MRI Features and Their Association With Outcomes in Children With Anti-NMDA Receptor Encephalitis.

OBJECTIVES: How brain MRI lesions associate with outcomes in pediatric anti-NMDA receptor encephalitis (pNMDARE) is unknown. In this study, we correlate T2-hyperintense MRI brain lesions with clinical outcomes in pNMDARE. METHODS: This was a multicenter retrospective cohort study from 11 institutions. Children younger than 18 years with pNMDARE were included. One-year outcomes were assessed by the modified Rankin Score (mRS) with good (mRS ≤2) and poor (mRS ≥3) outcomes. RESULTS: A total of 175 pNMDARE subjects were included, with 1-year mRS available in 142/175 (81%) and 60/175 (34%) had abnormal brain MRIs. The most common T2-hyperintense lesion locations were frontal, temporal, and parietal. MRI features that predicted poor 1-year outcomes included abnormal MRI, particularly T2 lesions in the frontal and occipital lobes. After adjusting for treatment within 4 weeks of onset, improvement within 4 weeks, and intensive care unit admission, MRI features were no longer associated with poor outcomes, but after multiple imputation for missing data, T2 frontal and occipital lesions associated with poor outcomes. DISCUSSION: Abnormal frontal and occipital lesions on MRI may associate with 1-year mRS in pNMDARE. MRI of the brain may be a helpful prognostication tool that should be examined in future studies.

Assessment of Pediatric Pseudotumor Cerebri Clinical Characteristics and Outcomes.

Pseudotumor cerebri also known as idiopathic intracranial hypertension is a relatively uncommon disorder of unknown pathophysiology. Although pseudotumor cerebri occurs in both children and adults, the pseudotumor cerebri literature is heavily dominated by adult studies. The aim of this study is to retrospectively describe the clinical presentation, imaging, treatment, and outcomes of a large pediatric pseudotumor cerebri population over a 23-year period. We also discuss secondary pseudotumor cerebri (44%) as well as the increasingly recognized patient subgroups without headache (13.3%) and without papilledema (7.3%). Female sex, obesity, and initial symptoms were consistent with the literature; however radiographic findings were surprisingly low in this cohort. Headache outcomes at 1 week, 1 month, and 3 months following initial lumbar puncture/treatment and visual function outcomes are reported.

Pediatric Multiple Sclerosis Severity Score in a large US cohort.

OBJECTIVE: To characterize disease severity and distribution of disability in pediatric-onset multiple sclerosis (POMS) and to develop an optimized modeling scale for measuring disability, we performed a multicenter retrospective analysis of disability scores in 873 persons with POMS over time and compared this to previously published data in adults with multiple sclerosis (MS). METHODS: This was a retrospective analysis of prospectively collected data collected from 12 centers of the US Network of Pediatric MS Centers. Patients were stratified by the number of years from first symptoms of MS to Expanded Disability Status Scale (EDSS) assessment and an MS severity score (Pediatric Multiple Sclerosis Severity Score [Ped-MSSS]) was calculated per criteria developed by Roxburgh et al. in 2005. RESULTS: In total, 873 patients were evaluated. In our cohort, 52%, 19.4%, and 1.5% of all patients at any time point reached an EDSS of 2.0, 3.0, and 6.0. Comparison of our Ped-MSSS scores and previously published adult Multiple Sclerosis Severity Scores (MSSS) showed slower progression of Ped-MSSS with increasing gaps between higher EDSS score and years after diagnosis. Decile scores in our POMS cohort for EDSS of 2.0, 3.0, and 6.0 were 8.00/9.46/9.94, 7.86/9.39/9.91, and 7.32/9.01/9.86 at 2, 5, and 10 years, respectively. Notable predictors of disease progression in both EDSS and Ped-MSSS models were ever having a motor relapse and EDSS at year 1. Symbol Digit Modalities Test (SDMT) scores were inversely correlated with duration of disease activity and cerebral functional score. CONCLUSIONS: Persons with POMS exhibit lower EDSS scores compared to persons with adult-onset MS. Use of a Ped-MSSS model may provide an alternative to EDSS scoring in clinical assessment of disease severity and disability accrual.

Pediatric-Onset Postural Orthostatic Tachycardia Syndrome in a Single Tertiary Care Center.

