parathyroid hormone, and kidney stones"
GeneReviews names kidney stones among the defining features.
Chronic kidney disease OCCASIONAL HP:0012622 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic kidney disease (HP:0012622). HP:0012622 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29788189 SUPPORT Human Clinical
"Most patients with JMC had undergone orthopedic surgical procedures, most had nephrocalcinosis, and two had advanced chronic kidney disease."
Two of the 24 patients in the largest cohort had advanced chronic kidney disease, which places the frequency in the OCCASIONAL band.
Head and Neck 3
Delayed tooth eruption Delayed eruption of teeth HP:0000684 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed eruption of teeth (HP:0000684). HP:0000684 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40638774 SUPPORT Human Clinical
"Dental manifestations include delayed eruption with impaction, crowding, and malocclusion."
GeneReviews enumerates the dental phenotype.
Dental malocclusion HP:0000689 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dental malocclusion (HP:0000689). HP:0000689 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40638774 SUPPORT Human Clinical
"Dental manifestations include delayed eruption with impaction, crowding, and malocclusion."
GeneReviews names malocclusion among the dental manifestations.
Prominent forehead HP:0011220 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prominent forehead (HP:0011220). HP:0011220 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40638774 SUPPORT Human Clinical
"Craniofacial features can include scaphocephaly, prominent forehead and supraorbital ridge, downslanted palpebral fissures, hypertelorism, telecanthus, wide nasal bridge, low-set ears, and retrognathia."
GeneReviews enumerates the craniofacial features.
Limbs 2
Metaphyseal widening HP:0003016 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metaphyseal widening (HP:0003016). HP:0003016 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40638774 SUPPORT Human Clinical
"Radiographs show bowing of the long bones, flaring or widening of the metaphyses, short phalanges, sclerosis of the skull base, fragmented vertebra, and, in some individuals, scoliosis."
GeneReviews lists metaphyseal widening among the radiographic findings.
Bowing of the legs HP:0002979 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bowing of the legs (HP:0002979). HP:0002979 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40638774 SUPPORT Human Clinical
"short-limb short stature with swelling of the joints in the extremities, bowing of the lower extremities, mild-to-severe scoliosis"
GeneReviews names bowing of the lower extremities as a defining feature.
Metabolism 2
Joint swelling HP:0001386 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint swelling (HP:0001386). HP:0001386 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40638774 SUPPORT Human Clinical
"short-limb short stature with swelling of the joints in the extremities, bowing of the lower extremities, mild-to-severe scoliosis"
GeneReviews names joint swelling among the defining clinical features.
Hypercalcemia HP:0003072 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypercalcemia (HP:0003072). HP:0003072 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40638774 SUPPORT Human Clinical
"hypercalcemia with low-normal or suppressed parathyroid hormone, and kidney stones"
GeneReviews states the hypercalcaemia and its PTH-independent character.
PMID:29788189 SUPPORT Human Clinical
"Postnatal calcium levels were normal in most patients, but elevated between 0.15 and 10 years (11.8 ± 1.37 mg/dL) and tended to normalize in adults (10.0 ± 1.03 mg/dL)."
Quantifies the age dependence, which is what limits the phenotype's diagnostic reliability.
Musculoskeletal 1
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40638774 SUPPORT Human Clinical
"short-limb short stature with swelling of the joints in the extremities, bowing of the lower extremities, mild-to-severe scoliosis"
GeneReviews names mild-to-severe scoliosis among the defining features.
Growth 1
Short stature VERY_FREQUENT HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29788189 SUPPORT Human Clinical
"Adult heights were well below the 3rd percentile for all patients, except for those with the T410R mutation."
Gives the frequency and the one genotype exception.
🧬

Genetic Associations

1
PTH1R
Gene: PTH1R hgnc:9608 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PTH1R (hgnc:9608). hgnc:9608 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:29788189 SUPPORT Human Clinical
"Five different activating PTH/PTH-related peptide (PTHrP) receptor (PTHR1) mutations have been reported as causes of Jansen metaphyseal chondrodysplasia (JMC), a rare disorder characterized by severe growth plate abnormalities and PTH-independent hypercalcemia."
Establishes the allelic spectrum and the two-part phenotype it causes.
PMID:29788189 SUPPORT In Vitro
"The five PTHR1 mutants showed varying degrees of constitutive and PTH-stimulated cAMP signaling activity when expressed in HEK293 reporter cells."
The functional measurement underpinning the allele-severity relationship.
PMID:7701349 SUPPORT Human Clinical
"A single heterozygous nucleotide exchange in exon M2 of the gene encoding the parathyroid hormone-parathyroid hormone-related peptide (PTH-PTHrP) receptor was identified in a patient with Jansen-type metaphyseal chondrodysplasia, which changes a strictly conserved histidine residue at position..."
The founding report identifying H223R and its structural location.
Variants (2)
PTH1R H223R
A histidine-to-arginine substitution at a strictly conserved residue in the first intracellular loop; the original and by far the commonest JMC allele.
PTH1R T410R
The milder allele. Transmitted through a father and two sons, and the only genotype in the series whose carriers reached adult heights at or above the third centile.
💊

Medical Actions

5
Hydration to Reduce Stone and Nephrocalcinosis Risk
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Behavioral / lifestyle
Generous fluid intake to reduce the risk of hypercalcaemia, hypercalciuria, nephrolithiasis and nephrocalcinosis. Simple, and the first line against the complication that accumulates irreversibly.
Mechanism Target:
MODULATES Nephrocalcinosis — Dilution reduces the urinary supersaturation that drives stone formation and nephrocalcinosis; it does not affect the calcium load itself.
Show evidence (1 reference)
PMID:40638774 SUPPORT Human Clinical
"intake of plenty of fluids to reduce risk of hypercalcemia, hypercalciuria, nephrolithiasis, and nephrocalcinosis"
GeneReviews states the intervention and its target complications.
Show evidence (1 reference)
PMID:40638774 SUPPORT Human Clinical
"intake of plenty of fluids to reduce risk of hypercalcemia, hypercalciuria, nephrolithiasis, and nephrocalcinosis"
GeneReviews management recommendation.
Bisphosphonate Therapy for Severe Hypercalcemia
Action: Bisphosphonate TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Bisphosphonate Therapy (NCIT:C198585). NCIT:C198585 is a clinical intervention from the NCI Thesaurus. NCIT:C198585
Platform: Small molecule
Considered for severe hypercalcaemia. Alendronate has been reported to control hypercalciuria in an adult with JMC. This addresses the consequence rather than the receptor.
Mechanism Target:
INHIBITS Renal and Skeletal Calcium Mobilization — Bisphosphonates suppress osteoclast-mediated bone resorption, reducing the skeletal contribution to the calcium load without touching the constitutive receptor signal.
Show evidence (1 reference)
PMID:22278430 SUPPORT Human Clinical
"Treatment with alendronate reduced hypercalciuria; however, normocalciuria was only obtained with the association of thiazide diuretic."
Shows the partial effect of bisphosphonate alone on the calcium phenotype, and that a thiazide was needed to normalise it. The incompleteness is the point: neither drug touches the receptor.
Show evidence (1 reference)
PMID:40638774 SUPPORT Human Clinical
"consider bisphosphonates if necessary for severe hypercalcemia"
GeneReviews states the indication, with its own conditional framing.
Thiazide Diuretic for Hypercalciuria
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: thiazide diuretic NCIT:C49185 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses thiazide diuretic (NCIT:C49185). NCIT:C49185 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Thiazides reduce urinary calcium excretion by increasing distal tubular reabsorption. In the one long-term follow-up available, alendronate alone reduced hypercalciuria but only the addition of a thiazide achieved normocalciuria - which is why it is curated as its own treatment rather than folded into the bisphosphonate entry.
Mechanism Target:
INHIBITS Hypercalciuria — Increased distal tubular calcium reabsorption lowers urinary calcium, acting on the excretion step rather than on the calcium load.
Show evidence (1 reference)
PMID:22278430 SUPPORT Human Clinical
"Treatment with alendronate reduced hypercalciuria; however, normocalciuria was only obtained with the association of thiazide diuretic."
Establishes the thiazide as the component that achieved normocalciuria.
Show evidence (1 reference)
PMID:22278430 SUPPORT Human Clinical
"Asymptomatic nephrolithiasis was diagnosed at 18 yr of age, prompting pharmacological management of hypercalciuria."
Gives the clinical trigger for treating hypercalciuria pharmacologically.
Orthopedic Surgery for Limb Deformity and Scoliosis
Action: Orthopedic Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Orthopedic Surgical Procedure (NCIT:C16186). NCIT:C16186 is a clinical intervention from the NCI Thesaurus. NCIT:C16186
Platform: Surgery
Most patients in the largest series had undergone orthopaedic surgical procedures. GeneReviews directs treatment of severe limb deformity and scoliosis to an orthopaedist.
Mechanism Target:
BYPASSES Short-Limbed Short Stature and Skeletal Deformity — Surgery corrects established deformity without altering the growth-plate lesion producing it, so it is a structural correction rather than a disease-modifying one.
Show evidence (1 reference)
PMID:29788189 SUPPORT Human Clinical
"Most patients with JMC had undergone orthopedic surgical procedures"
Documents that this is the usual course for the skeletal phenotype.
Show evidence (1 reference)
PMID:40638774 SUPPORT Human Clinical
"treatment of severe limb deformity and scoliosis per orthopedist"
GeneReviews management recommendation.
Physical Therapy and Mobility Support
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Platform: Behavioral / lifestyle
Show evidence (1 reference)
PMID:40638774 SUPPORT Human Clinical
"Physical therapy, shoe lifts for limb length discrepancy, assisted devices for mobility, or surgical intervention as indicated"
GeneReviews states the supportive management for mobility.
🔬

Biochemical Markers

2
Serum calcium (INCREASED)
Show evidence (1 reference)
PMID:29788189 SUPPORT Human Clinical
"Postnatal calcium levels were normal in most patients, but elevated between 0.15 and 10 years (11.8 ± 1.37 mg/dL) and tended to normalize in adults (10.0 ± 1.03 mg/dL)."
Gives the analyte values by age band.
Serum phosphate (DECREASED)
Show evidence (1 reference)
PMID:29788189 SUPPORT Human Clinical
"Mean phosphate levels were at the lower end of the age-specific normal ranges."
States the analyte finding with the hedge the authors used.
🔬

Diagnosis

4
Serum calcium, phosphate and PTH
The combination is what diagnoses, not any single value: hypercalcaemia with a low-normal or suppressed PTH. A raised calcium with a raised PTH is hyperparathyroidism, not this. Note the age dependence recorded in progression - normal calcium in an infant or an adult does not exclude JMC.
Show evidence (1 reference)
PMID:40638774 SUPPORT Human Clinical
"hypercalcemia with low-normal or suppressed parathyroid hormone, and kidney stones"
States the discriminating biochemical combination.
Skeletal radiographs
Radiographs carry the diagnosis when the biochemistry does not, which is most of infancy. The findings are specific enough to be diagnostic in a child too young to be hypercalcaemic.
Show evidence (2 references)
PMID:40638774 SUPPORT Human Clinical
"Radiographs show bowing of the long bones, flaring or widening of the metaphyses, short phalanges, sclerosis of the skull base, fragmented vertebra, and, in some individuals, scoliosis."
Enumerates the radiographic findings that support the diagnosis.
PMID:27410178 SUPPORT Human Clinical
"We therefore sought to provide radiographic findings supporting this diagnosis early in life."
States the purpose of the radiographic series: diagnosing infants in whom the biochemistry is uninformative.
PTH1R molecular genetic testing
Definitive confirmation. Five recurrent variants at three residues account for reported disease, so targeted testing is high-yield.
Show evidence (1 reference)
PMID:40638774 SUPPORT Human Clinical
"a heterozygous pathogenic variant in PTH1R identified by molecular genetic testing"
GeneReviews states the confirmatory test.
Renal and mineral surveillance
Not diagnostic but the monitoring that prevents the disease's least reversible outcome: annual serum calcium, serum phosphorus and 24-hour urine calcium, plus annual kidney and urinary tract ultrasound.
Show evidence (1 reference)
PMID:40638774 SUPPORT Human Clinical
"annual laboratory assessment of serum calcium, serum phosphorus, and 24-hour urine calcium; annual kidney and urinary tract ultrasound"
GeneReviews surveillance schedule for the mineral and renal domains.
📈

Progression

3
Infancy and early childhood, before hypercalcaemia is reliable
Age: Birth to about 2 years
Postnatal calcium was normal in most patients, and only became elevated between 0.15 and 10 years. Establishing the diagnosis in infancy is therefore genuinely difficult, especially without a family history, and the radiographic findings rather than the biochemistry are what carry it. A normal calcium in an infant does not exclude JMC.
Show evidence (2 references)
PMID:29788189 SUPPORT Human Clinical
"Postnatal calcium levels were normal in most patients, but elevated between 0.15 and 10 years (11.8 ± 1.37 mg/dL) and tended to normalize in adults (10.0 ± 1.03 mg/dL)."
Documents the age-dependence of the defining biochemical abnormality.
PMID:27410178 SUPPORT Human Clinical
"Establishing the diagnosis of JMC during infancy or early childhood can be challenging, especially in the absence of family history and/or overt hypercalcemia."
States the diagnostic difficulty this phase is about.
Childhood hypercalcaemia and progressive skeletal deformity
Age: Roughly 2 to 10 years
Calcium is elevated through childhood, urinary calcium/creatinine is consistently raised, and skeletal deformity progresses. Most patients undergo orthopaedic surgery.
Show evidence (2 references)
PMID:29788189 SUPPORT Human Clinical
"Urinary calcium/creatinine (mg/mg) were consistently elevated (children, 0.80 ± 0.40; adults, 0.28 ± 0.19)."
Quantifies hypercalciuria across both age groups.
PMID:29788189 SUPPORT Human Clinical
"Most patients with JMC had undergone orthopedic surgical procedures, most had nephrocalcinosis, and two had advanced chronic kidney disease."
Documents the surgical and renal burden of the cohort.
Adulthood — calcium normalises, renal damage does not
Serum calcium tends to normalise in adults, which is the trap in the other direction: an adult with normal calcium may still be affected, as in the 38-year-old mother diagnosed only after both her sons were. What does not normalise is the accumulated renal injury — most patients had nephrocalcinosis and two had advanced chronic kidney disease — nor adult height, which was below the third percentile in every patient except those carrying the milder T410R allele.
Show evidence (2 references)
PMID:27410178 SUPPORT Human Clinical
"Surprisingly, however, the now 38-year-old mother was never overtly hypercalcemic and was therefore not diagnosed until her sons were found to be affected by JMC at the ages of 28 months and 40 days, respectively."
The worked case showing that the biochemical signature can be absent lifelong in a genetically affected adult.
PMID:29788189 SUPPORT Human Clinical
"Adult heights were well below the 3rd percentile for all patients, except for those with the T410R mutation."
Documents the adult stature outcome and its allele dependence.
🌍

Epidemiology

1
Ultra-rare, with the largest series comprising 24 patients
JMC is ultra-rare. The largest natural-history series assembled comprises 24 patients, in whom the H223R allele accounted for 18 and the remaining four alleles for the rest. No population rate has been published.
Show evidence (2 references)
PMID:29788189 SUPPORT Human Clinical
"Assess the natural history of clinical and laboratory findings in 24 patients with JMC and characterize the disease-causing mutant receptors in vitro."
Establishes the size of the largest assembled cohort. The number is stated in the study's objectives rather than its results because it describes the cohort assembled, not a finding measured in it.
PMID:29788189 SUPPORT Human Clinical
"The H223R mutation occurred in 18 patients. T410P, I458R and I458K each occurred in single cases; T410R was present in a father and his two sons."
Gives the allelic distribution across the cohort.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Metaphyseal Chondrodysplasia, Jansen Type:

