TBX3 and TBX5 duplication: A family with an atypical overlapping Holt-Oram/ulnar-mammary syndrome phenotype.

Holt-Oram syndrome (HOS) is a rare, autosomal dominant heart-hand syndrome caused by mutations in the TBX5 gene. A wide spectrum of TBX5 mutations have been reported previously, most resulting in a null allele leading to haploinsufficiency. TBX5 gene duplications have been previously reported in association with typical and atypical HOS phenotypes. Ulnar-Mammary syndrome (UMS) is a distinct rare, autosomal dominant condition caused by mutations in the TBX3 gene. TBX5 and TBX3 are physically linked in cis on human chromosome 12 and contiguous chromosome 12q24 deletions comprising both TBX5 and TBX3 genes have been previously reported but to our knowledge, duplications have never been described. We report on a large German family with at least 17 affected individuals over 6 generations bearing a duplication at 12q24.21 identified on array-CGH comprising both TBX5 and TBX3 genes. Affected patients are presenting with HOS and UMS symptoms, consisting of variable limb anomalies involving the radial and the ulnar rays and cardiac findings such as congenital heart defects, persistent arterial duct or aortic stenosis, and non-classical symptoms, such as supernumerary nipples and cardiomyopathy. Fluorescence in situ hybridisation confirmed a tandem duplication at the 12q24.21 locus. This is the first report of a contiguous TBX3/TBX5 duplication associated with HOS/UMS phenotype.

Complex foot deformities associated with lower limb deformities: a new therapeutic strategy for simultaneous correction using Ilizarov procedure together with osteotomy and soft tissue release.

AIM: The aim of the current study is to introduce a new therapeutic strategy for simultaneous correction of complex foot deformities (CFD) and the associated lower limb deformities (LLD) by using Ilizarov technique with osteotomy and soft tissue procedure and to report its early clinical results. METHODS: A retrospective review of CFD associated with LLD simultaneous correction utilizing the Ilizarov procedure together with osteotomy and soft tissue balance from 2015 to 2019 was conducted. RESULTS: Thirty-two patients were followed for an average of 42.8 months. The mean external fixation time (EFT) was 6.5 months. The mean healing index (HI) was 1.7 months/cm. At the time of fixator removal, plantigrade feet were achieved in all patient and lower limb deformities were corrected. No recurrence of the deformities occurred. The mean LLRS AIM score was improved from 7.5 to 0.3. At the final follow-up, the ASAMI-Paley score was graded as excellent in all limbs in the aspect of bone results, and functional results were defined as excellent in 29 (90.6%) limbs and good in 3 (9.4%) limbs. The mean modified Dimeglio score was significantly improved from 7.2 to 1.3. No deep infection of the osteotomy site or nonunion was noted in the current study. CONCLUSION: The therapeutic strategy by using the Ilizarov procedure together with osteotomy and soft tissue balance is a safe and effective way to simultaneously correct CFD and LLD. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Correction of Genu Valgum in Patients With Congenital Fibular Deficiency.

BACKGROUND: Patients with congenital fibular deficiency often develop genu valgum secondary to lateral femoral condylar hypoplasia. Guided growth strategies are often performed to correct limb alignment when adequate skeletal growth remains. METHODS: A retrospective review of patients with postaxial hypoplasia of the lower extremity managed with an amputation strategy and who had a guided growth procedure for coronal plane limb malalignment during their course of treatment was performed. Clinical and radiographic data, including measures of coronal plane deformity and alignment, type of amputation, subsequent operative procedures, and complications were recorded. RESULTS: Seventeen patients (20 extremities) met study inclusion criteria (mean follow-up 8.8 y). Foot ablation and hemiepiphysiodesis for valgus deformity of the knee was performed in all extremities. The average age at the time of initial hemiepiphysiodesis was 11.2 years at an average of 8.8 years from the initial amputation procedure. The mean preoperative mechanical axis deviation was 26.5 mm, which was corrected to a mean mechanical axis deviation of 7.0 mm. Fifteen (75%) of the extremities had correction of the deformity to neutral alignment after the initial procedure. Lack of correction occurred in 3 extremities, and overcorrection occurred in 2 extremities. Additional procedures were required in 5 extremities for rebound valgus deformity after hardware removal. CONCLUSIONS: In patients with postaxial hypoplasia, regular monitoring of the residual limb for growth-related changes must occur to ensure optimal function and prosthetic fit. Timing of the guided growth procedure is critical, as younger patients may be more likely to experience rebound deformity. Families and patients should be made aware that growth might be unpredictable in this population with risks of both overcorrection and undercorrection. LEVEL OF EVIDENCE: Level IV-case series.

