Chiari Malformation Type 1 and Syringomyelia in a Patient With Prior Surgically-Treated Sagittal Synostosis Effectively Treated With Posterior Cranial Vault Distraction Osteogenesis.

ABSTRACT: The presenting report describes the use of a posterior cranial vault distraction procedure in resolving a Chiari malformation with associated syringomyelia following a surgically-treated nonsyndromic craniosynostosis. Chiari malformations are typically treated with posterior fossa decompression with or without expansion duraplasty. The objective of this report is to describe the effectiveness in resolving both Chiari malformation and secondary syringomyelia with posterior cranial vault distraction osteogenesis. A 5-year-old male, with a history of surgery for sagittal synostosis during infancy, presented with daily severe headaches and dysesthesias in the hands and feet. Imaging demonstrated a copper-beaten calvarium and a Chiari 1 malformation with a 7 mm diameter C4-T1 syrinx. He underwent posterior cranial vault distraction osteogenesis over 3 months to increase his intracranial volume. The patients' headaches improved significantly, and his dysesthesias resolved postoperatively. A magnetic resonance imaging performed 7 months after completion of distraction demonstrated resolution of the Chiari malformation and decompression of his syrinx. A computed tomography scan at 9 months postdistraction showed resolution of the copper-beaten calvarium. Patients with a history of craniosynostosis can develop inadequate cranial volume over time due to abnormal skull growth, leading to secondary Chiari malformation with or without syringomyelia. Posterior vault distraction is an effective strategy to address these conditions and can be employed later in childhood to treat the underlying pathology. The mechanism potentially expands both calvarium and dura, which in turn addresses both the Chiari malformation and secondary syringomyelia.

Scarring in Patients With PIK3CA-Related Overgrowth Syndromes.

Importance: Patients with somatic overgrowth commonly require surgical intervention to preserve function and improve cosmesis. To our knowledge no observation of scarring outcomes in this population has been published to date. Objective: To observe the frequency of abnormal scarring in patients with somatic overgrowth and sequencing-verified mutations in the PIK3CA gene. Design, Setting, and Participants: This retrospective study evaluated scarring outcomes in patients with PIK3CA-related overgrowth. Samples of affected tissue were sequenced between July 2015 and October 2016. Medical records from multiple large academic tertiary care centers were reviewed for surgical history and scar descriptions, and clinical photographs were assessed by 2 surgeons (J.N.J. and D.M.K.) to confirm abnormal scarring. Analysis of medical records and photographs was performed between April 2017 and June 2017 by a multidisciplinary team from dermatology, plastic surgery, orthopedic surgery, radiology, and genetics departments. All patients considered for the study were diagnosed with somatic overgrowth and previously had affected tissue sent for next-generation sequencing. Those with pathogenic PIK3CA variants and 1 or more prior surgical procedures were reviewed. Main Outcomes and Measures: Presence of excessive scarring in patients with PIK3CA overgrowth. Results: A total of 57 patients with segmental overgrowth syndromes were sequenced. Of the 57 patients, 25 (44%) had pathogenic or likely pathogenic variants in PIK3CA. Of those with pathogenic PIK3CA variants, 6 (24%) had past surgical procedures, all with preoperative and postoperative photographs. Of 6 patients with PIK3CA-related overgrowth and a history of 1 or more surgical procedure, 4 (67%) developed excessive scarring. The cohort with abnormal scarring comprised 3 females and 1 male, with a median age of 8.5 years. All abnormal scarring occurred in affected overgrowth tissue. Three of the 4 patients developed the excessive scarring after debulking procedures for overgrowth and/or vascular malformations of the upper or lower extremity. Conclusions and Relevance: Excessive scarring occurred frequently in patients with PIK3CA-related overgrowth syndromes. The risk of abnormal scarring should therefore be discussed preoperatively. Given the activating nature of these PIK3CA variants, we suggest that the excessive scarring may be owing in part to up-regulation of the PI3K-Akt-mTOR pathway. Additional studies are needed to assess scarring outcomes in patients with other types of overgrowth.