AIM: We characterize the pediatric postural orthostatic tachycardia syndrome (POTS) population seen at a single tertiary care referral center. METHOD: Retrospective chart review of all pediatric POTS patients seen in our center between 2015 and 2017. Pediatric POTS was defined as chronic, at least 3 months, symptoms of orthostatic intolerance associated with excessive orthostatic tachycardia as determined by tilt table testing with orthostatic heart rate increment of ≥40 bpm within 5 minutes of head-up tilt or absolute orthostatic heart rate ≥130 bpm for patients 13 years old and younger and ≥120 bpm for those 14 years and older. We looked at demographics, presenting symptoms, comorbidities, examination findings, investigation findings, treatment, and patient reported outcomes. Outcome measures were separated by patient report and group comparisons were made using 2-sample t tests or Mann-Whitney U tests for continuous variables and Fisher exact tests for categorical variables. RESULTS: One hundred thirty-four patients with pediatric onset POTS were identified. The mean age was 15 years. Seventy-nine percent of patients were female and 90% were white. The most common presenting symptoms included dizziness/lightheadedness (88%), syncope (54%), and palpitations (40%). Many patients had significant comorbidities attributable to numerous bodily systems, most commonly headache syndromes (migraine 43%, nonspecific headache 22%, chronic daily headache 14%, and new daily persistent headache 5%) and chronic fatigue (60%). Low vitamin D and insufficient iron stores were commonly seen. The majority of patients improved or had resolution of symptoms following treatment (70%). When separated by outcome, statistically significant differences were found for glucose (patients whose symptoms resolved had higher median glucose), palpitations (patients whose symptoms resolved were less likely to have palpitations), constipation (patients whose symptoms were stable/worsened were more likely to have constipation), and unexplained pain (patients whose symptoms were stable/worsened were more likely to have unexplained pain). CONCLUSIONS: Pediatric POTS is a chronic condition with a fairly good prognosis following appropriate treatment. It is associated with numerous comorbidities that necessitate multidisciplinary expert care.

Real-World Effectiveness of Initial Disease-Modifying Therapies in Pediatric Multiple Sclerosis.

OBJECTIVE: To assess real-world effectiveness of initial treatment with newer compared to injectable disease-modifying therapies (DMTs) on disease activity in pediatric multiple sclerosis (MS) and clinically isolated syndrome (CIS). METHODS: This is a cohort study of children with MS/CIS followed at 12 clinics in the US Network of Pediatric MS Centers, who received initial therapy with newer (fingolimod, dimethyl fumarate, teriflunomide, natalizumab, rituximab, ocrelizumab) or injectable (interferon-ß, glatiramer acetate) DMTs. Propensity scores (PSs) were computed, including preidentified confounders. Relapse rate while on initial DMT was modeled with negative binomial regression, adjusted for PS-quintile. Time to new/enlarging T2-hyperintense and gadolinium-enhancing lesions on brain magnetic resonance imaging were modeled with midpoint survival analyses, adjusted for PS-quintile. RESULTS: A total of 741 children began therapy before 18 years, 197 with newer and 544 with injectable DMTs. Those started on newer DMTs were older (15.2 vs injectable 14.4 years, p = 0.001) and less likely to have a monofocal presentation. In PS-quintile-adjusted analysis, those on newer DMTs had a lower relapse rate than those on injectables (rate ratio = 0.45, 95% confidence interval (CI) = 0.29-0.70, p < 0.001; rate difference = 0.27, 95% CI = 0.14-0.40, p = 0.004). One would need to treat with newer rather than injectable DMTs for 3.7 person-years to prevent 1 relapse. Those started on newer DMTs had a lower rate of new/enlarging T2 (hazard ratio [HR] = 0.51, 95% CI = 0.36-0.72, p < 0.001) and gadolinium-enhancing lesions (HR = 0.38, 95% CI = 0.23-0.63, p < 0.001) than those on injectables. INTERPRETATION: Initial treatment of pediatric MS/CIS with newer DMTs led to better disease activity control compared to injectables, supporting greater effectiveness of newer therapies. Long-term safety data for newer DMTs are required. ANN NEUROL 2020 ANN NEUROL 2020;88:42-55.

The Clinical Spectrum of Mosaic Neurofibromatosis in Children and Adolescents.

