Nonsyndromic craniosynostosis: novel coding variants.

BACKGROUND: Craniosynostosis (CS), the premature fusion of one or more neurocranial sutures, is associated with approximately 200 syndromes; however, about 65-85% of patients present with no additional major birth defects. METHODS: We conducted targeted next-generation sequencing of 60 known syndromic and other candidate genes in patients with sagittal nonsyndromic CS (sNCS, n = 40) and coronal nonsyndromic CS (cNCS, n = 19). RESULTS: We identified 18 previously published and 5 novel pathogenic variants, including three de novo variants. Novel variants included a paternally inherited c.2209C>G:p.(Leu737Val) variant in BBS9 of a patient with cNCS. Common variants in BBS9, a gene required for ciliogenesis during cranial suture development, have been associated with sNCS risk in a previous genome-wide association study. We also identified c.313G>T:p.(Glu105*) variant in EFNB1 and c.435G>C:p.(Lys145Asn) variant in TWIST1, both in patients with cNCS. Mutations in EFNB1 and TWIST1 have been linked to craniofrontonasal and Saethre-Chotzen syndrome, respectively; both present with coronal CS. CONCLUSIONS: We provide additional evidence that variants in genes implicated in syndromic CS play a role in isolated CS, supporting their inclusion in genetic panels for screening patients with NCS. We also identified a novel BBS9 variant that further shows the potential involvement of BBS9 in the pathogenesis of CS.

[Choroid plexus tumours in childhood: Experience in Sant Joan de Déu hospital]. / Tumores de plexo coroideo en la infancia: experiencia en el hospital Sant Joan de Déu.

Choroid plexus tumours are rare, with a peak incidence in the first two years of life. The most common location is the lateral ventricle in children, while in adults it is the fourth ventricle. The most common clinical manifestation is the signs and symptoms of intracranial hypertension. They are histologically classified as plexus papilloma, atypical plexus papilloma, and plexus carcinoma. A review is presented on choroid plexus tumours treated in the Hospital Sant Joan de Déu between 1980 and 2014. A total of 18 patients have been treated. An analysis was made of the demographic, clinical, histological data, treatment, and recurrences. The treatment of choice is complete resection, accompanied by adjuvant therapy in carcinomas. In atypical papillomas, the use of adjuvant therapies is controversial, reserving radiation therapy for recurrences. Papillomas have a good outcome, whereas atypical papillomas and carcinomas outcome is poor.

Low-grade gliomas in children: single institutional experience in 198 cases.

INTRODUCTION: In pediatric population (0-18 years), low-grade gliomas (PLGG) are the most frequent brain tumors and majority are amenable for surgical removal. PATIENTS AND METHODS: A retrospective review of 198 children diagnosed with PLGG between 1980 and 2010 at HSJD was carried out. Several variables were studied to find prognostic factors related to the outcomes (progression-free survival (PFS) and overall survival (OS)). RESULTS: Median age at onset was 88.8 months (3.1 to 214.5 months, SD 53). Surgery was performed in 175 patients (88.4%), achieving gross total resection (GTR) in 77 (44%), subtotal resection (STR) in 87 (49.7%), and 11 (6.3%) biopsies. Pathological review classified 84 tumors as WHO grade I (48%) and 89 as grade II (50.8%). Adjuvant therapy (AT) was given to 75 patients (37.9%), radiotherapy in 24 (12.1%), chemotherapy in 33 (16.7%), and combined in 18 (9.1%). Sixteen patients (8.1%) died, 89 (43.4%) are alive with no evidence of disease, and 93 (47%) alive with disease, median follow-up 65.2 months. Outcome is significantly correlated with age (p = 0001, worse OS for patients younger than 12 months) and extent of tumor resection (p < 0001). OS for GTR/STR/biopsy was >200, 154.3, and 101.9 months, respectively. Patients treated with AT presented worse OS/PFS (p < 0.001) than those not treated. Histology was non significantly related to outcomes. CONCLUSION: In our series of PLGG, the best prognostic markers are tumor location (cerebellar) and the extent of tumor resection (GTR). Infants and patients who require adjuvant therapy because of tumor progression or recurrence have worse outcome.

[Epidemiology and classification of arachnoid cysts in children]. / Epidemiología y clasificación de los quistes aracnoideos en niños.

