Impact of trametinib on the neuropsychological profile of NF1 patients.

PURPOSE: The use of trametinib in the treatment of pediatric low-grade gliomas (PLGG) and plexiform neurofibroma (PN) is being investigated in an ongoing multicenter phase II trial (NCT03363217). Preliminary data shows potential benefits with significant response in the majority of PLGG and PN and an overall good tolerance. Moreover, possible benefits of MEK inhibitor therapy on cognitive functioning in neurofibromatosis type 1 (NF1) were recently shown which supports the need for further evaluation. METHODS: Thirty-six patients with NF1 (age range 3-19 years) enrolled in the phase II study of trametinib underwent a neurocognitive assessment at inclusion and at completion of the 72-week treatment. Age-appropriate Wechsler Intelligence Scales and the Trail Making Test (for children over 8 years old) were administered at each assessment. Paired t-tests and Reliable Change Index (RCI) analyses were performed to investigate change in neurocognitive outcomes. Regression analyses were used to investigate the contribution of age and baseline score in the prediction of change. RESULTS: Stable performance on neurocognitive tests was revealed at a group-level using paired t-tests. Clinically significant improvements were however found on specific indexes of the Wechsler intelligence scales and Trail Making Test, using RCI analyses. No significant impact of age on cognitive change was evidenced. However, lower initial cognitive performance was associated with increased odds of presenting clinically significant improvements on neurocognitive outcomes. CONCLUSION: These preliminary results show a potential positive effect of trametinib on cognition in patients with NF1. We observed significant improvements in processing speed, visuo-motor and verbal abilities. This study demonstrates the importance of including neuropsychological evaluations into clinical trial when using MEK inhibitors for patients with NF1.

18F-Flurodeoxyglucose positron emission tomography with computed tomography (FDG PET/CT) findings in children with encephalitis and comparison to conventional imaging.

PURPOSE: FDG PET/CT is emerging as a new tool for the evaluation of acute encephalitis (AE). However, to date, there are no exclusively pediatric studies on the use of FDG PET for suspected AE. The objective of this study was to compare qualitative and quantitative brain PET to conventional brain imaging in a cohort of children, and to identify patterns of metabolic abnormalities characteristic of AE. METHODS: This retrospective study included 34 children imaged with PET/CT, CT and magnetic resonance imaging (MRI). The positivity rate of all three imaging modalities was measured. Besides visual assessment, quantification of relative regional brain metabolism (RRBM) was performed and compared to a database of normal pediatric brains. RESULTS: Fourteen subjects had a clinical diagnosis of autoimmune encephalitis (AIE) or encephalitis of unknown origin (EX), six of anti-N-methyl-D-aspartate receptor (anti-NMDAr) encephalitis, three of Hashimoto's encephalopathy, three of neurolupus and eight had other subtypes of encephalitis. Quantitative PET was abnormal in 100% of cases, visually assessed PET in 94.1% of subjects, MRI in 41.2% and CT in 6.9%. RRBM quantification demonstrated multiple hyper and hypo metabolic cortical regions in 82.3% of subjects, exclusively hypermetabolic abnormalities in 3%, and exclusively hypometabolic abnormalities in 14.7%. The basal ganglia were hypermetabolic in 26.5% of cases on visual assessment and in 58.8% of subjects using quantification. CONCLUSION: In our pediatric population FDG PET was more sensitive than conventional imaging for the detection of AE, and basal ganglia hypermetabolism was frequently encountered.

A phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway: TRAM-01.

