Eligibility for knee arthroplasty is associated with increased risk of acquired hallux valgus - a Mendelian randomized study.

OBJECTIVE: Clinically, it has been found that patients undergoing knee replacement have a high incidence of concomitant hallux valgus. In this study, we analyzed whether patients with osteoarthritis who underwent surgery and those patient who did not have surgery had an increased risk of hallux valgus by Mendelian randomization and performed reverse causal analysis. DESIGN: Genomewide association study (GWAS) data for osteoarthritis, categorized by knee arthritis with joint replacement, knee arthritis without joint replacement, hip arthritis with joint replacement, and hip arthritis without joint replacement.And acquired hallux valgus were downloaded for Mendelian randomized studies. MR analysis was performed using inverse variance-weighted (IVW), weighted median, and MR-Egger methods. MR-egger regression, MR pleiotropic residuals and outliers (MR-presso), and Cochran's Q statistical methods were used to evaluate heterogeneity and pleiotropy. RESULTS: The IVW results indicate that, compared to healthy individuals, patients who meet the criteria for knee osteoarthritis joint replacement surgery have a significantly higher risk of acquired hallux valgus. There were no significant causal relationships found for the remaining results. No significant heterogeneity or multiplicity was observed in all the Mr analyses. CONCLUSION: Our study supports the increased risk of acquired hallux valgus in patients eligible for knee replacement. There is necessary for clinicians to be concerned about the hallux valgus status of patients undergoing knee arthroplasty.

Effect of lentivirus-mediated miR-182 targeting FGF9 on hallux valgus.

The pathogenesis of hallux valgus is not clearly understood. However, genetics research about hallux valgus is rare. Therefore, the present study aimed to explore the pathogeny of hallux valgus from the perspective of genetics. Human samples were collected from normal bone tissue and hallux valgus region bone tissue. The bone samples were studied using real time-PCR, western blot and immunohistochemical. Lentivirus-mediated miR-182 transfected osteoblasts and tested the expression of FGF9 mRNA with real time-PCR. To test alkaline phosphatase activity, number of calcium nodules and proliferation of osteoblast with enzymatic activity analysis, calcium nodules stained and MTT assay. We found that (1) FGF9 expressed in hallux valgus region bone tissue was significantly higher than normal bone tissue. (2) miR-182 expression levels in hallux valgus region bone tissue were notably lower than those of normal bone tissue. (3) miR-182 could negatively regulate the expression of FGF9 in osteoblasts. (4) FGF9 may enhance osteoblasts proliferation. We have demonstrated that miR-182 promotes the formation of bone by targeting FGF9, implicating an essential role of miR-182 in the etiology of hallux valgus. Moreover, miR-182 might potentially be a therapeutic target for hallux valgus treatment.

Mechanical stress promotes angiogenesis through fibroblast exosomes.

BACKGROUND: Mechanical stress can induce multiple functional changes in vascular endothelial cells, including proliferation, differentiation, and migration. Furthermore, human fibroblasts are susceptible to external mechanical stress. In this work, we investigated whether mechanical stress can induce exosome secretion from fibroblasts to modulate angiogenesis. METHODS: A CCK-8 cell proliferation assay was used to determine mechanical parameters. Then, exosomes from fibroblasts were isolated and characterized with regard to concentration and markers. We subsequently explored the effect of exosomes on proliferation, migration, and angiogenesis. Additionally, high-throughput sequencing was used to screen differentially expressed miRNAs in the mechanical stress-induced exosomes. RESULTS: A static stretching of 15% significantly enhanced the cell viability of the fibroblasts (p < 0.05) and significantly induced the secretion of exosomes from the fibroblasts, which had a stronger internalization ability. Further experiments demonstrated that the presence of static stretching-induced exosomes significantly increased cell proliferation, migration, and angiogenesis by regulating the Erk1/2 signaling pathway. Additionally, 12 up-regulated and 12 down-regulated candidate miRNAs were discriminated in the static stretching-induced exosomes. CONCLUSION: Our findings conclusively demonstrate that static stretching-derived exosomes from fibroblasts promote angiogenesis through differentially expressed miRNAs, providing novel insights into the molecular mechanism by which mechanical stress influences angiogenesis.

