PlA2 Polymorphism of Platelet Glycoprotein IIb/IIIa and C677T Polymorphism of Methylenetetrahydrofolate Reductase (MTHFR), but Not Factor V Leiden and Prothrombin G20210A Polymorphisms, Are Associated with More Severe Forms of Legg-Calvé-Perthes Disease.

María Dolores García-Alfaro,Domingo González-Lamuño,María Isabel Pérez-Nuñez,María Teresa Amigo,Carmelo Arbona,María Ángeles Ballesteros

doi:10.3390/children8070614

Abstract

The possible association of common polymorphic variants related to thrombophilia (the rs6025(A) allele encoding the Leiden mutation, rs1799963(A), i.e., the G20210A mutation of the prothrombin F2 gene, the rs1801133(T) variant of the methylenetetrahydrofolate reductase (MTHFR) gene that encodes an enzyme involved in folate metabolism, and rs5918(C), i.e., the ‘A2’ allele of the platelet-specific alloantigen system that increases platelet aggregation induced by agonists), with the risk of Legg–Calvé–Perthes disease (LCPD) and the degree of hip involvement (Catterall stages I to IV) was analyzed in a cohort study, including 41 children of ages 2 to 10.9 (mean 5.4, SD 2.2), on the basis of clinical and radiological criteria of LCPD. In 10 of the cases, hip involvement was bilateral; thus, a total of 51 hips were followed-up for a mean of 75.5 months. The distribution of genotypes among patients and 118 controls showed no significant differences, with a slightly increased risk for LCPD in rs6025(A) carriers (OR: 2.9, CI: 0.2–47.8). Regarding the severity of LCPD based on Catterall classification, the rs1801133(T) variant of the MTHFR gene and the rs5918(C) variant of the platelet glycoprotein IIb/IIIa were associated with more severe forms of Perthes disease (Catterall III–IV) (p < 0.05). The four children homozygous for mutated MTHFR had a severe form of the disease (Stage IV of Catterall) and a higher risk of non-favorable outcome (Stulberg IV–V).

Highlights

It is generally accepted that the disruption of the blood supply to secondary ossification centers in the femoral epiphyses is a key element for avascular necrosis, resulting in deformity of the femoral head, there are few studies that address the implication of inherited thrombophilic status in the severity of Legg–Calvé–Perthes disease (LCPD)
There is evidence that remodeling of the extracellular matrix may be important in processes linked to mineralization and necrosis of the femoral head, and some thrombophilic factors involved in tissue damage after ischemic processes can be implied in extracellular matrix remodeling mechanisms, related to the severity of LCPD
We found that the occurrence of at least one PlA2 allele or two alleles for the C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR) presented a significantly increased risk of having Catterall III or IV LCPD (p = 0.05); their screening in at-risk children might be useful in the future as prognosis markers

Summary

Introduction

Legg–Calvé–Perthes disease (LCPD), characterized by avascular necrosis of the proximal femoral epiphysis [1,2,3,4], remains a controversial entity in child orthopedics. Hereditary thrombophilia has gained considerable attention as a risk factor for LCPD, there are still controversies about this association or its potential implication in the severity of the disease [7,8]. Familial osteonecrosis of the femoral head has been associated with variant mutations of collagen type II [9,10]; the extracellular matrix might have a role in the pathogenesis or outcomes of LCPD. The thrombophilic factors include platelet transmembrane receptors that facilitate cell adhesion within extracellular matrix ligands; we aimed to investigate the possible correlation between the severity of LCPD and the presence of prevalent and well-known thrombophilic polymorphisms implied in extracellular matrix and tissue remodeling

Objectives

Methods

Results

Discussion

Conclusion