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Evaluation of embryonic and perinatal myosin gene mutations and the etiology of congenital idiopathic clubfoot.

ABSTRACT: Congenital idiopathic clubfoot is the most common musculoskeletal birth defect that develops during the fetal period, but with no known etiology. MYH 2, 3, 7, and 8 are expressed embryonically or perinatally, the period during which congenital idiopathic clubfoot develops; are all components of Type II muscle, which is consistently decreased in clubfoot patients; and are associated with several muscle contracture syndromes that have associated clubfoot deformities. In this study, we hypothesized that a mutation in an embryonic or perinatal myosin gene could be associated with congenital idiopathic clubfoot.We screened the exons, splice sites, and predicted promoters of 24 bilateral congenital idiopathic clubfoot patients and 24 matched controls in MYH 1, 2, 3, and 8 via sequence-based analysis, and screened an additional 76 patients in each discovered SNP.Although many single-nucleotide polymorphisms were found; none proved to be significantly associated with the phenotype of congenital idiopathic clubfoot. Also, no known mutations that cause distal arthrogryposis syndromes were found in the congenital idiopathic clubfoot patients.These findings demonstrate that congenital idiopathic clubfoot has a different pathophysiology than the clubfoot seen in distal arthrogryposis syndromes, and defects in myosin are most likely not directly responsible for the development of congenital clubfoot. Given the complexity of early myogenesis, many regulatory candidate genes remain that could cause defects in the hypaxial musculature that is invariably observed in congenital idiopathic clubfoot.This study further differentiates congenital idiopathic clubfoot as distinct from other complex genetic syndromes that can present with similar deformities, and thus facilitates further research to improve the clinical diagnosis and treatment of congenital idiopathic clubfoot.

SUBMITTER: Shyy W

PROVIDER: S-EPMC2913130 | biostudies-literature | 2010 Apr-May

REPOSITORIES: biostudies-literature

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Evaluation of embryonic and perinatal myosin gene mutations and the etiology of congenital idiopathic clubfoot.

Shyy William W Wang Kai K Sheffield Val C VC Morcuende Jose A JA

Journal of pediatric orthopedics 20100401 3

<h4>Background</h4>Congenital idiopathic clubfoot is the most common musculoskeletal birth defect that develops during the fetal period, but with no known etiology. MYH 2, 3, 7, and 8 are expressed embryonically or perinatally, the period during which congenital idiopathic clubfoot develops; are all components of Type II muscle, which is consistently decreased in clubfoot patients; and are associated with several muscle contracture syndromes that have associated clubfoot deformities. In this stu ...[more]

PMID: 20357587

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Project description:BackgroundIdiopathic congenital talipes equinovarus (CTEV) is the commonest form of clubfoot. Its exact cause is unknown, although it is related to limb development. The aim of this study was to quantify the anatomy of the muscle, subcutaneous fat, tibia, fibula and arteries in the lower legs of teenagers and young adults with CTEV using 3D magnetic resonance imaging (MRI), and thus to investigate the anatomical differences between CTEV participants and controls.Methodology/principal findingsThe lower legs of six CTEV (2 bilateral, 4 unilateral) and five control young adults (age 12-28) were imaged using a 3T MRI Philips scanner. 5 of the CTEV participants had undergone soft-tissue and capsular release surgery. 3D T1-weighted and 3D magnetic resonance angiography (MRA) images were acquired. Segmentation software was used for volumetric, anatomical and image analysis. Kolmogorov-Smirnov tests were performed. The volumes of the lower affected leg, muscle, tibia and fibula in unilateral CTEV participants were consistently smaller compared to their contralateral unaffected leg, this was most pronounced in muscle. The proportion of muscle in affected CTEV legs was significantly reduced compared with control and unaffected CTEV legs, whilst proportion of muscular fat increased. No spatial abnormalities in the location or branching of arteries were detected, but hypoplastic anomalies were observed.Conclusions/significanceCombining 3D MRI and MRA is effective for quantitatively characterizing CTEV anatomy. Reduction in leg muscle volume appears to be a sensitive marker. Since 5/6 CTEV cases had soft-tissue surgery, further work is required to confirm that the treatment did not affect the MRI features observed. We propose that the proportion of muscle and intra-muscular fat within the lower leg could provide a valuable addition to current clinical CTEV classification. These measures could be useful for clinical care and guiding treatment pathways, as well as treatment research and clinical audit.

Project description:- A delegation of 6 pediatric orthopedic surgeons from the Dutch Orthopedic Association (NOV) and 2 members of the board of the Dutch Parents' Association for children with clubfoot created the guideline "The diagnosis and treatment of primary idiopathic clubfeet" between April 2011 and February 2014. The development of the guideline was supported by a professional methodologist from the Dutch Knowledge Institute of Medical Specialists. This evidence-based guideline process was new and unique, in the sense that the process was initiated by a parents' association. This is the first official guideline in pediatric orthopedics in the Netherlands, and to our knowledge it is also the first evidence-based guideline on clubfoot worldwide. The guideline was developed in accordance with the criteria of the international AGREE instrument (AGREE II: Appraisal of Guidelines for Research and Evaluation II). The scientific literature was searched and systematically analyzed. In the second phase, conclusions and recommendations in the literature were formulated according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method. Recommendations were developed considering the balance of benefits and harms, the type and quality of evidence, the values and preferences of the people involved, and the costs. The guideline is a solid foundation for standardization of clubfoot treatment in the Netherlands, with a clear recommendation of the Ponseti method as the optimal method of primary clubfoot treatment. We believe that the format used in the current guideline sets a unique example for guideline development in pediatric orthopedics that may be used worldwide. Our format ensured optimal collaboration between medical specialists and parents, and resulted in an important change in clubfoot care in the Netherlands, to the benefit of medical professionals as well as parents and patients. In this way, it is possible to improve professional collaboration between medical specialists and parents, resulting in an important change in clubfoot care in the Netherlands that will benefit medical professionals, parents, and patients. The guideline was published online, and is freely available from the Dutch Guideline Database ( www.richtlijnendatabase.nl ).

Dataset Information

Evaluation of embryonic and perinatal myosin gene mutations and the etiology of congenital idiopathic clubfoot.

Publications

Evaluation of embryonic and perinatal myosin gene mutations and the etiology of congenital idiopathic clubfoot.

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