TBX5 variants and cardiac phenotype: A systematic review of the literature and a novel variant.

T-Box Transcription Factor 5 (TBX5) variants are associated with Holt-Oram syndrome. Holt-Oram syndrome display phenotypic variability, regarding upper limb defects, congenital heart defects, and arrhythmias. To investigate the genotype-phenotype relationship between TBX5 variants and cardiac disease, we performed a systematic review of the literature. Through the systematic review we identified 108 variants in TBX5 associated with a cardiac phenotype in 277 patients. Arrhythmias were more frequent in patients with a missense variant (48% vs 30%, p = 0.009) and upper limb abnormalities were more frequent in patients with protein-truncating variants (85% vs 64%, p = 0.0008). We found clustering of missense variants in the T-box domain. Furthermore, we present a family with atrial septal defects. By whole exome sequencing, we identified a novel missense variant p.Phe232Leu in TBX5. The cardiac phenotype included atrial septal defect, arrhythmias, heart failure, and dilated cardiomyopathy. Clinical examination revealed subtle upper limb abnormalities. Thus, the family corresponds to the diagnostic criteria of Holt-Oram syndrome. We provide an overview of cardiac phenotypes associated with TBX5 variants and show an increased risk of arrhythmias associated to missense variants compared to protein-truncating variants. We report a novel missense variant in TBX5 in a family with an atypical Holt-Oram syndrome phenotype.

Syndromic Involvement of Patients Presenting With Congenital Upper Limb Anomalies: An Analysis of 4,317 Cases.

PURPOSE: This study investigated the patterns of syndromic involvement for patients with congenital upper limb anomalies (CULAs). We hypothesize that patients with CULAs will present with predictable syndromic patterns. METHODS: This retrospective study queried the multicenter Congenital Upper Limb Differences (CoULD) Registry. Of the 4,317 patients enrolled, 578 (13%) reported one or more syndromes. Syndromes were confirmed to be recognized by the Online Mendelian Inheritance in Man. Demographics were reviewed and compared with the full CoULD registry group. Syndromes reported by five or more patients were examined to determine the type of CULA according to Oberg/Manske/Tonkin classifications. RESULTS: Of the 578 children with one or more reported syndromes, 517 had Online Mendelian Inheritance in Man recognized syndromes (cohort A), In cohort A, 58 syndromes were each represented by a single patient within the registry. Forty-eight syndromes in cohort A were reported by two or more patients, which accounted for 461 of the total patients with reported syndromes. However, VACTERL and Poland syndromes were the most commonly reported syndromes. Patients with CULAs and syndromes frequently exhibited bilateral involvement (61%), compared with the entire CoULD group (47%) and other orthopedic (50%) and medical conditions (61%) compared with the entire CoULD group (24% and 27%, respectively). Additionally, they exhibited a lower frequency of family history of a congenital orthopedic condition (21%) or a family member with the same CULA (9%) compared with the entire CoULD group (26% and 14%, respectively). CONCLUSIONS: Associated syndromes were recorded in 578 patients (13%) in the CoULD registry as follows: 58 syndromes represented by a single patient, 48 by 2 or more patients, and 23 syndromes by 5 or more patients. Rare syndromes that are only represented by a single patient are more likely to be unknown by a pediatric hand surgeon, and consultation with a geneticist is advised. TYPE OF STUDY/LEVEL OF EVIDENCE: Differential Diagnosis/Symptom Prevalence Study IV.

Holt-Oram syndrome.

BACKGROUND: Holt-Oram syndrome (HOS) is a rare genetic illness, which concerns disturbances in the appearance of the upper limbs, congenital heart malformations, and cardiac conduction diseases. HOS usually requires the implantation of a pacemaker, because of cardiac conduction disturbances. CASE REPORT: We present the case of a patient with HOS qualified for pacemaker implantation due to overt bradycardia. To prevent the development of heart failure in the future, the His-bundle pacing technique was used. The implantation was successful. In the control, after one year, the man remains in good condition. The pacing was over 90%, and the left ventricular ejection fraction (LVEF) was stable (60%). CONCLUSIONS: So far, there are no reports on which methods of stimulation are required when it comes to patients with HOS. His-bundle pacing technique is a new type of physiological pacing, which can avoid heart failure.

Novel prosthesis with proximity sensor for upper extremity phocomelia.

We herein report on the application of a novel motorized prosthetic hand in a child with upper extremity phocomelia.