BACKGROUND: Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. Up to 50% will be refractory to conventional chemotherapy. It is now known that the majority of PLGG have activation of the MAPK/ERK pathway. The same pathway is also activated in plexiform neurofibromas (PNs) which are low-grade tumors involving peripheral nerves in patients with neurofibromatosis type 1 (NF1). These lesions are known to be refractory to chemotherapy. Specific MEK inhibitors such as trametinib are now available and have been approved for other cancers harboring mutations in the MAPK/ERK pathway such as melanoma. We have observed significant responses to trametinib in patients with refractory PLGG in our institutions and results from the phase I study are promising. The treatment appears not only efficacious but is also usually well tolerated. We hypothesize that we will observe responses in the majority of refractory PLGG and PN treated with trametinib in this phase 2 study. METHODS: The primary objective is to determine the objective response rate of trametinib as a single agent for treatment of progressing/refractory tumors with MAPK/ERK pathway activation. The TRAM-01 study is a phase II multicentric open-label basket trial including four groups. Group 1 includes NF1 patients with progressing/refractory glioma. Group 2 includes NF1 patients with plexiform neurofibroma. Group 3 includes patients with progressing/refractory glioma with KIAA1549-BRAF fusion. Group 4 includes other patients with progressing/refractory glioma with activation of the MAPK/ERK pathway. Eligible patients for a given study group will receive daily oral trametinib at full dose for a total of 18 cycles of 28 days. A total of 150 patients will be enrolled in seven Canadian centers. Secondary objectives include the assessment of progression-free survival, overall survival, safety and tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment. DISCUSSION: Trametinib will allow us to target directly and specifically the MAPK/ERK pathway. We expect to observe a significant response in most patients. Following our study, trametinib could be integrated into standard treatment of PLGG and PN. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03363217 December 6, 2017.

Joubert Syndrome in French Canadians and Identification of Mutations in CEP104.

Joubert syndrome (JBTS) is a primarily autosomal-recessive disorder characterized by a distinctive mid-hindbrain and cerebellar malformation, oculomotor apraxia, irregular breathing, developmental delay, and ataxia. JBTS is a genetically heterogeneous ciliopathy. We sought to characterize the genetic landscape associated with JBTS in the French Canadian (FC) population. We studied 43 FC JBTS subjects from 35 families by combining targeted and exome sequencing. We identified pathogenic (n = 32 families) or possibly pathogenic (n = 2 families) variants in genes previously associated with JBTS in all of these subjects, except for one. In the latter case, we found a homozygous splice-site mutation (c.735+2T>C) in CEP104. Interestingly, we identified two additional non-FC JBTS subjects with mutations in CEP104; one of these subjects harbors a maternally inherited nonsense mutation (c.496C>T [p.Arg166*]) and a de novo splice-site mutation (c.2572-2A>G), whereas the other bears a homozygous frameshift mutation (c.1328_1329insT [p.Tyr444fs*3]) in CEP104. Previous studies have shown that CEP104 moves from the mother centriole to the tip of the primary cilium during ciliogenesis. Knockdown of CEP104 in retinal pigment epithelial (RPE1) cells resulted in severe defects in ciliogenesis. These observations suggest that CEP104 acts early during cilia formation by regulating the conversion of the mother centriole into the cilia basal body. We conclude that disruption of CEP104 causes JBTS. Our study also reveals that the cause of JBTS has been elucidated in the great majority of our FC subjects (33/35 [94%] families), even though JBTS shows substantial locus and allelic heterogeneity in this population.

Identification and functional characterization of a novel MTFMT mutation associated with selective vulnerability of the visual pathway and a mild neurological phenotype.

Mitochondrial protein synthesis is initiated by formylated tRNA-methionine, which requires the activity of MTFMT, a methionyl-tRNA formyltransferase. Mutations in MTFMT have been associated with Leigh syndrome, early-onset mitochondrial leukoencephalopathy, microcephaly, ataxia, and cardiomyopathy. We identified compound heterozygous MTFMT mutations in a patient with a mild neurological phenotype and late-onset progressive visual impairment. MRI studies documented a progressive and selective involvement of the retrochiasmatic visual pathway. MTFMT was undetectable by immunoblot analysis of patient fibroblasts, resulting in specific defects in mitochondrial protein synthesis and assembly of the oxidative phosphorylation complexes. This report expands the clinical and MRI phenotypes associated with MTFMT mutations, illustrating the complexity of genotype-phenotype relationships in mitochondrial translation disorders.

Mutations in DOCK7 in individuals with epileptic encephalopathy and cortical blindness.

