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.

Pre-natal and post-natal diagnosis of congenital upper limb differences: The first 3 years of the Australian Hand Difference Register.

AIMS: Children with a congenital upper limb difference (CoULD) are a diverse group who often require multidisciplinary care and long-term support for functional and social impacts. The Australian Hand Difference Register (AHDR) provides a national database of children born with a CoULD and aims to facilitate research and improve health care for affected children. Using data from the first 3 years of its operation, we analysed the demographic and clinical features of participating families, including type of CoULDs and the frequency of pre-natal and syndromic diagnoses. METHODS: Families were recruited from tertiary plastic surgery, orthopaedic and genetics clinics, as well as by self-referral. Hand differences were classified by the consulting physician according to the Oberg-Manske-Tonkin classification system. Primary carers were invited to complete an online questionnaire covering demographic information, pregnancy and newborn outcomes and diagnostic details. RESULTS: Between August 2017 and September 2020, 822 families consented and 320 questionnaires were reviewed. CoULDs were detected pre-natally in 66 (20.6%) and post-natally in 248 children (77.5%); data for 6 (1.9%) children were missing. The most common CoULDs were radial polydactyly, symbrachydactyly with ectodermal elements and radial longitudinal deficiency, hypoplastic thumb. Twenty-seven children (8.4%) had an associated syndrome, 7 diagnosed pre-natally and 19 post-natally; the most common were VACTERL association, Poland anomaly, Holt-Oram and ectrodactyly-ectodermal dysplasia-clefting syndromes. CONCLUSIONS: The AHDR is a valuable resource for understanding the relative frequencies of CoULDs. Participation will assist future research into the diagnostic journeys of children with CoULDs, including risk factors, diagnosis and psychosocial impacts.

Epidemiology of congenital upper limb anomalies in Korea: A nationwide population-based study.

This study aimed to analyze the epidemiology of congenital upper limb anomalies (CULA) in Korea. We evaluated the incidence of each type of CULA, the presence of coexisting anomalies and the surgical treatment status in CULA patients. We conducted a retrospective cohort study of patients aged < 1 year between 2007 and 2016 who were registered with CULA in the Health Insurance Review and Assessment Service of Korea. In total, 10,704 patients had CULA, including 6,174 boys (57.7%) and 4,530 girls (42.3%). The mean annual incidence of CULA was 23.5 per 10,000 live births; it was significantly higher in boys than in girls (26.3 vs. 20.5, p < 0.001). Among the four categories of CULA-polydactyly, syndactyly, limb deficiency, and other anomalies-polydactyly was the most common. In total, 4,149 patients (38.8%) had other congenital anomalies and coexisting anomalies of the circulatory system (24.9%) were the most common. In total 4,776 patients (44.6%) underwent operative treatment for CULA within minimum three years of the diagnosis. The proportion of patients who underwent surgical treatment was significantly higher for polydactyly (73.4% vs. 16.8%, p < 0.001) and syndactyly (65.3% vs. 41.5%, p < 0.001), but it was significantly lower in limb deficiency (27.6% vs. 45.4%, p < 0.001) and other anomalies (10.0% vs. 69.8%, p < 0.001) than rest of CULA patients. Among the patients who had operations, 21.5% underwent multiple operations. The proportion of patients who underwent multiple operations was significantly higher in syndactyly (35.6% vs. 18.1%, p < 0.001), but it was significantly lower in polydactyly (4.0% vs. 95.5%, p < 0.001) and other anomalies (17.9% vs. 21.9%, p < 0.001) than rest of CULA patients. These results could provide a basis for estimating the national healthcare costs for CULA and the required number of CULA specialists.

Prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome derived from 2q11.1-q12.1 associated with fetal bilateral radial dysplasia.