The Natural History of Meniscus Tears.

BACKGROUND: In order to determine whether treatments are effective in the treatment of meniscus tears, it is first necessary to understand the natural history of meniscus tears. The purpose of this paper is to review the literature to ascertain the natural history of meniscus tears in children and adolescents. METHODS: A search of the Pubmed and Embase databases was performed using the search terms "meniscus tears," "natural history of meniscus tears," "knee meniscus," "discoid meniscus," and "natural history of discoid meniscus tears." RESULTS: A total of 2567 articles on meniscus tears, 28 articles on natural history of meniscus tears, 8065 articles on "menisci," 396 articles on "discoid meniscus," and only 2 on the "natural history of discoid meniscus" were found. After reviewing the titles of these articles and reviewing the abstracts of 237 articles, it was clear that there was little true long-term natural history data of untreated meniscus tears nor whether treating meniscus tears altered the natural history. Twenty-five articles were chosen as there was some mention of natural history in their studies. CONCLUSIONS: There are few long-term data on untreated meniscal tears or discoid meniscus, or tears in children and adolescents. The literature suggests that there is a higher incidence of chondral injury and subsequent osteoarthritis, but there are many confounding variables which are not controlled for in these relatively short-term papers.

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.

High tibial osteotomy accelerates lateral compartment osteoarthritis in discoid meniscus patients.

PURPOSE: The valgus high tibial osteotomy (HTO) in patients with medial osteoarthritis and discoid lateral meniscus can result in increased load on the lateral compartment and hence a higher chances of tear. This may accelerate the progression of osteoarthritis on lateral compartment. We, therefore, carried out the case control study with a hypothesis that an HTO would accelerate the progression of osteoarthritis (OA) on lateral compartment in patients with complete discoid meniscus. METHODS: The records of all patients with open wedge HTO from 2008 to 2012 were evaluated for complete lateral discoid meniscus. The patient who had a valgus HTO with or without partial meniscectomy for medial compartmental OA was included for this study. Cases to control were chosen to match age, body mass index (BMI), pre-operative osteoarthritis grade, and deformity angles in ratio 1:2. Patient's records were studied for demographic data, clinical examination records, and pre-operative knee functional scores and radiological scores and were compared with post-operative data. RESULTS: Thirty-six patients out of 674 patients, who underwent an HTO, consisted of discoid meniscus group. 72 patients were chosen as control group. Four patients showed progression of OA on the lateral compartment in discoid group compared to none in control group. Although control groups showed a little bit better functional outcomes, there were no statistical differences between two groups (n.s.). CONCLUSION: The high tibial osteotomy could result in accelerated lateral compartment osteoarthritis in patients with complete discoid meniscus, and the procedure should be used with caution in such patients. LEVEL OF EVIDENCE: IV.

Dynamic Lower Extremity Deformity in Children With Pseudoachondroplasia.

BACKGROUND: Pseudoachondroplasia is a diverse group of skeletal dysplasias with a common pathway of altered cartilage oligomeric matrix protein (COMP) production. This rhizomelic dwarfism is commonly associated with deformities of the lower extremities, accelerated osteoarthritis, and ligamentous laxity. One of the most common alignment problems is coronal knee angulation which combined with tibial torsion, results in a complex deformity. The outcome of surgical correction of these deformities is variable. METHODS: This study used 3-dimensional gait analysis to describe the kinematic deformities in 12 children (aged 3 to 15 y) and compared them to the static deformities measured on standing anteroposterior radiograph. RESULTS: Both gait analysis and radiographs showed large variability in the coronal deformities but strong correlation to each other. Gait analysis showed mean varus alignment of the knee to be 13.5±13.1 degrees; that mean is not statistically different from radiographs, which showed a mean varus of 16.2±17.1 degrees. The correlation coefficient between radiographic and kinematic measurement was 0.70. The kinematic internal tibial torsion measured an average 15±19 degrees, which was moderately correlated to knee varus (r=0.45, P<0.01). CONCLUSIONS: Measurements of varus-valgus alignment correlated well between gait analysis and radiographs. Tibial torsion correlated with varus. In the absence of gait analysis, anteroposterior standing leg length radiographs with the patella facing foreward can be used to assess deformity. As this study does not correlate these measurements to postoperative results, an appropriately powered prospective study and further investigation of biological effects of altered cartilage oligomeric matrix protein production are needed to explain the variable surgical outcomes. LEVEL OF EVIDENCE: Level IV-case series without control group).