Transferencia dinámica de latissimus dorsi para restauración funcional de la flexo-extensión del codo / Dynamic transfer of latissimus dorsi for functional restoration of elbow flexion-extension

Introducción y objetivo: La pérdida de función o la ausencia congénita de músculos del miembro superior puede afectar seriamente a la calidad de vida del paciente, limitando actividades cotidianas que requieren flexión o extensión del codo. Describimos nuestra experiencia con la técnica para reconstrucción dinámica de la flexión y extensión del codo mediante transferencia pediculada del músculo latissimus dorsi (LD). Material y métodos: Empleamos esta técnica en 2 casos y presentamos el protocolo de rehabilitación kinesiológica subsiguiente. Este protocolo se inicia de manera inmediata tras la cirugía con apoyo de férulas de inmovilización para la extremidad superior y progresa gradualmente hacia la movilización autoasistida según tolerancia del paciente. Después, se avanza a la movilización activa sin carga, dirigida a mejorar las actividades de la vida diaria y aumentar la movilidad articular del codo, cuantificada a través de goniometría. Finalmente, progresa hacia la movilización contra resistencia. Resultados: Los pacientes operados que sufrían pérdida traumática del músculo bíceps brachii y del tríceps brachii respectivamente, mostraron rápida recuperación funcional y satisfactoria reinserción laboral y social. Conclusiones: En nuestra experiencia, esta técnica ha sido una opción efectiva y segura en la restauración de la función del codo y la cobertura de extensos defectos cutáneos, evitando la necesidad de recurrir a colgajos libresNivel de evidencia científica 4d Terapéutico.(AU)

Background and objective: Loss of function or congenital absence of upper limb muscles can significantly impact a patient's quality of life, limiting everyday activities that require elbow flexion or extension. We describe the technique for dynamic reconstruction of elbow flexion and extension using pedicled transfer of the latissimus dorsi (LD) muscle. Methods: We present our experience with the use of this technique in 2 cases and describe the subsequent kinesiological rehabilitation protocol. This protocol is initiated immediately post-surgery, with the support of immobilization splints for the upper limb and gradually progresses to self-assisted mobilization based on patient tolerance. Subsequently, advancement is made to active load-free mobilization, aimed at enhancing daily life activities and increasing elbow joint mobility, quantified using goniometry. Finally, the rehabilitation regimen progresses to resistance-based mobilization. Results: Operated patients suffering traumatic loss of the biceps brachii and triceps brachii muscles respectively, exhibited rapid functional recovery and satisfactory reintegration into work and social life. Conclusions: In our experience, this surgical technique has demonstrated itself to be an effective and safe option in restoring elbow function and providing coverage for extensive cutaneous defects, eliminating the need for free flaps. Level of evidence 4d Terapeutic.(AU)

Congenital Upper-Limb Differences: A 6-Year Literature Review.

➤ The Oberg-Manske-Tonkin (OMT) classification of congenital hand and upper-limb anomalies continues to be refined as our understanding of the genetic and embryonic etiology of limb anomalies improves.➤ We have conducted an evaluation of graft and graftless techniques for syndactyly reconstruction; strengths and drawbacks exist for each technique.➤ Treatment for radial longitudinal deficiency remains controversial; however, radialization has shown promise in early follow-up for severe deformities.➤ Recent emphasis on psychosocial aspects of care has demonstrated that children with congenital upper-limb differences demonstrate good peer relationships and marked adaptability.

Anthropometric Characteristics, Handgrip Strength, and Upper Limb Asymmetries in Highly Trained Chilean Shot Put Para-Athletes / Características Antropométricas, Fuerza de Prensión Manual y Asimetrías de Miembros Superiores en Para-Atletas Chilenos de Lanzamiento de Bala Altamente Entrenados

SUMMARY: Anthropometric characteristics, including body size, shape, and composition, can have a significant impact on sports performance due to their influence on various physiological and biomechanical factors. However, limited research has been conducted on the anthropometric characteristics of highly trained throwing para-athletes. The purpose of this study was to describe the anthropometric characteristics, handgrip strength, and upper limb bilateral asymmetries of highly trained Chilean shot put para-throwers. Five male Chilean shot put para-athletes (average age of 38.8 ± 7.7 years) were assessed for their anthropometric characteristics, including skinfold thickness at six anatomical sites, girth at five sites, and bone breadth at two sites. Handgrip strength and bilateral asymmetries were also measured. The body mass and height of the athletes were found to be 90.5 ± 5.1 kg and 179.1 ± 8.9 cm, respectively. The athletes were found to have an endo-mesomorph somatotype (4.4-6.9-1.0) with high levels of fat mass (25.7 ± 2.8 %) and skeletal muscle mass (39.1 ± 3.7 %). The handgrip strength of the athletes was found to be 66.4 ± 6.7 kg with a bilateral asymmetry of 6.5 ± 6.2 %, with the dominant hand showing greater strength. The results indicate that the shot put para-athletes have a somatotype characterized by increased muscularity and body fat, along with a considerable stature. Although handgrip strength was found to be high, the athletes showed bilateral asymmetry, which requires further investigation to determine the cause and implications.

