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Split-hand/foot malformation (SHFM) is a clinically and genetically heterogeneous condition. We sequentially performed screening of the previously identified Japanese founder 17p13.3 duplication/triplication involving BHLHA9, array comparative genomic hybridization, and whole exome sequencing (WES) in newly recruited 41 Japanese families with non-syndromic and syndromic SHFM. We also carried out WES in seven families with nonsyndromic and syndromic SHFM in which underlying genetic causes including pathogenic copy-number variants (CNVs) remained undetected in our previous studies of 56 families. Consequently, we identified not only known pathogenic CNVs (17p13.3 duplications/triplications [n = 21], 2q31 deletion [n = 1], and 10q24 duplications [n = 3]) and rare variants in known causative genes (TP63 [n = 3], DLX5 [n = 1], IGF2 [n = 1], WNT10B [n = 3], WNT10B/PORCN [n = 1], and PORCN [n = 1]), but also a de novo 19q13.11 deletion disrupting UBA2 (n = 1) and variants that probably affect function in LRP6 (n = 1) and UBA2 (n = 1). Thus, together with our previous data based on testing of 56 families, molecular studies for a total of 97 families with SHFM revealed underlying genetic causes in 75 families, and clinical studies for the 75 families indicated a certain degree of correlation between genetic causes and phenotypes. The results imply that SHFM primarily occurs as a genetic disorder with genotype–phenotype correlations. Furthermore, the results together with previous data such as the development of SHFM in Lrp6 knockout mice, the presence of SHFM in two subjects with 19q13 deletions involving UBA2, and strong mouse Uba2 expression in the developing limb buds, imply that LRP6 and UBA2 represent plausible candidate genes for SHFM.

Background Children and young people make up an age group most vulnerable to falls. Various stability disorders may become instrumental in sustaining more frequent falls and resultant fractures. Correct morphological structure impacts overall efficiency of the foot, as well as offers significant diagnostic potential. Even minor foot disorders may affect the entire bio kinematic chain, also impacting the foot’s motility. Structural alterations within a foot may also impair balance in the standing position, and contribute to more frequent injuries. The study aimed to assess the relationship between feet deformities and postural stability deficits in schoolchildren prone to sustain accidental falls. Methods The study involved 200 children (101 girls and 99 boys) aged 10–15 years, randomly selected from primary schools. A 2D podoscan was used to assess the plantar part of the foot, while stabilometric examination was aided by the FreeMed dynamometric platform. Results Correlation between respective variables was reflected by Spearman’s rank coefficient. The subjects’ age negatively correlated with the COP range of movement along the Y axis, and the COP surface area, while their BMI negatively correlated with the COP trajectory’s length. Step regression analysis indicated that the width of the left foot, the left foot Wejsflog index, the left foot Clark’s angle, the hallux valgus angle were the essential predictors of stabilometric variables in girls. In boys, though, predictive value was associated with Clarke’s angle of the left and right foot, Wejsflog index of the right foot, and the width of both the left and right foot. Conclusions There is a statistically significant correlation between morphological variables of the foot and postural stability. When assessing the key variables of the foot and their interrelationship with postural stability, the Clarke’s angle, Wejsflog index, hallux valgus angle, and foot width, should be granted due prominence in the girls. As regards the boys, the following variables were established as predictive in assessing postural stability: Clarke’s angle, Wejsflog index, and foot width.

Background Congenital limb deficiency is a rare and intractable disease, which impairs both function and appearance of the limbs. To establish adequate medical care, it is necessary to reveal the actual conditions and problems associated with this disease. However, there have been no extensive epidemiological surveys in Japan addressing this disease. This is the first nationwide epidemiological survey of congenital limb deficiency in this country. Methods With the cooperation of epidemiology experts, we performed a two-stage nationwide survey to estimate the number of patients with congenital limb deficiency and reveal basic patient features. We targeted orthopaedic surgery, paediatric, and plastic surgery departments. Hospitals were categorized according to the institution type and the number of hospital beds; hospitals were randomly selected from these categories. We selected 2283 departments from a total 7825 departments throughout Japan. In this study, we defined congenital limb deficiency as partial or total absence of the limbs, proximal to the proximal interphalangeal joint of the fingers/lesser toes or interphalangeal joint of the thumb/great toe. We distributed the first survey querying the number of initial patient visits from January 2014 to December 2015. Targets of the second survey were departments that reported one or more initial patient visits in the first survey. Results In the first survey, 1767 departments responded (response rate: 77.4%). Among them, 161 departments reported one or more initial patient visits. We conducted the second survey among these 161 departments, of which 96 departments responded (response rate: 59.6%). The estimated number of initial visits by patients with congenital limb deficiency was 417 (95% confidence interval: 339–495) per year in 2014 and 2015. The estimated prevalence of congenital limb deficiency in Japan was 4.15 (95% confidence interval: 3.37–4.93) per 10,000 live births. The sex ratio was 1.40. Upper limbs were more affected than lower limbs. Conclusions We revealed the estimated number of initial patient visits per year and birth prevalence of congenital limb deficiency in Japan. Our results will contribute to establishing the disease concept and grades of severity of congenital limb deficiency.