Evaluation of the external fixator TrueLok Hexapod System for tibial deformity correction in children.

BACKGROUND: Tibial deformities are common in paediatric orthopaedic practice. Correcting multiplanar tibial deformities associated with lower limb length discrepancy can be challenging. Hexapod external fixation with gradual correction has been proven effective in this situation. OBJECTIVE: To assess clinical and radiological outcomes of gradual tibial deformity correction using the external fixator TL-HEX™ (Orthofix) in children. HYPOTHESIS: TL-HEX™ is effective in correcting tibial deformities in children. PATIENTS AND METHODS: This multicentre retrospective study collected data from the medical files of 26 patients with 31 tibial deformities treated by gradual correction using TL-HEX™. The tibial deformities were due to congenital defects in 11 (35%) cases, Blount's disease in 9 (29%) cases, pseudo-achondroplasia in 4 (13%) cases, and other causes in 7 (23%) cases. Mean age at surgery was 11.9 years. In each patient, antero-posterior long leg radiographs obtained pre-operatively and at last follow-up were used to measure parameters including the mechanical axis deviation (MAD), medial proximal tibia angle (MPTA), and leg length discrepancy (LLD). RESULTS: The mean healing index was 39.3 days/cm (range, 32-58 days/cm). The overall complication rate was 61%, with 11 unplanned visits. Superficial pin tract infection was the most common complication. Significant decreases between the pre-operative and post-operative assessments occurred in mean MAD (from 32.1mm to 10.2mm, P<0.001) and mean LLD (from 36.8mm to 9.1mm, P<0.001). Patients who underwent proximal tibial osteotomy had a significant improvement in MPTA, from 80.6° to 88.5° (P=0.006). DISCUSSION: This is the first clinical study specifically designed to assess outcomes of TL-HEX™ limb lengthening and deformity correction. MAD, MPTA, and LLD were significantly improved at last follow-up. MAD was greater than 10mm at last follow-up in only 11patients. The complication rate was similar to those reported with other external fixators. TL-HEX™ is effective in the management of tibial deformities in children. LEVEL OF EVIDENCE: IV (retrospective study).

Holt-Oram syndrome: Anesthetic challenges and safe outcome.

Holt-Oram syndrome (HOS) is an autosomal dominant disease with skeletal and cardiac manifestations. We here are presenting a 31-year-old man and a diagnosed case of HOS, with an ulceroproliferative lesion on lateral border of the tongue, was posted for wide excision of lesion with primary closure and left side radical neck dissection.

Prenatally Acquired Multiple Limb Ischemia in a Very Low Birth Weight Monochorionic Twin.

Limb ischemia is an extremely rare event occuring in monochorionic twin pregnancy complicated by twin-to-twin transfusion syndrome (TTTS) and twin anemia polycythemia sequence (TAPS). The authors describe a case of TTTS and TAPS treated successfully using amnioreduction and laser ablation. However, severe ischemia of both lower extremities in the recipient twin developed after the fetal treatment. This serious complication was diagnosed on MRI in utero and confirmed postnatally. Elective amputation of the affected limbs was performed. The etiology of the disease remains unclear despite profound clinical and histopathological examinations; although the role of thromboembolism in monochorionic pregnancy seems to be most likely, this unique case of multiple limb ischemia with distinct macroscopic findings has not yet been described.

Syndromic anorectal malformation associated with Holt-Oram syndrome, microcephaly, and bilateral corneal opacity: a case report.