Schmid metaphyseal chondrodysplasia
Overlapping Features The differential that actually arises at the bedside, where Blomstrand does not. Schmid is far commoner than JMC and shares the metaphyseal flaring and irregularity, so the radiographs alone do not separate them. What separates them is the biochemistry this entry stakes JMC's identity on: in Schmid and the other metaphyseal chondrodysplasias calcium and phosphorus metabolism is normal, whereas JMC is defined by PTH-independent hypercalcaemia with suppressed endogenous PTH. The radiographic picture is also mistaken for rickets, which is the error the cited case report documents.
Show evidence (2 references)
PMID:8644413 SUPPORT Human Clinical
"Other types are Schmid, Spahr, McKusick, Schwachman and Jansen, which can be separated by clinical, radiographic, genetic and biochemical criteria."
Places Schmid and Jansen in the same radiographic group and states that the separation rests on combined criteria rather than radiography alone.
PMID:8644413 SUPPORT Human Clinical
"The radiographic changes are similar to rickets, but calcium and phosphorus metabolism is normal."
Gives the discriminator: normal mineral metabolism in the rest of the group, against the hypercalcaemia that defines JMC.
Blomstrand lethal chondrodysplasia
Overlapping Features The mirror image at the same locus, and the most illuminating contrast in the disease's biology. Blomstrand is caused by homozygous or compound heterozygous PTH1R variants producing less-active or inactive receptors, and the growth plate phenotype runs the other way: accelerated chondrocyte differentiation and premature ossification, where JMC delays both. The two diseases bracket the receptor's dose-response and are not clinically confusable - Blomstrand is lethal in the perinatal period.
Show evidence (2 references)
PMID:10912527 SUPPORT Other
"Heterozygous PTH1R mutations that lead to constitutively activity were identified in Jansen metaphyseal chondrodysplasia, and homozygous or compound heterozygous mutations that lead to less-active or completely inactive receptors were identified in patients with Blomstrand lethal chondrodysplasia."
States both diseases at the same locus and the opposite direction of their receptor lesions.
PMID:10912527 SUPPORT Other
"Mice lacking PTHrP show accelerated chondrocyte differentiation, and thus premature ossification of those bones that are formed through an endochondral process, and similar but more-severe abnormalities are observed in PTH1R-ablated animals."
Gives the loss-of-function growth plate phenotype, which is the inverse of the JMC lesion this entry curates.
🐁

Animal Models

4
Humanized T410R-PTH1R knock-in mouse
The best available model, and the one that resolved the field's problem. Expressing the milder T410R allele from the endogenous locus gives mice with near-normal longevity and fertility - unlike the H223R humanized line, which dies early without breeding - while still showing misshapen long bones, expanded metaphyses, disarrayed chondrocyte zones, reduced primary spongiosa, elevated serum calcium and suppressed PTH. It reproduces both arms of the human disease in one animal, which no earlier model did.
Species
Mouse
Genotype
T410R-hPTH1R humanized knock-in
Publication
PMID:40455993
Pathograph links
SIK2/SIK3 Inhibition and Class IIa HDAC De-repression recapitulates fidelity: high This model supplies the decisive in vivo test of the SIK-HDAC route: genetic ablation of Hdac4 rescues the growth plate abnormalities, which is an epistasis result rather than a correlation.
Limitations: T410R is the mildest of the five human alleles, so quantitative severity does not transfer to H223R patients. The rescue is genetic ablation from conception, not a post-hoc intervention.
Readouts
Growth plate morphology after Hdac4 ablation
Direction: RESTORED
Interpretation: Removing the downstream HDAC restores the growth plate, placing the SIK-HDAC axis on the causal path rather than beside it.
Show evidence (1 reference)
PMID:40455993 SUPPORT Model Organism
"Genetic ablation of Hdac4 rescued the growth plate abnormalities in T410R mice, thereby establishing the PTH1R-Gαs-cAMP-PKA-SIK3-HDAC4/5 pathway as the main mediator of growth plate abnormalities in JMC."
The rescue experiment and the authors' own conclusion from it.
Show evidence (1 reference)
PMID:40455993 SUPPORT Model Organism
"Mutant mice show near-normal longevity and reproductive capacity yet exhibit a profound skeletal phenotype characteristic of the disease."
Establishes the model as viable and phenotypically faithful, which is what makes it usable for the mechanism test above.
Renal and Skeletal Calcium Mobilization recapitulates fidelity: high Serum calcium is elevated and endogenous PTH suppressed, reproducing the PTH-independent hypercalcaemia that defines the human disease.
Limitations: The allele is T410R, which in humans is the milder end of the spectrum and is not the common H223R; and murine mineral-ion handling differs from human in its calcium set point and renal phosphate response, so the magnitude of the abnormality does not transfer even though its direction and PTH-independence do.
Readouts
Serum calcium and endogenous PTH after PTH inverse agonist
Direction: RESTORED
Interpretation: Both parameters normalise on acute inverse-agonist injection, which is the first in vivo demonstration that the mineral-ion arm is pharmacologically reversible. The normalisation is reported after a single injection, so it establishes reversibility but says nothing about durability under chronic dosing.
Show evidence (1 reference)
PMID:40455993 SUPPORT Model Organism
"Serum calcium was elevated and endogenous PTH was suppressed in T410R mice, and both parameters could be normalized by acute injection of an optimized PTH inverse agonist peptide."
Reports both the baseline abnormality and its reversal.
Show evidence (1 reference)
PMID:40455993 SUPPORT Model Organism
"The T410R mouse thus represents a stable animal model of JMC that recapitulates the abnormalities in skeletal development and mineral ion homeostasis which characterize this disease."
The authors' summary that this model covers both arms of the disease.
Humanized H223R-PTH1R knock-in mouse
Expressing the common human allele from the endogenous locus, in all relevant target tissues. Its defining feature is severity: founders typically died within two months without reproducing, and F1 offspring were small with marked growth plate abnormalities. This model exists because the earlier transgenic lines did not work - promoter-restricted expression gave either excess bone mass or only minor growth plate change, and neither adequately recapitulated the human disease.
Species
Mouse
Genotype
H223R-hPTH1R expressed from the endogenous Pth1r promoter
Publication
PMID:37808400
Pathograph links
Delayed Growth Plate Chondrocyte Hypertrophy recapitulates fidelity: high Growth plates show markedly expanded proliferating and prehypertrophic zones with progressive loss of type X collagen-positive hypertrophic chondrocytes - the delayed-maturation lesion, seen directly.
Limitations: The line is barely viable: founders typically die within two months without reproducing, and only mosaic males produced offspring, which constrains what can be asked of it. Serum calcium and phosphate were not different from wild-type littermates, so this model does not reproduce the mineral-ion arm.
Readouts
Growth plate zone composition
Direction: ALTERED
Interpretation: Expanded proliferating/prehypertrophic zones with reduced hypertrophic chondrocytes is the histological signature of delayed maturation.
Show evidence (1 reference)
PMID:37808400 SUPPORT Model Organism
"revealed markedly expanded zones of type II collagen-positive, proliferating/prehypertrophic chondrocytes, abundant apoptotic cells in the growth plate center and a progressive reduction of type X collagen-positive hypertrophic chondrocytes and primary spongiosa"
The histological measurement behind this readout.
Show evidence (1 reference)
PMID:37808400 SUPPORT Model Organism
"We therefore generated "humanized" JMC mice in which the H223R-PTH1R allele was expressed via the endogenous mouse Pth1r promoter and, thus, in all relevant target tissues."
Establishes the design feature - endogenous, untargeted expression - that makes this model informative where the transgenics were not.
Sik2/Sik3 double-knockout mouse
A phenocopy model rather than a disease model, and the reason the SIK node is in this pathograph at all. Deleting the kinases that constitutively active PTH1R inhibits reproduces the JMC skeletal and molecular phenotype - that is, removing the brake from below does what jamming the receptor on does from above.
Species
Mouse
Genotype
Sik2 and Sik3 conditional double knockout in osteoblasts and osteocytes
Publication
PMID:31430259
Pathograph links
SIK2/SIK3 Inhibition and Class IIa HDAC De-repression recapitulates fidelity: moderate Combined Sik2/Sik3 deletion produces a skeletal and molecular phenotype closely resembling that of the constitutively active PTH1R.
Limitations: This is a phenocopy of the mechanism, not a model of the disease: the mice carry no PTH1R lesion, deletion is restricted to osteoblasts and osteocytes rather than chondrocytes, and no mineral-ion phenotype is reported. It cannot be used to test therapies, only to place the node.
Show evidence (1 reference)
PMID:31430259 SUPPORT Model Organism
"Combined deletion of Sik2 and Sik3 in osteoblasts and osteocytes led to a dramatic increase in bone mass that closely resembled the skeletal and molecular phenotypes observed when these bone cells express a constitutively active PTH1R that causes Jansen's metaphyseal chondrodysplasia."
The phenocopy result that places SIK inhibition on the causal path.
Jansen H223R-PTH1R transgenic mouse
Growth-plate-targeted expression of the constitutively active Jansen receptor delays chondrocyte differentiation, and it rescues the early lethality of PTHrP-null mice by preventing their accelerated chondrocyte differentiation. In PTH/PTHrP receptor-null mice the same transgene restored most bone abnormalities but did *not* prevent perinatal lethality, which the authors read as evidence that something besides the abnormal rib cage kills those animals. The informative part for JMC is the first result: a ligand-independent receptor substitutes for the ligand-dependent one in the growth plate and produces delay, which is what the human allele does.
Species
Mouse
Genotype
Collagen II promoter-driven H223R-PTH1R transgene
Publication
PMID:11713230
Pathograph links
Delayed Growth Plate Chondrocyte Hypertrophy recapitulates fidelity: moderate Expressing the human JMC allele in growth-plate chondrocytes reproduces the delayed-hypertrophy phenotype and rescues receptor-null mice.
Limitations: This is a transgenic overexpression model on a receptor-null background rather than a knock-in of the human heterozygous state, so expression level and cellular context differ from patients. It also addresses only the growth-plate arm; the mineral-ion and renal phenotypes are not what this model was built to test.
Show evidence (2 references)
PMID:11713230 SUPPORT Model Organism
"Expression of the Jansen transgene under the control of the type alpha1(II) collagen promoter was, furthermore, shown to delay chondrocyte differentiation and to prevent the dramatic acceleration of chondrocyte differentiation in PTHrP(-/-) mice, thus rescuing the early lethality of these animals."
Directly reports that the human Jansen allele, expressed in growth-plate chondrocytes, delays chondrocyte differentiation - the node this link targets.
+ 1 more reference
{ }

Source YAML

click to show 
name: Metaphyseal Chondrodysplasia, Jansen Type
creation_date: "2026-08-30T06:20:00Z"
category: Mendelian
parents:
- Skeletal Dysplasia
- Metaphyseal Chondrodysplasia
- Disorder of Calcium Homeostasis
synonyms:
- JMC
- Jansen metaphyseal chondrodysplasia
- PTH1R-related Jansen metaphyseal chondrodysplasia
- Murk Jansen type metaphyseal chondrodysplasia
- metaphyseal dysostosis, Jansen type
disease_term:
  preferred_term: metaphyseal chondrodysplasia, Jansen type
  term:
    id: MONDO:0007982
    label: metaphyseal chondrodysplasia, Jansen type
description: >-
  Jansen metaphyseal chondrodysplasia is an ultra-rare autosomal dominant
  skeletal dysplasia caused by heterozygous activating missense variants in
  PTH1R, the PTH/PTHrP receptor. The mutant receptor signals constitutively
  through Gs-alpha in the complete absence of ligand, and that one lesion
  accounts for both halves of the disease.

  In the growth plate, PTH1R signalling normally holds chondrocytes in
  proliferation and delays hypertrophy; locked on, it delays hypertrophy
  pathologically, producing metaphyseal widening, bowed limbs and severe short
  stature. In kidney and bone, the same constitutive signal produces
  hypercalcaemia and hypercalciuria with low or suppressed PTH — a
  PTH-independent hypercalcaemia that is close to unique among skeletal
  dysplasias and is the diagnostic signature.