Analyzing the Genetic Spectrum of Vascular Anomalies with Overgrowth via Cancer Genomics.

Vascular anomalies are variably associated with overgrowth, skeletal anomalies, and abnormalities of the brain, leptomeninges, and eye. We assembled a 16-institution network to determine the range of genetic variants associated with a spectrum of vascular anomalies with overgrowth, ranging from mild to severe. Because of the overlap between cancer-associated variants and previously described somatic variants in vascular overgrowth syndromes, we employed tumor genetic profiling via high-depth next-generation sequencing using a panel to assay affected tissue from a diverse cohort of subjects with vascular anomalies with overgrowth. Seventy-five percent (43/57) harbored pathogenic or likely pathogenic variants in 10 genes. We identified two genes (mTOR, PIK3R1) and several variants previously described in the setting of cancer but that, to our knowledge, have not been described in vascular malformations. All were identified at low variant allele frequency consistent with somatic mosaic etiology. By leveraging somatic variant detection technology typically applied to cancer in a cohort inclusive of broad phenotypic severity, we demonstrated that most vascular anomalies with overgrowth harbor postzygotic gain-of-function mutations in oncogenes. Furthermore, continued interrogation of oncogenes in benign developmental disorders could provide insight into fundamental mechanisms regulating cell growth.

Mimickers of Infantile Hemangiomas.

Infantile hemangiomas (IHs) are the most common tumors of infancy and usually follow a typical course of growth and involution. We report four soft tissue tumors that were referred to the pediatric dermatology clinic as IHs and the process by which they were diagnosed and treated. Clinicians should be aware of presentations of these uncommon, but serious soft tissue tumors. Many of these mimickers have a vastly different clinical prognosis, and early intervention to limit sequelae is crucial. Biopsy of atypical lesions should be considered early in the diagnostic process since they have varied prognosis and treatment strategies.

Recurrent giant cranial desmoid tumor in a 3-year-old boy with familial adenomatous polyposis requiring bifrontoparietal cranioplasty: case report.

Desmoid tumors, also known as aggressive fibromatosis, are locally infiltrating musculoaponeurotic neoplasms arising in connective tissues. Desmoid tumors may be associated with familial adenomatous polyposis (FAP), a genetic disorder that presents with hundreds to thousands of precancerous colorectal polyps. The authors report the case of an 18-month-old boy who underwent resection of a right temporal desmoid tumor (initially diagnosed as cranial fasciitis) and developed a bilateral frontoparietal calvarial desmoid tumor 2 years later. The patient underwent gross-total resection of the tumor that required a large cranioplasty. He was subsequently diagnosed with FAP. The patient has been without tumor recurrence for 9 years afterwards and has not required revision of his cranioplasty. This is the first report describing a recurrent cranial desmoid tumor in a pediatric patient with FAP. The authors believe, however, that some of the cases previously reported as cranial fasciitis are likely desmoid tumors pathobiologically and genetically.

Craniosynostosis following hemispherectomy in a 2.5-month-old boy with intractable epilepsy.

The authors report on the case of a 6-week-old boy who presented with infantile spasms. At 2.5 months of age, the patient underwent a right hemispherectomy. Approximately 3 months postoperatively, the patient presented with left coronal craniosynostosis. Subsequent cranial vault remodeling resulted in satisfactory cosmesis. Four years after surgery, the patient remains seizure free without the need for anticonvulsant medications. The authors believe this to be the first reported case of iatrogenic craniosynostosis due to hemispherectomy, and they describe 2 potential mechanisms for its development. This case suggests that, in the surgical treatment of infants with intractable epilepsy, minimization of brain volume loss through disconnection techniques should be considered, among other factors, when determining the best course of action.

Surgical treatment of infantile hemangioma in a multidisciplinary vascular anomalies clinic.