Variable pulmonary manifestations in Chitayat syndrome: Six additional affected individuals.

Hand hyperphalangism leading to shortened index fingers with ulnar deviation, hallux valgus, mild facial dysmorphism and respiratory compromise requiring assisted ventilation are the key features of Chitayat syndrome. This condition results from the recurrent heterozygous missense variant NM_006494.2:c.266A>G; p.(Tyr89Cys) in ERF on chromosome 19q13.2, encoding the ETS2 repressor factor (ERF) protein. The pathomechanism of Chitayat syndrome is unknown. To date, seven individuals with Chitayat syndrome and the recurrent pathogenic ERF variant have been reported in the literature. Here, we describe six additional individuals, among them only one presenting with a history of assisted ventilation, and the remaining presenting with variable pulmonary phenotypes, including one individual without any obvious pulmonary manifestations. Our findings widen the phenotype spectrum caused by the recurrent pathogenic variant in ERF, underline Chitayat syndrome as a cause of isolated skeletal malformations and therefore contribute to the improvement of diagnostic strategies in individuals with hand hyperphalangism.

Correlation analysis between vitamin D receptor gene polymorphism (BsmI) and hallux valgus.

Hallux valgus is a common foot deformity disease caused by various extrinsic and intrinsic factors, and systemic conditions, but the etiopathogenesis and pathogenesis of this deformity are still unknown. Hallux valgus affects 10-20% of Chinese adults. Although considered highly heritable, the candidate gene is unclear. We conducted the first candidate gene study of hallux valgus to identify the biological mechanism. Between June 2015 and July 2018, the records and radiographs of 80 patients diagnosed with hallux valgus and 80 controls who were treated were analyzed. In order to compare the differences in severity associated with this deformity, the charts of 80 patients were divided into 3 groups from the angle of hallux valgus. Clinical and basic studies were also statistically compared by PCR and data analysis. Patients and controls had significant differences in age and gender, however, there were no significant differences in age and gender among the light, moderate and severe groups. Post-operative groups resulted in significant improvements in all of the measured radiographic parameters compared with pre-operative groups. BsmI seemed to show a specific variation, and may serve as a useful bio-marker for the disease (OR = 5.88, 95% CI 1.54-22.35, P <0.001). In this paper, the article which proved the VDR polymorphisms (BsmI) playing an important role in hallux valgus were studied to understand and manage the hallux valgus more scientifically.

Relationship of vitamin D receptor gene polymorphisms with susceptibility, surgical outcome and prognosis of hallux valgus in a Chinese Han population.

BACKGROUND: This study aimed to identify the relationship between the vitamin D receptor (VDR) BsmI gene polymorphism and risk factors, surgical outcome and prognosis of hallux valgus (HV). METHODS: A case-control study was performed on a cohort of 236 HV patients and 236 controls in a Chinese Han population. Detection of the VDR BsmI/G2A polymorphism was performed using restriction fragment length polymorphism-polymerase chain reaction. RESULTS: We detected a statistically significant difference in the allele distribution of the BsmI polymorphism between cases and controls (p<0.01). Significant loss of hallux valgus angle (HVA) and intermetatarsal angle (IMA) correction was only noted in patients with the bb genotype during the 2-year follow-up period (p<0.01). The average American Orthopaedic Foot and Ankle Society (AOFAS) scores at the 2-year follow-up were decreased in both groups when compared with those at the 6 month follow-up, and 1.45 points more decrease in patients with the bb genotype was observed as compared to those with the BB and Bb genotypes (p<0.0001). The average visual analogue scales (VAS) also had the tendency with more pains in the bb genotype group (p<0.0001). Furthermore, larger numbers of transfer metatarsalgia were found in patients with the bb genotype upon 2-year follow-up (p=0.049). CONCLUSIONS: We report the first candidate gene polymorphism associated with susceptibility, surgical outcome and prognosis of HV in a Chinese Han population. Moreover, development of genetically-based method to predict the surgical outcome accurately and individualized therapy for HV are warranted.