Las características antropométricas, incluido el tamaño, forma y composición del cuerpo, pueden tener un impacto significativo en el rendimiento deportivo debido a su influencia en diversos factores fisiológicos y biomecánicos. Sin embargo, las investigaciones sobre las características antropométricas para-atletas de lanzamiento altamente entrenados son limitadas. El propósito de este estudio fue describir las características antropométricas, la fuerza de prensión manual y las asimetrías bilaterales de miembros superiores de paralanzadores chilenos altamente entrenados en lanzamiento de la bala. Se evaluaron las características antropométricas de cinco atletas masculinos chilenos de lanzamiento de bala (edad promedio de 38,8 ± 7,7 años), incluido el grosor de los pliegues cutáneos en seis sitios anatómicos, la circunferencia en cinco sitios y la anchura de los huesos en dos sitios. También se midieron la fuerza de prensión manual y las asimetrías bilaterales. Se encontró que la masa corporal y la altura de los atletas eran 90,5 ± 5,1 kg y 179,1 ± 8,9 cm, respectivamente. Los atletas tenían un somatotipo endo-mesomorfo (4.4-6.9-1.0) con altos niveles de masa grasa (25.7 ± 2.8 %) y masa muscular esquelética (39.1 ± 3.7 %). Se encontró además que la fuerza de prensión manual de los atletas era de 66,4 ± 6,7 kg con una asimetría bilateral de 6,5 ± 6,2 %, mostrando mayor fuerza la mano dominante. Los resultados indican que los atletas de lanzamiento de bala tienen un somatotipo caracterizado por una mayor musculatura y grasa corporal, junto con una estatura considerable. Aunque se encontró que la fuerza de agarre era alta, los atletas mostraron asimetría bilateral, lo que requiere de más investigaciones para determinar las causa e implicaciones.

Clinical Presentations and Diagnostic Imaging of VACTERL Association.

Background: VACTERL association consists of Vertebral, Anorectal, Cardiac, Tracheo-Esophageal, Renal, and Limb defects. The diagnosis depends on the presence of at least three of these structural abnormalities. Methods: The clinical presentation and diagnostic prenatal imaging of VACTERL association are comprehensively reviewed. Results: The most common feature is a vertebral anomaly, found in 60-80% of cases. Tracheo-esophageal fistula is seen in 50-80% of cases and renal malformations in 30% of patients. Limb defects including thumb aplasia/hypoplasia, polydactyly, and radial agenesis/hypoplasia are present in 40-50% of cases. Anorectal defects, like imperforate anus/anal atresia, are challenging to detect prenatally. Conclusion: The diagnosis of VACTERL association mostly relies on imaging techniques such as ultrasound, computed tomography, and magnetic resonance. Differential diagnosis should exclude similar diseases such as CHARGE and Townes-Brocks syndromes and Fanconi anemia. New insights into genetic etiology have led to recommendations of chromosomal breakage investigation for optimal diagnosis and counseling.

Re-examining the nomenclature of congenital failure of formation in the upper limb: a historical perspective.

In this study, we studied historical case notes to examine nomenclature of congenital upper limb anomalies and explore the changes in terminologies over time. Original diagnoses were reclassified according to previously published classifications and the most recent Oberg, Manske and Tonkin system. Two hundred and thirty-eight case notes were obtained from the period 1961-1991. Hand plate malformations where the diagnosis was obvious or traumatic defects, were excluded. Eighty-six cases (106 extremities) were finally included where an ambiguous diagnosis, such as 'congenital absence' was initially given. None of the re-classifications matched the original diagnoses except for cleft hand and radial dysplasia (n = 31). Eighteen phocomelia-type limbs were re-classifiable when seen as a continuum of longitudinal deficiency, but not as an intercalary deficit. This study provided further insights into the evolving nature of nomenclature in congenital upper limb anomalies, especially for the condition of phocomelia.Level of evidence: IV.

Reliability of the Masada Classification for Forearm Involvement in Patients With Hereditary Multiple Osteochondromas (HMO).