Background Septoplasty, i.e., surgical correction of the deviated nasal septum, is the most common ear, nose and throat (ENT) operation in adults. Currently the main indication to perform septoplasty is nasal obstruction. However, the effectiveness of septoplasty for nasal obstruction in adults with a deviated nasal septum remains uncertain. Scientific evidence is scarce and inconclusive, and internationally accepted guidelines are lacking. Moreover, there is no consensus on whether or not septoplasty should be combined with concurrent turbinate surgery. The objective of the current ongoing trial is to study the effectiveness of septoplasty (with or without concurrent turbinate surgery) as compared to non-surgical management for nasal obstruction in adults with a deviated nasal septum, both in terms of subjective (health-related quality of life) as well as objective (nasal patency) outcome measures. Methods/Design The study is designed as a pragmatic, multicenter, parallel-group, randomized controlled trial. A total of 200 adults will be enrolled with nasal obstruction based on a deviated nasal septum and an indication for septoplasty according to current medical practice in the Netherlands. Participants will be randomized to either septoplasty (with or without concurrent turbinate surgery as originally indicated by the otorhinolaryngologist) or a non-surgical watchful waiting strategy. Follow-up visits will be scheduled at 0, 3, 6, 12, and 24 months. During each follow-up visit, health-related quality of life questionnaires will be administered and measurements of four-phase rhinomanometry and peak nasal inspiratory flow will be performed. Costs will be studied using a patient-based diary. Effects of septoplasty on health-related quality of life (primary outcome) and nasal patency will be calculated as mean differences with 95 % confidence intervals. Subgroup analyses according to gender, age, and severity of the septal deviation will be performed. All analyses will be performed on an intention-to-treat basis. Discussion With the results of this study we aim to contribute to the development of evidence-based guidelines regarding indications for septoplasty. Trial registration Nederlands Trial Register/Dutch Trial Registry ( www.trialregister.nl ), trial identifying number: NTR3868 . Registered on 21 February 2013.

Dupuytren’s disease is a common fibroproliferative disorder that primarily affects the palm of the hand. While the disease is known for its characteristic palmar contractures, it also has a potential impact on the extensor mechanism of the hand, resulting in the development of boutonniere deformity, swan-neck deformity, and persistent metacarpophalangeal joint contracture due to extensor capsule stretching and tendon instability. These imbalances are challenging to correct under general or regional anesthesia. Wide awake local anesthesia without a tourniquet allows active range of motion and intraoperative patient collaboration. By understanding the underlying mechanisms and structures involved in these deformities and correcting them under local anesthesia without a tourniquet, hand surgeons can become more confident in correcting the deformity, demonstrating it to the patient, optimizing the rehabilitation protocol, and improving patient outcomes. •Examines Dupuytren's disease impact on extensor mechanism imbalances in the hand.•Principles of corrective surgery for extensor deformities secondary to Dupuytren.•Discuss pre- and postoperative hand therapy strategies.

VACTERL/VATER association is typically defined by the presence of at least three of the following congenital malformations: vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities. In addition to these core component features, patients may also have other congenital anomalies. Although diagnostic criteria vary, the incidence is estimated at approximately 1 in 10,000 to 1 in 40,000 live-born infants. The condition is ascertained clinically by the presence of the above-mentioned malformations; importantly, there should be no clinical or laboratory-based evidence for the presence of one of the many similar conditions, as the differential diagnosis is relatively large. This differential diagnosis includes (but is not limited to) Baller-Gerold syndrome, CHARGE syndrome, Currarino syndrome, deletion 22q11.2 syndrome, Fanconi anemia, Feingold syndrome, Fryns syndrome, MURCS association, oculo-auriculo-vertebral syndrome, Opitz G/BBB syndrome, Pallister-Hall syndrome, Townes-Brocks syndrome, and VACTERL with hydrocephalus. Though there are hints regarding causation, the aetiology has been identified only in a small fraction of patients to date, likely due to factors such as a high degree of clinical and causal heterogeneity, the largely sporadic nature of the disorder, and the presence of many similar conditions. New genetic research methods offer promise that the causes of VACTERL association will be better defined in the relatively near future. Antenatal diagnosis can be challenging, as certain component features can be difficult to ascertain prior to birth. The management of patients with VACTERL/VATER association typically centers around surgical correction of the specific congenital anomalies (typically anal atresia, certain types of cardiac malformations, and/or tracheo-esophageal fistula) in the immediate postnatal period, followed by long-term medical management of sequelae of the congenital malformations. If optimal surgical correction is achievable, the prognosis can be relatively positive, though some patients will continue to be affected by their congenital malformations throughout life. Importantly, patients with VACTERL association do not tend to have neurocognitive impairment.

Camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) is a rare autosomal recessive disease caused by mutation in proteoglycan 4 (PRG4) gene on chromosome 1q25-q31. We faced a dilemma and delay in diagnosis in two sisters. The elder sister had pericardial effusion with constrictive pericarditis, underwent pericardiectomy and received empirical treatment for suspected tuberculosis. After 2 years, she developed bilateral knee swelling with restriction of movement. At the same time, her younger sister also presented with bilateral knee swelling which aroused the suspicion of genetic disease. The whole-genome sequencing revealed homozygous PRG4 mutation suggestive of CACP syndrome.

Split-hand–split-foot malformation (SHFM) is a rare condition that occurs in 1 in 8500–25,000 newborns and accounts for 15% of all limb reduction defects. SHFM is heterogeneous and can be isolated, associated with other malformations, or syndromic. The mode of inheritance is mostly autosomal dominant with incomplete penetrance, but can be X-linked or autosomal recessive. Seven loci are currently known: SHFM1 at 7q21.2q22.1 (DLX5 gene), SHFM2 at Xq26, SHFM3 at 10q24q25, SHFM4 at 3q27 (TP63 gene), SHFM5 at 2q31 and SHFM6 as a result of variants in WNT10B (chromosome 12q13). Duplications at 17p13.3 are seen in SHFM when isolated or associated with long bone deficiency. Tandem genomic duplications at chromosome 10q24 involving at least the DACTYLIN gene are associated with SHFM3. No point variant in any of the genes residing within the region has been identified so far, but duplication of exon 1 of the BTRC gene may explain the phenotype, with likely complex alterations of gene regulation mechanisms that would impair limb morphogenesis. We report on 32 new index cases identified by array-CGH and/or by qPCR, including some prenatal ones, leading to termination for the most severe. Twenty-two cases were presenting with SHFM and 7 with monodactyly only. Three had an overlapping phenotype. Additional findings were identified in 5 (renal dysplasia, cutis aplasia, hypogonadism and agenesis of corpus callosum with hydrocephalus). We present their clinical and radiological findings and review the literature on this rearrangement that seems to be one of the most frequent cause of SHFM.

Thalidomide is a potent teratogen that induces a range of birth defects, most commonly of the developing limbs. The mechanisms underpinning the teratogenic effects of thalidomide are unclear. Here we demonstrate that loss of immature blood vessels is the primary cause of thalidomide-induced teratogenesis and provide an explanation for its action at the cell biological level. Antiangiogenic but not antiinflammatory metabolites/analogues of thalidomide induce chick limb defects. Both in vitro and in vivo, outgrowth and remodeling of more mature blood vessels is blocked temporarily, whereas newly formed, rapidly developing, angiogenic vessels are lost. Such vessel loss occurs upstream of changes in limb morphogenesis and gene expression and, depending on the timing of drug application, results in either embryonic death or developmental defects. These results explain both the timing and relative tissue specificity of thalidomide embryopathy and have significant implications for its use as a therapeutic agent.

Background François-Sigismond Jaccoud arthropathy (FSJA) is a rare, secondary joint disease characterised by joint deformities without bone erosions, with a “reducible” pattern. Substantial knowledge exists in this area; however, the pathogenesis of FSJA remains indefinite, and clear diagnostic criteria are lacking. Moreover, preventive measures and specialised treatment interventions for the development of FSJA are needed. Thus, in this novel report, we present the case of a 24-year-old male patient with secondary FSJA, characterised by a prolonged disease course, early atypical symptoms, and an unclear primary systemic lupus erythematosus (SLE) diagnosis. Our objective was to provide further guidance regarding the pathogenesis, diagnosis, and treatment of FSJA secondary to SLE. Case presentation The patient presented with a 9-year medical history of polyarthralgia. Furthermore, a generalised rash of the lower limbs and hand deformities manifested over a 6-month duration, with symptoms worsening over a week. Physical examination revealed butterfly-shaped facial erythema, hand deformities, and arthralgia. Radiography revealed joint deformities without bone erosions. Laboratory findings indicated proteinuria, positive antinuclear antibodies, and decreased levels of complement components 3 and 4. Based on the 2019 European League Against Rheumatism/American College of Rheumatology classification criteria, the diagnoses of lupus nephritis (LN) and FSJA, secondary to SLE were made. The patient’s SLE LN and joint symptoms improved after a year of intravenous belimumab infusion; in addition to oral methylprednisolone, hydroxychloroquine, and mycophenolate mofetil. Additionally, his hand deformities did not considerably worsen. Conclusions FSJA secondary to SLE is rare; nonetheless, further attention and studies regarding this condition are required. Clinically, the differential diagnosis of FSJA should routinely be performed to avoid a misdiagnosis. The manifestation of early joint symptoms without joint deformation requires regular examinations of the joints, in patients with SLE. The early diagnosis and prompt management of FSJA will thus be ensured, reducing the impact on their quality of life.