Difficult diagnosis and genetic analysis of fibrodysplasia ossificans progressiva: a case report.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP), an ultra-rare and disabling genetic disorder of skeletal malformations and progressive heterotopic ossification, is caused by heterozygous activating mutations in activin A receptor, type I/activin-like kinase 2 (ACVR1/ALK2). The rarity of the disease makes it common to make a misdiagnosis and cause mismanagement. CASE PRESENTATION: We reported a case of a sixteen-year-old male patient who had suffered from pain and swelling in the biopsy site for two months. His physical examination presented serious stiffness and multiple bony masses in the body, with his bilateral halluces characterized by hallux valgus deformity and macrodactyly. Imaging examinations showed widespread heterotopic ossification. All laboratory blood tests were normal except for the one on alkaline phosphatase. A de novo heterozygous mutation (c.617G > A; p.R206H) were found in the ACVR1/ALK2 using gene sequencing. CONCLUSION: Even though FOP is a rare disorder of genetic origin, which is generally misdiagnosed, the genetic analysis could provide definitive confirmation of the disease. Awareness of such an important approach can help clinicians to avoid the commonly practiced misdiagnosis and mismanagement of the rare disease.

Chitayat syndrome: hyperphalangism, characteristic facies, hallux valgus and bronchomalacia results from a recurrent c.266A>G p.(Tyr89Cys) variant in the ERF gene.

BACKGROUND: In 1993, Chitayat et al., reported a newborn with hyperphalangism, facial anomalies, and bronchomalacia. We identified three additional families with similar findings. Features include bilateral accessory phalanx resulting in shortened index fingers; hallux valgus; distinctive face; respiratory compromise. OBJECTIVES: To identify the genetic aetiology of Chitayat syndrome and identify a unifying cause for this specific form of hyperphalangism. METHODS: Through ongoing collaboration, we had collected patients with strikingly-similar phenotype. Trio-based exome sequencing was first performed in Patient 2 through Deciphering Developmental Disorders study. Proband-only exome sequencing had previously been independently performed in Patient 4. Following identification of a candidate gene variant in Patient 2, the same variant was subsequently confirmed from exome data in Patient 4. Sanger sequencing was used to validate this variant in Patients 1, 3; confirm paternal inheritance in Patient 5. RESULTS: A recurrent, novel variant NM_006494.2:c.266A>G p.(Tyr89Cys) in ERF was identified in five affected individuals: de novo (patient 1, 2 and 3) and inherited from an affected father (patient 4 and 5). p.Tyr89Cys is an aromatic polar neutral to polar neutral amino acid substitution, at a highly conserved position and lies within the functionally important ETS-domain of the protein. The recurrent ERF c.266A>C p.(Tyr89Cys) variant causes Chitayat syndrome. DISCUSSION: ERF variants have previously been associated with complex craniosynostosis. In contrast, none of the patients with the c.266A>G p.(Tyr89Cys) variant have craniosynostosis. CONCLUSIONS: We report the molecular aetiology of Chitayat syndrome and discuss potential mechanisms for this distinctive phenotype associated with the p.Tyr89Cys substitution in ERF.

Association of Vitamin D Receptor Gene TaqI, BsmI, FokI, and ApaI Polymorphisms and Susceptibility to Hallux Valgus in the Chinese Population.