  Two features make this entry mechanistically unusual. The severity tracks the
  intrinsic constitutive activity of the specific allele rather than being
  uniform, so genotype predicts phenotype in a way most dominant dysplasias do
  not. And the downstream transcriptional route is now identified: constitutive
  PTH1R inhibits salt-inducible kinases SIK2 and SIK3, de-repressing class IIa
  histone deacetylases, and combined Sik2/Sik3 deletion phenocopies the
  constitutively active receptor. There is no approved disease-specific therapy;
  PTH1R inverse-agonist peptides that suppress basal signalling are the leading
  mechanism-directed strategy.
definitions:
- name: PTH1R-JMC diagnostic criteria
  definition_type: CASE_DEFINITION
  description: >-
    Established in a proband with characteristic clinical and radiographic
    findings plus a heterozygous pathogenic PTH1R variant. Hypercalcaemia with
    low-normal or suppressed PTH is the biochemical signature, but it is not
    reliably present at every age — which is the diagnostic trap this entry
    records.
  scope: Disease-level ascertainment.
  evidence:
  - reference: PMID:40638774
    reference_title: PTH1R-Related Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of PTH1R-JMC is established in a proband with characteristic
      clinical and radiographic findings and a heterozygous pathogenic variant
      in PTH1R identified by molecular genetic testing.
    explanation: >-
      GeneReviews states the diagnostic criteria.
epidemiology:
- name: Ultra-rare, with the largest series comprising 24 patients
  description: >-
    JMC is ultra-rare. The largest natural-history series assembled comprises 24
    patients, in whom the H223R allele accounted for 18 and the remaining four
    alleles for the rest. No population rate has been published.
  evidence:
  - reference: PMID:29788189
    reference_title: Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Assess the natural history of clinical and laboratory findings in 24
      patients with JMC and characterize the disease-causing mutant receptors in
      vitro.
    explanation: >-
      Establishes the size of the largest assembled cohort. The number is stated
      in the study's objectives rather than its results because it describes the
      cohort assembled, not a finding measured in it.
  - reference: PMID:29788189
    reference_title: Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The H223R mutation occurred in 18 patients. T410P, I458R and I458K each
      occurred in single cases; T410R was present in a father and his two sons.
    explanation: >-
      Gives the allelic distribution across the cohort.
progression:
- phase: Infancy and early childhood, before hypercalcaemia is reliable
  age_range: Birth to about 2 years
  notes: >-
    Postnatal calcium was normal in most patients, and only became elevated
    between 0.15 and 10 years. Establishing the diagnosis in infancy is
    therefore genuinely difficult, especially without a family history, and the
    radiographic findings rather than the biochemistry are what carry it. A
    normal calcium in an infant does not exclude JMC.
  evidence:
  - reference: PMID:29788189
    reference_title: Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Postnatal calcium levels were normal in most patients, but elevated
      between 0.15 and 10 years (11.8 ± 1.37 mg/dL) and tended to normalize in
      adults (10.0 ± 1.03 mg/dL).
    explanation: >-
      Documents the age-dependence of the defining biochemical abnormality.
  - reference: PMID:27410178
    reference_title: Jansen Metaphyseal Chondrodysplasia due to Heterozygous H223R-PTH1R Mutations With or Without Overt Hypercalcemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Establishing the diagnosis of JMC during infancy or early childhood can be
      challenging, especially in the absence of family history and/or overt
      hypercalcemia.
    explanation: >-
      States the diagnostic difficulty this phase is about.
- phase: Childhood hypercalcaemia and progressive skeletal deformity
  age_range: Roughly 2 to 10 years
  notes: >-
    Calcium is elevated through childhood, urinary calcium/creatinine is
    consistently raised, and skeletal deformity progresses. Most patients
    undergo orthopaedic surgery.
  evidence:
  - reference: PMID:29788189
    reference_title: Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Urinary calcium/creatinine (mg/mg) were consistently elevated (children,
      0.80 ± 0.40; adults, 0.28 ± 0.19).
    explanation: >-
      Quantifies hypercalciuria across both age groups.
  - reference: PMID:29788189
    reference_title: Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most patients with JMC had undergone orthopedic surgical procedures, most
      had nephrocalcinosis, and two had advanced chronic kidney disease.
    explanation: >-
      Documents the surgical and renal burden of the cohort.
- phase: Adulthood — calcium normalises, renal damage does not
  notes: >-
    Serum calcium tends to normalise in adults, which is the trap in the other
    direction: an adult with normal calcium may still be affected, as in the
    38-year-old mother diagnosed only after both her sons were. What does not
    normalise is the accumulated renal injury — most patients had
    nephrocalcinosis and two had advanced chronic kidney disease — nor adult
    height, which was below the third percentile in every patient except those
    carrying the milder T410R allele.
  evidence:
  - reference: PMID:27410178
    reference_title: Jansen Metaphyseal Chondrodysplasia due to Heterozygous H223R-PTH1R Mutations With or Without Overt Hypercalcemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surprisingly, however, the now 38-year-old mother was never overtly
      hypercalcemic and was therefore not diagnosed until her sons were found to
      be affected by JMC at the ages of 28 months and 40 days, respectively.
    explanation: >-
      The worked case showing that the biochemical signature can be absent
      lifelong in a genetically affected adult.
  - reference: PMID:29788189
    reference_title: Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adult heights were well below the 3rd percentile for all patients, except
      for those with the T410R mutation.
    explanation: >-
      Documents the adult stature outcome and its allele dependence.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Most cases are de novo; transmission from an affected heterozygous parent is
    documented, including a father and two sons carrying T410R.
  evidence:
  - reference: PMID:40638774
    reference_title: PTH1R-Related Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PTH1R-JMC is inherited in an autosomal dominant manner. Although some
      individuals diagnosed with PTH1R-JMC have the disorder as the result of a
      pathogenic variant inherited from a heterozygous parent manifesting the
      skeletal features of the disorder, most individuals have the disorder as
      the result of a de novo pathogenic variant.
    explanation: >-
      GeneReviews states the mode of inheritance and the predominance of de novo
      variants.
  - reference: PMID:40638774
    reference_title: PTH1R-Related Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each child of an individual with PTH1R-JMC has a 50% chance of inheriting
      the PTH1R pathogenic variant.
    explanation: >-
      Gives the transmission risk that follows from the dominant mode, which is
      what genetic counseling actually turns on.
genetic:
- name: PTH1R
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: PTH1R
    term:
      id: hgnc:9608
      label: PTH1R
  notes: >-
    Five heterozygous activating missense variants at three residues account for
    reported JMC: H223R, T410P, T410R, I458R and I458K. H223R dominates
    numerically (18 of 24 in the largest series). Each renders the receptor
    constitutively active in a ligand-independent manner, and the five mutants
    show varying degrees of constitutive and PTH-stimulated cAMP signalling in
    reporter cells — which is the mechanistic basis for the genotype-phenotype
    relationship, since T410R patients were the only ones in the cohort whose
    adult height was not below the third centile.
  variants:
  - name: PTH1R H223R
    description: >-
      A histidine-to-arginine substitution at a strictly conserved residue in
      the first intracellular loop; the original and by far the commonest JMC
      allele.
  - name: PTH1R T410R
    description: >-
      The milder allele. Transmitted through a father and two sons, and the only
      genotype in the series whose carriers reached adult heights at or above
      the third centile.
  evidence:
  - reference: PMID:29788189
    reference_title: Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five different activating PTH/PTH-related peptide (PTHrP) receptor (PTHR1)
      mutations have been reported as causes of Jansen metaphyseal
      chondrodysplasia (JMC), a rare disorder characterized by severe growth
      plate abnormalities and PTH-independent hypercalcemia.
    explanation: >-
      Establishes the allelic spectrum and the two-part phenotype it causes.
  - reference: PMID:29788189
    reference_title: Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The five PTHR1 mutants showed varying degrees of constitutive and
      PTH-stimulated cAMP signaling activity when expressed in HEK293 reporter
      cells.
    explanation: >-
      The functional measurement underpinning the allele-severity relationship.
  - reference: PMID:7701349
    reference_title: A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A single heterozygous nucleotide exchange in exon M2 of the gene encoding
      the parathyroid hormone-parathyroid hormone-related peptide (PTH-PTHrP)
      receptor was identified in a patient with Jansen-type metaphyseal
      chondrodysplasia, which changes a strictly conserved histidine residue at
      position 223 in the receptor's first intracellular loop to arginine.
    explanation: >-
      The founding report identifying H223R and its structural location.
pathophysiology:
- name: Constitutively Active PTH1R
  biological_scale: MOLECULAR
  genetic_context:
    gene:
      preferred_term: PTH1R
      term:
        id: hgnc:9608
        label: PTH1R
    variant_origin: DE_NOVO
    zygosity: HETEROZYGOUS
    functional_impact_category: GAIN_OF_FUNCTION
    description: >-
      Heterozygous activating missense variants at H223, T410 or I458 stabilise
      the active receptor conformation. Most arise de novo; inherited cases are
      documented.
  molecular_functions:
  - preferred_term: constitutively active PTH/PTHrP receptor activity
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0004991
      label: parathyroid hormone receptor activity
  evidence:
  - reference: PMID:7701349
    reference_title: A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Constitutive, ligand-independent adenosine 3',5'-monophosphate
      accumulation was observed in COS-7 cells expressing the mutant PTH-PTHrP
      receptor but not in cells expressing the wild-type receptor.
    explanation: >-
      Direct demonstration of ligand-independent activity, with the wild-type
      control that makes it a gain of function rather than a measurement
      artefact.
  downstream:
  - target: Ligand-Independent Gs-alpha and cAMP Signaling
    causal_link_type: DIRECT
    description: >-
      The stabilised active receptor drives basal Gs-alpha coupling and cAMP
      accumulation with no hormone present.
    evidence:
    - reference: PMID:7701349
      reference_title: A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This finding explains the severe ligand-independent hypercalcemia and
        hypophosphatemia, and most likely the abnormal formation of endochondral
        bone, in this rare form of short-limbed dwarfism.
      explanation: >-
        The authors' own statement connecting constitutive signalling to both
        arms of the phenotype. Note their hedge on the skeletal arm is preserved
        in this entry's edge typing.
- name: Ligand-Independent Gs-alpha and cAMP Signaling
  biological_scale: MOLECULAR
  description: >-
    Basal Gs-alpha activation with elevated cAMP. Gs-alpha is the critical
    mediator of PTH1R action in growth-plate chondrocytes: chondrocyte-specific
    Gs-alpha knockout accelerates hypertrophy, the mirror image of what
    constitutive receptor activity does.
  biological_processes:
  - preferred_term: adenylate cyclase-activating G protein-coupled receptor signaling pathway
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0007189
      label: adenylate cyclase-activating G protein-coupled receptor signaling pathway
  evidence:
  - reference: PMID:15765186
    reference_title: Chondrocyte-specific knockout of the G protein G(s)alpha leads to epiphyseal and growth plate abnormalities and ectopic chondrocyte formation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These results show that G(s)alpha negatively regulates chondrocyte
      differentiation and is the critical signaling mediator of the PTH/PTH-rP
      receptor in growth plate chondrocytes.
    explanation: >-
      Establishes Gs-alpha as the mediator through which the receptor acts on
      chondrocyte differentiation.
  downstream:
  - target: SIK2/SIK3 Inhibition and Class IIa HDAC De-repression
    causal_link_type: DIRECT
    description: >-
      cAMP-dependent signalling inhibits salt-inducible kinases, which are the
      kinases that transduce PTH1R's skeletal actions.
    evidence:
    - reference: PMID:31430259
      reference_title: Salt-inducible kinases dictate parathyroid hormone 1 receptor action in bone development and remodeling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we showed that salt-inducible kinases (SIKs) are key kinases that
        control the skeletal actions downstream of PTH1R and that this GPCR,
        when activated, inhibited cellular SIK activity.
      explanation: >-
        States the kinase step and the direction of the effect.
  - target: Renal and Skeletal Calcium Mobilization
    causal_link_type: DIRECT
    description: >-
      The same constitutive signal in kidney and bone drives calcium
      reabsorption and release, producing hypercalcaemia without PTH.
    evidence:
    - reference: PMID:7701349
      reference_title: A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This finding explains the severe ligand-independent hypercalcemia and
        hypophosphatemia, and most likely the abnormal formation of endochondral
        bone, in this rare form of short-limbed dwarfism.
      explanation: >-
        Connects constitutive receptor signalling to the mineral-ion phenotype.
- name: SIK2/SIK3 Inhibition and Class IIa HDAC De-repression
  biological_scale: MOLECULAR
  description: >-
    The transcriptional route from receptor to skeletal phenotype. SIK
    inhibition de-represses class IIa histone deacetylases, and the genetic
    evidence for this being the operative path is unusually strong: combined
    Sik2/Sik3 deletion in osteoblasts and osteocytes produces a skeletal and
    molecular phenotype closely resembling that of the constitutively active
    PTH1R that causes JMC. That is a phenocopy in the direction that matters —
    removing the kinase reproduces the disease.
  cell_types:
  - preferred_term: growth plate chondrocyte
    term:
      id: CL:1000217
      label: growth plate cartilage chondrocyte
  - preferred_term: osteocyte
    term:
      id: CL:0000137
      label: osteocyte
  evidence:
  - reference: PMID:31430259
    reference_title: Salt-inducible kinases dictate parathyroid hormone 1 receptor action in bone development and remodeling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Combined deletion of Sik2 and Sik3 in osteoblasts and osteocytes led to a
      dramatic increase in bone mass that closely resembled the skeletal and
      molecular phenotypes observed when these bone cells express a
      constitutively active PTH1R that causes Jansen's metaphyseal
      chondrodysplasia.
    explanation: >-
      The phenocopy result placing SIK inhibition on the causal path.
  - reference: PMID:31430259
    reference_title: Salt-inducible kinases dictate parathyroid hormone 1 receptor action in bone development and remodeling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      genetic evidence demonstrated that class IIa histone deacetylases were key
      PTH1R-regulated SIK substrates in both chondrocytes and osteocytes
    explanation: >-
      Identifies the downstream substrate in both affected cell types.
  downstream:
  - target: Delayed Growth Plate Chondrocyte Hypertrophy
    causal_link_type: DIRECT
    description: >-
      The de-repressed transcriptional program holds chondrocytes in
      proliferation and delays their differentiation into hypertrophic cells.
    evidence:
    - reference: PMID:16831900
      reference_title: PTHrP and skeletal development.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        As chondrocytes go through a program of proliferation and then further
        differentiation into post-mitotic, hypertrophic chondrocytes, PTHrP
        action keeps chondrocytes proliferating and delays their further
        differentiation.
      explanation: >-
        States the normal function of the pathway whose constitutive activation
        produces this node.
- name: Delayed Growth Plate Chondrocyte Hypertrophy
  biological_scale: TISSUE
  description: >-
    Chondrocytes fail to progress to hypertrophy on schedule, disorganising the
    growth plate and producing the metaphyseal widening and irregularity that
    name the disease. In the normal PTHrP-Indian hedgehog feedback loop this
    delay is a regulated, transient signal; here it is permanent.
  cell_types:
  - preferred_term: growth plate chondrocyte
    term:
      id: CL:1000217
      label: growth plate cartilage chondrocyte
  - preferred_term: hypertrophic chondrocyte
    term:
      id: CL:0000743
      label: hypertrophic chondrocyte
  biological_processes:
  - preferred_term: growth plate cartilage chondrocyte differentiation
    modifier: DECREASED
    term:
      id: GO:0003418
      label: growth plate cartilage chondrocyte differentiation
  evidence:
  - reference: PMID:16831900
    reference_title: PTHrP and skeletal development.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PTHrP action keeps chondrocytes proliferating and delays their further
      differentiation.
    explanation: >-
      Names the effect of the signalling pathway on chondrocyte maturation.
  downstream:
  - target: Short-Limbed Short Stature and Skeletal Deformity
    causal_link_type: DIRECT
    description: >-
      Disordered endochondral bone formation produces metaphyseal widening,
      bowed long bones, scoliosis and severe short stature.
    evidence:
    - reference: PMID:40638774
      reference_title: PTH1R-Related Jansen Metaphyseal Chondrodysplasia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Radiographs show bowing of the long bones, flaring or widening of the
        metaphyses, short phalanges, sclerosis of the skull base, fragmented
        vertebra, and, in some individuals, scoliosis.
      explanation: >-
        The radiographic phenotype produced by this developmental lesion.
- name: Renal and Skeletal Calcium Mobilization
  biological_scale: ORGANISM
  description: >-
    Constitutive PTH1R signalling in kidney and bone raises serum calcium and
    lowers phosphate with low or suppressed PTH. Bone histomorphometry in two
    H223R patients shows what this looks like in tissue: increased osteoid with
    prolonged maturation, intense cortical osteoclast activity, marrow fibrosis,
    osteoid buildup within osteocyte lacunae, a shortened and sparser canalicular
    network, enhanced FGF23 and diminished sclerostin staining.
  cell_types:
  - preferred_term: osteocyte
    term:
      id: CL:0000137
      label: osteocyte
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  evidence:
  - reference: PMID:39950977
    reference_title: "Jansen's Disease: Bone Abnormalities Beyond Chondrodysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both patients with JMC displayed irregular bone architecture, increased
      osteoid, and a prolonged osteoid maturation process.
    explanation: >-
      Direct histomorphometric observation in patient bone.
  - reference: PMID:39950977
    reference_title: "Jansen's Disease: Bone Abnormalities Beyond Chondrodysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Remarkably, osteocytes in samples from patients with JMC had osteoid
      buildup within their lacunae and canaliculi that were both shorter and
      less abundant.
    explanation: >-
      The osteocyte-level lesion, which is where the constitutive receptor
      signal is being read out.
  downstream:
  - target: Hypercalciuria
    causal_link_type: DIRECT
    description: >-
      Sustained hypercalcaemia raises the filtered calcium load and produces
      persistent hypercalciuria.
    evidence:
    - reference: PMID:39950977
      reference_title: "Jansen's Disease: Bone Abnormalities Beyond Chondrodysplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Jansen metaphyseal chondrodysplasia (JMC) is an ultra-rare autosomal
        dominant disease that is caused by heterozygous, activating PTH1R
        mutations resulting in PTH- and PTHrP-independent hypercalcemia and
        hypercalciuria, leading to nephrocalcinosis and impaired renal function
        later in life.
      explanation: >-
        States the full renal chain from hypercalcaemia to impaired function.
- name: Short-Limbed Short Stature and Skeletal Deformity
  biological_scale: ORGANISM
  description: >-
    The skeletal endpoint: short-limb short stature with joint swelling, bowed
    lower limbs, scoliosis, and characteristic craniofacial and dental features.
    Intelligence is normal.
  evidence:
  - reference: PMID:40638774