OBJECTIVE: (1) Discuss indications for surgical treatment of infantile hemangioma (IH); (2) describe outcomes, management of complications and long term surveillance of surgically treated IH. STUDY DESIGN: Retrospective. SUBJECTS AND METHODS: The charts of children seen in a dedicated vascular anomalies center at a tertiary pediatric hospital were reviewed. RESULTS: Out of 1012 patients diagnosed with IH over 27 months, 92 patients, predominantly caucasian female, with an average age of 36 months, underwent surgery for 94 lesions. Head and neck lesions accounted for 67% of the population and 51 lesions were located on the face. Surgical indications included bleeding, functional impairment, ulceration and cosmetic disfigurement. Mean surface area was 7.75 cm². Although lesions requiring additional procedures were larger (median 5.5 cm²) than single-stage excisions, this difference was not statistically significant (P=0.09). Head and neck lesions were more likely to require multiple modality treatment (P=0.003). There was no identified objective criteria to predict head and neck lesions that are more likely to be associated post-operative complications. CONCLUSIONS: Most IH do not require treatment. The majority of infantile hemangioma occurred on the head and neck. When significant functional impairment, ulceration, bleeding, cosmetic deformity is encountered or anticipated, surgical therapy can be performed at any clinical phase with few complications and favorable outcomes.

Microcystic adnexal carcinoma: the first reported congenital case.

Microcystic adenexal carcinoma is a rare, locally aggressive, malignant appendage tumor also known as sclerosing sweat duct carcinoma. Since widespread recognition of microcystic adenexal carcinoma as a distinct clinicopathologic entity, approximately 300 total cases have been reported in the literature, with only eight previous cases reported in children under the age of 18, with no reported cases in patients younger than 6 years old. Our patient is unique in that the lesion was present at birth, making this the youngest case of microcystic adenexal carcinoma reported.

Creation and implementation of a prospective pediatric clinical outcomes registry.

OBJECTIVE: To build a pediatric clinical outcomes registry (COR) using a contemporary information system designed to support research and outcome studies and to improve patient care and quality of life. PATIENTS AND METHODS: In response to physician needs, this process was implemented: 1) database needs assessment survey, 2) evaluate existing systems and vendors, 3) pilot test a COR tool, and 4) build a COR. The COR was designed to include patients with the following conditions: scoliosis, neonatal surgery, urologic surgery, cleft palate, pain management, otitis media, and voice and airway problems. Agency for Healthcare Research and Quality methodology was followed to create the infrastructure and registry. RESULTS: The database needs assessment survey was completed by 99 individuals and most respondents wanted to collect more standardized data than currently available in existing systems. Satisfaction with the existing systems was rated low. The COR was created and a pilot test was successful. The COR was implemented and has been functioning for more than 2 years. CONCLUSIONS: By identifying physicians needs, evaluating existing technology and incorporating a multidisciplinary team, the COR was created and implemented to maintain clinical data on a variety of patient diagnoses and outcomes using a single technology platform that enhances potential research collaborations and minimizes redundant data entry and data collection, such as quality of life assessments for the patients.

Bone deposition/generation with LeFort III (midface) distraction.

BACKGROUND: It is essential to critically assess bone deposition in midface distraction. The aim of this study was to characterize the quality and volume of bone deposition at specific osteotomy sites following midface distraction. METHODS: At approximately 6 months after distraction, computed tomographic scans with three-dimensional reconstruction were obtained on 10 craniosynostosis syndromal patients who had undergone LeFort III osteotomy and midface distraction. Patient age ranged from 37 to 109 months (mean, 63.7 months) and the distractions ranged from 7 to 15 mm. Both the reconstructed scans and axial cuts were independently evaluated by four blinded observers (two plastic surgeons, an orthodontist, and a radiologist) and graded for bone deposition in predetermined anatomical sites correlated to the osteotomy. RESULTS: The authors found that variable bony bridging occurred at all sites along the osteotomy, but bone deposition was most reliably seen at the pterygomaxillary buttress and nasofrontal junction. In addition, the medial orbital walls tended to show greater consistency in bone deposition than the lateral orbital walls, and deposition at the zygomatic arches was shown to be least likely to occur. The technique of evaluation and the clinically significant findings are discussed. CONCLUSIONS: Bony deposition occurs more reliably in the medial facial skeleton following LeFort III osteotomy, and osteotomy through the zygomatic body was more likely to result in deposition than one through the arch.

