TMEM231 Gene Conversion Associated with Joubert and Meckel-Gruber Syndromes in the Same Family.

Joubert and Meckel-Gruber syndromes (JS and MGS) are ciliopathies with overlapping features. JS patients manifest the "molar tooth sign" on brain imaging and variable eye, kidney, and liver disease. MGS presents with polycystic kidneys, occipital encephalocele, and polydactyly; it is typically perinatally fatal. Both syndromes are genetically heterogeneous; some genes cause either syndrome. Here, we report two brothers married to unrelated women. The first brother had three daughters with JS and a son with polycystic kidneys who died at birth. The second brother's wife had a fetal demise due to MGS. Whole exome sequencing identified TMEM231 NM_001077416.2: c.784G>A; p.(Asp262Asn) in all children and the wife of the first brother; the second brother's wife had a c.406T>G;p.(Trp136Gly) change. In-depth analysis uncovered a rare gene conversion event in TMEM231, leading to loss of exon 4, in all the affected children of first brother. We believe that the combination of this gene conversion with different missense mutations led to a spectrum of phenotypes that span JS and MGS.

Mutations in human homologue of chicken talpid3 gene (KIAA0586) cause a hybrid ciliopathy with overlapping features of Jeune and Joubert syndromes.

BACKGROUND: In chicken, loss of TALPID3 results in non-functional cilia and short-rib polydactyly syndrome. This phenotype is caused by a frameshift mutation in the chicken ortholog of the human KIAA0586 gene, which encodes a novel coiled-coil domain protein essential for primary ciliogenesis, suggesting that KIAA0586 can be associated with ciliopathy in human beings. METHODS: In our patients with ciliopathy (http://www.clinicaltrials.gov: NCT00068224), we have collected extensive clinical and neuroimaging data from affected individuals, and performed whole exome sequencing on DNA from affected individuals and their parents. We analysed gene expression on fibroblast cell line, and determined the effect of gene mutation on ciliogenesis in cells derived from patients. RESULTS: We identified biallelic mutations in the human TALPID3 ortholog, KIAA0586, in six children with findings of overlapping Jeune and Joubert syndromes. Fibroblasts cultured from one of the patients with Jeune-Joubert syndrome exhibited more severe cilia defects than fibroblasts from patients with only Joubert syndrome; this difference was reflected in KIAA0586 RNA expression levels. Rescue of the cilia defect with full-length wild type KIAA0586 indicated a causal link between cilia formation and KIAA0586 function. CONCLUSIONS: Our results show that biallelic deleterious mutations in KIAA0586 lead to Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy. Furthermore, our results confirm that KIAA0586/TALPID3 is essential in cilia formation in human beings, expand the KIAA0586 phenotype to include features of Jeune syndrome and provide a pathogenetic connection between Joubert and Jeune syndromes, based on aberrant ciliogenesis.

Alternative Tendon Coaptations to the Pulvertaft Weave Technique: A Systematic Review and Meta-Analysis of Biomechanical Studies.

BACKGROUND: The Pulvertaft weave technique (PT) is frequently used during tendon repairs and transfers. However, this technique is associated with limitations. In this systematic review and meta-analysis, quantitative and qualitative analyses were performed on in vitro, biomechanical studies that compared the PT with alternative techniques. METHODS: Articles included for qualitative and/or qualitative analysis were identified following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies included in the meta-analysis were analyzed either as continuous data with inverse variance and random effects or as dichotomous data using a Mantel-Haenszel analysis assuming random effects to calculate an odds ratio. RESULTS: A comprehensive electronic search yielded 8 studies meeting inclusion criteria for meta-analysis. Two studies with a total of 65 tendon coaptations demonstrated no significant difference in strength between the PT and traditional side-to-side (STS) techniques (P = .92). Two studies with a total of 43 tendon coaptations showed that the STS with 1 weave has a higher yield strength than the PT (P = .03). Two studies with a total of 62 tendon repairs demonstrated no significant difference in strength between the PT and the step-cut (SC) techniques (P = .70). The final 2 studies included 46 tendon repairs and demonstrated that the wrap around (WA) technique has a higher yield strength than the PT (P < .001). CONCLUSIONS: The STS, SC, and WA techniques are preferred for improving tendon form. The STS and WA techniques have superior yield strengths than the PT, and the SC technique withstands similar stress to failure as the PT.

Modified Antia-Buch Flap Incorporating an Extended Temporal Scalp Incision.