BACKGROUND: Segmental neurofibromatosis was initially described by Miller and Sparks (1977) as manifestations of neurofibromatosis limited to a dermatomal, localized distribution. Now termed mosaic neurofibromatosis, previous literature described this disease in children and adolescents with individual case reports and small-numbered case series. This study presents a large series of children and adolescents with mosaic neurofibromatosis. METHODS: A retrospective chart review of a single institution medical record database was performed on all cases of mosaic neurofibromatosis diagnosed between the years 1998 and 2017. Eligible subjects were determined by 2 criteria: (1) segmental or unilateral expression of one of more signs of NF I according to those outlined in the NIH criteria and (2) were under 18 years of age at the time of diagnosis. Select information extracted include location of clinical features, NF manifestations (neurofibromas, plexiform neurofibromas, café-au-lait spots, freckling, Lisch nodules), presence of a diffuse area of cutaneous hyperpigmentation, and other significant medical conditions. RESULTS: Sixty-eight cases met established criteria. Average age at diagnosis was 8.28 ± 4.47 years. Thirty-seven (54%) were male and 31 (46%) were female. Localization of the dermatologic manifestations is as follows: left side in 28 (41%) cases, right side in 32 (47%) cases, and bilateral in 8 (11%) cases. Café-au-lait lesions appeared in 64 (94%) of cases and 14 (21%) had axillary and inguinal freckling. CONCLUSIONS: This study expands our understanding of the disease characteristics seen in children and adolescents with mosaic neurofibromatosis and confirms the need to focus on pigmentary changes in children with mosaic neurofibromatosis.

Cognitive processing speed in pediatric-onset multiple sclerosis: Baseline characteristics of impairment and prediction of decline.

BACKGROUND: Cognitive impairment occurs in approximately one-third of pediatric-onset multiple sclerosis (POMS) patients. The Symbol Digit Modalities Test (SDMT), a widely used cognitive screen in adults, has yet to be incorporated early into the standard care of POMS. OBJECTIVE: To screen for cognitive impairment early in the course of POMS and analyze predictive factors. METHODS: Of the 955 POMS or clinically isolated syndrome (CIS) patients prospectively assessed from March 2014 to July 2018, 500 POMS and 116 CIS patients met inclusion criteria (disease onset before the age of 18, one or more SDMTs, and 8 years or older at the time of testing). Those with relapse were analyzed separately from those who were relapse-free. RESULTS: At initial assessment, the mean (interquartile range (IQR)) age at symptom onset was 13.5 years (12.0, 15.9) and the mean (±SD) disease duration was 3.0 ± 2.9 years. Impaired processing speed occurred in 23.4% of POMS and in 16.4% of CIS. On serial testing (n = 383, mean follow-up: 1.8 years), 14.1% had clinically meaningful decline predicted by older age of multiple sclerosis (MS) onset and male gender. Disease relapse or steroid use led to transient worsening on the SDMT. CONCLUSION: Early in the disease, some POMS and CIS patients are at risk for cognitive impairment and subsequent decline.

Newer Treatment Approaches in Pediatric-Onset Multiple Sclerosis.

PURPOSE OF REVIEW: With the recognition that pediatric-onset multiple sclerosis (POMS) is characterized by more prominent disease activity, earlier age at onset of disability milestones, and more prominent cognitive impairment compared with physical disability earlier in the disease course compared with adult-onset multiple sclerosis (AOMS), there has been increasing interest in identifying optimal and safe treatment approaches to achieve better disease control in this group. Injectable therapies have been traditionally used as first line in this population, although not formally approved. This review focuses on current treatment and monitoring approaches in POMS. RECENT FINDINGS: In the past few years, and despite the paucity of FDA-approved medications for use in POMS, an increasing trend toward using newer disease-modifying therapies (DMTs) in this group is observed. However, escalation (as opposed to induction) remains the most frequent approach, and many children continue to be untreated before age 18, particularly before age 12. The only FDA- and EMA-approved disease-modifying therapy in POMS is fingolimod; however, dimethyl fumarate, teriflunomide, natalizumab, ocrelizumab, and alemtuzumab either have been evaluated in observational studies or are being currently investigated in formal randomized controlled trials for use in POMS and appear to be safe in this group. Autologous hematopoietic stem cell transplantation has also been evaluated in a small series. Clinical outcome measures and MS biomarkers have been poorly studied in POMS; however, the use of composite functional scores, neurofilament light chain, optical coherence tomography, and imaging findings is being increasingly investigated to improve early diagnosis and efficient monitoring of POMS. Off-label use of newer DMTs in POMS is increasing, and based on retrospective data, and phase 2 trials, this approach appears to be safe in children. Results from ongoing trials will help clarify the safety and efficacy of these therapies in the future. Fingolimod is the only FDA-approved medication for use in POMS. Outcome measures and biomarkers used in AOMS are being studied in POMS and are greatly needed to quantify treatment response in this group.

