Clinical Guidance

Given the ultra-rare nature of PTH1R-JMC, studies detailing genotype-phenotype correlation have not been performed.

Source: GeneReviews — "PTH1R-Related Jansen Metaphyseal Chondrodysplasia"

Penetrance

PTH1R-JMC has a high penetrance, and individuals with a PTH1R-JMC-related pathogenic variant are likely to develop some clinical and/or radiographic manifestations. There is wide heterogeneity in the phenotype in terms of clinical manifestations, onset, and severity. Short-limbed dwarfism appears to be a highly penetrant manifestation, seen in almost all affected individuals .

Source: GeneReviews — "PTH1R-Related Jansen Metaphyseal Chondrodysplasia"

Diagnostic Criteria

No consensus clinical diagnostic criteria for PTH1R-related Jansen metaphyseal chondrodysplasia (PTH1R-JMC) have been published. Short-limb short stature with flaring of the metaphyses in the extremities and hypercalcemia with low serum parathyroid hormone (PTH) levels are highly suggestive of PTH1R-JMC.

Suggestive Findings

PTH1R-JMC should be suspected in probands with the following clinical, laboratory, and imaging findings and family history.

Clinical findings

Source: GeneReviews — "PTH1R-Related Jansen Metaphyseal Chondrodysplasia"

Differential Diagnosis

Genetic disorders of interest in the differential diagnosis of PTH1R-related Jansen metaphyseal chondrodysplasia (PTH1R-JMC) are listed in .

Table 3.

Genes of Interest in the Differential Diagnosis of PTH1R-Related Jansen Metaphyseal Chondrodysplasia

Gene(s) | Disorder | MOI | Features of Disorder

Overlapping w/PTH1R-JMC | Distinguishing from PTH1R-JMC

COL10A1

| Schmid metaphyseal chondrodysplasia | AD | • Short stature

• Metaphyseal dysplasia

| No disturbances of mineral-ion homeostasis

COL2A1FN11 | Spondylometaphyseal dysplasia, corner fracture type | AD | • Short stature

• Irregular metaphysis

• Bowed legs

FGFR3

| Hypochondroplasia | AD | • Short stature

• Bowed legs

PHEX | X-linked hypophosphatemia (XLH) | XL | • Short stature

Management Guidelines

No clinical practice guidelines for PTH1R-related Jansen metaphyseal chondrodysplasia (PTH1R-JMC) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PTH1R-JMC, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

PTH1R-Related Jansen Metaphyseal Chondrodysplasia: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Skeletal abnormalities

| • Referral to orthopedist physiatrist for mgmt

• Skeletal radiographs to determine timing extent of surgical procedures to improve alignment range of motion

|

Growth

| Assess growth incl head circumference. |

Craniosynostosis

| • CT skull to help determine need for intervention in those w/craniosynostosis

• Referral to oromaxillofacial surgeon or neurosurgeon for mgmt in those w/craniosynostosis

|

Teeth/Malocclusion

| • Dental exam radiographs

• Referral to oromaxillofacial specialist as needed

|

Hearing

| Referral to otolaryngologist audiologist for audiogram tympanogram |

Eyes/ Visual deficits

| Referral to ophthalmologist for visual field exam, optical coherence tomography, orbital MRI (if indicated) to assess for optic canal narrowing |

Endocrine/Nephrocalcinosis

| • Referral to endocrinologist for laboratory assessment i...

Source: GeneReviews — "PTH1R-Related Jansen Metaphyseal Chondrodysplasia"

Clinical Guidance

Contact sports and other high-risk activities should likely be avoided in those with significant skeletal involvement. Individuals with PTH1R-JMC should be encouraged to participate in low-impact exercise as tolerated, such as swimming.

Source: GeneReviews — "PTH1R-Related Jansen Metaphyseal Chondrodysplasia"

Therapies Under Investigation

PTH-IA is a 30-amino-acid peptide expected to act as an inverse agonist, decreasing the proportion of parathyroid hormone/parathyroid hormone-related peptide receptors (PTH1R) in the constitutively active state, leading to a reduction in basal cAMP signaling. To date, information on PTH-IA is limited to cell and animal models . An Investigational New Drug approval was granted to a Phase I/II study evaluating the safety and efficacy of PTH-IA, which is expected to start enrolling soon. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "PTH1R-Related Jansen Metaphyseal Chondrodysplasia"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. There is no evidence informing the frequency of surveillance in individuals with PTH1R-JMC. The recommendations are based on the authors' experience. Table 6. PTH1R-Related Jansen Metaphyseal Chondrodysplasia: Recommended Surveillance

Source: GeneReviews — "PTH1R-Related Jansen Metaphyseal Chondrodysplasia"