    reference_title: PTH1R-Related Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PTH1R-related Jansen metaphyseal chondrodysplasia (PTH1R-JMC) is
      characterized by short-limb short stature with swelling of the joints in
      the extremities, bowing of the lower extremities, mild-to-severe scoliosis,
      hypercalcemia with low-normal or suppressed parathyroid hormone, and kidney
      stones.
    explanation: >-
      GeneReviews' summary of the clinical phenotype.
- name: Hypercalciuria
  biological_scale: ORGANISM
  description: >-
    The filtered calcium load rises with the serum calcium. Unlike serum
    calcium, urinary calcium/creatinine is consistently elevated in both
    children and adults, which is what makes it the durable marker of disease
    activity.
  evidence:
  - reference: PMID:29788189
    reference_title: Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Urinary calcium/creatinine (mg/mg) were consistently elevated (children,
      0.80 ± 0.40; adults, 0.28 ± 0.19).
    explanation: >-
      Documents persistent hypercalciuria across both age groups.
  downstream:
  - target: Nephrocalcinosis
    causal_link_type: DIRECT
    description: >-
      Sustained calcium excretion deposits calcium in the renal parenchyma.
    evidence:
    - reference: PMID:39950977
      reference_title: "Jansen's Disease: Bone Abnormalities Beyond Chondrodysplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        resulting in PTH- and PTHrP-independent hypercalcemia and hypercalciuria,
        leading to nephrocalcinosis and impaired renal function later in life
      explanation: >-
        States the causal step from hypercalciuria to nephrocalcinosis.
- name: Nephrocalcinosis
  biological_scale: TISSUE
  description: >-
    Calcium deposition in the renal parenchyma, present in most patients in the
    largest cohort. This is the lesion that accumulates: serum calcium
    normalises in adults, and nephrocalcinosis does not.
  evidence:
  - reference: PMID:29788189
    reference_title: Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most patients with JMC had undergone orthopedic surgical procedures, most
      had nephrocalcinosis, and two had advanced chronic kidney disease.
    explanation: >-
      Gives the frequency of nephrocalcinosis in the largest cohort.
  downstream:
  - target: Chronic Kidney Disease
    causal_link_type: DIRECT
    description: >-
      Accumulated nephrocalcinosis progresses over years to impaired renal
      function.
    evidence:
    - reference: PMID:39950977
      reference_title: "Jansen's Disease: Bone Abnormalities Beyond Chondrodysplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        leading to nephrocalcinosis and impaired renal function later in life
      explanation: >-
        States the progression to renal impairment and its late timing.
- name: Chronic Kidney Disease
  biological_scale: ORGANISM
  description: >-
    Advanced chronic kidney disease occurred in two of the 24 patients in the
    largest cohort. It is the least reversible consequence of the disease and
    the main argument for lifelong calcium and renal surveillance.
  evidence:
  - reference: PMID:29788189
    reference_title: Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      most had nephrocalcinosis, and two had advanced chronic kidney disease
    explanation: >-
      Gives the observed frequency of advanced renal disease.
phenotypes:
- category: Growth
  name: Short stature
  description: >-
    Short-limb short stature, below the third centile in adulthood in every
    patient except T410R carriers.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:29788189
    reference_title: Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adult heights were well below the 3rd percentile for all patients, except
      for those with the T410R mutation.
    explanation: >-
      Gives the frequency and the one genotype exception.
- category: Musculoskeletal
  name: Metaphyseal widening
  phenotype_term:
    preferred_term: Metaphyseal widening
    term:
      id: HP:0003016
      label: Metaphyseal widening
  evidence:
  - reference: PMID:40638774
    reference_title: PTH1R-Related Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiographs show bowing of the long bones, flaring or widening of the
      metaphyses, short phalanges, sclerosis of the skull base, fragmented
      vertebra, and, in some individuals, scoliosis.
    explanation: >-
      GeneReviews lists metaphyseal widening among the radiographic findings.
- category: Musculoskeletal
  name: Bowing of the legs
  phenotype_term:
    preferred_term: Bowing of the legs
    term:
      id: HP:0002979
      label: Bowing of the legs
  evidence:
  - reference: PMID:40638774
    reference_title: PTH1R-Related Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      short-limb short stature with swelling of the joints in the extremities,
      bowing of the lower extremities, mild-to-severe scoliosis
    explanation: >-
      GeneReviews names bowing of the lower extremities as a defining feature.
- category: Musculoskeletal
  name: Scoliosis
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:40638774
    reference_title: PTH1R-Related Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      short-limb short stature with swelling of the joints in the extremities,
      bowing of the lower extremities, mild-to-severe scoliosis
    explanation: >-
      GeneReviews names mild-to-severe scoliosis among the defining features.
- category: Musculoskeletal
  name: Joint swelling
  description: >-
    Swelling of the joints in the extremities, named by GeneReviews among the
    defining features.
  phenotype_term:
    preferred_term: Joint swelling
    term:
      id: HP:0001386
      label: Joint swelling
  evidence:
  - reference: PMID:40638774
    reference_title: PTH1R-Related Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      short-limb short stature with swelling of the joints in the extremities,
      bowing of the lower extremities, mild-to-severe scoliosis
    explanation: >-
      GeneReviews names joint swelling among the defining clinical features.
- category: Dental
  name: Delayed tooth eruption
  description: >-
    Delayed eruption with impaction, part of a dental phenotype that also
    includes crowding and malocclusion and that requires orthodontic care.
  phenotype_term:
    preferred_term: Delayed eruption of teeth
    term:
      id: HP:0000684
      label: Delayed eruption of teeth
  evidence:
  - reference: PMID:40638774
    reference_title: PTH1R-Related Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dental manifestations include delayed eruption with impaction, crowding,
      and malocclusion.
    explanation: >-
      GeneReviews enumerates the dental phenotype.
- category: Dental
  name: Dental malocclusion
  phenotype_term:
    preferred_term: Dental malocclusion
    term:
      id: HP:0000689
      label: Dental malocclusion
  evidence:
  - reference: PMID:40638774
    reference_title: PTH1R-Related Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dental manifestations include delayed eruption with impaction, crowding,
      and malocclusion.
    explanation: >-
      GeneReviews names malocclusion among the dental manifestations.
- category: Endocrine
  name: Hypercalcemia
  description: >-
    PTH-independent hypercalcaemia with low-normal or suppressed PTH. The
    defining biochemical abnormality, but age-dependent: normal in most infants,
    elevated between roughly 0.15 and 10 years, tending to normalise in adults.
  phenotype_term:
    preferred_term: Hypercalcemia
    term:
      id: HP:0003072
      label: Hypercalcemia
  evidence:
  - reference: PMID:40638774
    reference_title: PTH1R-Related Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypercalcemia with low-normal or suppressed parathyroid hormone, and
      kidney stones
    explanation: >-
      GeneReviews states the hypercalcaemia and its PTH-independent character.
  - reference: PMID:29788189
    reference_title: Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Postnatal calcium levels were normal in most patients, but elevated
      between 0.15 and 10 years (11.8 ± 1.37 mg/dL) and tended to normalize in
      adults (10.0 ± 1.03 mg/dL).
    explanation: >-
      Quantifies the age dependence, which is what limits the phenotype's
      diagnostic reliability.
- category: Renal
  name: Hypercalciuria
  phenotype_term:
    preferred_term: Hypercalciuria
    term:
      id: HP:0002150
      label: Hypercalciuria
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:29788189
    reference_title: Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Urinary calcium/creatinine (mg/mg) were consistently elevated (children,
      0.80 ± 0.40; adults, 0.28 ± 0.19).
    explanation: >-
      Reports consistent elevation across both age groups, unlike serum calcium.
- category: Renal
  name: Nephrocalcinosis
  phenotype_term:
    preferred_term: Nephrocalcinosis
    term:
      id: HP:0000121
      label: Nephrocalcinosis
  frequency: FREQUENT
  evidence:
  - reference: PMID:29788189
    reference_title: Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most patients with JMC had undergone orthopedic surgical procedures, most
      had nephrocalcinosis, and two had advanced chronic kidney disease.
    explanation: >-
      "Most" supports a FREQUENT band in the largest cohort.
- category: Renal
  name: Nephrolithiasis
  phenotype_term:
    preferred_term: Nephrolithiasis
    term:
      id: HP:0000787
      label: Nephrolithiasis
  evidence:
  - reference: PMID:40638774
    reference_title: PTH1R-Related Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypercalcemia with low-normal or suppressed parathyroid hormone, and
      kidney stones
    explanation: >-
      GeneReviews names kidney stones among the defining features.
- category: Renal
  name: Chronic kidney disease
  description: >-
    A minority of patients progress to advanced chronic kidney disease, the
    endpoint of sustained hypercalciuria and nephrocalcinosis rather than a
    primary renal action of the mutant receptor.
  phenotype_term:
    preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:29788189
    reference_title: Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most patients with JMC had undergone orthopedic surgical procedures, most
      had nephrocalcinosis, and two had advanced chronic kidney disease.
    explanation: >-
      Two of the 24 patients in the largest cohort had advanced chronic kidney
      disease, which places the frequency in the OCCASIONAL band.
- category: Cardiovascular
  name: Hypertension
  description: >-
    Elevated blood pressure is a recognised management concern in PTH1R-JMC.
    GeneReviews places blood pressure measurement at every visit and names
    angiotensin-pathway drugs as the treatment when it is elevated, which is a
    care recommendation for the disorder rather than for an unrelated
    comorbidity. Whether it is a primary feature of the receptor defect remains
    the open question the single neonatal report poses in its own title; no
    frequency is recorded because no series reports one.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: PMID:40638774
    reference_title: PTH1R-Related Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      drugs targeting the angiotensin receptor pathway as needed for elevated
      blood pressure
    explanation: >-
      GeneReviews carries a disorder-specific treatment recommendation for
      elevated blood pressure, which is independent of the single case report
      and is what makes this more than a one-patient observation. Graded
      INDIRECT because the quote instructs clinicians to treat elevated blood
      pressure and the phenotype claim follows from that by one inference step,
      rather than being asserted outright.
  - reference: PMID:31977144
    reference_title: Severe hypertension-An infantile feature of Jansen metaphyseal chondrodysplasia?
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on a patient presenting in the neonatal period with clinical
      signs of JMC in addition to severe hypertension. A pathogenic mutation in
      PTH1R was demonstrated, but investigations for hypertension yielded normal
      results.
    explanation: >-
      A single neonate with molecularly confirmed JMC and severe hypertension
      whose secondary workup was negative. Graded INDIRECT because one case with
      a negative workup is consistent with, but does not establish, a causal
      link to the receptor defect.
- category: Craniofacial
  name: Prominent forehead
  description: >-
    One of the craniofacial features, alongside scaphocephaly, a prominent
    supraorbital ridge, downslanted palpebral fissures, hypertelorism,
    telecanthus, wide nasal bridge, low-set ears and retrognathia.
  phenotype_term:
    preferred_term: Prominent forehead
    term:
      id: HP:0011220
      label: Prominent forehead
  evidence:
  - reference: PMID:40638774
    reference_title: PTH1R-Related Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Craniofacial features can include scaphocephaly, prominent forehead and
      supraorbital ridge, downslanted palpebral fissures, hypertelorism,
      telecanthus, wide nasal bridge, low-set ears, and retrognathia.
    explanation: >-
      GeneReviews enumerates the craniofacial features.
biochemical:
- name: Serum calcium
  presence: INCREASED
  notes: >-
    Elevated with low-normal or suppressed PTH, which is the combination that
    makes this hypercalcaemia PTH-independent and close to unique among skeletal
    dysplasias. Age-dependent: normal in most neonates, elevated through
    childhood, tending to normalise in adults.
  evidence:
  - reference: PMID:29788189
    reference_title: Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Postnatal calcium levels were normal in most patients, but elevated
      between 0.15 and 10 years (11.8 ± 1.37 mg/dL) and tended to normalize in
      adults (10.0 ± 1.03 mg/dL).
    explanation: >-
      Gives the analyte values by age band.
- name: Serum phosphate
  presence: DECREASED
  notes: >-
    Mean phosphate sits at the lower end of the age-specific normal range rather
    than being frankly low in most patients, which is a weaker signal than the
    calcium and should not be relied on for diagnosis.
  evidence:
  - reference: PMID:29788189
    reference_title: Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mean phosphate levels were at the lower end of the age-specific normal
      ranges.
    explanation: >-
      States the analyte finding with the hedge the authors used.
diagnosis:
- name: Serum calcium, phosphate and PTH
  description: >-
    The combination is what diagnoses, not any single value: hypercalcaemia with
    a low-normal or suppressed PTH. A raised calcium with a raised PTH is
    hyperparathyroidism, not this. Note the age dependence recorded in
    progression - normal calcium in an infant or an adult does not exclude JMC.
  evidence:
  - reference: PMID:40638774
    reference_title: PTH1R-Related Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypercalcemia with low-normal or suppressed parathyroid hormone, and
      kidney stones
    explanation: >-
      States the discriminating biochemical combination.
- name: Skeletal radiographs
  description: >-
    Radiographs carry the diagnosis when the biochemistry does not, which is
    most of infancy. The findings are specific enough to be diagnostic in a
    child too young to be hypercalcaemic.
  evidence:
  - reference: PMID:40638774
    reference_title: PTH1R-Related Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiographs show bowing of the long bones, flaring or widening of the
      metaphyses, short phalanges, sclerosis of the skull base, fragmented
      vertebra, and, in some individuals, scoliosis.
    explanation: >-
      Enumerates the radiographic findings that support the diagnosis.
  - reference: PMID:27410178
    reference_title: Jansen Metaphyseal Chondrodysplasia due to Heterozygous H223R-PTH1R Mutations With or Without Overt Hypercalcemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We therefore sought to provide radiographic findings supporting this
      diagnosis early in life.
    explanation: >-
      States the purpose of the radiographic series: diagnosing infants in whom
      the biochemistry is uninformative.
- name: PTH1R molecular genetic testing
  description: >-
    Definitive confirmation. Five recurrent variants at three residues account
    for reported disease, so targeted testing is high-yield.
  evidence:
  - reference: PMID:40638774
    reference_title: PTH1R-Related Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a heterozygous pathogenic variant in PTH1R identified by molecular genetic
      testing
    explanation: >-
      GeneReviews states the confirmatory test.
- name: Renal and mineral surveillance
  description: >-
    Not diagnostic but the monitoring that prevents the disease's least
    reversible outcome: annual serum calcium, serum phosphorus and 24-hour urine
    calcium, plus annual kidney and urinary tract ultrasound.
  evidence:
  - reference: PMID:40638774
    reference_title: PTH1R-Related Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      annual laboratory assessment of serum calcium, serum phosphorus, and
      24-hour urine calcium; annual kidney and urinary tract ultrasound
    explanation: >-
      GeneReviews surveillance schedule for the mineral and renal domains.
differential_diagnoses:
- name: Schmid metaphyseal chondrodysplasia
  description: >-
    The differential that actually arises at the bedside, where Blomstrand does
    not. Schmid is far commoner than JMC and shares the metaphyseal flaring and
    irregularity, so the radiographs alone do not separate them. What separates
    them is the biochemistry this entry stakes JMC's identity on: in Schmid and
    the other metaphyseal chondrodysplasias calcium and phosphorus metabolism is
    normal, whereas JMC is defined by PTH-independent hypercalcaemia with
    suppressed endogenous PTH. The radiographic picture is also mistaken for
    rickets, which is the error the cited case report documents.
  evidence:
  - reference: PMID:8644413
    reference_title: "[Metaphyseal chondrodysplasia as differential diagnosis to rickets]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other types are Schmid, Spahr, McKusick, Schwachman and Jansen, which can
      be separated by clinical, radiographic, genetic and biochemical criteria.
    explanation: >-
      Places Schmid and Jansen in the same radiographic group and states that
      the separation rests on combined criteria rather than radiography alone.
  - reference: PMID:8644413
    reference_title: "[Metaphyseal chondrodysplasia as differential diagnosis to rickets]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The radiographic changes are similar to rickets, but calcium and
      phosphorus metabolism is normal.
    explanation: >-
      Gives the discriminator: normal mineral metabolism in the rest of the
      group, against the hypercalcaemia that defines JMC.
- name: Blomstrand lethal chondrodysplasia
  description: >-
    The mirror image at the same locus, and the most illuminating contrast in
    the disease's biology. Blomstrand is caused by homozygous or compound
    heterozygous PTH1R variants producing less-active or inactive receptors, and
    the growth plate phenotype runs the other way: accelerated chondrocyte
    differentiation and premature ossification, where JMC delays both. The two
    diseases bracket the receptor's dose-response and are not clinically
    confusable - Blomstrand is lethal in the perinatal period.
  evidence:
  - reference: PMID:10912527
    reference_title: Role of parathyroid hormone-related peptide and Indian hedgehog in skeletal development.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Heterozygous PTH1R mutations that lead to constitutively activity were
      identified in Jansen metaphyseal chondrodysplasia, and homozygous or
      compound heterozygous mutations that lead to less-active or completely
      inactive receptors were identified in patients with Blomstrand lethal
      chondrodysplasia.
    explanation: >-
      States both diseases at the same locus and the opposite direction of their
      receptor lesions.
  - reference: PMID:10912527
    reference_title: Role of parathyroid hormone-related peptide and Indian hedgehog in skeletal development.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mice lacking PTHrP show accelerated chondrocyte differentiation, and thus
      premature ossification of those bones that are formed through an
      endochondral process, and similar but more-severe abnormalities are
      observed in PTH1R-ablated animals.
    explanation: >-
      Gives the loss-of-function growth plate phenotype, which is the inverse of
      the JMC lesion this entry curates.
treatments:
- name: Hydration to Reduce Stone and Nephrocalcinosis Risk
  description: >-
    Generous fluid intake to reduce the risk of hypercalcaemia, hypercalciuria,
    nephrolithiasis and nephrocalcinosis. Simple, and the first line against the
    complication that accumulates irreversibly.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Nephrocalcinosis
    treatment_effect: MODULATES
    description: >-
      Dilution reduces the urinary supersaturation that drives stone formation
      and nephrocalcinosis; it does not affect the calcium load itself.
    evidence:
    - reference: PMID:40638774
      reference_title: PTH1R-Related Jansen Metaphyseal Chondrodysplasia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        intake of plenty of fluids to reduce risk of hypercalcemia,
        hypercalciuria, nephrolithiasis, and nephrocalcinosis
      explanation: >-
        GeneReviews states the intervention and its target complications.
  evidence:
  - reference: PMID:40638774
    reference_title: PTH1R-Related Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      intake of plenty of fluids to reduce risk of hypercalcemia,