The Antia-Buch flap is a popular reconstructive method for full-thickness ear defects involving the helical rim. However, scaphal or conchal resection is often required to prevent ear distortion. Noel et al described a modified technique to the Antia-Buch flap, which includes an incision in the temporal scalp and complete detachment of the preauricular helical root to increase mobility of the flap. Since then, no studies have reported on the use of this modification. We report our experience in implementing Noel et al's modification of the Antia-Buch flap for helical rim defects. Methods: The modified technique differs from the original Antia-Buch flap by completely detaching the root of the helix and adding a vertical incision to the temporal scalp to increase mobility of the flap. No scaphal resection is necessary. After complete elevation of the flaps, the flaps are advanced and inset toward each other followed by closure. Results: In our practice, 10 patients have been treated with Noel et al's modification to the Antia-Buch flap. In each of these patients, acceptable reconstruction of the helical rim was able to be achieved. All the patients were pleased with their reconstructive outcome and ear anatomy was able to be successfully maintained. Conclusions: The modified Antia-Buch flap has shown to be an excellent method for large, helical rim defects, creating versatility by adding the temporal scalp incision. Our outcomes with Noel et al's modification to the original Antia-Buch flap support this method as a versatile technique for wide full-thickness helical rim defects.

Mandibular Myofibroma and Severe Trismus: A Complex Case and Review of Complications.

A female child was investigated for insidious onset of temporomandibular joint dysfunction and trismus in the setting of a mandibular myofibroma. Myofibromas, benign mesenchymal neoplasms composed of spindle cells, are rarely found in the oral cavity, most commonly in the mandible. These lesions are historically described as indolent with a high cure rate and minimal recurrence rates following surgical resection. The patient initially presented with concerns regarding snoring, retrognathia, and jaw ankylosis, as well as a history of trouble latching as an infant but without obvious physical deformities. Imaging revealed a large expansile lytic mass of the mandible, but no temporomandibular joint involvement; surgical biopsy evidenced myofibroma, and the lesion was resected. Over the course of disease, the lesion continued to expand, and the patient's maximal incisal opening continued to decrease despite conservative management with jaw physiotherapy; eventually she could not open her mouth despite the absence of joint involvement. Re-exploration along with formal jaw physiotherapy was achieved and optimal jaw opening was maintained. Myofibromas are rare benign desmoid tumors that can present anywhere in the body in solitary and multicentric forms, and previously did not present significant challenges to surgical and medical management. Tumors of the mandible may present with trismus and soft tissue ankylosis, which can mimic temporomandibular joint dysfunction in the absence of joint involvement. Physical therapy, rehabilitation, and soft tissue contracture release are key to management and improving outcomes in oral cancer patients, regardless of tumor pathology.

A Case Report of Misdiagnosed Breast Implant-associated Anaplastic Large Cell Lymphoma with Lymphatic Extension.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare peripheral T-cell lymphoma associated with textured implants and usually presents as a late-onset periprosthetic seroma. We present a 70-year-old woman with a history of left breast invasive ductal carcinoma treated with mastectomy and textured implant-based reconstruction, and subsequent adjuvant chemotherapy due to lymphovascular extension. Eleven years following her reconstruction, the patient developed a periprosthetic seroma. Fine needle aspiration and partial capsulectomy were performed, but appropriate pathologic evaluation was not initially submitted. She then presented with lymphadenopathy, which was biopsied and revealed BIA-ALCL within an axillary lymph node. Despite implant explantation, complete capsulectomy, axillary lymph node dissection, and excision of groin lymphadenopathy, no evidence of primary ALCL was appreciated. This initially misdiagnosed case demonstrates the importance of following the National Comprehensive Cancer Network guidelines when a patient presents with late onset breast periprosthetic effusions.

Layered Closure of Lumbosacral Myelomeningocele Defects with Bilateral Paraspinous Muscle and Composite Fasciocutaneous Flaps.

Robust, reliable, and reproducible closure of lumbosacral myelomeningocele defects remains a challenge. In infants with lumbosacral myelomeningocele defects, multiple methods of soft tissue coverage have been described. These include various cutaneous, fascial, and muscle flaps and grafts. This is done with relative ease when ample soft tissue is present but becomes extremely difficult for large and distally located defects. We present here our closure technique of lumbosacral myelomeningocele defects in newborns, with associated short- and medium-term outcomes. We demonstrate the anatomy of this technique with fresh cadaver dissection and present a review of demographic and outcome data of 12 consecutive patients treated with this method from June 2014 to August 2019. No major intra- or postoperative complications have been encountered, with a mean follow-up of 22.2 months and median follow up of 18 months. After the neurosurgical repair of lumbosacral myelomeningocele, bilateral composite fascial flaps composed of thoracolumbar and gluteus maximus fascia are elevated in continuity. The paraspinous muscle flaps are then elevated, disinserted distally, and medialized to provide complete muscular coverage of the dural repair. The bilateral composite fascial flaps are medialized and closed over the deep paraspinous muscle flap repair. Two patients experienced areas of small, superficial skin necrosis, one of which healed by secondary intention and the other by debridement and full-thickness skin grafting. Use of bilateral paraspinous muscle flaps and bilateral composite fascial flaps composed of thoracolumbar and gluteus maximus fascia provides robust coverage of lumbosacral defects following myelomeningocele repair in infants.