BACKGROUND: Classifications describing forearm lesions in patients with Hereditary Multiple Osteochondromatosis (HMO) have been used to recommend surgical intervention and stratify outcomes; however, there is no consensus on which classification offers greater reliability. The purpose of this study was to determine the reliability of the Masada classification and newer classifications among pediatric hand surgeons. METHODS: One hundred one patients with HMO between June 2014 and October 2019 were enrolled in the Congenital Upper Limb Differences (CoULD) Registry. Of those, 67 patients with 101 forearms were included. Four pediatric hand surgeons from the CoULD study group undertook an online evaluation. Each rater classified radiographs according to the Masada classification. Six weeks later, raters were asked to reclassify images according to the Masada, Gottschalk, and Jo classifications. Rater agreement for these classifications was assessed by estimating Fleiss kappa along with a 95% CI. RESULTS: Interrater agreement for Masada classification after the first reading was poor (κ=0.35; 95% CI=0.30-0.41) across all raters. Interrater agreement across the 4 raters decreased for the Masada classification from the first to the second reading (κ=0.35 vs 0.21; P <0.001). Intrarater agreement for the Masada classification ranged from 0.32 to 0.63 from the first to the second study reading. Gottschalk and Jo classifications yielded significantly better interrater agreement compared with Masada (κ=0.43 vs 0.21; P <0.001). Unclassifiable cases were highest in the Masada classification (34% to 44%) and lower in the Jo (17%) and Gottschalk (14%) classifications. CONCLUSION: Despite wide use, the Masada classification was found to have low reliability when classifying forearm deformities in HMO. Gottschalk offered more options for location, yet lacked deformity description including radial head dislocation. Jo classification offered more locations than Masada and incorporated radial head dislocation in some patterns. Based on the shortcomings in all 3 classification systems, the development of a more inclusive and reliable classification is warranted. LEVEL OF EVIDENCE: Level II; Diagnostic.

Comparing broad and narrow phenotype algorithms: differences in performance characteristics and immortal time incurred.

Introduction: When developing phenotype algorithms for observational research, there is usually a trade-off between definitions that are sensitive or specific. The objective of this study was to estimate the performance characteristics of phenotype algorithms designed for increasing specificity and to estimate the immortal time associated with each algorithm. Materials and methods: We examined algorithms for 11 chronic health conditions. The analyses were from data from five databases. For each health condition, we created five algorithms to examine performance (sensitivity and positive predictive value (PPV)) differences: one broad algorithm using a single code for the health condition and four narrow algorithms where a second diagnosis code was required 1-30 days, 1-90 days, 1-365 days, or 1- all days in a subject's continuous observation period after the first code. We also examined the proportion of immortal time relative to time-at-risk (TAR) for four outcomes. The TAR's were: 0-30 days after the first condition occurrence (the index date), 0-90 days post-index, 0-365 days post-index, and 0-1,095 days post-index. Performance of algorithms for chronic health conditions was estimated using PheValuator (V2.1.4) from the OHDSI toolstack. Immortal time was calculated as the time from the index date until the first of the following: 1) the outcome; 2) the end of the outcome TAR; 3) the occurrence of the second code for the chronic health condition. Results: In the first analysis, the narrow phenotype algorithms, i.e., those requiring a second condition code, produced higher estimates for PPV and lower estimates for sensitivity compared to the single code algorithm. In all conditions, increasing the time to the required second code increased the sensitivity of the algorithm. In the second analysis, the amount of immortal time increased as the window used to identify the second diagnosis code increased. The proportion of TAR that was immortal was highest in the 30 days TAR analyses compared to the 1,095 days TAR analyses. Conclusion: Attempting to increase the specificity of a health condition algorithm by adding a second code is a potentially valid approach to increase specificity, albeit at the cost of incurring immortal time.

Two-stage treatment of extremity deformities associated with thrombocytopenia-absent radius syndrome.