OBJECTIVE: We present prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome (sSMC) derived from 2q11.1-q12.1 associated with fetal bilateral radial dysplasia. CASE REPORT: A 27-year-old woman underwent amniocentesis at 18 weeks of gestation because of club hands on fetal ultrasound. The internal organs of the fetus were normal. Amniocentesis revealed a karyotype of 47,XY,+mar [13]/46,XY [11]. The parental karyotypes were normal. Simultaneous array comparative genomic hybridization (aCGH) analysis of the DNA extracted from uncultured amniocytes revealed the result of arr 2q11.1q12.1 (95,529,039-102,825,556) × 3.0 [GRCh37 (hg19)]. The pregnancy was terminated at 20 weeks of gestation, and a malformed fetus was delivered with isolated bilateral radial dysplasia. The cord blood had a karyotype of 47,XY,+mar[24]/46,XY[16]. Polymorphic DNA marker analysis of the DNAs extracted from umbilical cord and parental bloods excluded uniparental disomy for chromosome 2. Metaphase fluorescence in situ hybridization analysis confirmed an sSMC derived from chromosome 2q11.1-q12.1 in cultured amniocytes. CONCLUSION: High-level mosaicism for an sSMC derived from chromosome 2q11.1-q12.1 can be associated with fetal abnormalities.

Upper limb phocomelia: A prenatal case of thrombocytopenia-absent radius (TAR) syndrome illustrating the importance of chromosomal microarray in limb reduction defects.

OBJECTIVE: To describe the ultrasonographic, pathologic and molecular findings in a fetus with TAR syndrome, and to illustrate the contribution of chromosomal microarray analysis (CMA) to the etiological investigation of fetal upper limb reduction defects. CASE REPORT: A 35-year-old woman was referred for Genetic Counseling after pregnancy termination for severe upper limb bilateral phocomelia detected in the second trimester. Fetal autopsy showed severe shortening of the arms and forearms. The fetal skeletal survey confirmed the absence of the radii, ulnae and humeri. CMA revealed an interstitial deletion in 1q21 including the RBM8A gene. Subsequent Sanger sequencing of this gene identified a hypomorphic mutant allele, c.-21G > A, confirming the diagnosis of TAR syndrome. CONCLUSION: The differential diagnosis of upper limb defects is broad. Identification of their cause is essential for adequate genetic counseling including prognosis and recurrence risk estimation. CMA should be considered in fetuses with upper limb reduction defects, especially when the thumbs are present.

Upper extremity anomalies in children with femoral and fibular deficiency.

Defects occurring in the femoral-fibular-ulnar developmental field are believed to cause the cluster of anomalies seen with femoral, fibular and ulnar limb deficiencies. Upper limb function must be considered in the management of lower limb deficiencies. The purpose of this study is to determine the frequency and type of upper extremity anomalies found in children with femoral and/or fibular deficiency. A retrospective review of 327 consecutive patients with the diagnosis of femoral and/or fibular deficiency was performed using existing records and radiographs. Characteristics of those with and without upper extremity anomalies were compared. Upper extremity anomalies were identified in 56 patients. They were more common among those with bilateral, compared with unilateral, lower extremity deficiencies (P < 0.0001). Seventy-five upper limbs were involved with 50 ulnar deficiencies, nine congenital transhumeral deficiencies, four congenital shoulder disarticulations, seven cleft hands, two radial head dislocations and one each - radial deficiency, syndactyly and capitate-lunate coalition. Two patients with bilateral upper extremity anomalies had ulnar deficiency on one side and a transverse deficiency on the other. Upper extremity anomalies are found in 17% of children with femoral and/or fibular deficiency, especially with bilateral lower extremity involvement. Ulnar deficiency is the most common type but one-third had other anomalies. The frequent finding of congenital transverse upper extremity deficiencies suggests there may be common embryology.

Bilateral reversed palmaris longus muscle: a case report and systematic literature review.