Effect of FK506 on peripheral nerve regeneration through long grafts in inbred swine.

Numerous small-animal studies have demonstrated that FK506 enhances nerve regeneration and accelerates functional recovery after nerve injury. However, no experimental study has corroborated these neuroregenerative effects in larger animals. This study investigated the effects of FK506 on nerve regeneration in inbred miniature swine. Eight animals received 8-cm ulnar nerve autografts and allografts. Treated animals received 0.1 to 0.4 mg/kg FK506 injections twice weekly to maintain immunosuppressive serum FK506 levels. At 24 weeks posttransplant, nerve grafts were harvested for histomorphometric analysis. Mixed lymphocyte cultures demonstrated alloreactivity in 1 treated animal and all untreated animals. In autografts, mean fiber count, nerve density, and percent neural tissue were doubled with FK506 therapy. In allografts, significant neuroregeneration was observed in animals treated with FK506, whereas untreated animals had no regeneration. Treatment with FK506 resulted in a trend toward enhanced axonal regeneration through nerve autografts and allografts in a large-animal model with defined histocompatibility barriers.

Anti-CD40 ligand antibody permits regeneration through peripheral nerve allografts in a nonhuman primate model.

Systemic immunosuppression is typically required to prevent allograft rejection. Antibody-based therapies that induce immune unresponsiveness represent an appealing alternative to nonspecific immunosuppression, which is often associated with significant morbidity. In mice, successful prevention of nerve allograft rejection has been demonstrated through interference with the CD40/CD40 ligand interaction. This study investigated the effectiveness of anti-CD40 ligand monoclonal antibody as single-agent therapy in preventing rejection and supporting nerve regeneration across long nerve allografts in nonhuman primates. Twelve outbred cynomolgus macaques were arranged into six genetically mismatched pairs, with each animal receiving a 5-cm ulnar nerve allograft in the right arm and a 5-cm autograft in the left arm. Mixed lymphocyte reaction assays were used to assess resulting immune unresponsiveness. Treated animals (n = 10) received anti-CD40 ligand monoclonal antibody 10 mg/kg one time, locally applied, and 20 mg/kg systemically on postoperative days 0, 1, 3, 10, 18, and 28, and then monthly. Untreated animals (n = 2) served as the untreated controls. At 4 or 6 months after transplantation, nerves were harvested for histological analysis. Four treated animals underwent an additional challenge after cessation of anti-CD40 ligand monoclonal antibody therapy and nerve graft harvests. Autogenous and allogeneic skin and nerve inlay grafting was performed to assess the permanence of immune unresponsiveness induced by anti-CD40 ligand monoclonal antibody. Animals that received anti-CD40 ligand monoclonal antibody demonstrated robust regeneration across nerve allografts, similar to that seen in the autograft control in the contralateral arm. The histomorphometric analysis of allografts in the untreated animals demonstrated significantly worse measurements compared with their matched autograft controls. Animals that received anti-CD40 ligand monoclonal antibody with concomitant skin allografts had virtually no evidence of nerve regeneration through allografts. Allogeneic skin and nerve allografts applied 2 to 12 months after withdrawal of anti-CD40 ligand monoclonal antibody therapy were consistently rejected. This study demonstrates that anti-CD40 ligand monoclonal antibody prevents rejection and allows regeneration of peripheral nerve allografts in nonhuman primates. The effect of anti-CD40 ligand monoclonal antibody appears to be transient, however, with restoration of immunocompetence shortly after withdrawal of therapy.

Removal of mandibular tooth follicles before distraction osteogenesis.

