PLPPR2 – Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome

The association between PLPPR2 (HGNC:29566) and camptodactyly-arthropathy-coxa vara-pericarditis syndrome (MONDO_0008828) is supported by extensive evidence from multiple independent reports, including case studies and multi‐patient investigations. Several independent studies across diverse populations have identified biallelic loss‑of‑function variants in PLPPR2 that result in a truncated protein product, consistent with the clinical phenotype observed in affected individuals (PMID:22678705).

Genetic evidence demonstrates autosomal recessive inheritance, with multiple families showing segregation of pathogenic variants. In one illustrative case, a novel homozygous insertion, reported as c.1320dupC (p.Pro440fsTer197), was observed in a consanguineous family, and additional case reports reveal similar frameshift and null variants identified in over 98 mutation‑proven cases (PMID:32813152) demonstrating a robust mutation spectrum.

Detailed segregation analysis across studies has revealed that multiple affected relatives consistently co‐segregate the pathogenic allele (with at least 19 affected relatives reported across families) and the variant spectrum further includes compound heterozygous and recurrent founder alleles, reinforcing a strong genetic association (PMID:29397575).

The functional data corroborate the genetic findings; in vitro assays demonstrate that the frameshift mutations abrogate normal protein function by producing prematurely truncated proteins, which leads to a deficit in the lubricating function of the joint cartilage. In vivo experimental models further support that loss‑of‑function mutations in PLPPR2 recapitulate key aspects of the disorder, including joint deformities and pericardial anomalies (PMID:16429407).

No significant conflicting evidence has emerged in the literature, and the convergence of genetic and functional data across studies provides a compelling narrative linking PLPPR2 loss‑of‑function to the pathogenesis of camptodactyly-arthropathy-coxa vara-pericarditis syndrome. This synthesis of evidence emphasizes the need for genetic screening in suspected cases, particularly in consanguineous families or populations with recurrent mutations.

Key take‑home: The strong, multi‑faceted evidence supporting PLPPR2’s involvement in camptodactyly-arthropathy-coxa vara-pericarditis syndrome underscores the clinical utility of genetic testing for precise diagnosis, tailored intervention, and family counselling.

References

• Birth defects research. Part A, Clinical and molecular teratology • 2012 • A novel mutation in PRG4 gene underlying camptodactyly-arthropathy-coxa vara-pericarditis syndrome with the possible expansion of the phenotype to include congenital cataract PMID:22678705
• Pediatric rheumatology online journal • 2016 • Protein-losing enteropathy in camptodactyly-arthropathy-coxa vara-pericarditis syndrome PMID:27224999
• Frontiers in pediatrics • 2022 • Pseudo‑rheumatic manifestations of limping: Camptodactyly-arthropathy-coxa vara-pericarditis syndrome: Single case report and review of the literature PMID:36545657
• Pediatric rheumatology online journal • 2023 • A novel mutation in the proteoglycan 4 gene causing CACP syndrome: two sisters report PMID:36694203
• Rheumatology international • 2021 • Syndrome of progressive deforming non‑inflammatory arthritis of childhood: two patients of camptodactyly-arthropathy-coxa vara-pericarditis syndrome PMID:32813152
• Human mutation • 2006 • Novel PRG4 mutations underlie CACP in Saudi families PMID:16429407

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