      hypercalciuria, nephrolithiasis, and nephrocalcinosis
    explanation: >-
      GeneReviews management recommendation.
- name: Bisphosphonate Therapy for Severe Hypercalcemia
  description: >-
    Considered for severe hypercalcaemia. Alendronate has been reported to
    control hypercalciuria in an adult with JMC. This addresses the consequence
    rather than the receptor.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Bisphosphonate Therapy
    term:
      id: NCIT:C198585
      label: Bisphosphonate Therapy
  target_mechanisms:
  - target: Renal and Skeletal Calcium Mobilization
    treatment_effect: INHIBITS
    description: >-
      Bisphosphonates suppress osteoclast-mediated bone resorption, reducing the
      skeletal contribution to the calcium load without touching the
      constitutive receptor signal.
    evidence:
    - reference: PMID:22278430
      reference_title: "Potential effects of alendronate on fibroblast growth factor 23 levels and effective control of hypercalciuria in an adult with Jansen's metaphyseal chondrodysplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Treatment with alendronate reduced hypercalciuria; however,
        normocalciuria was only obtained with the association of thiazide
        diuretic.
      explanation: >-
        Shows the partial effect of bisphosphonate alone on the calcium
        phenotype, and that a thiazide was needed to normalise it. The
        incompleteness is the point: neither drug touches the receptor.
  evidence:
  - reference: PMID:40638774
    reference_title: PTH1R-Related Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      consider bisphosphonates if necessary for severe hypercalcemia
    explanation: >-
      GeneReviews states the indication, with its own conditional framing.
- name: Thiazide Diuretic for Hypercalciuria
  description: >-
    Thiazides reduce urinary calcium excretion by increasing distal tubular
    reabsorption. In the one long-term follow-up available, alendronate alone
    reduced hypercalciuria but only the addition of a thiazide achieved
    normocalciuria - which is why it is curated as its own treatment rather than
    folded into the bisphosphonate entry.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: thiazide diuretic
      term:
        id: NCIT:C49185
        label: Thiazide Diuretic
  target_mechanisms:
  - target: Hypercalciuria
    treatment_effect: INHIBITS
    description: >-
      Increased distal tubular calcium reabsorption lowers urinary calcium,
      acting on the excretion step rather than on the calcium load.
    evidence:
    - reference: PMID:22278430
      reference_title: "Potential effects of alendronate on fibroblast growth factor 23 levels and effective control of hypercalciuria in an adult with Jansen's metaphyseal chondrodysplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Treatment with alendronate reduced hypercalciuria; however,
        normocalciuria was only obtained with the association of thiazide
        diuretic.
      explanation: >-
        Establishes the thiazide as the component that achieved normocalciuria.
  evidence:
  - reference: PMID:22278430
    reference_title: "Potential effects of alendronate on fibroblast growth factor 23 levels and effective control of hypercalciuria in an adult with Jansen's metaphyseal chondrodysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Asymptomatic nephrolithiasis was diagnosed at 18 yr of age, prompting
      pharmacological management of hypercalciuria.
    explanation: >-
      Gives the clinical trigger for treating hypercalciuria pharmacologically.
- name: Orthopedic Surgery for Limb Deformity and Scoliosis
  description: >-
    Most patients in the largest series had undergone orthopaedic surgical
    procedures. GeneReviews directs treatment of severe limb deformity and
    scoliosis to an orthopaedist.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Orthopedic Surgical Procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  target_mechanisms:
  - target: Short-Limbed Short Stature and Skeletal Deformity
    treatment_effect: BYPASSES
    description: >-
      Surgery corrects established deformity without altering the growth-plate
      lesion producing it, so it is a structural correction rather than a
      disease-modifying one.
    evidence:
    - reference: PMID:29788189
      reference_title: Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Most patients with JMC had undergone orthopedic surgical procedures
      explanation: >-
        Documents that this is the usual course for the skeletal phenotype.
  evidence:
  - reference: PMID:40638774
    reference_title: PTH1R-Related Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      treatment of severe limb deformity and scoliosis per orthopedist
    explanation: >-
      GeneReviews management recommendation.
- name: Physical Therapy and Mobility Support
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:40638774
    reference_title: PTH1R-Related Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physical therapy, shoe lifts for limb length discrepancy, assisted devices
      for mobility, or surgical intervention as indicated
    explanation: >-
      GeneReviews states the supportive management for mobility.
animal_models:
- name: Humanized T410R-PTH1R knock-in mouse
  species: Mouse
  genotype: T410R-hPTH1R humanized knock-in
  publication: PMID:40455993
  description: >-
    The best available model, and the one that resolved the field's problem.
    Expressing the milder T410R allele from the endogenous locus gives mice with
    near-normal longevity and fertility - unlike the H223R humanized line, which
    dies early without breeding - while still showing misshapen long bones,
    expanded metaphyses, disarrayed chondrocyte zones, reduced primary spongiosa,
    elevated serum calcium and suppressed PTH. It reproduces both arms of the
    human disease in one animal, which no earlier model did.
  modeled_mechanisms:
  - target: SIK2/SIK3 Inhibition and Class IIa HDAC De-repression
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      This model supplies the decisive in vivo test of the SIK-HDAC route:
      genetic ablation of Hdac4 rescues the growth plate abnormalities, which is
      an epistasis result rather than a correlation.
    limitations: >-
      T410R is the mildest of the five human alleles, so quantitative severity
      does not transfer to H223R patients. The rescue is genetic ablation from
      conception, not a post-hoc intervention.
    readouts:
    - name: Growth plate morphology after Hdac4 ablation
      target: SIK2/SIK3 Inhibition and Class IIa HDAC De-repression
      direction: RESTORED
      interpretation: >-
        Removing the downstream HDAC restores the growth plate, placing the
        SIK-HDAC axis on the causal path rather than beside it.
      evidence:
      - reference: PMID:40455993
        reference_title: "A mouse model of Jansen's metaphyseal chondrodysplasia for investigating disease mechanisms and candidate therapeutics."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Genetic ablation of Hdac4 rescued the growth plate abnormalities in
          T410R mice, thereby establishing the PTH1R-Gαs-cAMP-PKA-SIK3-HDAC4/5
          pathway as the main mediator of growth plate abnormalities in JMC.
        explanation: >-
          The rescue experiment and the authors' own conclusion from it.
    evidence:
    - reference: PMID:40455993
      reference_title: "A mouse model of Jansen's metaphyseal chondrodysplasia for investigating disease mechanisms and candidate therapeutics."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Mutant mice show near-normal longevity and reproductive capacity yet
        exhibit a profound skeletal phenotype characteristic of the disease.
      explanation: >-
        Establishes the model as viable and phenotypically faithful, which is
        what makes it usable for the mechanism test above.
  - target: Renal and Skeletal Calcium Mobilization
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Serum calcium is elevated and endogenous PTH suppressed, reproducing the
      PTH-independent hypercalcaemia that defines the human disease.
    limitations: >-
      The allele is T410R, which in humans is the milder end of the spectrum and
      is not the common H223R; and murine mineral-ion handling differs from
      human in its calcium set point and renal phosphate response, so the
      magnitude of the abnormality does not transfer even though its direction
      and PTH-independence do.
    readouts:
    - name: Serum calcium and endogenous PTH after PTH inverse agonist
      target: Renal and Skeletal Calcium Mobilization
      direction: RESTORED
      interpretation: >-
        Both parameters normalise on acute inverse-agonist injection, which is
        the first in vivo demonstration that the mineral-ion arm is
        pharmacologically reversible. The normalisation is reported after a
        single injection, so it establishes reversibility but says nothing about
        durability under chronic dosing.
      evidence:
      - reference: PMID:40455993
        reference_title: "A mouse model of Jansen's metaphyseal chondrodysplasia for investigating disease mechanisms and candidate therapeutics."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Serum calcium was elevated and endogenous PTH was suppressed in T410R
          mice, and both parameters could be normalized by acute injection of an
          optimized PTH inverse agonist peptide.
        explanation: >-
          Reports both the baseline abnormality and its reversal.
    evidence:
    - reference: PMID:40455993
      reference_title: "A mouse model of Jansen's metaphyseal chondrodysplasia for investigating disease mechanisms and candidate therapeutics."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The T410R mouse thus represents a stable animal model of JMC that
        recapitulates the abnormalities in skeletal development and mineral ion
        homeostasis which characterize this disease.
      explanation: >-
        The authors' summary that this model covers both arms of the disease.
- name: Humanized H223R-PTH1R knock-in mouse
  species: Mouse
  genotype: H223R-hPTH1R expressed from the endogenous Pth1r promoter
  publication: PMID:37808400
  description: >-
    Expressing the common human allele from the endogenous locus, in all
    relevant target tissues. Its defining feature is severity: founders
    typically died within two months without reproducing, and F1 offspring were
    small with marked growth plate abnormalities. This model exists because the
    earlier transgenic lines did not work - promoter-restricted expression gave
    either excess bone mass or only minor growth plate change, and neither
    adequately recapitulated the human disease.
  modeled_mechanisms:
  - target: Delayed Growth Plate Chondrocyte Hypertrophy
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Growth plates show markedly expanded proliferating and prehypertrophic
      zones with progressive loss of type X collagen-positive hypertrophic
      chondrocytes - the delayed-maturation lesion, seen directly.
    limitations: >-
      The line is barely viable: founders typically die within two months
      without reproducing, and only mosaic males produced offspring, which
      constrains what can be asked of it. Serum calcium and phosphate were not
      different from wild-type littermates, so this model does not reproduce the
      mineral-ion arm.
    readouts:
    - name: Growth plate zone composition
      target: Delayed Growth Plate Chondrocyte Hypertrophy
      direction: ALTERED
      interpretation: >-
        Expanded proliferating/prehypertrophic zones with reduced hypertrophic
        chondrocytes is the histological signature of delayed maturation.
      evidence:
      - reference: PMID:37808400
        reference_title: "Substantially Delayed Maturation of Growth Plate Chondrocytes in \"Humanized\" PTH1R Mice with the H223R Mutation of Jansen's Disease."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          revealed markedly expanded zones of type II collagen-positive,
          proliferating/prehypertrophic chondrocytes, abundant apoptotic cells in
          the growth plate center and a progressive reduction of type X
          collagen-positive hypertrophic chondrocytes and primary spongiosa
        explanation: >-
          The histological measurement behind this readout.
    evidence:
    - reference: PMID:37808400
      reference_title: "Substantially Delayed Maturation of Growth Plate Chondrocytes in \"Humanized\" PTH1R Mice with the H223R Mutation of Jansen's Disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We therefore generated "humanized" JMC mice in which the H223R-PTH1R
        allele was expressed via the endogenous mouse Pth1r promoter and, thus,
        in all relevant target tissues.
      explanation: >-
        Establishes the design feature - endogenous, untargeted expression - that
        makes this model informative where the transgenics were not.
- name: Sik2/Sik3 double-knockout mouse
  species: Mouse
  genotype: Sik2 and Sik3 conditional double knockout in osteoblasts and osteocytes
  publication: PMID:31430259
  description: >-
    A phenocopy model rather than a disease model, and the reason the SIK node
    is in this pathograph at all. Deleting the kinases that constitutively
    active PTH1R inhibits reproduces the JMC skeletal and molecular phenotype -
    that is, removing the brake from below does what jamming the receptor on
    does from above.
  modeled_mechanisms:
  - target: SIK2/SIK3 Inhibition and Class IIa HDAC De-repression
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Combined Sik2/Sik3 deletion produces a skeletal and molecular phenotype
      closely resembling that of the constitutively active PTH1R.
    limitations: >-
      This is a phenocopy of the mechanism, not a model of the disease: the mice
      carry no PTH1R lesion, deletion is restricted to osteoblasts and
      osteocytes rather than chondrocytes, and no mineral-ion phenotype is
      reported. It cannot be used to test therapies, only to place the node.
    evidence:
    - reference: PMID:31430259
      reference_title: Salt-inducible kinases dictate parathyroid hormone 1 receptor action in bone development and remodeling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Combined deletion of Sik2 and Sik3 in osteoblasts and osteocytes led to a
        dramatic increase in bone mass that closely resembled the skeletal and
        molecular phenotypes observed when these bone cells express a
        constitutively active PTH1R that causes Jansen's metaphyseal
        chondrodysplasia.
      explanation: >-
        The phenocopy result that places SIK inhibition on the causal path.
- name: Jansen H223R-PTH1R transgenic mouse
  species: Mouse
  genotype: Collagen II promoter-driven H223R-PTH1R transgene
  publication: PMID:11713230
  description: >-
    Growth-plate-targeted expression of the constitutively active Jansen
    receptor delays chondrocyte differentiation, and it rescues the early
    lethality of PTHrP-null mice by preventing their accelerated chondrocyte
    differentiation. In PTH/PTHrP receptor-null mice the same transgene restored
    most bone abnormalities but did *not* prevent perinatal lethality, which the
    authors read as evidence that something besides the abnormal rib cage kills
    those animals. The informative part for JMC is the first result: a
    ligand-independent receptor substitutes for the ligand-dependent one in the
    growth plate and produces delay, which is what the human allele does.
  modeled_mechanisms:
  - target: Delayed Growth Plate Chondrocyte Hypertrophy
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Expressing the human JMC allele in growth-plate chondrocytes reproduces
      the delayed-hypertrophy phenotype and rescues receptor-null mice.
    limitations: >-
      This is a transgenic overexpression model on a receptor-null background
      rather than a knock-in of the human heterozygous state, so expression
      level and cellular context differ from patients. It also addresses only
      the growth-plate arm; the mineral-ion and renal phenotypes are not what
      this model was built to test.
    evidence:
    - reference: PMID:11713230
      reference_title: Partial rescue of PTH/PTHrP receptor knockout mice by targeted expression of the Jansen transgene.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Expression of the Jansen transgene under the control of the type
        alpha1(II) collagen promoter was, furthermore, shown to delay
        chondrocyte differentiation and to prevent the dramatic acceleration of
        chondrocyte differentiation in PTHrP(-/-) mice, thus rescuing the early
        lethality of these animals.
      explanation: >-
        Directly reports that the human Jansen allele, expressed in growth-plate
        chondrocytes, delays chondrocyte differentiation - the node this link
        targets.
    - reference: PMID:11713230
      reference_title: Partial rescue of PTH/PTHrP receptor knockout mice by targeted expression of the Jansen transgene.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        the type alpha1(II) collagen promoter Jansen transgene restored most of
        the bone abnormalities in PPR(-/-) mice, but did not prevent their
        perinatal lethality
      explanation: >-
        Bounds what the model rescues, which is why the fidelity is recorded as
        MODERATE rather than HIGH.
discussions:
- discussion_id: allele_specific_constitutive_activity_sets_severity
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does the intrinsic constitutive activity of each PTH1R allele quantitatively
    predict clinical severity, and if so can it be used prospectively?
  attaches_to:
  - pathophysiology#Constitutively Active PTH1R
  rationale: >-
    The ingredients for a dose-response account are present and the account has
    not been made. Five mutants show varying degrees of constitutive cAMP
    signalling in reporter cells; separately, adult height was below the third
    centile in every patient except the T410R carriers. Those two observations
    are consistent with severity tracking basal activity, but they have not been
    fitted against each other, and with 24 patients across five alleles — 18 of
    them a single allele — the series cannot support it. Two things would need
    separating: whether basal activity predicts severity at all, and whether it
    predicts the skeletal and renal arms to the same degree, which is not
    obvious given that they act through different tissues. Until that is done,
    genotype cannot be used prospectively to counsel a newly diagnosed infant.
  evidence:
  - reference: PMID:29788189
    reference_title: Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The five PTHR1 mutants showed varying degrees of constitutive and
      PTH-stimulated cAMP signaling activity when expressed in HEK293 reporter
      cells.
    explanation: >-
      The in vitro half of the proposed relationship.
  - reference: PMID:29788189
    reference_title: Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adult heights were well below the 3rd percentile for all patients, except
      for those with the T410R mutation.
    explanation: >-
      The clinical half, and the single data point that suggests the two are
      related.
- discussion_id: inverse_agonist_translation
  kind: KNOWLEDGE_GAP
  prompt: >-
    PTH1R inverse agonists suppress basal signalling of every JMC mutant in
    vitro. What would a clinical trial in an ultra-rare disease with an
    age-dependent biochemical endpoint and an irreversible skeletal one actually
    measure?
  attaches_to:
  - pathophysiology#Ligand-Independent Gs-alpha and cAMP Signaling
  rationale: >-
    This is the one mechanism-directed strategy for JMC and the pharmacology is
    encouraging: the inverse agonist reduced basal cAMP signalling for each of
    the five mutant receptors, so it acts on the lesion rather than a
    consequence. The difficulty is on the trial side, and it is structural
    rather than pharmacological. Serum calcium, the obvious biomarker, is
    normal in most infants and normalises in adults, so it is only informative
    in a window; urinary calcium/creatinine is elevated in both children and
    adults and is the better candidate. Adult height is a decisive endpoint but
    takes two decades and is unavailable to anyone diagnosed late. And
    nephrocalcinosis, the complication that accumulates, is what a trial would
    most want to prevent and is the slowest to read out. An endpoint strategy is
    a prerequisite here, not an afterthought.
  evidence:
  - reference: PMID:29788189
    reference_title: Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      reduced basal cAMP signaling for each PTHR1 mutant
    explanation: >-
      Establishes that the strategy works against every reported allele in
      vitro, which is what makes the translational question the live one.
  - reference: PMID:29788189
    reference_title: Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Urinary calcium/creatinine (mg/mg) were consistently elevated (children,
      0.80 ± 0.40; adults, 0.28 ± 0.19).
    explanation: >-
      The one mineral-ion measure that is abnormal across all ages, and
      therefore the most usable candidate endpoint.
references:
- reference: PMID:40638774
  title: PTH1R-Related Jansen Metaphyseal Chondrodysplasia.
  tags:
  - GeneReviews
- reference: PMID:29788189
  title: Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia.
- reference: PMID:7701349
  title: A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia.
notes: >-
  Naming hazard. kb/disorders/Chung-Jansen_Syndrome.yaml is a different disease
  (PHIP-related) sharing only the eponym. Nothing was cited across between the
  two entries, and no Chung-Jansen source was consulted.

