Neuropathology of holoprosencephaly.

Holoprosencephaly (HPE) is a primary disorder of neural induction and patterning of the rostral neural tube resulting in noncleavage of the forebrain with failure to form two separate distinct hemispheres. The spectrum of HPE is very broad and encompasses various neuropathological phenotypes of different severity. The recent literature has demonstrated that the phenotypic variability of HPE ranges from aprosencephaly-atelencephaly, at the most severe end, to milder forms such as the "middle interhemispheric variant" of HPE at the less severe end of the spectrum. Between them, different intermediate forms demonstrate a continuum in a wide phenotypic spectrum rather than well-defined categories. Although the term "HPE" suggests a disorder affecting only the prosencephalon, other brain structures are involved, underlining the complexity of the malformation. Because of close spatiotemporal interactions and common signaling pathways contributing to the development of both brain and face, concomitant facial and ocular anomalies are associated with brain malformation. In this review, the characteristic neuropathological features of the various forms of HPE are described as well as their associated brain, face, and ocular malformations, to delineate the different phenotypes.

Congenital Melanocytic Nevus Syndrome: A Case Series. / Síndrome del nevus melanocítico congénito. Serie de casos.

Congenital melanocytic nevus syndrome (CMNS) is the result of an abnormal proliferation of melanocytes in the skin and central nervous system caused by progenitor-cell mutations during embryonic development. Mutations in the NRAS gene have been detected in many of these cells. We present 5 cases of giant congenital melanocytic nevus, 3 of them associated with CMNS; NRAS gene mutation was studied in these 3 patients. Until a few years ago, surgery was the treatment of choice, but the results have proved unsatisfactory because aggressive interventions do not improve cosmetic appearance and only minimally reduce the risk of malignant change. In 2013, trametinib was approved for use in advanced melanoma associated with NRAS mutations. This drug, which acts on the intracellular RAS/RAF/MEK/pERK/MAPK cascade, could be useful in pediatric patients with CMNS. A better understanding of this disease will facilitate the development of new strategies.

Risk factors for Dandy-Walker malformation: a population-based assessment.

Dandy-Walker malformation (DWM) is the most common congenital malformation of the cerebellum, but its causes are largely unknown. An increasing number of genes associated with congenital cerebellar malformations have been identified; however, few studies have examined the potential role of non-genetic, potentially modifiable risk factors. From the National Birth Defects Prevention Study, we examined maternal, paternal, and infant characteristics and maternal conditions and periconceptional exposures (from 1 month before to 3 months after conception) among infants with DWM (n = 160) and unaffected controls (n = 10,200), delivered between 1997 and 2009. Odds ratios, crude (cOR) and adjusted (aOR) were computed using logistic regression. Maternal factors associated with DWM included non-Hispanic black race/ethnicity (aOR = 2.0, 95%CI: 1.3-3.2). Among maternal conditions, a history of infertility increased the risk for DWM (all: aOR = 2.4, 95%CI: 1.3-4.6; multiple: aOR = 3.9, 95%CI: 1.7-8.9). The lack of association with many maternal exposures supports the hypothesis of a major contribution of genetic factors to the risk for DWM; however, the observed associations with maternal non-Hispanic black race/ethnicity and maternal history of infertility indicate that further research into factors underlying these characteristics may uncover potentially modifiable risk factors, acting alone or as a component of gene-environment interactions.

Long-term operative failure of endoscopic third ventriculostomy in pediatric patients: the role of cine phase-contrast MR imaging.

OBJECT: Although a rarely reported occurrence, late failure of endoscopic third ventriculostomy (ETV) may occur in children as a result of a variety of factors. Delay in recognition of symptoms can lead to harmful deterioration in the patient's condition. The authors undertook this study to assess the capacity of cine phase-contrast MR imaging to identify late failure in asymptomatic pediatric patients treated with ETV for hydrocephalus. METHODS: This study was a retrospective evaluation of cases involving patients who underwent ETV between January 1, 1999, and December 31, 2008, at the pediatric neurological surgery service of the University of Padua. Before 2004, patients were routinely followed up with cine MR imaging at 3, 6, and 12 months after ETV. In 2004, a protocol of annual cine MR follow-up was instituted as a result of a case of fatal late failure. The authors evaluated all cases of late failure identified through cine MR imaging and performed a statistical analysis to investigate the relationship between ETV failure and several variables, including the cause of hydrocephalus for which ETV was originally indicated. RESULTS: In a series of 84 patients (age range 6 days-16 years), 17 patients had early ETV failure. Of the remaining 67 patients, 5 (7%) were found to have no CSF flow through the fenestration and recurrent ventriculomegaly when assessed with cine MR imaging at 1, 2, 3, 4, and 7 years after ETV. The patient in whom ETV failure was identified 1 year postoperatively had Dandy-Walker malformation. The patients in whom ETV failure was identified 2, 3, and 4 years postoperatively all had undergone ETV for treatment of postinfective hydrocephalus. The patient in whom ETV failure was identified 7 years postoperatively had a cystic arachnopathy in the fourth ventricle after cerebellar astrocytoma removal. CONCLUSIONS: Patients who undergo ETV for infective hydrocephalus and Dandy-Walker malformation should receive long-term follow-up, because late closure of the stoma may occur progressively and slowly. Intraoperative observation of thickened arachnoid membranes at the level of the interpeduncular cisterns at the first ETV and a progressive decreasing of CSF flow through the stoma on routine cine MR imaging should be considered unfavorable elements entailing a significant risk of deterioration.

