Gianluca Piatelli

Medulloblastoma Variants: Age-Dependent Occurrence and Relation to Gorlin Syndrome—A New Clinical Perspective

Purpose: We aimed to test the hypothesis that medulloblastoma (MB) variants show a different age distribution and clinical behavior reflecting their specific biology, and that MB occurring at very young age is associated with cancer predisposition syndromes such as Gorlin syndrome (GS). Experimental Design: We investigated the frequency, age distribution, location, response to treatment, outcome, and association with familial cancer predisposition syndromes in a series of 82 cases of MB in patients ages <14 years diagnosed at the Giannina Gaslini Childrens Hospital, Genoa, between 1987 and 2004. Results: Desmoplastic MB and MB with extensive nodularity (MBEN), were present in 22 of 82 cases (27%) and were more frequent in children ages ≤3 years (13 of 25; 52%). In this age group, MBEN was significantly more frequent than desmoplastic MB and classic MB (P < 0.001) and had a good prognosis. MBEN was associated with GS in 5 of 12 cases. Overall, 8 cases occurred in the context of familial tumor predisposition syndromes (5 GS, 1 each NF1, Li-Fraumeni, and Fragile X) and 7 of these patients were ages ≤3 years at diagnosis. Desmoplastic histology and a more intensive treatment represented independent favorable prognostic factors in multivariate analysis (P = 0.003 and P = 0.0139, respectively). Metastasis was a predictor of bad outcome (P = 0.0001). Conclusions: Our data indicate that biologically different MB entities warrant risk-adapted treatment and that MBEN is strongly associated with GS. Patients, ages ≤3 years, with MB and their families should be investigated for tumor predisposition syndromes such as GS.

FZD6 is a novel gene for human neural tube defects

Neural tube defects (NTDs) are severe malformations of the central nervous system, affecting 1 of 1,000 live births. Mouse models were instrumental in defining the signaling pathways defective in NTDs, including the planar cell polarity (PCP), also called noncanonical Frizzled/Disheveled pathway. Based on the highly penetrant occurrence of NTDs in double Fzd3/Fzd6−/− mutant mice, we investigated the role of the human orthologues, FZD3 and FZD6, by resequencing a cohort of 473 NTDs patients and 639 ethnically matched controls. While we could not demonstrate a significant contribution of FZD3 gene, we identified five rare FZD6 variants that were absent in all controls and predicted to have a functional effect by computational analysis: one de novo frameshift mutation (c.1843_1844insA), three missense changes (p.Arg405Gln, p.Arg511Cys p.Arg511His), and one substitution (c.*20C>T) affecting the 3′‐untranslated region (UTR) of the gene. The overall rate of predicted deleterious variants of FZD6 was 5.1‐fold higher in cases compared to controls, resulting in a significantly increased NTDs mutation burden. This study demonstrates that rare nonsynonymous variants in FZD6 may contribute to NTDs in humans and enlarges the spectrum of mutations that link PCP pathway to NTDs. Hum Mutat 33:384–390, 2012.

Maternal periconceptional factors affect the risk of spina bifida-affected pregnancies: an Italian case–control study

PurposeNeural tube defects, including spina bifida and anencephaly, are the second most common birth defects with an incidence in Italy of 0.4–1/1,000. Information on factors playing a role in the pathogenesis of spina bifida is based on populations with different exposures, lifestyle, social and cultural habits compared to Italian people. Our objective was to fill this gap by using data from a case–control interview study carried out at the G. Gaslini Children’s Hospital, Genoa, from 2000 to 2008.MethodsWe surveyed questionnaires from 133 case mothers and 273 control women providing information on periconceptional risk factors. Univariate and multivariate logistic regression analyses were used to estimate risks by odds ratios (ORs) and 95% confidence intervals (95% CIs).ResultsUnivariate results suggest that birth order, low maternal educational level, age, smoking habits, alcohol consumption, high caffeine intake, lack of folate supplementation, low and high calorie diet, occasional consumption of fruit and vegetables, high emotional stress, and environmental pollution are associated with an increased spina bifida risk. Nevertheless, high caffeine intake (OR = 10.82; 95% CI, 3.78–31), low calorie diet (OR = 5.15; 95%CI, 1.79–14), occasional consumption of fruit and vegetables (OR = 3.38; 95% CI, 1.67–6.82), alcohol consumption (OR = 3.05; 95% CI, 1.24–7.50) and, above all, lack of folate supplementation at any time of pregnancy (OR = 20.54; 95% CI, 5.41–77) mainly determined spina bifida risk in the multivariate analysis.ConclusionOur findings point out that a common underlying mechanism, a disturbed folate/homocysteine metabolism, may be causative for the burden of spina bifida in the Italian population.