The prevalence of arachnoid cysts in children is 1-3%. They are more frequent in boys. They can be located intracranially or in the spine. Intracranial cysts are classified as supratentorial, infratentorial, and supra-infratentorial (tentorial notch). Supratentorial are divided into middle cranial fossa, convexity, inter-hemisferic, sellar region, and intraventricular. Infratentorial are classified into supracerebellar, infracerebellar, hemispheric, clivus, and cerebellopontine angle. Finally spinal arachnoid cysts are classified taking into account whether they are extra- or intradural, and nerve root involvement.

Quantification of facial skeletal shape variation in fibroblast growth factor receptor-related craniosynostosis syndromes.

BACKGROUND: fibroblast growth factor receptor (FGFR) -related craniosynostosis syndromes are caused by many different mutations within FGFR-1, 2, 3, and certain FGFR mutations are associated with more than one clinical syndrome. These syndromes share coronal craniosynostosis and characteristic facial skeletal features, although Apert syndrome (AS) is characterized by a more dysmorphic facial skeleton relative to Crouzon (CS), Muenke (MS), or Pfeiffer syndromes. METHODS: Here we perform a detailed three-dimensional evaluation of facial skeletal shape in a retrospective sample of cases clinically and/or genetically diagnosed as AS, CS, MS, and Pfeiffer syndrome to quantify variation in facial dysmorphology, precisely identify specific facial features pertaining to these four syndromes, and further elucidate what knowledge of the causative FGFR mutation brings to our understanding of these syndromes. RESULTS: Our results confirm a strong correspondence between genotype and facial phenotype for AS and MS with severity of facial dysmorphology diminishing from Apert FGFR2(S252W) to Apert FGFR2(P253R) to MS. We show that AS facial shape variation is increased relative to CS, although CS has been shown to be caused by numerous distinct mutations within FGFRs and reduced dosage in ERF. CONCLUSION: Our quantitative analysis of facial phenotypes demonstrate subtle variation within and among craniosynostosis syndromes that might, with further research, provide information about the impact of the mutation on facial skeletal and nonskeletal development. We suggest that precise studies of the phenotypic consequences of genetic mutations at many levels of analysis should accompany next-generation genetic research and that these approaches should proceed cooperatively.

Regulatory elements in SEM1-DLX5-DLX6 (7q21.3) locus contribute to genetic control of coronal nonsyndromic craniosynostosis and bone density-related traits.

Purpose: The etiopathogenesis of coronal nonsyndromic craniosynostosis (cNCS), a congenital condition defined by premature fusion of 1 or both coronal sutures, remains largely unknown. Methods: We conducted the largest genome-wide association study of cNCS followed by replication, fine mapping, and functional validation of the most significant region using zebrafish animal model. Results: Genome-wide association study identified 6 independent genome-wide-significant risk alleles, 4 on chromosome 7q21.3 SEM1-DLX5-DLX6 locus, and their combination conferred over 7-fold increased risk of cNCS. The top variants were replicated in an independent cohort and showed pleiotropic effects on brain and facial morphology and bone mineral density. Fine mapping of 7q21.3 identified a craniofacial transcriptional enhancer (eDlx36) within the linkage region of the top variant (rs4727341; odds ratio [95% confidence interval], 0.48[0.39-0.59]; P = 1.2E-12) that was located in SEM1 intron and enriched in 4 rare risk variants. In zebrafish, the activity of the transfected human eDlx36 enhancer was observed in the frontonasal prominence and calvaria during skull development and was reduced when the 4 rare risk variants were introduced into the sequence. Conclusion: Our findings support a polygenic nature of cNCS risk and functional role of craniofacial enhancers in cNCS susceptibility with potential broader implications for bone health.

Pituitary dysfunction after traumatic brain injury in children: is there a need for ongoing endocrine assessment?

BACKGROUND: Hypopituitarism has been widely described in adults after traumatic brain injury (TBI); however, the available data in paediatric populations are scarce. Here, we report the results of a prospective, long-term study in children, adolescents and young adults. STUDY GROUP: Thirty-seven children (age, 2 months to 19·9 years) of 51 eligible patients were followed for 1 year. Clinical and baseline endocrine variables were assessed in all 3 and 12 months after TBI; children ≥ 6 years underwent two stimulation tests (glucagon stimulation and megatest). RESULTS: In the group ≥6 years, 11 of 23 patients (47·8%) had a subnormal GH peak 3 months after TBI that persisted in 8 of 23 patients (34%) after 1 year. The GH response showed no correlation with injury severity (GCS, Marshall classification). Growth velocity was normal in all patients, except for one. Body mass index (BMI) SDS increased significantly in the group with low GH response. A suboptimal cortisol was observed in 10 of 23 subjects, which normalized in all but three, 1 year thereafter. All patients but one showed a pubertal response to GnRH testing. No clinical or hormonal abnormalities were detectable in children <6 years. CONCLUSION: Our results recommend to prospectively follow children after TBI: firstly, because the impairment of pituitary function cannot be predicted, and secondly, to avoid the potential consequences of pituitary dysfunction. Prospective clinical trials are needed before recommending a systematic screening after TBI and/or GH therapy either in postpubertal children or in prepubertal children who grow normally.

