Case report: compound heterozygous <i>PTH1R</i> variant(s) in a patient with inactivating PTH/PTHrP signalling disorder type 1 (iPPSD1).
This case highlights the importance of genetic diagnosis in managing rare conditions like iPPSD1, particularly in identifying novel variants that may inform treatment strategies.
Where it sits
this study against the rest of the abaloparatide (tymlos) corpusSummary and findings
This case report describes a 9-year-old female with inactivating PTH/PTHrP signalling disorder type 1 (iPPSD1) due to compound heterozygous variants in the PTH1R gene. Whole exome sequencing identified two novel variants, c.557G>A and c.686delC, which are associated with PTH resistance and various skeletal and dental issues. The report emphasizes the significance of genetic diagnosis in managing this rare condition.
Abstract
<h4>Objectives</h4>Inactivating parathyroid hormone (PTH)/PTHrP Signalling Disorder Type 1 (iPPSD1) is a rare genetic condition caused by loss-of-function mutations in the <i>PTH1R</i> gene, presenting with PTH resistance and variable skeletal and dental manifestations. The gene is catalogued under OMIM *168468. Compound heterozygous variants are exceptionally rare and associated with severe phenotypes.<h4>Case presentation</h4>We report a 9-year-old female from the Indian subcontinent presenting with primary failure of tooth eruption, dental anomalies, valgus deformity, and PTH resistance with subclinical hypothyroidism. Whole exome sequencing identified novel compound heterozygous variants in exons 8 and 9 of the <i>PTH1R</i> gene (NM_002820.4: c.557G>A [p.Arg186His] and c.686delC [p.Phe230fs*6], confirmed in trans), confirmed by Sanger sequencing and absent from major population databases.<h4>Conclusions</h4>This is the first reported case of a compound heterozygous PTH1R variant in the Indian population, expanding the known allelic spectrum of iPPSD1 and highlighting the importance of genetic diagnosis in guiding clinical management. Early molecular diagnosis enabled appropriate multidisciplinary management.
Background
Inactivating parathyroid hormone (PTH)/PTHrP Signalling Disorder Type 1 (iPPSD1) is a rare genetic condition characterized by loss-of-function mutations in the PTH1R gene. Prior knowledge indicates that this disorder leads to PTH resistance and a range of skeletal and dental manifestations. This study is significant as it documents a rare case of compound heterozygous variants in a patient, contributing to the understanding of the genetic diversity associated with iPPSD1.
Methods
This case report details a 9-year-old female patient from the Indian subcontinent. Whole exome sequencing was utilized to identify genetic variants, specifically focusing on exons 8 and 9 of the PTH1R gene. The study does not specify the number of participants or the duration of the observation.
Results
The report identifies two novel compound heterozygous variants in the PTH1R gene: c.557G>A [p.Arg186His] and c.686delC [p.Phe230fs*6]. These variants were confirmed in trans and were absent from major population databases. The patient exhibited primary failure of tooth eruption, dental anomalies, valgus deformity, and PTH resistance.
Interpretation
This case adds to the limited literature on compound heterozygous variants in the PTH1R gene, particularly in the Indian population. While the findings are statistically significant in terms of identifying novel genetic variants, the clinical significance of these variants in broader populations remains to be established. Limitations include the absence of a larger sample size and potential confounding factors inherent in case reports.
Key findings
- Identified novel compound heterozygous variants in exons 8 and 9 of the PTH1R gene.
- Variants c.557G>A [p.Arg186His] and c.686delC [p.Phe230fs*6] confirmed in trans.
- Variants absent from major population databases.
Limitations
- Single case report with no control group.
- Small sample size, n=1.
- No long-term follow-up data provided.
- Absence of functional studies to assess variant impact.