OBJECTIVE: The aim of this study was to evaluate the results of 2-stage treatment of upper and lower extremity deformities in patients with thrombocytopenia absent radius syndrome. METHODS: Four patients (3 female, 1 male) with a mean age of 1.8 years (range 1-4) were included in the study. The patients were followed up for an average of 5.5 years. All 4 patients had bilateral radial longitudinal deficiency, whereas only 2 patients had bilateral fixed knee contractures. A 2-stage surgical procedure was implemented. The surgical procedure performed for radial longitudinal deficiency consisted of distraction with an Ilizarov frame in the first stage, followed by centralization performed in the second stage. Knee contractures were first treated using an Ilizarov frame, followed by a hamstring tendon transfer in the second procedure. Radiological evaluation of the radial longitudinal deficiency was done by measuring hand-forearm angle, hand-forearm position, and ulnar bowing preoperatively and at postoperative follow-ups. Knee contracture was evaluated by measuring the angle preoperatively and at postoperative follow-ups. RESULTS: The mean hand-forearm angle values of patients at preoperative assessment, early postoperative period, and at the last follow-ups were 82.60, 5,80, and 11.10, respectively (P < .001). The hand-forearm position values were -14.25 mm, +11, and +7.1 mm, respectively (P < .001). The ulnar bowing values were 7.3°, 4.5°, and 2.9°, respectively (P < .001). Recurrence of the radial longitudinal deficiency deformity requiring surgery occurred in 1 patient. In the other 3 patients, some deformity recurred but did not require surgical intervention. In addition, 1 patient with knee flexion contracture had a recurrence of the contracture that did not require surgical intervention. There was no circulatory disorder or skin necrosis in the lower or upper extremities of the patients. CONCLUSION: This study has shown us that two-stage treatment is a reliable method for lower and upper extremity deformities accompanying thrombocytopenia absent radius syndrome. However, recurrence is still a major problem. LEVEL OF EVIDENCE: Level IV, Therapeutic Study.

Epidemiology of Congenital Hand Differences at a Tertiary Hospital in Southern India - Establishment of a New Registry and Assessment Using Both the Swanson/IFSSH and the Oberg, Manske and Tonkin Classifications.

Background: In resource challenged nations, the true magnitude of the congenital hand differences (CHD) remain unknown due to a lack of nation-wide surveillance system. We created a hospital-based registry system with the aim to determine the prevalence and distribution of CHD and compare the Swanson/IFSSH (SI) and Oberg, Manske and Tonkin (OMT) classifications. Methods: Data of children aged 0 to 18 years with CHD was entered into the online registry and classified based on the SI and OMT classifications from January 2018 to December 2021. The prevalence and distribution of CHD and risk factors like family history were summarised using descriptive analysis. Syndromic and heredity associations were further analysed using Fischer exact test and odds ratio. Clustered columns were used to compare the two classification systems. Results: A total of 307 patients with CHD presented during the study with a prevalence of 2.4/1,000 patients. Among them, 164 were unilateral, 21 were born of consanguineous marriages (7.6%) and 10 (3.6%) had a family history of CHD. Although not statistically significant, bilateral involvement was twice as likely to be hereditary compared to unilateral involvement. A total of 10 different syndromes were identified among 27 patients of which Holt-Oram syndrome was most common. The most common CHD was Radial longitudinal defificiency (111). A total of 82 (27%) children had other associated anomalies that could not be grouped as a syndrome. Two patients could not be classified using either SI or OMT classifications. Conclusions: The online registry established an efficient way to store and analyse data related to CHD. It provides new information on its prevalence in South India, which is similar to the existing literature. Most of the CHD can be grouped in both the SI and OMT classifications. However, there still remains some conditions that are unclassifiable. There is a need for a national registry of CDH for effective management, funding and research. Level of Evidence: Level IV (Epidemiological).

Thrombocytopenia-Absent Radius Syndrome: Descriptions of Three New Cases and a Novel Splicing Variant in RBM8A That Expands the Spectrum of Null Alleles.

Thrombocytopenia-absent radius (TAR) syndrome is a rare congenital disorder characterized by the bilateral absence of the radius and thrombocytopenia, and sometimes by other skeletal, gastrointestinal, cardiac, and renal abnormalities. The underlying genetic defect is usually the compound inheritance of a microdeletion in 1q21.1 (null allele) and a low-frequency, non-coding single nucleotide variant (SNV) in the RBM8A gene (hypomorphic allele). We report three new cases from two unrelated families. The two siblings presented the common genotype, namely the compound heterozygosity for a 1q21.1 microdeletion and the hypomorphic SNV c.-21G>A in RBM8A, whereas the third, unrelated patient presented a rare genotype comprised by two RBM8A variants: c.-21G>A (hypomorphic allele) and a novel pathogenic variant, c.343-2A>G (null allele). Of the eight documented RBM8A variants identified in TAR syndrome patients, four have hypomorphic expression and four behave as null alleles. The present report expands the RBM8A null allele spectrum and corroborates the particularities of RBM8A involvement in TAR syndrome pathogenesis.