  Deep research. One OpenScientist report was generated
  (research/Metaphyseal_Chondrodysplasia_Jansen_Type-deep-research-openscientist.md).
  It was the cleanest of the five reports in this batch: 32/32 references
  verified, 33/34 terms verified, and one label mismatch (GO:0007050, whose
  ontology label resolves as the bare identifier because the term is obsolete —
  it is not used here).

  Review round 1 (PR #10146) added, from evidence already in the branch or one
  fetch away: joint swelling and two dental phenotypes from the GeneReviews
  clinical characteristics; a diagnosis section and the Blomstrand
  loss-of-function contrast as a differential; the thiazide, which had been
  described only inside an explanation string; three animal models, including
  the T410R humanized knock-in whose Hdac4 rescue is the decisive in vivo
  support for the SIK-HDAC node this entry already carried; and a split of the
  bundled renal node into hypercalciuria, nephrocalcinosis and chronic kidney
  disease. GO:0004930 was replaced with GO:0004991, the parathyroid hormone
  receptor activity term, which is what the node actually describes.

  It is worth recording that this report *declined to guess* the MONDO ID,
  writing "MONDO ID not resolved in this investigation" rather than supplying a
  plausible-looking wrong one. Three of the other four reports in this batch
  offered a disease-level MONDO term that named an entirely different disease
  while reporting a confabulation rate of 0.0. Abstaining was the correct
  behaviour and is the reason this entry needed no MONDO correction.

  Care guidance recorded here rather than modelled, because none of it is an
  intervention with a mechanism target. Contact sports and other high-risk
  activities are to be avoided in those with significant skeletal involvement.
  The full GeneReviews surveillance programme also covers growth and limb-length
  measurement every six to twelve months in children, dental review with
  radiographs, audiometry and ophthalmic assessment every one to two years, and
  blood pressure at each visit; the mineral and renal elements of it are
  modelled as a diagnosis record because they are what prevent the disease's
  least reversible outcome.

  Deliberately not curated. No prevalence record: no population rate has been
  published, and the largest series is 24 patients. The FGF23 elevation reported
  in JMC is real but the quotable statements attach it either to bisphosphonate
  pharmacology or to immunohistochemical staining intensity rather than to a
  measured circulating disease phenotype, so no biochemical record is made for
  it; the osteocyte staining finding is carried in the pathophysiology node
  description instead. The craniofacial series (PMID:39830149) was consulted but
  not curated as its own phenotype record: it needs frequency data the abstract
  does not carry. Its cache is deliberately not shipped, because an uncited
  reference cache belongs to no entry - which is also why the earlier claim here
  that it "is cached" became wrong once the uncited-cache pruning pass ran. Hypertension was initially left out on the same reasoning - the only
  dedicated report is a single neonate, and its own title poses the association
  as a question - but that reading missed that GeneReviews independently tells
  clinicians to measure blood pressure at every visit and to treat elevation with
  angiotensin-pathway drugs. A disorder-specific management recommendation is not
  a single case, so hypertension is now curated with no frequency band and the
  case report attached as INDIRECT.

  Two validator catches worth recording. A first draft quoted the article title
  of PMID:11713230 as the transgenic-mouse evidence; the reference validator
  rejected it, the abstract turned out to contain a far better sentence, and
  reading it also corrected the entry - the transgene rescues PTHrP-null
  lethality but does *not* prevent perinatal lethality in receptor-null mice,
  which the first draft had conflated. Separately, the inverse-agonist snippet
  originally included the peptide's bracketed residue notation and failed to
  match, because bracketed spans are stripped before matching unless
  conf/reference_validator_config.yaml lists a literal_bracket_patterns entry.
  Rather than widen that shared config for one quote, the snippet was shortened
  to a bracket-free span of the same sentence.

  Frequency bands are given for short stature, hypercalciuria and
  nephrocalcinosis, where the cohort text supports "all patients except",
  "consistently elevated" and "most" respectively. Everything else is unbanded.
📚

References & Deep Research

References

3
PMID:40638774
PTH1R-Related Jansen Metaphyseal Chondrodysplasia.
No top-level findings curated for this source.
PMID:29788189
Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia.
No top-level findings curated for this source.
PMID:7701349
A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

Naming hazard. kb/disorders/Chung-Jansen_Syndrome.yaml is a different disease (PHIP-related) sharing only the eponym. Nothing was cited across between the two entries, and no Chung-Jansen source was consulted. Deep research. One OpenScientist report was generated (research/Metaphyseal_Chondrodysplasia_Jansen_Type-deep-research-openscientist.md). It was the cleanest of the five reports in this batch: 32/32 references verified, 33/34 terms verified, and one label mismatch (GO:0007050, whose ontology label resolves as the bare identifier because the term is obsolete — it is not used here). Review round 1 (PR #10146) added, from evidence already in the branch or one fetch away: joint swelling and two dental phenotypes from the GeneReviews clinical characteristics; a diagnosis section and the Blomstrand loss-of-function contrast as a differential; the thiazide, which had been described only inside an explanation string; three animal models, including the T410R humanized knock-in whose Hdac4 rescue is the decisive in vivo support for the SIK-HDAC node this entry already carried; and a split of the bundled renal node into hypercalciuria, nephrocalcinosis and chronic kidney disease. GO:0004930 was replaced with GO:0004991, the parathyroid hormone receptor activity term, which is what the node actually describes. It is worth recording that this report *declined to guess* the MONDO ID, writing "MONDO ID not resolved in this investigation" rather than supplying a plausible-looking wrong one. Three of the other four reports in this batch offered a disease-level MONDO term that named an entirely different disease while reporting a confabulation rate of 0.0. Abstaining was the correct behaviour and is the reason this entry needed no MONDO correction. Care guidance recorded here rather than modelled, because none of it is an intervention with a mechanism target. Contact sports and other high-risk activities are to be avoided in those with significant skeletal involvement. The full GeneReviews surveillance programme also covers growth and limb-length measurement every six to twelve months in children, dental review with radiographs, audiometry and ophthalmic assessment every one to two years, and blood pressure at each visit; the mineral and renal elements of it are modelled as a diagnosis record because they are what prevent the disease's least reversible outcome. Deliberately not curated. No prevalence record: no population rate has been published, and the largest series is 24 patients. The FGF23 elevation reported in JMC is real but the quotable statements attach it either to bisphosphonate pharmacology or to immunohistochemical staining intensity rather than to a measured circulating disease phenotype, so no biochemical record is made for it; the osteocyte staining finding is carried in the pathophysiology node description instead. The craniofacial series (PMID:39830149) was consulted but not curated as its own phenotype record: it needs frequency data the abstract does not carry. Its cache is deliberately not shipped, because an uncited reference cache belongs to no entry - which is also why the earlier claim here that it "is cached" became wrong once the uncited-cache pruning pass ran. Hypertension was initially left out on the same reasoning - the only dedicated report is a single neonate, and its own title poses the association as a question - but that reading missed that GeneReviews independently tells clinicians to measure blood pressure at every visit and to treat elevation with angiotensin-pathway drugs. A disorder-specific management recommendation is not a single case, so hypertension is now curated with no frequency band and the case report attached as INDIRECT. Two validator catches worth recording. A first draft quoted the article title of PMID:11713230 as the transgenic-mouse evidence; the reference validator rejected it, the abstract turned out to contain a far better sentence, and reading it also corrected the entry - the transgene rescues PTHrP-null lethality but does *not* prevent perinatal lethality in receptor-null mice, which the first draft had conflated. Separately, the inverse-agonist snippet originally included the peptide's bracketed residue notation and failed to match, because bracketed spans are stripped before matching unless conf/reference_validator_config.yaml lists a literal_bracket_patterns entry. Rather than widen that shared config for one quote, the snippet was shortened to a bracket-free span of the same sentence. Frequency bands are given for short stature, hypercalciuria and nephrocalcinosis, where the cohort text supports "all patients except", "consistently elevated" and "most" respectively. Everything else is unbanded.

Create: Metaphyseal Chondrodysplasia, Jansen Type · 2026-08-30T07:12:58Z · View source

De novo curation of Jansen metaphyseal chondrodysplasia (MONDO:0007982, PTH1R), using GeneReviews PMID:40638774 as the phenotype baseline plus the 24-patient natural-history series and the SIK/HDAC mechanism work. One OpenScientist deep-research report was generated and read; it was the cleanest of this batch, with 32/32 references verified and 33/34 terms verified, its single label mismatch being the obsolete GO:0007050, which is not used. Notably this report declined to guess a MONDO ID, writing that it was not resolved, where three of the other four reports in the batch supplied a disease-level MONDO term naming a different disease. Two validator catches: a first draft quoted the article title of PMID:11713230 as animal-model evidence and the reference validator rejected it; reading the actual abstract supplied a better sentence and corrected a factual error, since the transgene rescues PTHrP-null lethality but does not prevent perinatal lethality in receptor-null mice, which the draft had conflated. Separately the inverse-agonist snippet failed to match because bracketed residue notation is stripped before matching; rather than widen conf/reference_validator_config.yaml for one quote, the snippet was shortened to a bracket-free span. Named Entity Confusion: Chung-Jansen syndrome (PHIP) shares only the eponym and nothing was cited across. Validated with just validate (53/53 snippets verified), check-entity-refs, check-duplicate-keys, check-snippet-length, check-title-snippets, check-snippet-grading and check-folded-hyphens.

OpenScientist ▸
1. Disease Information
openscientist-autonomous 31 citations 2026-08-30T06:54:40.576573

1. Disease Information

Overview. JMC is a rare form of short-limbed dwarfism (metaphyseal chondrodysplasia) characterized by severe growth-plate abnormalities with metaphyseal widening/irregularity, progressive skeletal deformity, distinctive craniofacial features, and — uniquely among the metaphyseal chondrodysplasias — PTH-independent hypercalcemia with low/normal circulating PTH and PTHrP.

Key identifiers:

Resource Identifier
OMIM (disease) #156400
Gene PTH1R (aka PTHR1, PTH/PTHrP receptor); OMIM 168468; HGNC:PTH1R; UniProt Q03431*
MONDO Metaphyseal chondrodysplasia, Jansen type (Mendelian; MONDO ID not resolved in this investigation)
Category Mendelian, autosomal dominant

Synonyms / alternative names: Jansen metaphyseal chondrodysplasia; Jansen-type metaphyseal dysplasia; Jansen's disease; metaphyseal dysostosis, Jansen type; Murk Jansen type metaphyseal chondrodysplasia.

Source of information. Because JMC is ultra-rare, the knowledge base derives from aggregated disease-level resources (OMIM, Orphanet) and published case reports / small case series rather than large EHR cohorts. The largest natural-history dataset assembled to date comprised 24 patients (PMID: 29788189).

2. Etiology

Primary cause — genetic. JMC is caused by heterozygous activating (gain-of-function) missense mutations in PTH1R. In HEK293/COS-7 reporter cells the mutant receptors exhibit constitutive, ligand-independent cAMP accumulation. Disease is autosomal dominant; most cases arise de novo, though multigenerational transmission (e.g., a father and two sons with T410R) is documented (Finding F001; PMID: 29788189; PMID: 27160269).

"Five different activating PTH/PTH-related peptide (PTHrP) receptor (PTHR1) mutations have been reported as causes of Jansen metaphyseal chondrodysplasia (JMC), a rare disorder characterized by severe growth plate abnormalities and PTH-independent hypercalcemia." — PMID: 29788189

Genetic risk factors. The causal variants themselves are the risk factors; there are no known common susceptibility loci or modifier alleles in humans. Because the mechanism is a dominant, activating point mutation, the mutation is both necessary and sufficient.

Environmental risk factors. None established. There are no known toxic, infectious, occupational, or lifestyle causes. Family history is relevant only in the minority of inherited (non-de novo) cases.

Protective factors. No genetic or environmental protective factors have been identified.

Gene–environment interactions. None established for disease causation. Environmental modulation is limited to symptom management (e.g., dietary calcium restriction, hydration reducing the hypercalcemia/hypercalciuria burden).

3. Phenotypes

JMC is a multisystem disorder with a defining skeletal + mineral-ion phenotype plus renal, ocular, and possibly cardiovascular involvement (Findings F002, F009, F012).

Skeletal / physical manifestations (clinical signs; congenital-to-childhood onset; progressive)

  • Metaphyseal widening and irregularity of long bones; disorganized growth-plate cartilage. HPO: HP:0003025 Metaphyseal widening; HP:0000944 Abnormality of the metaphysis.
  • Short-limbed short stature / dwarfism — adult heights well below the 3rd percentile in all patients except those with the milder T410R mutation (F010; PMID: 29788189). HPO: HP:0004322 Short stature.
  • Bowed limbs / progressive limb deformity; most patients undergo orthopedic surgery. HPO: HP:0002751 Kyphoscoliosis; HP:0002986 Radial bowing.
  • Craniofacial dysmorphism (prominent supraorbital ridges, midface hypoplasia, micrognathia). HPO: HP:0000316 Hypertelorism; HP:0000347 Micrognathia.

Mineral-ion / laboratory abnormalities (biochemical; childhood-predominant)

  • PTH-independent hypercalcemia (normal at birth; elevated ~0.15–10 yr, mean 11.8 ± 1.37 mg/dL; tends to normalize in adults, 10.0 ± 1.03 mg/dL). HPO: HP:0003072 Hypercalcemia. CHEBI:29108 calcium(2+).
  • Hypercalciuria (urinary Ca/creatinine children 0.80 ± 0.40; adults 0.28 ± 0.19). HPO: HP:0002150 Hypercalciuria.
  • Hypophosphatemia (lower end of age-specific ranges); reported FGF23 elevation. HPO: HP:0002148 Hypophosphatemia. CHEBI:43474 hydrogenphosphate.
  • Low / normal PTH despite hypercalcemia — the diagnostic hallmark.

"Postnatal calcium levels were normal in most patients, but elevated between 0.15 and 10 years (11.8 ± 1.37 mg/dL) and tended to normalize in adults (10.0 ± 1.03 mg/dL)." — PMID: 29788189

Renal (progressive)

  • Nephrocalcinosis (most patients), nephrolithiasis, and advanced chronic kidney disease in a subset (2/24). HPO: HP:0000121 Nephrocalcinosis; HP:0012622 Chronic kidney disease.

"Most patients with JMC had undergone orthopedic surgical procedures, most had nephrocalcinosis, and two had advanced chronic kidney disease." — PMID: 29788189

Other systems

  • Ocular findings characterized in JMC (calcium-deposition context; PMID: 39108358).
  • Severe infantile hypertension proposed as a previously unrecognized feature (PMID: 31977144). HPO: HP:0000822 Hypertension.