Previous studies have indicated that vitamin D receptor (VDR) TaqI, BsmI, FokI and ApaI gene polymorphisms are associated with the risk of skeletal malformations with inflammation. However, the potential association of VDR gene polymorphisms with the susceptibility to hallux valgus remains unclear. To clarify this association, we compared the genotypes of 228 patients with hallux valgus with those of 200 controls using the Multiplex SNaPshot system. The χ2 test was used to compare the allele and genotype frequencies between groups, and p ≤ .05 was considered statistically significant. The frequencies of the mutant allele C in TaqI (p= .036; odds ratio [OR] 1.57; 95% confidence interval [CI] 1.03-2.39) and mutant allele A in BsmI (p= .036; OR 1.33; 95% CI 1.02-1.74) were significantly greater in the patients than in the controls. In addition, after adjusting for sex and age, TaqI (p= .047; OR 1.61; 95% CI 1.00-2.58) and BsmI (p= .025; OR 1.67; 95% CI 1.06-2.61) were associated with the risk of hallux valgus through a dominant genetic model. A homozygous genetic model of BsmI was also significantly associated with the risk of hallux valgus (p= .033; OR 1.81; 95% CI 1.05-2.57). However, neither ApaI nor FokI were associated with increased susceptibility. To the best of our knowledge, we have reported for the first time that VDR gene TaqI and BsmI polymorphisms might contribute to the increased risk of hallux valgus in Chinese population.

Genome-wide association meta-analyses to identify common genetic variants associated with hallux valgus in Caucasian and African Americans.

OBJECTIVE: Hallux valgus (HV) affects ∼36% of Caucasian adults. Although considered highly heritable, the underlying genetic determinants are unclear. We conducted the first genome-wide association study (GWAS) aimed to identify genetic variants associated with HV. METHODS: HV was assessed in three Caucasian cohorts (n=2263, n=915 and n=1231 participants, respectively). In each cohort, a GWAS was conducted using 2.5 M imputed SNPs. Mixed-effect regression with the additive genetic model adjusted for age, sex, weight and within-family correlations was used for both sex-specific and combined analyses. To combine GWAS results across cohorts, fixed-effect inverse-variance meta-analyses were used. Following meta-analyses, top-associated findings were also examined in an African American cohort (n=327). RESULTS: The proportion of HV variance explained by genome-wide genotyped SNPs was 50% in men and 48% in women. A higher proportion of genetic determinants of HV were sex specific. The most significantly associated SNP in men was rs9675316 located on chr17q23-a24 near the AXIN2 gene (p=0.000000546×10(-7)); the most significantly associated SNP in women was rs7996797 located on chr13q14.1-q14.2 near the ESD gene (p=0.000000721×10(-7)). Genome-wide significant SNP-by-sex interaction was found for SNP rs1563374 located on chr11p15.1 near the MRGPRX3 gene (interaction p value =0.0000000041×10(-9)). The association signals diminished when combining men and women. CONCLUSIONS: The findings suggest that the potential pathophysiological mechanisms of HV are complex and strongly underlined by sex-specific interactions. The identified genetic variants imply contribution of biological pathways observed in osteoarthritis as well as new pathways, influencing skeletal development and inflammation.

Atypical fibrodysplasia ossificans progressiva diagnosed by whole-exome sequencing.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by congenital malformations of the great toes and progressive heterotopic ossification of connective tissue that begins during the first decade of life. Our patient presented with intrauterine growth retardation, respiratory distress, neonatal onset soft tissue masses, bilateral hallux valgus, and congenital anomalies of the thyroid and uterus. She was initially diagnosed with atypical infantile myofibromatosis based on clinical and pathological findings. She underwent whole-exome sequencing (WES) as part of the FORGE study to identify the gene for infantile myofibromatosis; however a de novo dominant mutation in ACVR1 (NM_001105.4:c.617G>A) revised the diagnosis to FOP. This patient highlights the utility of WES as an early diagnostic tool in the investigation of patients with unusual presentations of rare diseases, thereby providing clinicians with accurate molecular diagnoses and the opportunity to tailor clinical management to improve patient care.

Fibrodysplasia ossificans progressiva in a newborn with cardiac involvement.

Fibrodysplasia ossificans progressiva is a rare genetic disease that manifests in early life with malformed big toes and progressive heterotopic ossification that forms qualitatively normal bone in characteristic extraskeletal sites. Mutation c.617G>A in the activin A receptor type I gene is reported in all patients with fibrodysplasia ossificans progressiva. No cases of cardiac involvement have been described in children. We report the case of a child with halluces valgi at birth, along with two tender, firm, immovable masses located on the right and left parietal-occipital region, a transitory subluxation of the right hip and an unusual ventricular septal hypertrophy. We hypothesize that the ventricular septal hypertrophy could be the result of a thickening of the fibrous portion of the septum, and a possible new element of the phenotype, probably resulting from the mechanical stimuli secondary to the significant hemodynamic changes occurring at birth.