PAX3-FOXO1 drives miR-486-5p and represses miR-221 contributing to pathogenesis of alveolar rhabdomyosarcoma.

Rhabdomyosarcoma is the most common soft-tissue sarcoma in childhood and histologically resembles developing skeletal muscle. Alveolar rhabdomyosarcoma (ARMS) is an aggressive subtype with a higher rate of metastasis and poorer prognosis. The majority of ARMS tumors (80%) harbor a PAX3-FOXO1 or less commonly a PAX7-FOXO1 fusion gene. The presence of either the PAX3-FOXO1 or PAX7-FOXO1 fusion gene foretells a poorer prognosis resulting in clinical re-classification as either fusion-positive (FP-RMS) or fusion-negative RMS (FN-RMS). The PAX3/7-FOXO1 fusion genes result in the production of a rogue transcription factors that drive FP-RMS pathogenesis and block myogenic differentiation. Despite knowing the molecular driver of FP-RMS, targeted therapies have yet to make an impact for patients, highlighting the need for a greater understanding of the molecular consequences of PAX3-FOXO1 and its target genes including microRNAs. Here we show FP-RMS patient-derived xenografts and cell lines display a distinct microRNA expression pattern. We utilized both loss- and gain-of function approaches in human cell lines with knockdown of PAX3-FOXO1 in FP-RMS cell lines and expression of PAX3-FOXO1 in human myoblasts and identified microRNAs both positively and negatively regulated by the PAX3-FOXO1 fusion protein. We demonstrate PAX3-FOXO1 represses miR-221/222 that functions as a tumor suppressing microRNA through the negative regulation of CCND2, CDK6, and ERBB3. In contrast, miR-486-5p is transcriptionally activated by PAX3-FOXO1 and promotes FP-RMS proliferation, invasion, and clonogenic growth. Inhibition of miR-486-5p in FP-RMS xenografts decreased tumor growth, illustrating a proof of principle for future therapeutic intervention. Therefore, PAX3-FOXO1 regulates key microRNAs that may represent novel therapeutic vulnerabilities in FP-RMS.

Molecular targeted therapy for pancreatic adenocarcinoma: A review of completed and ongoing late phase clinical trials.

Molecular targeted therapy is widely utilized and effective in a number of solid tumors. In pancreatic adenocarcinoma, targeted therapy has been extensively evaluated; however, survival improvement of this aggressive disease using a targeted strategy has been minimal. The purpose of this study is to review therapeutic molecular targets in completed and ongoing later phase (II and III) clinical trials to have a better understanding of the rationale and progress towards targeted molecular therapies for pancreatic cancer. The PubMed database and the NCDI clinical trial website (www.clinicaltrials.gov) were queried to identify phase II and III completed and published (PubMed) and ongoing (clinicaltrials.gov) trials using the keywords: pancreatic cancer and molecular targeted therapy. The search engines were further limited by adding Phase II or III, active enrollment and North American. A total of 14 completed and published phase II/III clinical trials and 17 ongoing trials were identified. Evaluated strategies included inhibition of growth factor receptors (EGFR, PDGFR, VGFR, IGF-1R), tyrosine kinase inhibitors, MEK1/2, mTOR blockade and PI3K and HER2-neu pathway inhibitors. Only one trial conducted by the National Cancer Institute of Canada and the PANTAR trial have demonstrated a survival improvement from EGFR inhibition using erlotinib. These trials ultimately led to FDA approval of erlotinib/Tarceva in advanced stage disease. It remains unclear whether new combinations of cytotoxic chemotherapy or immunotherapy plus molecular targeted therapy will be beneficial in management of pancreatic adenocarcinoma. Despite a number of phase II and III trials, to date, only erlotinib has emerged as an approved targeted therapy in pancreatic adenocarcinoma. There are several ongoing late phase trials evaluating a number of targets, the results of which will become available over the next 1 to 2 years.