Brain stem tumors in children and adolescents: single institutional experience.

PURPOSE: Pediatric brain stem tumors (BsT) are a heterogeneous group of diseases. Our aim was to analyze our experience to find out prognostic factors. METHOD: A retrospective study with BsT patients was performed. Imaging characteristics, extension of surgery, pathology, and adjuvant therapy were analyzed and correlated with overall survival (OS) and progression-free survival (PFS) as outcome measures. RESULT: Since 1980 to 2010, we analyzed 65 BsT patients, 41 of them girls (63%), median age of 8 years (range 13.9 months to 17.6 years). Twenty-two patients (33.8%) had diffuse intrinsic pontine gliomas (DIPG) and 43 (66.2%) presented with focal BsT. Histology was available in 42 patients; the most frequent is low-grade glioma in 24/42 patients (57%). DIPG's histology (obtained usually at necropsy) confirmed five high-grade gliomas. After median follow-up of 49.3 months (0.5-175 months), 20/22 DIPG patients have died (90.9%), while 27/43 with focal tumors were alive (62.8%). Variables related to outcome were histology (better for low-grade glioma (LGG) OS p < 0.001), surgery (better if operated OS p < 0.001), and adjuvant therapy (worse if given, PFS p = 0.001, OS p = 0.024). The outcome for DIPG was dismal, median OS/EFS of 14.2/9.4 months, significantly worse than focal BsT (p = 0.000), while OS/EFS was 122.8/87.2 months for focal intrinsic, 88.2/47.1 months for exophytic, and 124.4/54 months for cervico-medullary tumors: no differences were found among them, except the histology (OS p < 0.001 for low-grade vs high-grade tumors). CONCLUSION: BsT in children comprised two different groups: diffuse (DIPG) and focal gliomas. The DIPGs continue having a dismal prognosis, needing new approaches, while focal tumors including LGG have better prognosis.

Clinical Role of Subtraction Ictal SPECT Coregistered to MR Imaging and (18)F-FDG PET in Pediatric Epilepsy.

UNLABELLED: A precise assessment of the drug-resistant epileptic pediatric population for surgical candidacy is often challenging, and to date there are no evidence-based guidelines for presurgical identification of the epileptogenic zone. To evaluate the usefulness of radionuclide imaging techniques for presurgical evaluation of epileptic pediatric patients, we compared the results of video-electroencephalography (EEG), brain MR imaging, interictal SPECT, ictal SPECT, subtraction ictal SPECT coregistered to MR imaging (SISCOM), and interictal PET with (18)F-FDG. METHODS: Fifty-four children with drug-resistant epilepsy who had undergone video-EEG monitoring, brain MR imaging, interictal and ictal brain perfusion SPECT, SISCOM, and (18)F-FDG PET were included in this study. All abnormal findings revealed by these neuroimaging techniques were compared with the presumed location of the epileptogenic zone (PEZ) as determined by video-EEG and clinical data. The proportion of localizing studies for each technique was statistically compared. In the 18 patients who underwent resective brain surgery, neuroimaging results were compared with histopathology results and surgical outcome. RESULTS: SISCOM and (18)F-FDG PET concordance with the PEZ was significantly higher than MR imaging (P < 0.05). MR imaging showed localizing results in 21 of 54 cases (39%), SISCOM in 36 of 54 cases (67%), and (18)F-FDG PET in 31 of 54 cases (57%). If we consider SISCOM and (18)F-FDG PET results together, nuclear medicine imaging techniques showed coinciding video-EEG results in 76% of patients (41/54). In those cases in which MR imaging failed to identify any epileptogenic lesion (61% [33/54]), SISCOM or (18)F-FDG PET findings matched PEZ in 67% (22/33) of cases. CONCLUSION: SISCOM and (18)F-FDG PET provide complementary presurgical information that matched video-EEG results and clinical data in three fourths of our sample. SISCOM was particularly useful in those cases in which MR imaging findings were abnormal but no epileptogenic lesion was identified. Radionuclide imaging techniques are both useful and reliable, extending the possibility of surgical treatment to patients who may have been discouraged without a nuclear medicine approach.

Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy.

For most lysosomal storage diseases (LSDs) affecting the CNS, there is currently no cure. The BBB, which limits the bioavailability of drugs administered systemically, and the short half-life of lysosomal enzymes, hamper the development of effective therapies. Mucopolysaccharidosis type IIIA (MPS IIIA) is an autosomic recessive LSD caused by a deficiency in sulfamidase, a sulfatase involved in the stepwise degradation of glycosaminoglycan (GAG) heparan sulfate. Here, we demonstrate that intracerebrospinal fluid (intra-CSF) administration of serotype 9 adenoassociated viral vectors (AAV9s) encoding sulfamidase corrects both CNS and somatic pathology in MPS IIIA mice. Following vector administration, enzymatic activity increased throughout the brain and in serum, leading to whole body correction of GAG accumulation and lysosomal pathology, normalization of behavioral deficits, and prolonged survival. To test this strategy in a larger animal, we treated beagle dogs using intracisternal or intracerebroventricular delivery. Administration of sulfamidase-encoding AAV9 resulted in transgenic expression throughout the CNS and liver and increased sulfamidase activity in CSF. High-titer serum antibodies against AAV9 only partially blocked CSF-mediated gene transfer to the brains of dogs. Consistently, anti-AAV antibody titers were lower in CSF than in serum collected from healthy and MPS IIIA-affected children. These results support the clinical translation of this approach for the treatment of MPS IIIA and other LSDs with CNS involvement.

[Metastatic plexus papilloma in the paediatric age: a case report and review of the literature]. / Plexopapiloma metástasico en la edad pediátrica: caso clínico y revisión de la bibliografía.

INTRODUCTION: Tumours of the choroid plexus are uncommon, with a peak incidence in the early years of life. Clinically they usually produce intracranial hypertension. Histologically, they can be divided into papillomas and carcinomas. Metastasis rarely occurs in the case of papillomas. CASE REPORT: An 11-year-old female with an intracranial lesion in the 4th ventricle and a sacral intradural lesion. A sub-occipital craniotomy with total resection of the ventricular lesion was performed and this was followed later by partial exeresis of the spinal lesion. The histological study provides the diagnosis of typical choroid plexus papilloma in the intracranial lesion and choroid plexus papilloma metastasis in the spinal lesion. A review of the literature showed that choroid plexus papillomas with metastatic lesions are very rarely found at the paediatric age. There is no general agreement on the treatment of plexus papilloma metastasis at the paediatric age, expectant management being adopted in two cases and surgical treatment involving a laminectomy in the other. CONCLUSIONS: Choroid plexus papillomas are rare, benign lesions with a good prognosis. Metastasis seldom exists. Preferred treatment is total resection of the lesion. For the treatment of metastases, there is no evidence as to which is the best approach and different alternatives have been suggested.

[Five years' experience in a paediatric epilepsy unit]. / Experiencia de cinco años en una unidad de epilepsia pediátrica.

INTRODUCTION AND AIMS: The epilepsy monitoring unit is a space inside a hospital, which objective is to reproduce epileptic seizures in order to better study of an epileptic patient. We have analysed data from all the patients admitted to our pediatric epilepsy unit in the last 5 years. PATIENTS AND METHODS: 191 patients have been admitted in our unit, and we have obtained seizures in 186 admissions (monitoring efficacy, 85.9%). In this report we summarize characteristics of these children, type of seizures and treatment. RESULTS: The most frequent cause of epilepsy in our series is cortical development malformation. Patients are often late in their admission, with a median time of 3 to 4 years from epileptic onset to admission in the epilepsy unit. After the study, 22 patients underwent functional epilepsy surgery, all of them with excellent results, 9 patients underwent vagal nerve stimulator implantation and in 66 patients their previous pharmacological treatment was modified. CONCLUSIONS: The efficacy of our monitoring unit is similar to previously published, 85.9%. After the admission, we have changed diagnose in 57% of the patients and pharmacological treatment in 29%. We recommend the study in a monitoring epilepsy unit of every patient with refractory epilepsy, meaning an epilepsy that does not respond to 2-3 different appropriate treatments.