Epileptic encephalopathies are increasingly thought to be of genetic origin, although the exact etiology remains uncertain in many cases. We describe here three girls from two nonconsanguineous families affected by a clinical entity characterized by dysmorphic features, early-onset intractable epilepsy, intellectual disability, and cortical blindness. In individuals from each family, brain imaging also showed specific changes, including an abnormally marked pontobulbar sulcus and abnormal signals (T2 hyperintensities) and atrophy in the occipital lobe. Exome sequencing performed in the first family did not reveal any gene with rare homozygous variants shared by both affected siblings. It did, however, show one gene, DOCK7, with two rare heterozygous variants (c.2510delA [p.Asp837Alafs(∗)48] and c.3709C>T [p.Arg1237(∗)]) found in both affected sisters. Exome sequencing performed in the proband of the second family also showed the presence of two rare heterozygous variants (c.983C>G [p.Ser328(∗)] and c.6232G>T [p.Glu2078(∗)]) in DOCK7. Sanger sequencing confirmed that all three individuals are compound heterozygotes for these truncating mutations in DOCK7. These mutations have not been observed in public SNP databases and are predicted to abolish domains critical for DOCK7 function. DOCK7 codes for a Rac guanine nucleotide exchange factor that has been implicated in the genesis and polarization of newborn pyramidal neurons and in the morphological differentiation of GABAergic interneurons in the developing cortex. All together, these observations suggest that loss of DOCK7 function causes a syndromic form of epileptic encephalopathy by affecting multiple neuronal processes.

A Phase II feasibility study of oral etoposide given concurrently with radiotherapy followed by dose intensive adjuvant chemotherapy for children with newly diagnosed high-risk medulloblastoma (protocol POG 9631): A report from the Children's Oncology Group.

BACKGROUND: Children with high-risk medulloblastoma historically have had a poor prognosis. The Children's Oncology Group completed a Phase II study using oral etoposide given with radiotherapy followed by intensive chemotherapy. PROCEDURE: Patients enrolled in the study had high-risk disease defined as ≥1.5 cm2 of residual disease postsurgery or definite evidence of central nervous metastasis. All patients underwent surgery followed by radiotherapy. During radiation, the patients received oral etoposide (21 days on, 7 off) at an initial dose of 50 mg/m2 per day (treatment 1), which was reduced to 35 mg/m2 per day (treatment 2) due to toxicity. After radiotherapy, the patients received chemotherapy with three cycles of cisplatin and oral etoposide, followed by eight courses of cyclophosphamide and vincristine. RESULTS: Between November 1998 and October 2002, 53 patients were accrued; 15 received treatment 1 and 38 treatment 2. Forty-seven patients (89%) were eligible. Response to radiation was excellent, with 19 (40.4%) showing complete response, 24 (51.1%) partial response, and four (8.5%) no recorded response. The overall 2- and 5-year progression-free survival (PFS) was 76.6 ± 6% and 70.2 ± 7%, respectively. The 2- and 5-year overall survival (OS) was 80.9 ± 6% and 76.6 ± 6%, respectively. Clinical response postradiation and PFS/OS were not significantly different between the treatment groups. There was a trend toward a difference in 5-year PFS between those without and with metastatic disease (P = 0.072). CONCLUSIONS: Oral etoposide was tolerable at 35 mg/m2 (21 days on and 7 days off) when given during full-dose irradiation in patients with high-risk medulloblastoma with encouraging survival data.

De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy.

KIF1A is a neuron-specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic paraparesis or sensory and autonomic neuropathy type-2. Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, and p.R316W) in KIF1A in 14 individuals, including two monozygotic twins. Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases. All these de novo mutations are located in the motor domain (MD) of KIF1A. Structural modeling revealed that they alter conserved residues that are critical for the structure and function of the MD. Transfection studies suggested that at least five of these mutations affect the transport of the MD along axons. Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy. Our findings thus indicate that de novo missense mutations in the MD of KIF1A cause a phenotype that overlaps with, while being more severe, than that associated with recessive mutations in the same gene.

Derivation and validation of a clinical decision rule to identify young children with skull fracture following isolated head trauma.

BACKGROUND: There is no clear consensus regarding radiologic evaluation of head trauma in young children without traumatic brain injury. We conducted a study to develop and validate a clinical decision rule to identify skull fracture in young children with head trauma and no immediate need for head tomography. METHODS: We performed a prospective cohort study in 3 tertiary care emergency departments in the province of Quebec. Participants were children less than 2 years old who had a head trauma and were not at high risk of clinically important traumatic brain injury (Glasgow Coma Scale score < 15, altered level of consciousness or palpable skull fracture). The primary outcome was skull fracture. For each participant, the treating physician completed a standardized report form after physical examination and before radiologic evaluation. The decision to order skull radiography was at the physician's discretion. The clinical decision rule was derived using recursive partitioning. RESULTS: A total of 811 patients (49 with skull fracture) were recruited during the derivation phase. The 2 predictors identified through recursive partitioning were parietal or occipital swelling or hematoma and age less than 2 months. The rule had a sensitivity of 94% (95% confidence interval [CI] 83%-99%) and a specificity of 86% (95% CI 84%-89%) in the derivation phase. During the validation phase, 856 participants (44 with skull fracture) were recruited. The rule had a sensitivity of 89% and a specificity of 87% during this phase. INTERPRETATION: The clinical decision rule developed in this study identified about 90% of skull fractures among young children with mild head trauma who had no immediate indication for head tomography. Use of the rule would have reduced the number of radiologic evaluations by about 60%.