BACKGROUND: The occurrence of an anorectal malformation with Holt-Oram syndrome, microcephaly, and bilateral corneal opacity is rare and to the best of our knowledge has not previously been reported in the literature. Hence, there is a need to document our experience in this case and learn as much as possible from it. CASE PRESENTATION: We present the case of a Nigerian female neonate with a postnatal diagnosis of syndromic anorectal malformation associated with Holt-Oram syndrome, microcephaly, and bilateral corneal opacity. The infant had successful staged correction of her anorectal malformation but developed a metastatic Wilms' tumor and died before other corrective procedures could be instituted. CONCLUSIONS: An anorectal malformation is here reported to occur with Holt-Oram syndrome, an association that has not been reported previously. To enhance the prognosis and quality of life of children with syndromic anorectal malformation, prenatal ultrasound monitoring of high-risk pregnancies and expertise in prenatal detection of congenital anomalies are invaluable in antenatal care.

Absent Left Main Coronary Artery and Separate Ostia of Left Coronary System in a Patient with Holt-Oram Syndrome and Sinus Node Dysfunction.

BACKGROUND: Holt-Oram syndrome (HOS) is a rare but significant syndrome consisting of structural heart defects, conduction abnormalities, and upper extremity anomalies. It was first described in the British Heart Journal in 1960 by Mary Holt and Samuel Oram as a report of atrial septal defect, conduction disturbances, and hand malformations occurring in family members. Patients can present with heart blocks or symptoms of underlying congenital heart defects. CASE REPORT: A 41-year-old man with Holt-Oram syndrome presented with seizure-like activity and was found to have an underlying conduction disturbance. Physical exam showed bilateral atrophic upper extremities with anatomic disfiguration, and weakness of the intrinsic hand muscles. Cardiovascular exam revealed a slow heart rate with irregular rhythm. EKG showed sinus arrest with junctional escape rhythm. Cardiac catheterization revealed coronary anomalies, including absent left main coronary artery and separate ostia of the left anterior ascending and left circumflex coronary artery. Coronary arteries were patent. Following electrophysiology study, sick sinus syndrome and AV block were diagnosed, and the patient received implantation of a permanent pacemaker. CONCLUSIONS: This patient presented with a seizure-like episode attributed to hypoxia during asystole from an underlying cardiac conduction defect associated with Holt-Oram syndrome. Arrhythmias and heart blocks are seen in these patients, and conduction defects are highly associated with congenital heart defects. Holt-Oram syndrome rarely presents with coronary artery anomalies. There is no reported case of separate coronary ostia and absent left main coronary artery. Prompt diagnosis is important since anomalies in coronary and upper extremity vasculature might be challenging for invasive procedures.

The management of the painful bipartite patella: a systematic review.

PURPOSE: This study aimed to identify the most effective method for the treatment of the symptomatic bipartite patella. METHODS: A systematic review of the literature was completed, and all studies assessing the management of a bipartite patella were included. Owing to the paucity of randomised controlled trials, a narrative review of 22 studies was completed. A range of treatments were assessed: conservative measures, open and arthroscopic fixation or excision and soft tissue release and excision. RESULTS: All of the methods provided results ranging from good to excellent, with acceptable complication rates. CONCLUSIONS: This is a poorly answered treatment question. No firm guidance can be given as to the most appropriate method of treating the symptomatic bipartite patella. This study suggests that there are a number of effective treatments with acceptable complication rates and it may be that treatments that conserve the patella are more appropriate for larger fragments. LEVEL OF EVIDENCE: IV.

Symptomatic Accessory Medial Meniscus Associated With Popliteal Pterygium Syndrome.

BACKGROUND: Anomalies of the meniscus are uncommon. These anomalous formations have been predominately described in the lateral compartment of the knee. Congenital abnormalities of the medial meniscus are rare. METHODS: Chart and radiographic review of a single patient with a symptomatic congenital abnormality of the medial meniscus. RESULTS: The patient was a 5-year-old boy with popliteal pterygium who developed painful snapping in the medial knee after anterior hemiepiphyseodesis to improve his knee extension. The patient had achieved full-knee extension from a preoperative 45-degree flexion contracture. The newly developed snapping was attributed to the hemiepiphyseodesis implants. After implant removal, the snapping persisted and was localized at the medial joint line. Through an arthrotomy, a medial meniscus abnormality was identified and excised with resolution of symptoms. CONCLUSIONS: This report describes a symptomatic congenital abnormality of the medial meniscus in a child with popliteal pterygium. The patient was treated with excision of the anomalous structure with complete resolution of the symptoms. This is the first report of an intra-articular knee anomaly associated with popliteal pterygium syndrome.