Genetic Analysis of Disheveled 2 and Disheveled 3 in Human Neural Tube Defects

Neural tube defects are severe malformations affecting 1/1,000 live births. The planar cell polarity pathway controls the neural tube closure and has been implicated in the pathogenesis of neural tube defects both in animal models and human cohorts. In mouse disruption of Dvl2 alone (Dvl2−/−) or Dvl2 and Dvl3 (Dvl2−/−; Dvl3+/−, Dvl2+/−; Dvl3−/−) results in incomplete neurulation, suggesting a role for Disheveled in neural tube closure. Disheveled is a multifunctional protein that is involved in both the canonical Wnt signaling and the noncanonical planar cell polarity pathway. In this study, we analyzed the role of the human orthologs DVL2 and DVL3 in a cohort of 473 patients with neural tube defects. Rare variants were genotyped in 639 ethnically matched controls. We identified seven rare missense mutations that were absent in all controls analyzed. Two of these mutations, p.Tyr667Cys and p.Ala53Val, identified in DVL2 were predicted to be detrimental in silico. Significantly, a 1-bp insertion (c.1801_1802insG) in exon 15 of DVL2 predicted to lead to the truncation of the protein was identified in a patient with a complex form of caudal agenesis. In summary, we demonstrate a possible role for rare variants in DVL2 gene as risk factors for neural tube defects.

Planar cell polarity gene mutations contribute to the etiology of human neural tube defects in our population

Neural Tube Defects (NTDs) are congenital malformations that involve failure of the neural tube closure during the early phases of development at any level of the rostro-caudal axis. The planar cell polarity (PCP) pathway is a highly conserved, noncanonical Wnt-Frizzled-Dishevelled signaling cascade, that was first identified in the fruit fly Drosophila. We are here reviewing the role of the PCP pathway genes in the etiology of human NTDs, updating the list of the rare and deleterious mutations identified so far. We report 50 rare nonsynonymous mutations of PCP genes in 54 patients having a pathogenic effect on the protein function. Thirteen mutations that have previously been reported as novel are now reported in public databases, although at very low frequencies. The mutations were private, mostly missense, and transmitted by a healthy parent. To date, no clear genotype-phenotype correlation has been possible to create. Even if PCP pathway genes are involved in the pathogenesis of neural tube defects, future studies will be necessary to better dissect the genetic causes underlying these complex malformations.

Majewski osteodysplastic primordial dwarfism type II (MOPD II) syndrome previously diagnosed as Seckel syndrome: Report of a novel mutation of the PCNT gene

We report on a 3‐year‐old boy with prenatal onset of proportionate dwarfism, postnatal severe microcephaly, high forehead with receded hairline, sparse scalp hair, beaked nose, mild retrognathia and hypotonia diagnosed at birth as Seckel syndrome. At age 3 years, he became paralyzed due to a cerebrovascular malformation. Based on the clinical and radiological features showing evidence of skeletal dysplasia, the diagnosis was revised to Majewski osteodysplastic primordial dwarfism type II (MOPD II) syndrome. Western blot analysis of the patients lymphoblastoid cell line lysate showed the absence of the protein pericentrin. Subsequent molecular analysis identified a novel homozygous single base insertion (c.1527_1528insA) in exon 10 of the PCNT gene, which leads to a frameshift (Treo510fs) and to premature protein truncation. PCNT mutations must be considered diagnostic of MOPD II syndrome. A possible role of pericentrin in the development of cerebral vessels is suggested.