Factors related to prevalence of hallux valgus in female university students: a cross-sectional study.

BACKGROUND: We investigated the prevalence of hallux valgus (HV) and examined its association with various factors in a cross-sectional study of Japanese female university students. METHODS: A questionnaire survey of foot symptoms, lifestyle, and body mass index (BMI) was administered to 343 women who provided informed consent at a women's university. Footprints were obtained and bone density was measured. Associations of HV with various factors were analyzed by logistic regression analysis. RESULTS: Big toe pain was reported in 26.5% of the women. HV (HV angle, ≥15°) was present in the left foot in 22.4%, the right foot in 20.7%, and unilaterally or bilaterally in 29.7% of women. Mild HV (HV angle, ≥15° to <20°) was noted in the left foot and right foot in 13.4% and 13.1% of women, respectively; no severe HV (HV angle, ≥40°) was observed. HV was associated with big toe pain (adjusted OR: 3.56, 95% CI: 2.01-6.32), history of HV in the mother or maternal grandmother (adjusted OR: 2.45, 95% CI: 1.19-5.02), and history of HV in other family members (adjusted OR: 3.09, 95% CI: 1.35-7.06). Moderate HV was associated with big toe pain (adjusted OR: 4.58, 95% CI: 2.17-9.66) and history of HV in the mother or maternal grandmother (adjusted OR: 3.36, 95% CI: 1.40-8.07). The proportion of women with big toe pain increased significantly with HV severity. CONCLUSIONS: HV was present in about 30% of female university students. Young women with big toe pain or a family history of HV should be evaluated for HV.

Genetic influences on hallux valgus in Koreans: the healthy twin study.

Hallux valgus (HV) is a common foot deformity of multifactorial etiology, but knowledge about the relative importance of genetics and environments on HV has been limited. In order to estimate genetic influences on HV, 1,265 adults, including 175 monozygotic twin (MZ) pairs, 31 dizygotic twin (DZ) pairs, and 853 first-degree singleton family members of the twins were included from the Healthy Twin study, a population-based twin-family cohort in Korea. All participants underwent foot examination and weight-bearing radiographic assessment (anterior-posterior and lateral) in addition to a general health survey. Of the subjects, 208 (16.4%) were classified as HV (as HV angle >20°). The genetic influence on HV was estimated to be substantial; the heritability of HV was 0.51 (95% CI 0.42-0.59) and the heritability of HV angle was 0.47 (0.38-0.56), while contributions from shared environmental effects were negligible. These findings suggest that genetic factors play an important role in determining HV deformity.

Clinical features in adult patient with Wolf-Hirschhorn syndrome.

The Wolf-Hirschhorn syndrome (WHS) encompasses deletions at the distal part of the short arm of one chromosome 4 (4p16 region). Clinical signs frequently include a typical facial appearance, mental retardation, intrauterine and postnatal growth retardation, hypotonia with decreased muscle bulk and seizures besides congenital heart malformations, midline defects, urinary tract malformations and brain, hearing and ophthalmologic malformations. Pathogenesis of WHS is multigenic and many factors are involved in prediction of prognosis such as extent of deletion, the occurrence of severe chromosome anomalies, the severe of seizures, the existence of serious internal, mainly cardiac, abnormalities and the degree of mental retardation. The phenotype of adult with WHS is in general similar to that of childhood being facial dysmorphism, growth retardation and mental retardation the rule in both adults and children. Avoid long-term complications and provide rehabilitation programs and genetic counseling may be essential in these patients.

Congenital hallux valgus occurs in Fibrodysplasia Ossificans Progressiva and BMPR1B-associated dysplasia: an important distinction.