Long-term visual outcome of methylmalonic aciduria and homocystinuria, cobalamin C type.

OBJECTIVE: To describe the long-term ophthalmologic outcomes of patients with methylmalonic aciduria and homocystinuria, cobalamin C type (cblC). DESIGN: Retrospective case series. PARTICIPANTS: All patients with cblC referred to the Department of Ophthalmology of the Centre Hospitalier Universitaire Sainte-Justine from 1984 through 2012 were studied. Twelve such patients were identified. METHODS: Clinical ophthalmic examinations, neuroimaging, electroretinography, and the results of MMACHC mutation analysis were reviewed retrospectively. MAIN OUTCOME MEASURES: We examined visual acuity, ocular alignment, presence of maculopathy and peripheral retinopathy, optic atrophy, and nystagmus. Photopic and scotopic electroretinograms were reviewed. We examined and compared mutations in the MMACHC gene. Neuroimaging abnormalities were compiled when available. RESULTS: Twelve cblC patients were followed up from 2 to 23 years (average, 10 years). Eleven of 12 patients were diagnosed before the age of 1 year (range, birth-2 years). An initial ophthalmic examination was performed within the first year of age in 9 of 12 patients. Visual acuity at the time of presentation was variable, ranging from light perception to 20/20. Visual acuity was worse than 20/100 in 75% (9/12) of patients at last follow-up. Eight patients (67%) had obvious maculopathy on fundus examination. Other findings included peripheral retinopathy (8/12 [67%]), nystagmus (8/12 [67%]), strabismus (5/12 [42%]), and optic atrophy (6/12 [50%]). Funduscopic deterioration was documented in 1 patient, whereas electrophysiologic changes occurred in 4 patients. Neuroimaging results were available in 7 of the patients, revealing corpus callosum atrophy (7/7 [100%]) and periventricular white matter loss (6/7 [85%]). CONCLUSIONS: Most children in our series had early-onset disease with neurologic manifestations and abnormal ophthalmologic examination results. Despite early treatment, many early-onset cblC patients have poor visual function.

Surveillance imaging in children with malignant CNS tumors: low yield of spine MRI.

Magnetic resonance imaging (MRI) is routinely obtained in patients with central nervous system (CNS) tumors, but few studies have been conducted to evaluate this practice. We assessed the benefits of surveillance MRI and more specifically spine MRI in a contemporary cohort. We evaluated MRI results of children diagnosed with CNS tumors from January 2000 to December 2011. Children with at least one surveillance MRI following the diagnosis of medulloblastoma (MB), atypical teratoid rhabdoid tumor (ATRT), pineoblastoma (PB), supratentorial primitive neuroectodermal tumor, supratentorial high-grade glioma (World Health Organization grade III-IV), CNS germ cell tumors or ependymoma were included. A total of 2,707 brain and 1,280 spine MRI scans were obtained in 258 patients. 97% of all relapses occurred in the brain and 3% were isolated to the spine. Relapse was identified in 226 (8%) brain and 48 (4%) spine MRI scans. The overall rate of detecting isolated spinal relapse was 9/1,000 and 7/1,000 for MB patients. MRI performed for PB showed the highest rate for detecting isolated spinal recurrence with 49/1,000. No initial isolated spinal relapse was identified in patients with glioma, supratentorial primitive neuroectodermal tumor and ATRT. Isolated spinal recurrences are infrequent in children with malignant CNS tumors and the yield of spine MRI is very low. Tailoring surveillance spine MRI to patients with higher spinal relapse risk such as PB, MB with metastatic disease and within 3 years of diagnosis could improve allocation of resources without compromising patient care.

Visual acuity of children treated with chemotherapy for optic pathway gliomas.