Dandy-Walker syndrome and chromosomal abnormalities.

Dandy-Walker syndrome (DWS) is a brain malformation of unknown etiology, but several reports have been published indicating that there is a causal relationship to various types of chromosomal abnormalities and malformation syndromes. In the present article, we present a bibliographical survey of several previously issued reports on chromosomal abnormalities associated with DWS, including our case of DWS found in trisomy 18. There are various types of chromosomal abnormalities associated with DWS; most of them are reported in chromosome 3, 9, 13 and 18. We also summarize some other chromosomal abnormalities and various congenital malformation syndromes.

Familial Dandy-Walker malformation associated with macrocephaly, facial anomalies, developmental delay, and brain stem dysgenesis: prenatal diagnosis and postnatal outcome in brothers. A new syndrome?

Brothers are reported with an apparently new constellation of manifestations including Dandy-Walker complex (DWC), migrational brain disorder, macrocephaly, and facial anomalies. The first brother presented at birth, the second was detected prenatally with DWC and the pregnancy terminated. Fetal brain histopathology showed DWC associated with brainstem dysgenesis. Inheritance is likely autosomal or X-linked recessive. An extensive review of the differential diagnosis of DWC is provided.

Hereditary cerebellar vermis defect in the Lewis rat.

We report a new rat model of hereditary cerebellar vermis defect. Mutant rats exhibited hind-leg paralysis from about 14 days old. Gross pathology showed the cerebellar vermis defect, fused cerebellar hemispheres and cyst formation. Ectopic dysplastic cerebellar tissues existed in the cerebello-pontine junctional zones. Mild disarrangement of lamination was also observed in the fused cerebellar hemispheres. The present mutant may serve as a valid model for studying the cerebellar vermis defect under the genetic control.

Molybdenum cofactor deficiency associated with Dandy-Walker complex.

Molybdenum cofactor deficiency is a rare and devastating disease leading to intractable seizures in the neonatal period. Severe loss of neocortical neurons, gliosis, and cystic necrosis of cerebral white matter resulting in significant cerebral volume loss are the neuropathological findings. The mechanism of cerebral injury is unknown, but sulphite excess, and sulphate or uric acid deficiencies are possible factors. We present here a new case of Molybdenum cofactor deficiency associated with Dandy-Walker complex with a history of three dead siblings, the latter also having Dandy-Walker malformation. We speculate that severe cerebral volume loss due to the above mentioned mechanisms may lead to an appearance resembling Dandy-Walker malformation.

Hypothalamic hamartoma, gelastic epilepsy, precocious puberty--a diffuse cerebral dysgenesis.

Childhood epileptic syndrome characterized by early onset gelastic seizures, hypothalamic hamartoma and precocious puberty is well recognized though rare. We report association of agenesis of corpus callosum, Dandy-Walker complex and heterotopic gray matter with this childhood epileptic syndrome which is hitherto an unreported association. The child showed a satisfactory response to gonadotropin releasing hormone agonist.

[Joubert syndrome. Clinical and anatomo-pathologic study. Etiopathogenetic hypotheses]. / Le syndrome de Joubert. Etude clinique et anatomo-pathologique. Hypothèses étiopathogéniques.

Joubert's syndrome is characterized by an agenesis of the vermis and an unique respiratory abnormality consisting of bouts of extreme tachypnea and prolonged apneas. Three patients with this syndrome are reported with a polygraphic study and a recording of intracranial pressure in one of them and a pathological study in another. It is suggested that the agenesis of the vermis is caused by a prenatal hydrocephalus as is probably the case in the Dandy-Walker syndrome. A comparison is established between these two syndromes. The periods of tachypnea-apnea could represent the persistence of a fetal pattern of respiration with an excessive response to various stimuli, and might be explained by the delayed maturation of inhibitory mechanisms necessary for the establishment of the normal pattern of respiration and sleep. The possible role of a total vermian agenesis in the pathogenesis of respiratory abnormality is discussed.

Dandy-Walker syndrome and monochorionic twins: insight into a possible etiological mechanism.

OBJECTIVE: Dandy-Walker syndrome (DWS) is a developmental malformation of the central nervous system characterized by complete or partial absence of the cerebellar vermis, the presence of a posterior fossa cyst, and ventriculomegaly. Although DWS can be seen with Mendelian and chromosomal disorders, the actual pathophysiologic mechanism responsible for the syndrome is unknown. The incidence of DWS is approximately 1-8/100,000 births. We have noted a higher than expected incidence of DWS in a population of twins referred as complicated monochorionic twins, to include twin-twin transfusion syndrome (TTTS). The purpose of this study was to assess the incidence of DWS in monochorionic twins. METHODS: The database of all patients referred with complicated monochorionic twins was queried for the diagnosis of DWS. TTTS was defined sonographically as the combined presence of a maximum vertical pocket (MVP) of >or=8 cm in the recipient and

Agenesis of the vermis cerebelli and malformations of the posterior fossa in childhood and adolescence.

Three cases of cerebellar vermis agenesis are reported and the relevant literature (19 other cases) is reviewed. Other posterior fossa malformations, such as a mega-cisterna magna, arachnoid cyst and Dandy-Walker syndrome, are discussed both from the pathological and clinical view point. We put forward a hypothesis that agenesis of the cerebellar vermis and Dandy-Walker syndrome could be regarded as two different stages of the same malformation.