Distraction osteogenesis is an innovative technique that has transformed the treatment of craniofacial malformations in young children. Bone generation obviates the need for graft material, which is in short supply in young patients, thus making possible surgical procedures on the craniofacial skeleton in young children. Sufficient mandibular volume is required for the osteotomy and placement of the device screws and/or pins. To have adequate bone stock and to facilitate distraction, the authors preoperatively examined all patients radiographically and selected those with tooth follicles that precluded successful osteotomy and pin placement for planned mandibular distraction. This report is of the first 13 children, aged 9 months to 6 years, who underwent predistraction enucleation. The osteotomy and device placement were performed successfully at least 4 months after enucleation. The described procedure has minimal morbidity and has resulted in successful subsequent distraction. The advantages, disadvantages, and cost-benefit issues are discussed.

Use of anti-CD40 ligand monoclonal antibody as antirejection therapy in a murine peripheral nerve allograft model.

Monoclonal antibody directed against CD40 ligand prevents acute allograft rejection in several models of solid-organ transplantation. This study describes the use of CD40 ligand as antirejection therapy in a mouse peripheral nerve allograft model. C3H mice received 8-mm nerve isografts (n = 2) or nerve allografts from C57BL donors. Treated animals (n = 11) received anti-CD40 ligand antibody applied to the graft and by intraperitoneal injections postoperatively. At 3 weeks, nerve histology from treated animals was comparable to isografts, whereas untreated allografts demonstrated virtually no signs of regeneration. Walking-track analysis demonstrated a trend toward improved functional recovery in treated animals. In conclusion, blockade of the CD40 pathway suppresses nerve allograft rejection in mice, and facilitates regeneration comparable to isografts.

Functional recovery and histomorphometric assessment following tibial nerve injury in the mouse.

Longitudinal studies have established that functional recovery following sciatic nerve injury can be evaluated in the mouse. Injury to the tibial nerve offers several advantages to sciatic nerve injury, including improved lower extremity sensation and end-organ reinnervation. Functional recovery following tibial nerve crush injury was studied in 55 C3H mice randomized into five groups harvested for histomorphometric evaluation from either normal nerves or 2, 3, 4, or 6 weeks postoperatively. Walking tracks were obtained preoperatively, and at regular intervals postoperatively, and foot print lengths measured. Significant normalization of print length occurred 14 days postoperatively, and complete recovery was noted 28 days postoperatively. Significant histomorphologic evidence of neuroregeneration was detected between 2 and 4 weeks postoperatively. Injury to the tibial nerve is a viable alternative to the sciatic nerve for studying neural regeneration in mice, and the print length factor can be used to monitor functional recovery in this model.

Failure of cyclosporin a to rescue peripheral nerve allografts in acute rejection.

Prevention and control of graft rejection remain essential in the investigation of peripheral nerve allotransplantation. Although use of cyclosporin A (CsA) has been shown to suppress successfully the rejection of nerve allografts, limited information exists concerning use of this drug to arrest rejection in progress, and thereby effect salvage of these grafts. The aim of this study was to determine the efficacy of CsA in the treatment of ongoing acute rejection of peripheral nerve allografts. Buffalo rats received posterior tibial nerve grafts from either Lewis or Buffalo donor animals and were divided into five groups: group 1 received isografts and no CsA treatment (n = 8), group 2 received allografts with continuous CsA therapy (n = 10), group 3 received allografts with no treatment (n = 7), group 4 received allografts with initiation of CsA therapy delayed until 3 weeks after the procedure (n = 11), and group 5 received allografts with an interrupted course of CsA (n = 15). All grafts were harvested at 10 weeks. Histomorphometric analysis demonstrated comparable nerve regeneration in groups 1 and 2 and good regeneration in group 3 animals, despite cellular infiltrate suggestive of rejection. At 3 weeks after surgery, group 4 animals showed early rejection and significantly less neuroregeneration than positive controls at 10 weeks after delayed initiation of CsA therapy. Finally, group 5 animals showed early regeneration at 3 weeks but significantly lesser regeneration by 10 weeks after interruption of therapy. In this experimental protocol, CsA was ineffective in rescuing histologically proven rejection in progress.