BACKGROUND: Fibrodysplasia Ossificans Progressiva (FOP; OMIM #135100) is an ultrarare genetic disorder characterised by congenital bilateral hallux valgus (CBHV), intermittent soft tissue swellings and progressive heterotopic ossification. We report a three-month-old girl with great toe abnormalities similar to FOP, in whom comprehensive clinical workup and genetic investigations illustrates an alternative diagnosis. CASE PRESENTATION: A three-month-old girl presented with CBHV. The antenatal period was unremarkable, she was born by spontaneous vaginal delivery with an uneventful subsequent course, except for maternal concern of her bent toes which received reassurance from several health professionals. Her mother's persisting concerns were explored via the internet and social media leading her to request referral to an expert bone centre for consideration of FOP. On examination, she was thriving, there was no dysmorphism, subcutaneous lumps, skeletal or extra-skeletal deformity except for shortened great toes with lateral deviation of the proximal and distal phalanges. FOP was a feasible diagnosis, for which CBHV is highlighted as an early sign. A cautionary potential diagnosis of FOP was counselled, including advice to defer intramuscular immunisations until genetic results available. Genetic investigation was undertaken through rapid whole genomic sequencing (WGS), with analysis of data from a skeletal dysplasia gene panel, which demonstrated no ACVR1variants. The only finding was a heterozygous variant of unknown significance in BMPR1B (c1460T>A, p.(Val487Asp)), which encodes a bone morphogenic receptor involved in brachydactyly syndromes A1, A2 and D and acromesomelic dysplasia 3 (only the latter being an autosomal recessive condition). CONCLUSION: This report highlights that CBHV serves as a vital diagnostic indicator of FOP and affected infants should be considered and investigated for FOP, including precautionary management whilst awaiting genetic studies. The second educational aspect is that CBHV may not represent a generalised skeletal disorder, or one much less significant than FOP. Receptor-ligand BMP and Activins mediated interactions are instrumental in the intricate embryology of the great toe. Recognition of non-FOP conditions caused by alterations in different genes are likely to increase with new genomic technology and large gene panels, enhancing understanding of bone signaling pathways.

Impact of Vitamin D Receptor Genotypes on Taiwan Hallux Valgus.

BACKGROUND/AIM: Hallux valgus (HV) is the most prevalent deformity affecting the forefoot; however, its genetic etiology remains unclear. In the literature, vitamin D receptor (VDR) genotypes have been reported to be associated with the risk of skeletal malformations accompanied by inflammation. This study aimed to examine the hypothesis that VDR genotypes are associated with the risk of HV. MATERIALS AND METHODS: The VDR rs731236, rs1544410, rs2228570 and rs7975232 genotypes of 150 HV patients and 600 non-HV subjects were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology and examined regarding their associations with HV risk. RESULTS: The results showed that none of the genetic frequency distributions of VDR rs731236, rs1544410, rs2228570, or rs7975232 were significant between the HV cases and non-HV controls (p for trend=0.4055, 0.2170, 0.7220, 0.5509, respectively). Additionally, allelic frequency analysis showed that none of the allelic frequencies of VDR rs731236, rs1544410, rs2228570, or rs7975232 were significantly distributed (p=0.2285, 0.1572, 0.9278, and 0.5547, respectively). Furthermore, stratified analysis showed that no correlation was observed between VDR rs731236 and different age groups (either younger or older than 51) or sex (p=0.3953 and p=0.9576). Moreover, no correlation was found between VDR rs731236 genotype and the risk of HV in individuals within subgroups of height, weight, or body mass index (BMI) (p=0.8317, 0.5346, and p=0.8783, respectively). CONCLUSION: VDR rs731236, rs1544410, rs2228570, and rs7975232 may not serve as indicators for a higher risk of HV.

Hallux valgus in males--part 1: demographics, etiology, and comparative radiology.