"Hypertension has not been previously associated with JMC." — PMID: 31977144

  • Hypercalcemia symptom complex in infants: failure to thrive, poor feeding, constipation, polyuria, irritability, lethargy, seizures, hypotonia (PMID: 33990852).

"Hypercalcaemia presents clinically with a range of symptoms including failure to thrive, poor feeding, constipation, polyuria, irritability, lethargy, seizures and hypotonia." — PMID: 33990852

Quality-of-life impact. Substantial: severe short stature and progressive limb deformity requiring repeated orthopedic surgery impair mobility and function; nephrocalcinosis/CKD add chronic renal morbidity. No disease-specific EQ-5D/SF-36 data are available (ultra-rare disease).

Onset / severity / progression / frequency (summary):

Phenotype HPO Onset Severity Progression Frequency
Short stature HP:0004322 Childhood Severe (except T410R) Progressive Nearly all
Metaphyseal widening HP:0003025 Congenital/childhood Severe Progressive All
Hypercalcemia HP:0003072 Infancy–childhood Variable Peaks in childhood, normalizes in adults Most
Hypercalciuria HP:0002150 Childhood Moderate–severe Persistent Consistent
Nephrocalcinosis HP:0000121 Childhood Variable Progressive Most
CKD HP:0012622 Later Severe Progressive Subset (2/24)

4. Genetic / Molecular Information

Causal gene: PTH1R (chromosome 3p21.31), encoding a class B1 (secretin-family) G-protein-coupled receptor.

Pathogenic variant spectrum (all heterozygous, activating):

Variant Location Frequency in largest cohort Constitutive activity Phenotype
H223R 1st intracellular loop (exon M2) 18/24 patients (most common) High Severe
T410P TM helix Single case Moderate–high Severe
T410R TM helix Father + 2 sons Lower Milder
I458R TM7 Single case ~8× basal vs WT Severe-like
I458K TM7 Single case High Severe

(F001; PMID: 29788189; PMID: 10487664)

"The H223R mutation occurred in 18 patients. T410P, I458R and I458K each occurred in single cases; T410R was present in a father and his two sons." — PMID: 29788189

  • Variant classification (ACMG/AMP): pathogenic (functional constitutive-activation evidence + segregation). Some newly reported PTH1R variants are classified VUS (e.g., p.E465K, PMID: 37840415).
  • Variant type: all missense.
  • Allele frequency: absent from population databases (gnomAD) — private/de novo pathogenic variants.
  • Origin: germline (de novo in most; inherited in some pedigrees). Germline mosaicism is plausible but not systematically documented.
  • Functional consequence: gain of function — constitutive, ligand-independent Gsα–cAMP signaling (F001; PMID: 27160269).

"Constitutive, ligand-independent cAMP accumulation was observed in HEK293T cells expressing the Mut-PTH1R." — PMID: 27160269

Allelic disorder spectrum (differential diagnosis; F007). PTH1R variants cause a spectrum defined by signaling direction and zygosity:

Disorder Zygosity Effect Skeletal consequence
JMC Heterozygous Gain of function (constitutive) Delayed ossification + hypercalcemia
Blomstrand lethal chondrodysplasia Homozygous / compound-het Severe loss of function Neonatal-lethal, accelerated ossification
Eiken syndrome Homozygous Milder LOF Delayed ossification
PHP-like (hypocalcemia/hyperphosphatemia) Homozygous (e.g., R186H) LOF Mineral-ion disturbance
Primary failure of tooth eruption (PFE) Heterozygous LOF Non-syndromic dental
Brachydactyly type E syndrome (H8 variants E465K, E469K) Heterozygous Impaired signaling Mild short stature, dental anomalies

"Heterozygous PTH1R mutations that lead to constitutively activity were identified in Jansen metaphyseal chondrodysplasia, and homozygous or compound heterozygous mutations that lead to less-active or completely inactive receptors were identified in patients with Blomstrand lethal chondrodysplasia." — PMID: 10912527

"Severe loss-of-function homozygous mutations in PTH1R are incompatible with life as in Blomstrand's lethal chondrodysplasia, characterized by accelerated growth plate ossification." — PMID: 40904804

Modifier genes / epigenetics / chromosomal abnormalities. No human modifier genes are established. Downstream class IIa HDACs are key epigenetic effectors of PTH1R signaling in bone (mechanistic, mouse; see §6). No chromosomal abnormalities are involved (JMC is a point-mutation disorder).

5. Environmental Information

Not applicable as a cause. JMC is a purely monogenic, constitutively-active-receptor disorder. No environmental factors, lifestyle factors, or infectious agents cause or trigger the disease. Environmental variables are relevant only to symptom modulation (dietary calcium, fluid intake affecting stone/nephrocalcinosis risk).

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream)

Heterozygous activating PTH1R mutation (H223R / T410P/R / I458R/K)
│  (stabilizes active receptor conformation)
▼
Constitutive, ligand-independent Gsα activation
│
▼
Elevated basal cAMP  →  PKA  →  inhibition of SIK2/SIK3
│                              │
│                              ▼
│                 de-repression of class IIa HDACs / CRTC
│                              │
▼                              ▼
GROWTH PLATE:                    Transcriptional program of
delayed chondrocyte              constitutively-active PTH1R
hypertrophy; prolonged           (= phenocopy of Sik2/Sik3 loss)
hypertrophic zone;                      │
disorganized metaphysis  ◄──────────────┘
│
▼
Metaphyseal widening, bowed limbs, short stature

KIDNEY / MINERAL: constitutive renal PTH1R signaling
   → ↑ Ca reabsorption / bone Ca release → HYPERCALCEMIA (PTH-independent)
   → hypercalciuria, ↑FGF23 → hypophosphatemia
   → nephrocalcinosis → CKD

Molecular pathways

  • PTH/PTHrP receptor → Gsα → adenylyl cyclase → cAMP → PKA is the primary driver. PTH1R also couples to Gq/PLC, but the JMC phenotype is dominated by the Gsα–cAMP arm (PMID: 15765186; PMID: 40571720).
  • cAMP–SIK–HDAC axis: PTH1R activation inhibits SIKs; combined Sik2/Sik3 deletion phenocopies constitutively active PTH1R, with class IIa HDACs as the key regulated substrates in chondrocytes and osteocytes (F003; PMID: 31430259).

"Combined deletion of Sik2 and Sik3 in osteoblasts and osteocytes led to a dramatic increase in bone mass that closely resembled the skeletal and molecular phenotypes observed when these bone cells express a constitutively active PTH1R that causes Jansen's metaphyseal chondrodysplasia." — PMID: 31430259

"genetic evidence demonstrated that class IIa histone deacetylases were key PTH1R-regulated SIK substrates in both chondrocytes and osteocytes" — PMID: 31430259

Developmental mechanism — the PTHrP–Ihh loop (F006)

In normal endochondral development, PTHrP (made in the periarticular growth plate) acts on PTH1R to keep chondrocytes proliferating and delay hypertrophy; Ihh (from prehypertrophic chondrocytes) induces PTHrP, forming a negative-feedback loop that sets the pace of differentiation and the site of bone-collar formation. Gsα is the critical mediator: chondrocyte-specific Gsα knockout accelerates hypertrophy (phenocopying receptor knockout), whereas constitutive PTH1R activation (JMC) does the opposite — delaying hypertrophy.

"As chondrocytes go through a program of proliferation and then further differentiation into post-mitotic, hypertrophic chondrocytes, PTHrP action keeps chondrocytes proliferating and delays their further differentiation." — PMID: 16831900

"These results show that G(s)alpha negatively regulates chondrocyte differentiation and is the critical signaling mediator of the PTH/PTH-rP receptor in growth plate chondrocytes." — PMID: 15765186

Downstream effectors delaying hypertrophy/apoptosis include Bcl-2 upregulation, suppression of p57 and Runx2, SOX9 phosphorylation, and upregulation of Zfp521 (a rescue target — see §15).

"PTHrP increases the expression of Bcl-2, a protein that controls programmed cell death in several cell types, in growth plate chondrocytes both in vitro and in vivo, leading to delays in their maturation towards hypertrophy and apoptotic cell death." — PMID: 9008714

Cellular processes / tissue damage

  • Delayed chondrocyte hypertrophic differentiation and prolonged persistence of hypertrophic chondrocytes (growth-plate disorganization).
  • High-turnover bone disease: histomorphometry in H223R children shows irregular architecture, increased osteoid, prolonged osteoid maturation, intense cortical osteoclast activity, marrow fibrosis, and osteocytes with osteoid buildup in lacunae/shortened canaliculi — a PTH-like bone phenotype (F009; PMID: 39950977).

"Cortical bone displayed areas of intense osteoclast activity and scattered marrow fibrosis." — PMID: 39950977

Protein dysfunction / structural basis (F011)

PTH1R is a prototypical class B1 GPCR coupling to both Gs and Gq (UniProt Q03431). Cryo-EM structures with PTH, PTHrP, abaloparatide, LA-PTH, and M-PTH(1-14) show the agonist N-terminus engaging the transmembrane bundle to drive Gαs activation (PMID: 37148874; PMID: 40571720). The JMC mutations map to activation-critical regions: H223 in the first intracellular loop near the G-protein interface, and T410/I458 in transmembrane helices — positions where substitutions stabilize the active conformation, producing ligand-independent signaling.

"we describe cryo-EM structures of the PTH1R in complex with fragments of the two hormones, PTH and PTH-related protein, the drug abaloparatide, as well as the engineered tool compounds, long-acting PTH (LA-PTH) and the truncated peptide, M-PTH(1-14)" — PMID: 37148874

"The critical N terminus of each agonist engages the transmembrane bundle in a topologically similar fashion, reflecting similarities in measures of Gαs activation." — PMID: 37148874

Metabolic / immune / molecular profiling

  • Metabolic: dysregulated calcium/phosphate homeostasis (hypercalcemia, hypophosphatemia, hypercalciuria; FGF23 elevation contributing to renal phosphate wasting).

"Hypophosphatemia is also a hallmark of JMC, and recently, increased fibroblast growth factor 23 (FGF23) levels have been reported in this syndrome." — PMID: 22278430

  • Immune involvement: none established.
  • Molecular profiling (F013): No large-scale human transcriptomic/proteomic/metabolomic/single-cell datasets specific to JMC exist in public repositories (GEO/ArrayExpress/PRIDE/MetaboLights). The molecular signature comes from mouse/cell models — the SIK–HDAC transcriptional program (PMID: 31430259) and the Col2a1-H223R growth-plate delayed-maturation program (PMID: 9391087). Human-level "omics" is limited to targeted biochemistry and bone histomorphometry/IHC.

"immunohistochemical analysis demonstrated increased in PTH1R expression in both osteoblasts and fibroblastic cells on the bone surface" — PMID: 39950977

Suggested GO terms: GO:0007189 (adenylate cyclase-activating GPCR signaling), GO:0002062 (chondrocyte differentiation), GO:0003416 (endochondral bone growth), GO:0071107 (response to parathyroid hormone), GO:0007050 (cell cycle arrest). Suggested CL terms: CL:0000138 (chondrocyte), CL:0000743 (hypertrophic chondrocyte), CL:0000062 (osteoblast), CL:0000137 (osteocyte), CL:0000092 (osteoclast).

7. Anatomical Structures Affected

Organ / system level (primary → secondary): - Skeletal system (primary): long-bone metaphyses, growth plates (physes), cranium, mandible, spine. UBERON:0002515 metaphysis; UBERON:0002481 growth plate cartilage / physis; UBERON:0001474 bone element. - Urinary system (secondary): kidney (nephrocalcinosis, CKD). UBERON:0002113 kidney. - Ocular (secondary): cornea/eye (calcium deposition). UBERON:0000970 eye. - Cardiovascular (candidate): systemic vasculature (infantile hypertension). UBERON:0001981 blood vessel. - Endocrine / mineral-homeostasis axis (functionally central).

Tissue / cell level: - Cartilage / growth-plate chondrocytes (proliferative and hypertrophic zones). CL:0000138 chondrocyte; CL:0000743 hypertrophic chondrocyte. - Bone: osteoblasts, osteocytes, osteoclasts (high-turnover remodeling). CL:0000062 osteoblast; CL:0000137 osteocyte; CL:0000092 osteoclast.

Subcellular level: plasma membrane (receptor); cytoplasmic cAMP/PKA signaling; nucleus (HDAC/CRTC-regulated transcription). GO:0005886 plasma membrane; GO:0005737 cytoplasm; GO:0005634 nucleus.

Localization / lateralization: skeletal involvement is generalized and bilateral/symmetric (systemic germline receptor activation).

8. Temporal Development

Onset: congenital-to-early-childhood; radiographic metaphyseal changes present early; serum calcium normal at birth, then rises between ~0.15 and 10 years (F002). Onset pattern is chronic/insidious.

Progression: - Skeletal deformity is progressive through childhood; short stature is established and permanent (except milder T410R). - Hypercalcemia peaks in childhood and tends to normalize in adulthood — a distinctive age-dependent course (PMID: 29788189). - Renal disease (nephrocalcinosis → CKD) is progressive in a subset.

Disease course: chronic, lifelong. No spontaneous remission of the skeletal phenotype; the hypercalcemia component partially self-attenuates with age.

Critical periods / windows of opportunity: the growth-plate–active childhood window is the key period for skeletal morbidity and the theoretical window for mechanism-directed (inverse-agonist) intervention before physeal closure.

9. Inheritance and Population

Epidemiology. JMC is ultra-rare — only a few dozen well-documented patients worldwide (largest cohort n=24; PMID: 29788189). Precise prevalence/incidence are not established (Orphanet: <1/1,000,000).

Inheritance: autosomal dominant. Most cases are de novo; vertical transmission occurs (e.g., T410R father→sons; H223R mother→sons).

Penetrance / expressivity: high penetrance but variable expressivity — an H223R-carrier mother "was never overtly hypercalcemic and was therefore not diagnosed until her sons were found to be affected" (F010; PMID: 27410178). Incomplete penetrance has been reported for some novel PTH1R variants (PMID: 37840415).

"the now 38-year-old mother was never overtly hypercalcemic and was therefore not diagnosed until her sons were found to be affected by JMC" — PMID: 27410178

Genotype–phenotype correlation (F010): severity tracks with the degree of constitutive activity. H223R → profound hypercalcemia + severe short stature; T410R → milder (only mutation with near-normal adult height; near-normal longevity in humanized mice).

"Adult heights were well below the 3rd percentile for all patients, except for those with the T410R mutation." — PMID: 29788189

Anticipation / mosaicism / founder effects / consanguinity / carrier frequency: No genetic anticipation (not a repeat-expansion disorder). No founder effects; consanguinity is not relevant (dominant, de novo). Carrier frequency is not applicable. (Consanguinity is relevant instead to the recessive allelic disorders — Blomstrand, Eiken.)

Demographics: no ethnic predilection; no strong sex bias reported (dominant, sporadic). Presents in infancy/childhood.

10. Diagnostics

Biochemical (cornerstone): the diagnostic signature is hypercalcemia + hypercalciuria + hypophosphatemia with LOW/NORMAL PTH (PTH-independent hypercalcemia). FGF23 may be elevated. This distinguishes JMC from PTH-dependent hypercalcemias (F002, F012). LOINC: serum calcium, phosphate, intact PTH; urine calcium/creatinine ratio.

Imaging: skeletal radiographs show metaphyseal widening/irregularity, cupping, sclerotic and lucent changes, and progressive deformity — the defining radiographic features (case reports PMID: 10901979; PMID: 6974367). Renal ultrasound demonstrates nephrocalcinosis.

Genetic testing (confirmatory): targeted single-gene sequencing of PTH1R or skeletal-dysplasia/hypercalcemia gene panels; WES/WGS in undiagnosed cases. Detection of a heterozygous activating variant (H223R, T410P/R, I458R/K) is confirmatory. Chromosomal microarray/karyotype are not informative (point-mutation disorder).

Bone biopsy / histomorphometry: high-turnover changes (increased osteoid, osteoclast activity, marrow fibrosis; increased PTH1R IHC) — research/selected use (PMID: 39950977).

