Marco Pavanello

High levels of PROM1 (CD133) transcript are a potential predictor of poor prognosis in medulloblastoma

The surface marker PROM1 is considered one of the most important markers of tumor-initiating cells, and its expression is believed to be an adverse prognostic factor in gliomas and in other malignancies. To date, to our knowledge, no specific studies of its expression in medulloblastoma series have been performed. The aims of our study were to evaluate the expression profile of the PROM1 gene in medulloblastoma and to assess its possible role as a prognostic factor. The PROM1 gene expression was evaluated by quantitative- polymerase chain reaction on 45 medulloblastoma samples by using specific dye-labeled probe systems. A significantly higher expression of PROM1 was found both in patients with poorer prognosis (P= .007) and in those with metastasis (P= .03). Kaplan-Meier analysis showed that both overall survival (OS) and progression-free survival (PFS) were shorter in patients with higher PROM1 mRNA levels than in patients with lower expression, even when the desmoplastic cases were excluded (P= .0004 and P= .002, for OS and PFS for all cases, respectively; P= .002 and P= .008 for OS and PFS for nondesmoplastic cases, respectively). Cox regression model demonstrated that PROM1 expression is an independent prognostic factor (hazard ratio, 4.56; P= .008). The result was validated on an independent cohort of 42 cases by microarray-based analysis (P= .019). This work suggests that high mRNA levels of PROM1 are associated with poor outcome in pediatric medulloblastoma. Furthermore, high PROM1 expression levels seem to increase the likelihood of metastases. Such results need to be confirmed in larger prospective series to possibly incorporate PROM1 gene expression into risk classification systems to be used in the clinical setting.

Sinus pericranii: diagnosis and management in 21 pediatric patients.

OBJECT Sinus pericranii (SP) is a rare venous anomaly abnormally connecting the intracranial dural sinuses with the epicranial veins. In the present study the authors aimed to clarify this clinicoradiological entity, define the role of angiography in its preoperative assessment, and suggest a diagnostic-therapeutic flow chart for management purposes. METHODS The authors retrospectively reviewed the clinical charts and neuroimages of 21 patients with SP. All patients underwent brain MRI, MR venography, and craniocerebral CT. Diagnostic digital subtraction angiography was performed in 19 of 21 patients, and the SPs were categorized as dominant (draining the majority of the intracranial venous outflow) or accessory (draining only a minority of the intracranial venous outflow). RESULTS SP was median or paramedian in 20 patients and lateral in 1 patient. There were 5 dominant and 14 accessory SPs. The dominant SPs were not treated. Among the patients with accessory SP, 4 were not treated, 2 underwent surgical ligature, and 8 were treated endovascularly (with either transvenous or percutaneous embolization). No complications were observed, and symptoms disappeared after treatment in all cases. CONCLUSIONS Accepted guidelines or recommendations concerning the management, diagnosis, and treatment of SP are still lacking. The authors define here a diagnostic-therapeutic flow chart, in which angiography plays a crucial role in the classification of SP and choice of the optimal treatment. Only accessory SP is amenable to treatment, whereas dominant SP must be preserved. The endovascular approach is becoming increasingly relevant and has proven to be safe and effective.

Solitary infantile myofibromatosis of the cranial vault: case report.