PURPOSE: We present a case of a bilateral reversed palmaris longus muscle and a systematic review of the literature on this anatomical variation. METHODS: Routine dissection of a 90-year-old male cadaver revealed a rare bilateral reversed palmaris longus. This was documented photographically, and length and relation to anatomical landmarks were recorded. This finding stimulated a systematic review of the literature on the reversed palmaris longus variation, from which measurements were collated and statistical analysis performed to determine the prevalence, average length, relationship to side and sex, and to discuss its clinical and evolutionary implications. RESULTS: The average length of the muscle belly and tendon of reversed palmaris longus was 135 mm and 126 mm, respectively. Statistical analysis revealed no disparity in presentation due to sex and side; however, bilateral reversed palmaris longus has only been reported in males. A high proportion (70.8%) of reversed palmaris longus were discovered in the right upper limb compared to the left. CONCLUSION: Variations in palmaris longus are purported to be as a result of phylogenetic regression. Clinically, patients with this variant may present with pain or swelling of the distal forearm, often as a result of intense physical exertion related to occupation or sport. Clinicians should be aware of this muscle variant as its presence could lead to confusion during tendon allograft harvesting procedures in reconstructive and tendon grafting surgery.

Thrombocytopenia with absent radii (TAR) syndrome in a female neonate: a case report.

Thrombocytopenia absent radius (TAR) syndrome is a rare congenital disorder that is consistently associated with skeletal abnormality and thrombocytopenic haemorrhage. This is a case of a neonate with bilateral absent radius and thrombocytopenia. The rarity of this case prompted this report.

Classification of congenital upper limb anomalies: towards improved communication, diagnosis, and discovery.

Recently the International Federation of Societies for Surgery of the Hand replaced the Swanson scheme for classifying congenital upper limb anomalies with the Oberg, Manske, Tonkin (OMT) classification. This review explores the reasons for this change after nearly 50 years of using the Swanson classification. In particular, it documents the state of our understanding regarding genetics and limb development at the time Swanson generated his classification. It also describes the continued progress in clinical genetics and developmental biology. Such progress drives the need to embrace and incorporate these changes within a new classification scheme; one that will improve communication, diagnosis, and support further discovery of the pathogenesis of congenital hand anomalies.

Postmortem Diagnosis of Heart-hand Syndrome Associated With a 7p22.1p22.3 Deletion in a 16-week-old Fetus.

We report a male fetus with a 6.8 Mb deletion on chromosome 7p22.1p22.3 at 16 weeks of gestation. The fetus presented a heart-hand syndrome with great artery malposition, bilateral radial ray deficiency, a single pelvic kidney, and growth retardation. This deletion involves a minimal deleted region for cardiac malformation and the RAC1 gene, previously described in limb anomalies in mice. This fetus is the third human case with limb defects and RAC1 deletion.

Holt-Oram Syndrome in a Patient with Crohn's Disease: a Rare Case Report and Literature Review.

INTRODUCTION: Holt-Oram syndrome (HOS) is an uncommon autosomal dominant disorder defined by congenital cardiac defects, some anatomical deformities in the upper limb and conduction abnormalities. Sequence alteration of TBX5 gene located on chromosome 12 has associated with HOS. CASE REPORT: We present the case of a 26-year-old female with known upper limb alteration and ventricular septal defect who later in life developed Crohn's disease. CONCLUSION: To the best of our knowledge association of Holt-Oram syndrome with Crohn's disease has not been reported in literature before. Therefore, a possible genetic connection between Holt-Oram syndrome and Crohn's disease remains to be determined.

Congenital limb deficiency in Japan: a cross-sectional nationwide survey on its epidemiology.

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.

Documenting Combined Congenital Upper Limb Anomalies Using the Oberg, Manske, and Tonkin Classification: Implications for Epidemiological Research and Outcome Comparisons.