BACKGROUND: Chemotherapy is the most common primary treatment modality for pediatric optic pathway gliomas (OPGs). Due to the risk of severe visual impairment, visual acuity (VA) has become a clinical parameter of fundamental importance for children with OPGs. Despite this reality, most studies omit crucial information necessary for analysis of the effect of chemotherapy on VA in patients with cerebral gliomas. The principal goal of this study was to determine the immediate and long-term visual outcome of children treated first with chemotherapy for OPGs. PROCEDURE: Retrospective, non-comparative, case series of children with OPGs treated initially with chemotherapy. VA was measured prior to chemotherapy, directly following chemotherapy, as well as at last follow-up. RESULTS: Seven children (14 eyes) were positive for the neurofibromatosis type-1 (NF1) mutation and 10 children (20 eyes) were without the NF1 mutation (sporadic). Three deaths, all in the sporadic cohort, occurred as a result of their OPG. Median follow-up time of survivors was 10.54 ± 4.36 (SD) years. Both NF1 mutation positive and sporadic cohorts had deterioration in VA over time; however, deterioration was only statistically significant in the sporadic population. The percentage of eyes with vision weaker than 20/200 prior to chemotherapy, directly following chemotherapy and at last follow-up grew from 18% to 24% to 38%, respectively. CONCLUSIONS: In both NF1 mutant and sporadic OPGs, VA deteriorated directly following chemotherapy as well as at long-term follow-up. Despite chemotherapy, eyes with severe functional impairment gradually increased over time.

Disruption of TBC1D7, a subunit of the TSC1-TSC2 protein complex, in intellectual disability and megalencephaly.

BACKGROUND: Mutations in TSC1 or TSC2 cause the tuberous sclerosis complex (TSC), a disorder characterised by the development of hamartomas or benign tumours in various organs as well as the variable presence of epilepsy, intellectual disability (ID) and autism. TSC1, TSC2 and the recently described protein TBC1D7 form a complex that inhibits mTORC1 signalling and limits cell growth. Although it has been proposed that mutations in TBC1D7 might also cause TSC, loss of its function has not yet been documented in humans. METHODS AND RESULTS: We used homozygosity mapping and exome sequencing to study a consanguineous family with ID and megalencephaly but without any specific features of TSC. We identified only one rare coding variant, c.538delT:p.Y180fsX1 in TBC1D7, in the regions of homozygosity shared by the affected siblings. We show that this mutation abolishes TBC1D7 expression and is associated with increased mTORC1 signalling in cells of the affected individuals. CONCLUSIONS: Our study suggests that disruption of TBC1D7 causes ID but without the other typical features found in TSC. Although megalencephaly is not commonly observed in TSC, it has been associated with mTORC1 activation. Our observation thus reinforces the relationship between this pathway and the development of megalencephaly.

Development of a semi-automatic segmentation technique based on mean magnetic resonance imaging intensity thresholding for volumetric quantification of plexiform neurofibromas.

Rationale and objectives: Plexiform neurofibromas (PNs) are peripheral nerve tumors that occur in 25-50 % of patients with neurofibromatosis type 1. PNs may have complex, diffused, and irregular shapes. The objective of this work was to develop a volumetric quantification method for PNs as clinical assessment is currently based on unidimensional measurement. Materials and methods: A semi-automatic segmentation technique based on mean magnetic resonance imaging (MRI) intensity thresholding (SSTMean) was developed and compared to a similar and previously published technique based on minimum image intensity thresholding (SSTMini). The performance (volume and computation time) of the two techniques was compared to manual tracings of 15 tumors of different locations, shapes, and sizes. Performance was also assessed using different MRI sequences. Reproducibility was assessed by inter-observer analysis. Results: When compared to manual tracing, quantification performed with SSTMean was not significantly different (mean difference: 1.2 %), while volumes computed by SSTMini were significantly different (p < .0001, mean difference: 13.4 %). Volumes quantified by SSTMean were also significantly different than the ones assessed by SSTMini (p < .0001). Using SSTMean, volumes quantified with short TI inversion recovery, T1-, and T2-weighted imaging were not significantly different. Computation times used by SSTMean and SSTMini were significantly lower than for manual segmentation (p < .0001). The highest difference measured by two users was 8 cm3. Conclusion: Our method showed accuracy compared to a current gold standard (manual tracing) and reproducibility between users. The refined segmentation threshold and the possibility to define multiple regions-of-interest to initiate segmentation may have contributed to its performance. The versatility and speed of our method may prove useful to better monitor volumetric changes in lesions of patients enrolled in clinical trials to assessing response to therapy.