BACKGROUND: The high frequency of hallux valgus deformities in females is well known and has been widely reported in the literature. This finding tends to obscure the importance and the characteristic details of hallux valgus deformities in males. The severity of the deformity, its onset at an earlier age, and its inheritability seem to be more frequent in males, but there are no reports in the literature to substantiate these concepts. The purpose of this study was to analyze these questions in regard to males with hallux valgus. METHODS: The records and plain radiographs of 31 males (53 feet) with a diagnosis of hallux valgus that were treated over a 20-year period (1985-2005) were analyzed. During that same period, the senior author (CN) performed 812 procedures for the correction of hallux valgus deformities in women. In order to compare gender-related differences associated with this deformity, 31 women's charts-paired by age and affected side-were randomly selected and both clinical and radiological data were statistically compared. RESULTS: The onset of the complaints of first ray pain in males was equally distributed by decades, indicating that the deformity begins earlier in this group. Among males, we found 68% of the subjects had a familial history of bunion deformities-58% were maternal and 10% were fraternal. In the control group of females, only 35% of the women reported inheritance of the deformity. No correlation with footwear was found among males. The radiographic measurements were significantly higher in the male group, which included the hallux valgus angle (HVA), the distal metatarsal articular angle (DMAA), and the tarsal metatarsal angle (TMA). The main gender difference was found to be the DMAA with first metatarsophalangeal (MTP) joint congruence being much more common in males (males = 57%, females = 30%). No correlations were found for metatarsus primus varus or pes planus. CONCLUSION: Based on our observations, we conclude that hallux valgus in males is commonly hereditary in nature and is mainly transmitted by the mother, with early onset and higher severity when compared to women. We report a female/male ratio of 15:1. The main intrinsic factor associated with a hallux valgus deformity in males is a high DMAA. LEVEL OF EVIDENCE: Level III, retrospective comparative series.

Causal relationship between thyroid dysfunction and hallux valgus: A two-sample Mendelian randomization study.

Introduction: Previous observational studies have reported that thyroid dysfunction is associated with hallux valgus (HV). However, the causal effect of thyroid dysfunction on hallux valgus is still unknown. To assess whether there is a causal relationship between thyroid dysfunction and hallux valgus, we performed a two-sample Mendelian randomization (MR) study. Methods: The data of the two-sample Mendelian randomization study were obtained from public databases. In this study, hypothyroidism, hyperthyroidism, free thyroxine (FT4), and thyrotropin (TSH) were chosen as exposures. The single nucleotide polymorphisms (SNP) of hypothyroidism and hyperthyroidism were from the genome-wide association studies (GWAS) of the IEU database, including 337,159 subjects. Data for FT4 and TSH (72,167 subjects) were extracted from the ThyroidOmics Consortium. HV was used as the outcome. The SNPs associated with HV were selected from a GWAS of 202,617 individuals in the fignngen database. The inverse variance weighted (IVW) method was used as the primary analysis. Four complementary methods were applied, including MR-presso, MR-Egger, and weighted median. In addition, Cochran's Q test, MR-presso, MR-Egger regression, and the leave-one-out test were used as sensitivity analysis, and the MR-pleiotropy test was performed to examine pleiotropy. Results: According to the results of IVW, we found that there was a causal relationship between hypothyroidism and HV, and hypothyroidism increased the incidence of HV (OR = 2.838 (95% CI: 1.116-7.213); p = 0.028). There were no significant causal effects of hyperthyroidism, FT4, and TSH on HV (p > 0.05). Sensitivity analyses showed that the results were robust and reliable, and no horizontal pleiotropy was detected. Conclusions: Our findings provided genetic support that hypothyroidism might increase the risk of HV. It will predict the occurrence of HV in patients with hypothyroidism and provide suggestions for early prevention and intervention.

Hallux valgus interphalangeus and a novel mutation in HOXA13. Part of the broadening spectrum of Hand-Foot-Genital syndrome.

When evaluating foot and hand malformations in children, the orthopaedic surgeon must always consider the possibility of a more serious underlying syndrome with other accompanying abnormalities of organogenesis. We report the case of a 13-year-old female with Hand-Foot-Genital syndrome presenting to our foot and ankle clinic with tarsal coalition and hallux valgus interphalangeus - an unusual variation on the previously reported hallux varus associated with the syndrome. She was subsequently found to have a novel mutation in the HOXA13 gene. To our knowledge, this is the first report of Hand-Foot-Genital syndrome in the orthopaedic literature.