Risk factors for renal function impairment in a series of 502 patients born with spinal dysraphisms

OBJECTIVE To evaluate the risk of renal damage in a large series of patients affected by spinal dysraphism. METHODS Renal function was studied in 502 spinal dysraphisms treated over the last 25 years in a single center: 283 meningomyelocele (MMC), 90 caudal regression syndrome (CRS) and 129 spinal lipoma (SL) cases. In patients with normal and impaired renal function, we compared congenital renal anomalies, vesicoureteric reflux, bladder voiding pattern and upper tract dilatation, analyzing the results with the Fisher test. RESULTS Neuropathic bladder was observed in 97% of MMC, 60% of CRS, and 39% of SL cases. There was some degree of renal function impairment in 19 MMC (6.7%), 11 CRS (12%, increased to 20% if considering only neuropathic bladder patients), and two SL (1.5%) cases. Renal agenesis was more frequent in CRS (13%), but was not associated with decreased renal function. Overall, vesicoureteric reflux and upper tract dilatation were more frequent in patients with renal damage. Insufficient bladder voiding was statistically associated with renal damage only in the CRS population. Intermittent catheterization did not represent a protective factor against renal damage in patients able to void without significant residual urine. CONCLUSION This study has increased our understanding of the prognostic risk factors for renal deterioration. More prospective studies are necessary to confirm these results and correlate treatment with renal outcome.

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.

Expanding the mutational spectrum associated to neural tube defects: Literature revision and description of novel VANGL1 mutations

BACKGROUND Neural Tube Defects (NTD) are a common class of birth defects that occur in approximately 1 in 1000 live births. Both genetic and nongenetic factors are involved in the etiology of NTD. Planar cell polarity (PCP) genes plays a critical role in neural tube closure in model organisms. Studies in humans have identified nonsynonymous mutations in PCP pathway genes, including the VANGL genes, that may play a role as risk factors for NTD. METHODS Here, we present the results of VANGL1 and VANGL2 mutational screening in a series of 53 NTD patients and 27 couples with a previous NTD affected pregnancy. RESULTS We identified three heterozygous missense variants in VANGL1, p.Ala187Val, p.Asp389His, and p.Arg517His, that are absent in controls and predicted to be detrimental on the protein function and, thus, we expanded the mutational spectrum of VANGL1 in NTD cases. We did not identify any new variants having an evident pathogenic effect on protein function in VANGL2. Moreover, we reviewed all the rare nonsynonymous or synonymous variants of VANGL1 and VANGL2 found in patients and controls so far published and re-evaluated them for their pathogenic role by in silico prediction tools. Association tests were performed to demonstrate the enrichment of deleterious variants in reviewed cases versus controls from Exome Variant Server (EVS). CONCLUSION We showed a significant (p = 7.0E-5) association between VANGL1 rare genetic variants, especially missense mutations, and NTDs risk.

Cerebellar medullomyoblastoma with melanotic tubular structures

This report describes a midline cerebellar primitive neuroectodermal tumor with muscular differentiation, that is, medullomyoblastoma with melanotic tubular structures, which developed in the cerebellar vermis in a 23‐month‐old male. Rhabdomyoblastic differentiation consisted both of striated muscle fibers and undifferentiated cells showing immunoreactivity for desmin and myogenic transcription factors. The presence of melanotic epithelial structures raised the issue of a teratomatous tumor. This case demonstrates the occurrence of this very rare tumor in early childhood as well as the utility of a careful search for the presence of myogenic and/or melanotic features in medulloblastomas. Pediatr Blood Cancer 2008;50:183–185.