Mortality in pediatric hydrocephalus.

AIM: To clarify the extent to which medical comorbidities and goals-of-care decisions influence death among individuals with childhood-onset hydrocephalus. METHOD: This was a retrospective cohort study of 1705 individuals (759 males, 946 females, mean age 11y 5mo, SD 6y 6mo, range 0-37y 7mo at last follow-up) with childhood-onset hydrocephalus, of whom 88 (5.2%) were deceased. Existing medical records, death records, and publicly available internet sources were analyzed. We estimated hazard ratios for putative risk factors through Cox regression based upon 10 529 person-years of data and quantitatively and qualitatively analyzed the circumstances surrounding each death. RESULTS: Mortality did not differ statistically by demographic factors, although higher proportions of non-White and Hispanic individuals were deceased. Most deaths were related to medical comorbidities rather than hydrocephalus itself. Of the 14 deaths directly related to hydrocephalus, seven were caused by shunt complications and four occurred after decisions to forgo treatment, apparently in response to poor outcomes predicted by the medical team. Half the deaths were preceded by shifts to comfort-based care; however, these decisions appeared to substantially change the patient's clinical trajectory only half the time. INTERPRETATION: Children are more likely to die with, rather than from, hydrocephalus. Our results emphasize the complexities of medical decision-making and the influence of clinicians in guiding these choices.

Expanding phenotype with severe midline brain anomalies and missense variant supports a causal role for FOXA2 in 20p11.2 deletion syndrome.

Rare individuals with 20p11.2 proximal deletions have been previously reported, with a variable phenotype that includes heterotaxy, biliary atresia, midline brain defects associated with panhypopituitarism, intellectual disability, scoliosis, and seizures. Deletions have ranged in size from 277 kb to 11.96 Mb. We describe a newborn with a de novo 2.7 Mb deletion of 20p11.22p11.21 that partially overlaps previously reported deletions and encompasses FOXA2. Her clinical findings further expand the 20p11.2 deletion phenotype to include severe midline cranial and intracranial defects such as aqueductal stenosis with hydrocephalus, mesencephalosynapsis with diencephalic-mesencephalic junction dysplasia, and pyriform aperture stenosis. We also report one individual with a missense variant in FOXA2 who had abnormal glucose homeostasis, panhypopituitarism, and endodermal organ dysfunction. Together, these findings support the critical role of FOXA2 in panhypopituitarism and midline defects.

A genotype-specific surgical approach for patients with Pfeiffer syndrome due to W290C pathogenic variant in FGFR2 is associated with improved developmental outcomes and reduced mortality.

PURPOSE: Among children with FGFR2-associated Pfeiffer syndrome, those with the W290C pathogenic variant (PV) are reported to have the worst clinical outcomes. Mortality is high, and severe neurocognitive impairment has been reported in all surviving patients. However, it is unclear whether these poor outcomes are an unavoidable consequence of the PV itself, or could be improved with a genotype-specific treatment approach. The purpose of this report is to describe the more intensive surgical approach used for each of the three patients with W290C PV in FGFR2 at our center, all of whom survived and have normal neurocognitive functioning. METHODS: Retrospective chart review. RESULTS: In contrast to other patients with Pfeiffer syndrome at our center, all three patients who were subsequently found to have a W290C PV required a similar and more aggressive approach based on early cephalocranial disproportion. In contrast to previously reported W290C cases, each of our three patients survived and demonstrate normal neurocognitive functioning. CONCLUSION: While previously reported outcomes in W290C-associated Pfeiffer syndrome have been extremely poor, we present three patients who underwent an intensive surgical approach and have normal development. This suggests that a personalized and aggressive surgical approach for children with W290C PV may dramatically improve clinical outcome.

Rhombencephalosynapsis: Fused cerebellum, confused geneticists.