Relapse patterns in pediatric embryonal central nervous system tumors.

Embryonal tumors of the central nervous system (CNS) share histological features and were therefore initially grouped as primitive neuroectodermal tumors (PNET) and treated similarly. We sought to determine the relapse patterns of specific embryonal CNS tumors. We conducted a historical cohort study of children diagnosed with CNS embryonal tumors from January 2000 to December 2011 in two pediatric neuro-oncology centers. Patients of 21 years of age or younger at time of presentation with a diagnosis of medulloblastoma, supratentorial PNET, pineoblastoma or atypical teratoid/rhabdoid tumor (ATRT) and at least one surveillance MRI were included. A total of 133 patients met inclusion criteria and 49 (37 %) patients relapsed during the observation period. The majority (79 %) of sPNET relapses were local, whereas all (100 %) PB relapses were associated with diffuse leptomeningeal disease. Relapse patterns for MB were more diverse with local recurrence in 27 %, distant recurrence in 35 % and diffuse leptomeningeal disease in 38 %. The frequency of relapses involving the spine differed (p < 0.001) between tumor types (MB 28/55 [51 %], sPNET 3/33 [9 %], ATRT 3/7 [43 %] and PB 12/12 [100 %]). No sPNET patients had isolated spinal relapse (0/14). Embryonal tumors were found to have divergent patterns of recurrence. While medulloblastoma has variable relapse presentations, sPNET relapses locally and pineoblastoma recurs with diffuse leptomeningeal disease involving the spine. These results point toward possibly new upfront treatment stratification among embryonal tumors in accordance with relapse pattern.

Effectiveness of pamidronate as treatment of symptomatic osteonecrosis occurring in children treated for acute lymphoblastic leukemia.

BACKGROUND: Osteonecrosis (ON) is a severe complication of acute lymphoblastic leukemia (ALL) treatments. Recent studies suggest that bisphosphonates might reduce pain and loss of motor function in patients with ON. We assessed the effects of pamidronate compared to standard care in patients with symptomatic ON (sON) and studied whether steroids might be continued after diagnosis of ON in some patients. METHODS: We evaluated 17 patients with sON as complication of primary ALL treatment between 2000 and 2008. Fourteen patients were treated with pamidronate. Mobility and pain control were monitored in all patients. Affected joints were classified by magnetic resonance imaging (MRI) at ON diagnosis and after 6-72 months. RESULTS: Out of 220 patients with ALL, 17 (7.7%) patients developed sON. The median age at ALL diagnosis was 11 years (range: 2.7-16.6 years) and sON occurred a median of 13.4 months (range: 2.5-34 months) after ALL diagnosis. Affected joints were hip, knee and ankle. MRI scans showed 7 severe, 4 moderate, and 6 mild ON lesions. Fourteen patients showed improvement in pain (77% of patients) and motor function (59% of patients), even though corticoids were reintroduced in 4 patients. MRI demonstrated improvement, stability or worsening in 6, 3, and 5 cases, respectively. CONCLUSIONS: Pamidronate seems to be effective in the management of pain and motor function recovery in sON. Further studies are needed to provide evidence as to whether bisphosphonates can be recommended for the treatment or the prevention of ON in childhood ALL patients.

Four-film X-ray series is more sensitive than 2-film for diagnosis of skull fractures in children.

OBJECTIVE: The objective of this study was to compare the sensitivity and specificity of 2- and 4-film x-ray series when interpreted by pediatric emergency medicine physicians in the diagnosis of skull fracture in children. METHODS: A noninferiority crossover study was performed. The skull radiographs of the 50 most recent cases of skull fracture for which a 4-film radiography series was available and 50 controls matched for age were reviewed. Two modules, containing a random sequence of 2- and 4-film series of each child, were constructed to have all children evaluated twice (once with 2 films and once with 4 films). Pediatric emergency physicians evaluated both modules 2 to 4 weeks apart. The interpretation of the 4-film series by a pediatric radiologist served as the criterion standard. The sensitivity and specificity of the 2-film versus the 4-film skull x-ray series, in the identification of fracture, were compared. RESULTS: Thirteen pediatric emergency physicians participated in the study. For sensitivity, the mean difference between the 2- and 4-view series was higher than the noninferiority margin of 0.055 with an absolute mean difference of 0.060 (4-view minus 2-view series) and a 1-sided 95% higher confidence limit of 0.099. However for specificity, the mean difference was within the margin with an absolute mean difference of 0.011 and a 1-sided 95% higher confidence limit of 0.033. CONCLUSIONS: For children sustaining a head trauma, the 2-film skull radiography series is not as sensitive as the 4-film series in the detection of fracture, when interpreted by pediatric emergency physicians.