Admixture mapping reveals evidence of differential multiple sclerosis risk by genetic ancestry.

Multiple sclerosis (MS) is an autoimmune disease with high prevalence among populations of northern European ancestry. Past studies have shown that exposure to ultraviolet radiation could explain the difference in MS prevalence across the globe. In this study, we investigate whether the difference in MS prevalence could be explained by European genetic risk factors. We characterized the ancestry of MS-associated alleles using RFMix, a conditional random field parameterized by random forests, to estimate their local ancestry in the largest assembled admixed population to date, with 3,692 African Americans, 4,915 Asian Americans, and 3,777 Hispanics. The majority of MS-associated human leukocyte antigen (HLA) alleles, including the prominent HLA-DRB1*15:01 risk allele, exhibited cosmopolitan ancestry. Ancestry-specific MS-associated HLA alleles were also identified. Analysis of the HLA-DRB1*15:01 risk allele in African Americans revealed that alleles on the European haplotype conferred three times the disease risk compared to those on the African haplotype. Furthermore, we found evidence that the European and African HLA-DRB1*15:01 alleles exhibit single nucleotide polymorphism (SNP) differences in regions encoding the HLA-DRB1 antigen-binding heterodimer. Additional evidence for increased risk of MS conferred by the European haplotype were found for HLA-B*07:02 and HLA-A*03:01 in African Americans. Most of the 200 non-HLA MS SNPs previously established in European populations were not significantly associated with MS in admixed populations, nor were they ancestrally more European in cases compared to controls. Lastly, a genome-wide search of association between European ancestry and MS revealed a region of interest close to the ZNF596 gene on chromosome 8 in Hispanics; cases had a significantly higher proportion of European ancestry compared to controls. In conclusion, our study established that the genetic ancestry of MS-associated alleles is complex and implicated that difference in MS prevalence could be explained by the ancestry of MS-associated alleles.

Several household chemical exposures are associated with pediatric-onset multiple sclerosis.

BACKGROUND: There is limited information about the potential associations of multiple sclerosis (MS) and commonly used household chemicals. METHODS: We performed a case-control study of exposures to common household chemicals during childhood in children with MS and healthy pediatric controls. Exposures to household products were collected from a comprehensive questionnaire (http://www.usnpmsc.org/Documents/EnvironmentalAssessment.pdf) completed by parents at the time of enrollment in the study. Cases included children diagnosed with MS or clinically isolated syndrome with at least two silent T2 bright lesions on MRI, recruited within 4 years of disease onset from 16 pediatric MS clinics in the USA. Multivariate analyses using logistic regression were adjusted for possible confounders including age, sex, race, ethnicity, mother's highest level of education, and urban versus rural living. RESULTS: Questionnaire responses to household chemicals were available for 312 eligible cases (median age 15.7 years, 63% girls) and 490 healthy controls (median age 15.0, 57% girls). Exposure to rodenticides (odds ratio [OR] 2.10, 95% confidence interval [CI] 1.35-3.26, P ≤ 0.001), weed control agents (OR 1.99, 95% CI 1.36-2.92, P ≤ 0.001) and products for plant/tree disease control (OR 2.72, 95% CI 1.54-4.82, P ≤ 0.001) anytime during childhood were associated with an increased risk for pediatric-onset MS in adjusted and multiple comparisons analyses. CONCLUSIONS: Our findings suggest that exposure to specific household chemicals during early childhood is associated with the risk of developing pediatric-onset MS. Future studies are needed to elucidate a causal relationship and the exact agents involved.

Urban air quality and associations with pediatric multiple sclerosis.

BACKGROUND: We previously identified air quality as a risk factor of interest for pediatric multiple sclerosis. The purpose of this study is to more closely examine the association between the six criteria air pollutants and pediatric MS as well as identify specific areas of toxic release using data from the Toxic Release Inventory. METHODS: Pediatric MS cases (N = 290) and healthy controls (N = 442) were included as part of an ongoing case-control study. We used the National Emissions Inventory system to estimate particulate exposure by county of residence for each participant. Proximity to Toxic Release Inventory (TRI) sites was also assessed using ArcGIS mapping tools. Risk-Screening Environmental Indicators (RSEI) classified counties at risk to exposure of environmental toxic releases. RESULTS: Fine particulate matter (PM 2.5), carbon monoxide (CO), sulfur dioxide (SO 2), and lead air emissions were associated with increased odds for pediatric MS (P < 0.01) for those residing within 20 miles of an MS center. Most study participants (75%) resided within 5 miles of at least one TRI site; however, the mean total pounds of stack air releases was higher for sites near MS cases (81,000 tons) compared to those near healthy controls (35,000 tons, P = 0.002). Average RSEI scores did not differ significantly between cases and controls. CONCLUSION: Out of several air pollutants examined, we show that fine particulate matter and three other criteria pollutants (SO 2, CO, and lead) were statistically associated with higher odds for pediatric MS.