Rhombencephalosynapsis (RES) is a unique cerebellar malformation characterized by fusion of the cerebellar hemispheres with partial or complete absence of a recognizable cerebellar vermis. Subsets of patients also have other brain malformations such as midbrain fusion with aqueductal stenosis, characteristic craniofacial features (prominent forehead, flat midface, hypertelorism, ear abnormalities), and somatic malformations (heart, kidney, spine, and limb defects). Similar to known genetic brain malformations, the RES cerebellar malformation is highly stereotyped, yet no genetic causes have been identified. Here, we outline our current understanding of the genetic basis for RES, discuss limitations, and outline future approaches to identifying the causes of this fascinating brain malformation.

Interpreting the clinical significance of combined variants in multiple recessive disease genes: systematic investigation of Joubert syndrome yields little support for oligogenicity.

PurposeNext-generation sequencing (NGS) often identifies multiple rare predicted-deleterious variants (RDVs) in different genes associated with a recessive disorder in a given patient. Such variants have been proposed to contribute to digenicity/oligogenicity or "triallelism" or to act as genetic modifiers.MethodsUsing the recessive ciliopathy Joubert syndrome (JBTS) as a model, we investigated these possibilities systematically, relying on NGS of known JBTS genes in a large JBTS and two control cohorts.Results65% of affected individuals had a recessive genetic cause, while 4.9% were candidates for di-/oligogenicity, harboring heterozygous RDVs in two or more genes, compared with 4.2-8% in controls (P = 0.66-0.21). Based on Exome Aggregation Consortium (ExAC) allele frequencies, the probability of cumulating RDVs in any two JBTS genes is 9.3%. We found no support for triallelism, as no unaffected siblings carried the same biallelic RDVs as their affected relative. Sixty percent of individuals sharing identical causal RDVs displayed phenotypic discordance. Although 38% of affected individuals harbored RDVs in addition to the causal mutations, their presence did not correlate with phenotypic severity.ConclusionOur data offer little support for triallelism or digenicity/oligogenicity as clinically relevant inheritance modes in JBTS. While phenotypic discordance supports the existence of genetic modifiers, identifying clinically relevant modifiers remains challenging.

Mortality in Joubert syndrome.

Joubert syndrome (JS) is a rare, recessively inherited neurodevelopmental disorder characterized by a distinctive mid-hindbrain malformation. Little is known about mortality in affected individuals. Identifying the timing and causes of death will allow for development of healthcare guidelines for families and providers and, thus, help to prolong and improve the lives of patients with JS. We evaluated information on 40 deceased individuals with JS to characterize age and cause of death. We compared this population with 525 living individuals with JS to estimate associations between risk of death and extra-neurological features. Genetic causes were examined in both groups. Mean age of death in this cohort was 7.2 years, and the most prevalent causes of death were respiratory failure (35%), particularly in individuals younger than 6 years, and kidney failure (37.5%), which was more common in older individuals. We identified possible associations between risk of death and kidney disease, liver fibrosis, polydactyly, occipital encephalocele, and genetic cause. This work highlights factors (genetic cause, extra-neurological organ involvement, and other malformations) likely to be associated with higher risk of mortality in JS, which should prompt increased monitoring for respiratory issues, kidney disease, and liver fibrosis.

Anatomical configurations associated with posthemorrhagic hydrocephalus among premature infants with intraventricular hemorrhage.

OBJECTIVE Intraventricular hemorrhage (IVH) is a complication of prematurity often associated with ventricular dilation, which may resolve over time or progress to posthemorrhagic hydrocephalus (PHH). This study investigated anatomical factors that could predispose infants with IVH to PHH. METHODS The authors analyzed a cohort of premature infants diagnosed with Grade III or IV IVH between 2004 and 2014. Using existing ultrasound and MR images, the CSF obstruction pattern, skull shape, and brain/skull ratios were determined, comparing children with PHH to those with resolved ventricular dilation (RVD), and comparing both groups to a set of healthy controls. RESULTS Among 110 premature infants with Grade III or IV IVH, 65 (59%) developed PHH. Infants with PHH had more severe ventricular dilation compared with those with RVD, although ranges overlapped. Intraventricular CSF obstruction was observed in 36 (86%) of 42 infants with PHH and 0 (0%) of 18 with RVD (p < 0.001). The distribution of skull shapes in infants with PHH was similar to those with RVD, although markedly different from controls. No significant differences in supratentorial brain/skull ratio were observed; however, the mean infratentorial brain/skull ratio of infants with PHH was 5% greater (more crowded) than controls (p = 0.006), whereas the mean infratentorial brain/skull ratio of infants with RVD was 8% smaller (less crowded) than controls (p = 0.004). CONCLUSIONS Among premature infants with IVH, intraventricular obstruction and infratentorial crowding are strongly associated with PHH, further underscoring the need for brain MRI in surgical planning. Prospective studies are required to determine which factors are cause and which are consequence, and which can be used to predict the need for surgical intervention.