Infantile myofibromatosis is a mesenchymal disorder of early childhood characterized by the formation of tumors in the skin, muscle, viscera, bone, and subcutaneous tissue. Although relatively rare overall, it represents the most common fibrous tumor of infancy. The etiology of this disorder is unknown. Infantile myofibromatosis can present as a solitary or multicentric form. With the multicentric form, bone is often involved, but solitary bone lesions account for only 10% of the cases. Imaging findings are not pathognomonic, and the differential diagnosis usually includes eosinophilic granuloma (Langerhans cell histiocytosis), osteomyelitis, metastasis, osteoblastoma, epidermoid cyst, hemangioma, fibrous dysplasia, fibrosarcoma, and meningioma. A histological pattern is typical, but there are no histopathological differences between the solitary and multicentric forms. Solitary lesions generally have a favorable prognosis if totally removed, with a 10% recurrence rate; incompletely resected lesions recur. We report the case of a 9-year-old boy who came to our attention with a solitary infantile myofibroma of the calvarium, appearing as a tight–elastic, lightly tender mass in the left frontal area, eroding both the inner and the outer tables. Histopathologically, the specimens showed a spindle-cell tumor with dense reticulin fiber network and expression of smooth muscle actin. Fifty-eight months MR follow-up after total removal showed no residual or relapse.

Noninvasive ventilation in a child affected by achondroplasia respiratory difficulty syndrome

Achondroplasia can result in respiratory difficulty in early infancy, from anatomical abnormalities such as mid‐facial hypoplasia and/or adenotonsillar hypertrophy, leading to obstructive apnea, or to pathophysiological changes occurring in nasopharyngeal or glossal muscle tone, related to neurological abnormalities (foramen magnum and/or hypoglossal canal problems, hydrocephalus), leading to central apnea. More often, the two respiratory components (central and obstructive) are both evident in mixed apnea. Polysomnographic recording should be used during preoperative and postoperative assessment of achondroplastic children and in the subsequent follow‐up to assess the adequacy of continuing home respiratory support, including supplemental oxygen, bilevel positive airway pressure, or assisted ventilation.

Interstitial 9p24.3 deletion involving only DOCK8 and KANK1 genes in two patients with non-overlapping phenotypic traits.

Chromosome 9p deletion represents a clinically and genetically heterogeneous condition characterized by a wide spectrum of phenotypic manifestations and a variable size of the deleted region. The deletion breakpoint occurs from 9p22 to 9p24 bands, and the large majority of cases have either terminal deletions or translocations involving another chromosome. Here we report on two patients with similar inherited interstitial 9p24.3 deletion involving only DOCK8 and KANK1 genes. Interestingly, the two patients showed non-overlapping phenotypic traits ranging from a complex phenotype in one to only trigonocephaly with minor dysmorphic features and hand anomalies in the other one. The factors underlying the phenotypic variation associated with seemingly identical genomic alterations are not entirely clear, even if smaller variants, single-nucleotide changes, and epigenetic or stochastic factors altering the expression of genes within functionally relevant pathways have been recently shown to contribute to phenotypic variation. We discuss the role of the two genes and propose possible explanations for the clinical heterogeneity of the phenotype of the two patients.

Pituitary deficiency and congenital infiltrating lipomatosis of the face in a girl with deletion of chromosome 1q24.3q31.1

Interstitial deletions of the long arm of chromosome 1 are rare and they are classified as proximal or intermediate. The intermediate interstitial deletions span 1q24–1q32. We describe a 6‐year‐old girl with multiple pituitary hormone deficiency, severe cognitive impairment, bilateral cleft lip and palate, midline facial capillary malformation, erythema of hands and feet and dysplastic cranial vessels, low anti‐thrombin III activity, hemifacial overgrowth due to progressive infiltrating lipomatosis with bone overgrowth, marked vascular proliferation and erythema of hands and feet, and abnormal cranial vessels. The girls karyotype showed an apparently de novo interstitial deletion 1q24.3q31.1, which was defined by array‐CGH. The deleted region contains numerous genes, but only eight (CENPL, LHX4, LAMC1, LAMC2, PTGS2, ANGPTL1, TNN, and TNR) are good candidates to explain, at least partially, the phenotype of the proposita. We, therefore, discuss the involvement of these genes and the observed phenotype.

Craniosynostosis, hydrocephalus, Chiari I malformation and radioulnar synostosis: probably a new syndrome.