Heterogeneity in association of remote herpesvirus infections and pediatric MS.

OBJECTIVE: While prior Epstein-Barr virus (EBV) infection has been consistently associated with subsequent risk of developing multiple sclerosis (MS), the association with other common herpesviruses has been more controversial. Our objectives were to determine whether remote infection with EBV and other common herpesviruses affect the susceptibility to pediatric MS and if there are interactions between genetic and demographic factors and viral infections. METHODS: Cases with pediatric-onset MS or clinically isolated syndrome within 4 years of disease onset, and controls were recruited from 16 American pediatric MS centers. Logistic regression models adjusted for potential confounders assessed the association between case status and serological evidence for past infection with EBV, cytomegalovirus (CMV), Herpes Simplex viruses-1 (HSV-1) and -2. We determined the heterogeneity of the effect of viral infection on the risk of having MS according to race, ethnicity and HLA-DRB1:1501 status. RESULTS: A total of 356 pediatric cases and 493 controls were recruited. In multivariable models, EBV-viral capsid antigen (VCA) seropositivity was associated with increased odds of having MS by 7.4 times (95% CI: 4.5-12.0, P < 0.001). Seropositivity for HSV-1 was also associated with increased odds of having MS (OR 1.54, 95% CI: 1.06-2.25, P = 0.025) but this increase was seen only in Whites (OR = 2.18, 95% CI 1.35-3.52, P < 0.001) and those negative for HLA-DRB1*1501 (OR = 1.89, 95% CI 1.17-3.03, P = 0.009). The effect of remote EBV infection on the risk of pediatric MS depended on race and HLA-DRB1*15:01 status. INTERPRETATION: EBV seropositivity is strongly associated with pediatric MS, as is HSV-1 seropositivity in subjects negative for HLA-DRB1*15:01. Our report of interactions between select viral exposures, and age, race and DRB1 status suggests a complex effect of environmental and genetic risk factors on MS development.

Early infectious exposures are not associated with increased risk of pediatric-onset multiple sclerosis.

OBJECTIVE: We sought to determine if early infectious exposures such as daycare, early use of antibiotics, vaccinations and other germ exposures including pacifier use and playing on grass are associated with multiple sclerosis (MS) risk in children. METHODS: This was a case-control study of children with MS or clinically isolated syndrome (CIS) and healthy controls enrolled at sixteen clinics participating in the US Network of Pediatric MS Centers. Parents completed a comprehensive environmental questionnaire that captured early infectious exposures, habits, and illnesses in the first five years of life. A panel of at least two pediatric MS specialists confirmed diagnosis of participants. Association of early infectious variables with diagnosis was assessed via multivariable logistic regression analyses, adjusting for age, sex, race, ethnicity, US birth region, and socioeconomic status (SES). RESULTS: Questionnaire responses for 326 eligible cases (mean age 14.9, 63.5% girls) and 506 healthy pediatric subjects (mean age 14.4, 56.9% girls) were included in analyses. History of flu with high fever before age five (p = 0.01), playing outside in grass and use of special products to treat head lice or scabies (p = 0.04) were associated with increased risk of MS in unadjusted analyses. In the multivariable model adjusted for age, sex, race, ethnicity, and mother's highest educational attainment, these results were not statistically significant. Notably, antibiotic use (p = 0.22) and regular daycare attendance before age 6 (p = 0.09) were not associated with odds of developing MS. CONCLUSION: Early infectious factors investigated in this study were not associated with MS risk.

Pediatric-Onset Multiple Sclerosis: A Single Center Study.