PURPOSE: Congenital upper limb anomalies (CULAs) exhibit a wide spectrum of phenotypic manifestations. To help the clinician evaluating this variety of CULAs, the Oberg, Manske, and Tonkin (OMT) classification was recently introduced. The OMT classification allows for documentation of combined hand anomalies. However, subsequent epidemiological and validation studies using the OMT scheme commonly registered only the main anomaly per arm. This study illustrates both the deficits of single diagnosis documentation as well as the merits of registering every anomaly for epidemiological research, outcome comparison, and overall applicability of the classification. METHODS: We retrospectively reviewed patients visiting the Erasmus MC - Sophia Children's Hospital between 2012 and 2014. All congenital anomalies of both limbs were classified according to the OMT scheme. The frequency of combined diagnoses as well as recurrent combinations were analyzed. The relation to the coregistered syndromes was studied. RESULTS: We included 746 patients, 79.5% of whom could be documented with a single OMT diagnosis. In 20.5%, a combination of OMT diagnoses was documented. We documented 149 different combinations: 102 were documented once, 47 were documented repeatedly (n = 196); for example, in patients with Greig syndrome. The prevalence of this syndrome was significantly higher in patients with a combination of radial polydactyly, ulnar polydactyly, and/or syndactyly (2.9% vs 33.3% and 60% in patients with 1 vs 2 and 3 diagnoses). CONCLUSIONS: Documentation of combined OMT diagnoses is required in a fifth of the patients. Not doing so will cause loss of phenotypic information and can hamper outcome comparison and epidemiological research. Documentation of combined OMT diagnoses can help to identify subgroups within a population, for example, patients with an underlying syndrome. Last, combined documentation of diagnoses improves flexibility of the classification and thereby better allows universal application. CLINICAL RELEVANCE: Consensus on the application of the OMT classification is critical to achieving the universal adoption of the system by hand surgeons and other medical professionals.

Non-syndromic bilateral ulnar aplasia with humero-radial synostosis and oligo-ectro-dactyly.

Congenital anomalies of the upper limbs are rare and etiologically heterogeneous. Herein, we report a male infant with non-syndromic bilateral Type Vb ulnar longitudinal dysplasia with radiohumeral synostosis (apparent humeral bifurcation), and bilateral oligo-ectro-syndactyly who was born following an uncomplicated pregnancy, with no maternal use of prescription or illicit medication. Array CGH (60,000 probes) and chromosomal breakage analysis (DEB) were normal. Similar appearances have been reported in children exposed to thalidomide or cocaine, but sporadic patients have also been reported without a prior history of exposure to known teratogens.

Controversies in Poland Syndrome: Alternative Diagnoses in Patients With Congenital Pectoral Muscle Deficiency.

PURPOSE: Poland syndrome was first described as a deficiency of the pectoral muscle with ipsilateral symbrachydactyly. Currently, numerous case reports describe variations of Poland syndrome in which pectoral muscle deficiency is often used as the only defining criterion. However, more syndromes can present with pectoral muscle deficiency. The aim of this review is to illustrate the diversity of the phenotypic spectrum of Poland syndrome and to create more awareness for alternative diagnoses in pectoral muscle deficiency. METHODS: A systematic literature search was performed. Articles containing phenotypical descriptions of Poland syndrome were included. Data extraction included number of patients, sex, familial occurrence, and the definition of Poland syndrome used. In addition, hand deformities, thoracic deformities, and other deformities in each patient were recorded. Alternative syndrome diagnoses were identified in patients with a combination of hand, thorax, and other deformities. RESULTS: One hundred-and-thirty-six articles were included, describing 627 patients. Ten different definitions of Poland syndrome were utilized. In 58% of the cases, an upper extremity deformity was found and 43% of the cases had an associated deformity. Classic Poland syndrome was seen in 29%. Fifty-seven percent of the patients with a pectoral malformation, a hand malformation, and another deformity had at least 1feature that matched an alternative syndrome. CONCLUSIONS: Pectoral muscle hypoplasia is not distinctive for Poland syndrome alone but is also present in syndromes with other associated anomalies with a recognized genetic cause. Therefore, in patients with an atypical phenotype, we recommend considering other diagnoses and/or syndromes before diagnosing a patient with Poland syndrome. This can prevent diagnostic and prognostic errors. CLINICAL RELEVANCE: Differentiating Poland syndrome from the alternative diagnoses has serious consequences for the patient and their family in terms of inheritance and possible related anomalies.