Exome Sequencing Identifies DYNC1H1 Variant Associated With Vertebral Abnormality and Spinal Muscular Atrophy With Lower Extremity Predominance.

BACKGROUND: Molecular diagnosis of the distal spinal muscular atrophies or distal hereditary motor neuropathies remains challenging because of clinical and genetic heterogeneity. Next generation sequencing offers potential for identifying de novo mutations of causative genes in isolated cases. PATIENT DESCRIPTION: We present a 3.6-year-old girl with congenital scoliosis, equinovarus, and L5/S1 left hemivertebra who demonstrated delayed walking and lower extremities atrophy. She was negative for SMN1 deletion testing, and parents show no sign of disease. RESULTS: Whole exome sequencing of the affected girl showed a novel de novo heterozygous missense mutation c.1792C>T (p.Arg598Cys) in the tail domain of the DYNC1H1 gene encoding for cytoplasmic dynein heavy chain 1. The mutation changed a highly conserved amino acid and was absent from both parents. CONCLUSION: De novo mutations of DYNC1H1 have been found in individuals with autosomal dominant mental retardation with neuronal migration defects. Dominantly inherited mutations of DYNC1H1 have been reported to cause spinal muscular atrophy with predominance of lower extremity involvement and Charcot-Marie-Tooth type 2O. This is the first report of a de novoDYNC1H1 mutation associated with the spinal muscular atrophy with predominance of lower extremity phenotype with a spinal deformity (lumbar hemivertebrae). This case also demonstrates the power of next generation sequencing to discover de novo mutations on a genome-wide scale.

Syngnathia and obstructive apnea in a case of popliteal pterygium syndrome.

UNLABELLED: We describe an infant with popliteal pterygia, syngnathia, cleft lip and palate, and retrognathia diagnosed with popliteal pterygium syndrome (PPS). The neonatal course was complicated by severe obstructive apnea necessitating tracheostomy. CONCLUSION: This report illustrates the potential for airway compromise in PPS patients and the need for thorough neonatal airway assessment.

Total knee arthroplasty in a patient with thrombocytopenia-absent radius syndrome.

Thrombocytopenia-absent radius (TAR) syndrome is a rare genetic condition with a complex inheritance pattern. This syndrome is classically characterized by hypomegakaryocytic thrombocytopenia as well as bilateral absent radii, shortened ulna, and radially deviated 5-digit hands. During infancy, the predominant manifestations are hemorrhagic complications. Later in life, the bleeding disorder typically improves, but the musculoskeletal abnormalities become of greater concern because of the effects on quality of life. Although the classic musculoskeletal manifestations of TAR syndrome involve the upper extremity, multiple lower-extremity abnormalities have been described, especially dysplasia of the knee. Knee abnormalities include genu varum, varying degrees of laxity or stiffness, patellar abnormalities, concave distal femur, convex medial tibial plateau, and/or absence of the anterior cruciate ligament and posterior cruciate ligament. Several management strategies for lower-extremity abnormalities in TAR syndrome have been described, especially for pediatric patients. Management strategies have not halted the natural progression of knee disease in these patients, and the effect that these knee abnormalities have in adulthood is unclear. Management of knee abnormalities in adults with TAR syndrome is poorly described in the current literature. The authors report a 59-year-old patient with TAR syndrome and knee abnormalities who underwent successful total knee arthroplasty. The patient was followed to the 3-year postoperative visit. At various postoperative time points (7 weeks, 6 months, 1 year, and 3 years), Knee Society Scores and 12-Item Short Form Health Survey scores were recorded. Radiographs obtained at each clinical visit showed well-positioned, well-fixed components. The authors concluded that total knee arthroplasty may be a safe and effective surgical intervention for adults with TAR syndrome and associated knee osteoarthritis.