Pediatric-onset multiple sclerosis (POMS), once thought to be rare, is now being diagnosed in increasing numbers in children. Despite improvements to diagnostic criteria, the diagnosis and management of POMS remains challenging. The aim of this study is to retrospectively describe a growing POMS patient population seen at a single center over a 13 year period. Epidemiologic, clinical, neuroimaging, laboratory features and therapeutic management and outcome data were collected and analyzed. These data support associations between MS and environmental triggers such as obesity and vitamin D deficiency. Presenting symptoms, magnetic resonance imaging and laboratory findings were consistent with the existing literature; however, the prevalence of cortical lesions and abnormal saccadic pursuit is higher than other reports. Data also demonstrate a shift in practice from first- to second-line therapies over the observed period.

Examining the contributions of environmental quality to pediatric multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a presumed autoimmune disease caused by genetic and environmental factors. It is hypothesized that environmental exposures (such as air and water quality) trigger the innate immune response thereby activating a pro-inflammatory cascade. OBJECTIVE: To examine potential environmental factors in pediatric MS using geographic information systems (GIS). METHODS: Pediatric MS cases and healthy controls were identified as part of an ongoing multicenter case-control study. Subjects' geographic locations were mapped by county centroid to compare to an Environmental Quality Index (EQI). The EQI examines 5 individual environmental components (air, land, water, social, built factors). A composite EQI score and individual scores were compared between cases and controls, stratified by median proximity to enrollment centers (residence <20 or ≥20 miles from the recruiting center), using logistic regression. RESULTS: Of the 287 MS cases and 445 controls, 46% and 49% respectively live in areas where the total EQI is the highest (worst environmental quality). Total EQI was not significantly associated with the odds for MS (p = 0.90 < 20 miles from center; p = 0.43 ≥ 20 miles); however, worsening air quality significantly impacted the odds for MS in those living near a referral center (OR = 2.83; 95%CI 1.5, 5.4) and those who reside ≥ 20 miles from a referral center (OR = 1.61; 95%CI 1.2, 2.3). CONCLUSION: Among environmental factors, air quality may contribute to the odds of developing MS in a pediatric population. Future studies will examine specific air constituents and other location-based air exposures and explore potential mechanisms for immune activation by these exposures.

Multiple sclerosis in the very young: a case report and review of the literature.

Onset of multiple sclerosis (MS) in the very young (<10 years) is uncommon. We describe a 2 year old girl with MS, the youngest reported case in the USA. She presented to an outside hospital with acute onset of ataxia on three occasions before presenting to our institution, initially misdiagnosed as acute disseminated encephalomyelitis and treated with intravenous methylprednisolone. MRI of the brain during each presentation revealed new areas of demyelination. Initial cerebrospinal fluid (CSF) studies and MRI of the spine were normal. Repeat MRI of the brain at our institution, 7 months later, revealed new demyelinating lesions and CSF analysis revealed elevated myelin basic protein, negative oligoclonal band and neuromyelitis optica immunoglobulin and normal IgG synthesis. Her clinical presentation with multiple relapses and new MRI findings validated the diagnosis of MS.

Massive Soft Tissue Neurofibroma (Elephantiasis Neuromatosa): Case Report and Review of Literature.

The authors review the literature on massive soft tissue neurofibroma. The methods included a review of 71 reports (PubMed search 1929-2012) with a total of 91 massive soft tissue neurofibroma patients and illustration of clinical and radiological progression of massive soft tissue neurofibroma on a patient with neurofibromatosis type 1. The mean age at initial examination was 21 years. Tumor onset was mostly in childhood years. The commonest affected body segment was the lower extremity (46%), followed by head/neck (30%). Surgical management was pursued in the majority of cases (79%). Bleeding was a common complication (25%). Recurrence was described in 12%; multiple resections cases were described. Malignant transformation occurred in 5%. Although massive soft tissue neurofibroma may be present early in life, massive tumor overgrowth may take years. Predicting disease progression and/or benefit of surgical intervention early in the disease course is challenging. Recurrence and malignant transformation are possible. Massive soft tissue neurofibroma does not respond to chemotherapy or radiotherapy and is associated with life-threatening surgical complications.

ZEB2 gene mutation and duplication of 22q11.23 in Mowat-Wilson syndrome.

Mowat-Wilson syndrome is a recently delineated multiple congenital anomaly syndrome characterized by a distinctive facial appearance in association with intellectual disability, microcephaly, agenesis of the corpus callosum, seizures, congenital heart disease, Hirschsprung disease, short stature, and genitourinary anomalies. We report a 2-year-10-month-old white female with this syndrome caused by mutations in the ZEB2 gene, and in addition a duplication of the 22q11.23, a previously undocumented occurrence.