Differential diagnosis (F007, F012): - Other metaphyseal chondrodysplasias — Schmid, McKusick, Spahr, Shwachman — separable by clinical/radiographic/biochemical criteria; only JMC has hypercalcemia (PMID: 8644413). - Rickets (a classic radiographic mimic). - PTH-dependent hypercalcemias: neonatal severe hyperparathyroidism, familial hypocalciuric hypercalcemia (FHH) — these have high PTH (PMID: 33990852). - Other PTH-independent pediatric hypercalcemias: Williams-Beuren syndrome, hypophosphatasia, idiopathic infantile hypercalcemia (PMID: 34774247).

"Other types are Schmid, Spahr, McKusick, Schwachman and Jansen, which can be separated by clinical, radiographic, genetic and biochemical criteria." — PMID: 8644413

"Hypercalcemia can rarely be associated with immobilization, genetic diseases in children such as Williams-Beuren syndrome, Hypophosphatasia, Jansen Metaphyseal Chondrodysplasia (JMC)" — PMID: 34774247

Screening: No population newborn screening. Cascade genetic testing of at-risk relatives is appropriate in familial cases; prenatal/preimplantation testing is feasible once the family variant is known.

11. Outcome / Prognosis

Survival / mortality: JMC is generally compatible with survival into adulthood (contrast with neonatal-lethal Blomstrand chondrodysplasia). No formal life-expectancy tables exist; prognosis is dominated by renal (CKD from nephrocalcinosis) and orthopedic morbidity.

Morbidity / function: substantial lifelong disability from severe short stature and progressive limb deformity (most patients require orthopedic surgery), plus chronic renal disease in a subset. Hypercalcemia-related symptoms burden infancy/childhood.

Disease course / complications: nephrocalcinosis, nephrolithiasis, progressive CKD (2/24 advanced), skeletal deformity requiring surgery, and candidate infantile hypertension.

Prognostic factors: the specific mutation is the strongest predictor — T410R milder, H223R more severe. The natural attenuation of hypercalcemia in adulthood is a favorable biochemical trend.

12. Treatment

No approved disease-specific therapy exists. Management is symptomatic/supportive (F004, F008).

Supportive medical management: - Hydration; dietary calcium restriction; control of hypercalcemia/hypercalciuria. - Bisphosphonate (alendronate) reduced hypercalciuria in an adult H223R patient; normocalciuria required adding a thiazide diuretic; FGF23 remained normal under treatment (PMID: 22278430). NCIT: bisphosphonate therapy; thiazide diuretic.

"Treatment with alendronate reduced hypercalciuria; however, normocalciuria was only obtained with the association of thiazide diuretic." — PMID: 22278430

Orthopedic surgery: frequently required for limb deformity/correction. NCIT: orthopedic surgical procedure.

Rehabilitation / renal care: physical therapy; nephrology management of nephrocalcinosis/CKD.

Mechanism-directed / experimental — PTH1R inverse agonists (leading strategy; F004): - N-terminally truncated PTH/PTHrP antagonist peptides act as inverse agonists, reducing the high basal cAMP of JMC mutant receptors in vitro; [L11,dW12,W23,Y36]PTHrP(7-36) reduced basal cAMP for all five mutants (PMID: 31693237). - An inverse-agonist ligand partially rescued skeletal defects in a JMC mouse model (PMID: 31693237). - A backbone-modified long-acting peptide functions as an inverse agonist of PTH1R-H223R in vitro and in vivo (PMID: 38417010). - A synthetic PTH inverse agonist (PTH-IA) is in clinical development, with anti-drug-antibody assays already established (PMID: 42572867).

"we found that certain N-terminally truncated PTH and PTHrP antagonist peptides function as inverse agonists and thus can reduce the high rates of basal cAMP signaling exhibited by the mutant PTHR1s of JMC in vitro" — PMID: 31693237

"a peptidic PTH1R inhibitor that displays prolonged activity as an antagonist of wild-type PTH1R and an inverse agonist of the constitutively active PTH1R-H223R mutant both in vitro and in vivo" — PMID: 38417010

Personalized medicine: because severity and receptor pharmacology are mutation-specific, an inverse agonist confirmed active against all five mutants supports a genotype-agnostic-yet-mechanism-targeted approach. Structure-guided design also extends to de novo GPCR-targeting miniproteins (PMID: 42168559).

13. Prevention

  • Primary prevention: not possible for de novo dominant mutations. In familial cases, genetic counseling, prenatal diagnosis, and preimplantation genetic testing can prevent recurrence.
  • Secondary prevention: early biochemical detection (Ca/Pi/PTH) and imaging in symptomatic infants; early nephrology surveillance to limit nephrocalcinosis/CKD.
  • Tertiary prevention: manage hypercalciuria (bisphosphonate + thiazide) to reduce stone/nephrocalcinosis burden; orthopedic monitoring; renal protection.
  • Counseling: genetic counseling is central — clarifying AD inheritance, high de novo rate, and variable expressivity (a mildly affected/undiagnosed parent may carry the variant; PMID: 27410178).
  • Immunization / public health / environmental interventions: not applicable.

14. Other Species / Natural Disease

  • Taxonomy / orthologs: PTH1R is highly conserved. Functional models exist in mouse (Mus musculus, NCBI Taxon 10090); the ortholog is Pth1r. Zebrafish and other vertebrates possess conserved PTH1R signaling.
  • Natural disease in animals: No well-established naturally-occurring JMC-equivalent (constitutively-active PTH1R) disease is documented in companion animals or wildlife in this investigation (OMIA not confirmed here).
  • Comparative biology: the PTHrP–Ihh–PTH1R growth-plate circuit is evolutionarily conserved; mouse models faithfully reproduce the human causal chain (see §15), making JMC a strong example of conserved endochondral-development mechanisms.
  • Transmission: not applicable (non-infectious, genetic).

15. Model Organisms

JMC is unusually well-modeled in the mouse, providing the mechanistic backbone of the field (F005).

Model Type Key phenotype Reference
Col2a1-HKrk-H223R transgenic Constitutively active receptor under α1(II) collagen promoter (chondrocyte-targeted) Delayed mineralization; decelerated proliferative→hypertrophic conversion; prolonged hypertrophic chondrocytes PMID: 9391087
Col1a1-H223R transgenic Osteoblast-targeted Bone phenotype (↑ cortical bone) mirroring JMC PMID: 11713230
Humanized H223R-hPTH1R knock-in Knock-in Early lethal; cannot breed; substantially delayed growth-plate chondrocyte maturation PMID: 37808400; PMID: 40455993
Humanized T410R-hPTH1R knock-in Knock-in (milder allele) Near-normal longevity/breeding; misshapen long bones, expanded metaphyses, disarrayed growth-plate zones, reduced primary spongiosa PMID: 40455993
Sik2/Sik3 double KO Conditional KO (phenocopy) Bone phenotype closely resembling constitutively active PTH1R PMID: 31430259
Zfp521 deletion in Jansen chondrocytes Genetic rescue Restores chondrocyte differentiation; partial rescue of bone length PMID: 21642473
Chondrocyte-specific Gsα KO Conditional KO (opposite phenotype) Accelerated hypertrophy (mirror of JMC) PMID: 15765186

"The targeted expression of constitutively active PTH/PTHrP receptors led to delayed mineralization, decelerated conversion of proliferative chondrocytes into hypertrophic cells in skeletal segments that are formed by the endochondral process, and prolonged presence of hypertrophic chondr[ocytes]." — PMID: 9391087

"The long bones of T410R mice are markedly misshapen and have expanded metaphyses with disarrayed chondrocyte zones in growth plates and reduced primary spongiosa." — PMID: 40455993

"Its ablation from Jansen chondrocytes restored normal cell differentiation, thus initiating chondrocyte apoptosis at the chondro-osseous junction, leading to partial rescue of endochondral bone formation shown by proper bone length." — PMID: 21642473

Phenotype recapitulation: Excellent for the growth-plate/skeletal phenotype and for genetic-rescue proof-of-concept (Zfp521; inverse agonists). Limitations: the severe H223R humanized model is early-lethal and cannot breed, complicating long-term/therapeutic studies; the milder T410R model was engineered specifically to enable these. Renal/mineral-ion aspects and human natural history (adulthood normalization of calcium) are only partially captured.

Model applications: dissecting the PTHrP–Ihh–Gsα–SIK–HDAC pathway; testing inverse-agonist therapeutics in vivo; studying genotype–severity relationships. Resources: MGI (mouse); model lines maintained by originating academic laboratories.

Mechanistic Model / Interpretation

JMC is best understood as a "receptor stuck ON" disorder — the biochemical and developmental inverse of Blomstrand chondrodysplasia (receptor OFF). A single class of lesion (heterozygous activating PTH1R missense mutation) produces the entire multisystem phenotype through constitutive Gsα–cAMP signaling:

      LOSS OF FUNCTION  ◄─────  PTH1R  ─────►  GAIN OF FUNCTION
   (Blomstrand, Eiken,           │            (JANSEN — JMC)
    PFE, PHP-like)               │
   accelerated ossification      │            delayed hypertrophy,
   ± hypocalcemia                │            PTH-INDEPENDENT hypercalcemia
                         ▼
     constitutive Gsα → cAMP → PKA → ↓SIK2/3 → ↑class IIa HDAC
                         │
┌────────────────────────┼─────────────────────────┐
▼                        ▼                          ▼
  GROWTH PLATE              BONE REMODELING            KIDNEY
  delayed hypertrophy       high turnover              ↑Ca reabsorption
  (metaphyseal dysplasia,   (osteoid, osteoclasts,     ↑FGF23 → ↓phosphate
   short stature)            marrow fibrosis)          nephrocalcinosis→CKD

Upstream vs downstream: the mutation (upstream) → constitutive cAMP (proximal effector) → SIK inhibition / HDAC de-repression (transcriptional node) → cell-type-specific outputs (downstream): delayed chondrocyte hypertrophy in cartilage, high-turnover remodeling in bone, and altered mineral handling in kidney. Cell types: growth-plate chondrocytes (proliferative + hypertrophic), osteoblasts, osteocytes, osteoclasts, and renal tubular cells. Therapeutic logic follows directly: inverse agonists that suppress the receptor's basal activity restore signaling toward normal and partially rescue the skeletal phenotype in mice — the most promising path to a disease-modifying treatment.

Evidence Base

PMID Title (abbrev.) Supports
7701349 Constitutively active mutant PTH-PTHrP receptor in JMC Landmark 1995: H223R → constitutive cAMP (F008)
29788189 Progression of mineral ion abnormalities (n=24) Mutation spectrum; mineral-ion natural history (F001, F002, F009, F010)
27160269 Characterization of a PTH1R missense mutation Constitutive ligand-independent cAMP (F001)
10487664 Novel PTH1R mutation (I458R) I458R ~8× basal cAMP; H223R most frequent (F001)
31430259 SIKs dictate PTH1R action in bone SIK–HDAC downstream mechanism; molecular signature source (F003, F013)
16831900 PTHrP and skeletal development Normal PTH1R role in delaying hypertrophy (F006)
15765186 Chondrocyte Gsα knockout Gsα is critical PTH1R mediator (F006)
9008714 Bcl-2 downstream of PTHrP Bcl-2 delays chondrocyte maturation (F006)
9391087 Targeted constitutively active receptors Original Col2a1-H223R mouse model (F005, F013)
21642473 Deletion of Zfp521 Genetic rescue of Jansen growth plate (F005)
40455993 Humanized JMC mouse model H223R vs milder T410R knock-ins (F005, F010)
37808400 Delayed maturation in humanized mice Growth-plate delay in humanized model (F003, F005)
31693237 Inverse agonist rescues skeletal defects Inverse agonists suppress mutant signaling (F004)
38417010 Backbone-modified long-acting inverse agonist H223R inverse agonist in vivo (F004)
42572867 ECL bridging assay for PTH inverse agonist Clinical development of PTH-IA (F004)
22278430 Alendronate + thiazide in adult JMC Symptomatic hypercalciuria management; FGF23 (F002, F008)
39950977 Bone abnormalities beyond chondrodysplasia High-turnover histomorphometry; PTH1R IHC (F009, F013)
31977144 Severe hypertension in JMC Candidate cardiovascular feature (F009)
39108358 Ocular findings in JMC Ocular involvement (F009)
10912527 Role of PTHrP and Ihh GOF vs LOF dichotomy (F007)
40904804 Human diseases from homozygous PTH1R mutations Blomstrand LOF contrast (F007)
8644413 Metaphyseal chondrodysplasia vs rickets Differential diagnosis (F007)
33990852 Genetic neonatal/infantile hypercalcaemia JMC in hypercalcemia differential (F012)
34774247 Rare causes of hypercalcemia JMC as rare hypercalcemia cause (F012)
27410178 H223R with/without overt hypercalcemia Variable expressivity (F010)
37148874 Peptide agonist engagement with PTH1R Cryo-EM structural basis (F011)
40571720 G-protein coupling preference cryo-EM Class B1 GPCR structure (F011)
42168559 De novo design of GPCR-targeting miniproteins Structure-guided therapeutic design (F011)

Evidence source types: human clinical (case series/reports, biochemistry, histomorphometry), model organism (mouse transgenics/knock-ins/rescues), in vitro (HEK293/COS-7 cAMP reporter assays), and computational/structural (cryo-EM, de novo design).

Limitations and Knowledge Gaps

  1. No human omics datasets (F013). The molecular signature of JMC is inferred from mouse (SIK–HDAC) and cell models, not human transcriptomic/proteomic/metabolomic/single-cell data — a direct consequence of ultra-rarity and inaccessible growth-plate tissue.
  2. Small n / no formal epidemiology. Prevalence, incidence, precise sex ratio, and life-expectancy tables are not established; the largest cohort is 24 patients.
  3. Newer/candidate features under-characterized. Ocular findings and infantile hypertension are reported in single/few patients and need replication before being considered core features.
  4. Therapeutics are pre-approval. Inverse-agonist efficacy is demonstrated in vitro and in mouse models with only partial skeletal rescue; human efficacy, dosing window (before physeal closure), and immunogenicity remain to be established.
  5. MONDO ID not resolved in this investigation; OMIM #156400 is the authoritative identifier used.
  6. Renal/cardiovascular mechanisms (FGF23 elevation, hypertension) are incompletely dissected relative to the skeletal phenotype.

Proposed Follow-up Experiments / Actions

  1. Clinical trial of a PTH1R inverse agonist in JMC patients (building on PMID: 42572867, PMID: 38417010), prioritizing dosing during the growth-active childhood window, with skeletal, mineral-ion, and renal endpoints.
  2. Patient-derived iPSC → chondrocyte/organoid models to generate the first human JMC transcriptomic/proteomic signatures and validate the SIK–HDAC axis in human cells.
  3. Longitudinal natural-history registry capturing genotype (H223R vs T410R vs others), skeletal growth, renal function trajectory, and the adulthood normalization of hypercalcemia — powering genotype–phenotype and prognostic modeling.
  4. Systematic characterization of the renal and cardiovascular phenotypes (FGF23 biology, nephrocalcinosis progression, infantile hypertension) in the milder T410R humanized mouse, which permits long-term/breeding studies (PMID: 40455993).
  5. Structure-guided next-generation inverse agonists / de novo miniproteins (PMID: 42168559) optimized against all five mutant receptors, using the available cryo-EM structures (PMID: 37148874).
  6. Resolve MONDO mapping and reconcile Orphanet/OMIM/ICD identifiers for knowledge-base ingestion.

Report compiled from 13 confirmed findings and 43 reviewed papers across 5 investigation iterations. Evidence sources span human clinical case series, mouse genetic models, in vitro receptor pharmacology, and cryo-EM structural biology.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 32
Resolved 32
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 30
Quoted claims found in source 30
Quoted claims not found in source 0
References weighed for topical relevance 32
On topic 19
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 34
Resolved 33
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 0
Terms whose name was checked 16
Terms named correctly 13
Terms named as a different term 1
Terms whose name is worth a second look 2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • GO:0007050 (1 mention) - the report calls it "cell cycle arrest"; GO calls it GO_0007050

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0007050 (GO_0007050) (1 mention) - replaced by GO:0051726

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0003025 (2 mentions) - the report calls it "Metaphyseal widening"; HP calls it Metaphyseal irregularity, and lists "Metaphyseal fraying" among its other names
  • GO:0007189 (1 mention) - the report calls it "adenylate cyclase-activating GPCR signaling"; GO calls it adenylate cyclase-activating G protein-coupled receptor signaling pathway, and lists "adenylate cyclase-activating GPCR signaling pathway" among its other names