We report on clinical and molecular findings of two brothers that both presented with sagittal craniosynostosis, hydrocephalus, Chiari I malformation, blepharophimosis, small low-set ears, hypoplastic philtrum, radioulnar synostosis, kidney malformation, and hypogenitalism. Their father presented mild brachydactyly. Conventional cytogenetic and array CGH screening did not show any chromosomal gains or losses. Furthermore, molecular genetic screening of genes involved in different craniosynostosis syndromes, namely FGFR1, FGFR2, FGFR3, TWIST, RECQL4, and POR genes failed to detect any mutations in genomic DNA. The unique range of clinical manifestations in these two patients and the negative findings of the molecular genetic screening suggest the hypothesis of a previously unrecognized syndrome.

Cystic angiomatosis of the craniocervical junction associated with Chiari I malformation

IntroductionCystic angiomatosis of the skull and spine is an exceptionally rare, benign vascular lesion. Both the vertebral bones and the skull may be affected. Diagnosis and treatment of this disease is multidisciplinary.DiscussionHistological examination is ultimately required to make a diagnosis. When the craniocervical junction is involved, the site of biopsy should be carefully selected so as to reduce procedure-related morbidity, including cerebrospinal fluid leakage and spinal deformity. We present a case report of a 4-year-old boy with cystic angiomatosis of the skull base and upper cervical spine associated with a Chiari I malformation and provide a review of the pertinent literature.

Moyamoya syndrome in children with neurofibromatosis type 1: Italian-French experience

Moyamoya syndrome (MMS) is the most common cerebral vasculopathy among children with neurofibromatosis type 1 (NF1). In this study, we clinically, radiologically, and genetically examined a cohort that was not previously described, comprising European children with NF1 and MMS. The NF1 genotyping had been registered. This study included 18 children. The mean age was 2.93 ± 3.03 years at the NF1 diagnosis and 7.43 ± 4.27 years at the MMS diagnosis. In seven patients, MMS was diagnosed before or at the same time as NF1. Neuroimaging was performed in 10 patients due to clinical symptoms, including headache (n = 6), cerebral infarction (n = 2), and complex partial seizures (n = 2). The remaining eight children (47%) had MMS diagnosed incidentally. Sixteen children were characterized molecularly. The features of MMS were similar between patients with and without NF1. Additionally, the NF1 phenotype and genotype were similar between children with and without MMS. Interestingly, three children experienced tumors with malignant histology or behavior. The presence of two first cousins in our cohort suggested that there may be potential genetic factors, not linked to NF1, with an additional role respect of NF1 might play a role in MMS pathogenesis. The incidental diagnosis of MMS, and the observation that, among children with NF1, those with MMS were clinically indistinguishable from those without MMS, suggested that it might be worthwhile to add an angiographic sequence to brain MRIs requested for children with NF1. A MMS diagnosis may assist in properly addressing an NF1 diagnosis in very young children who do not fulfill diagnostic criteria.

De Novo MGC4607 Gene Heterozygous Missense Variants in a Child with Multiple Cerebral Cavernous Malformations

Cavernous malformations are angiographically occult, low-pressure neurovascular lesions with distinct imaging and clinical characteristics; main clinical manifestations are seizure, focal neurological deficits and epileptic attacks. Here we describe the molecular characterization of an Italian child, a symptomatic patient, affected by multiple cerebral cavernous malformations, without a family history of the disease and harbouring a new MGC4607 gene mutation. We identified two de novo missense variants in exon 6 of the gene both present on the same allele (cis configuration). DNA analysis for KRIT1, and PDCD10 gene variation through direct sequencing and MLPA analysis excluded further mutations. STR multiplex assay, allele-specific analysis and DHPLC analysis were performed for a better genetic characterization. Our findings emphasize the importance of the genetic test in subjects presenting multiple cerebral cavernomas for an adequate counselling, as well as for disease management since early identification of genetic abnormalities enable patients to have their lesions removed before they haemorrhage and cause deficit and/or epilepsy.