LRPPRC mutations cause a phenotypically distinct form of Leigh syndrome with cytochrome c oxidase deficiency.

BACKGROUND: The natural history of all known patients with French-Canadian Leigh disease (Saguenay-Lac-St-Jean cytochrome c oxidase deficiency, MIM220111, SLSJ-COX), the largest known cohort of patients with a genetically homogeneous, nuclear encoded congenital lactic acidosis, was studied. RESULTS: 55 of 56 patients were homozygous for the A354V mutation in LRPPRC. One was a genetic compound (A354V/C1277Xdel8). Clinical features included developmental delay, failure to thrive, characteristic facial appearance and, in 90% of patients, acute crises that have not previously been detailed, either metabolic (fulminant lactic acidosis) and/or neurological (Leigh syndrome and/or stroke-like episodes). Survival ranged from 5 days to >30 years. 46/56 patients (82%) died, at a median age of 1.6 years. Of 73 crises, 38 (52%) were fatal. The immediate causes of death were multiple organ failure and/or Leigh disease. Major predictors of mortality during crises (p<0.005) were hyperglycaemia, hepatic cytolysis, and altered consciousness at admission. Compared to a group of SURF1-deficient Leigh syndrome patients assembled from the literature, SLSJ-COX is distinct by the occurrence of metabolic crises, leading to earlier and higher mortality (p=0.001). CONCLUSION: SLSJ-COX is clinically distinct, with acute fatal acidotic crises on a backdrop of chronic moderate developmental delay and hyperlactataemia. Leigh syndrome is common. Stroke-like episodes can occur. The Leigh syndrome of SLSJ-COX differs from that of SURF1-related COX deficiency. SLSJ-COX has a different spectrum of associated abnormalities, acidotic crises being particularly suggestive of LRPPRC related Leigh syndrome. Even among A354V homozygotes, pronounced differences in survival and severity occur, showing that other genetic and/or environmental factors can influence outcome.

Infantile onset carnitine palmitoyltransferase 2 deficiency: Cortical polymicrogyria, schizencephaly, and gray matter heterotopias in an adolescent with normal development.

OBJECTIVE: To report an adolescent with infantile-onset carnitine palmitoyltransferase 2 (CPT2) deficiency and cerebral malformations and to review the occurrence of brain malformations in CPT2 deficiency. The patient presented clinically at age 5 months with dehydration and hepatomegaly. He also has an unrelated condition, X-linked nephrogenic diabetes insipidus. He had recurrent rhabdomyolysis but normal psychomotor development. At age 17 years, he developed spontaneous focal seizures. Cerebral magnetic resonance imaging revealed extensive left temporo-parieto-occipital polymicrogyria, white matter heterotopias, and schizencephaly. Neuronal migration defects were previously reported in lethal neonatal CPT2 deficiency but not in later-onset forms. DESIGN AND METHODS: We searched PubMed, Google Scholar, and the bibliographies of the articles found by these searches, for cerebral malformations in CPT2 deficiency. All antenatal, neonatal, infantile, and adult-onset cases were included. Exclusion criteria included insufficient information about age of clinical onset and lack of confirmation of CPT2 deficiency by enzymatic assay or genetic testing. For each report, we noted the presence of cerebral malformations on brain imaging or pathological examination. RESULTS: Of 26 neonatal-onset CPT2-deficient patients who met the inclusion criteria, brain malformations were reported in 16 (61.5%). In 19 infantile-onset cases, brain malformations were not reported, but only 3 of the 19 reports (15.8%) include brain imaging or neuropathology data. In 276 adult-onset cases, no brain malformations were reported. CONCLUSION: To the best of our knowledge, this is the first report of cerebral malformations in an infantile onset CPT2-deficient patient. Brain imaging should be considered in patients with CPTII deficiency and neurological manifestations, even in those with later clinical onset.