Clinical and Surgical Factors Associated With Increased Epilepsy Risk in Children With Hydrocephalus.

BACKGROUND: Children with hydrocephalus are at risk for epilepsy both due to their underlying condition and as a consequence of surgical treatment; however, the relative contributions of these factors remain unknown. OBJECTIVE: The authors sought to characterize epilepsy among children with infancy-onset hydrocephalus and to examine the risks of epilepsy associated with hydrocephalus subtype and with factors related to surgical treatment. METHODS: We conducted a longitudinal cohort study of all children with infancy-onset hydrocephalus treated at a major regional children's hospital during 2002 to 2012, with follow-up to ascertain risk factors and epilepsy outcome through April 2015. Poisson regression was used to calculate adjusted risk ratios and 95% confidence intervals for associations. RESULTS: Among 379 children with hydrocephalus, 86 (23%) developed epilepsy (mean onset age = 2.7 years), almost one fifth of whom had a history of infantile spasms. Relative to spina bifida-associated hydrocephalus, children with other major hydrocephalus subtypes had fourfold higher risks of developing epilepsy. Among children who underwent surgery, surgical infection doubled the risk of epilepsy (risk ratio = 2.0, 95% confidence interval = 1.4 to 3.0). Epilepsy was associated with surgical failure for intracranial reasons but not extracranial reasons (risk ratio = 1.7, 95% confidence interval = 1.1 to 2.7; risk ratio = 1.1, 95% confidence interval = 0.7 to 1.9, respectively). CONCLUSIONS: Epilepsy is common among children with hydrocephalus. Compared with children with spina bifida-associated hydrocephalus, children with other major hydrocephalus subtypes have a markedly increased risk of epilepsy. Surgical infection doubles the risk of epilepsy.

Prenatal presentation of pyruvate dehydrogenase complex deficiency.

We present the case of a female infant referred for prenatal MR evaluation of ventriculomegaly, which had been attributed by the referring obstetrician to aqueductal stenosis. Fetal MR confirmed ventriculomegaly but also demonstrated cerebral volume loss and white matter abnormalities. After birth, the infant developed persistent lactic acidosis. A diagnosis of pyruvate dehydrogenase complex deficiency was made on the basis of metabolic and molecular genetic studies. Ventriculomegaly is a common referral reason for fetal MR, yet there are few published reports of the radiographic findings that accompany inborn errors of metabolism, one potentially under-recognized cause of enlarged ventricles. This case contributes to this small body of literature on the imaging features of pyruvate dehydrogenase complex deficiency by describing pre- and postnatal MR findings and key clinical details. Our report emphasizes the necessity of considering pyruvate dehydrogenase complex deficiency and other metabolic disorders as potential etiologies for fetal ventriculomegaly since prompt diagnosis may allow for early initiation of treatment and improve outcome.

Two Hundred Thirty-Six Children With Developmental Hydrocephalus: Causes and Clinical Consequences.

Few systematic assessments of developmental forms of hydrocephalus exist. We reviewed magnetic resonance images (MRIs) and clinical records of patients with infancy-onset hydrocephalus. Among 411 infants, 236 had hydrocephalus with no recognizable extrinsic cause. These children were assigned to 1 of 5 subtypes and compared on the basis of clinical characteristics and developmental and surgical outcomes. At an average age of 5.3 years, 72% of children were walking independently and 87% could eat by mouth; in addition, 18% had epilepsy. Distinct patterns of associated malformations and syndromes were observed within each subtype. On average, children with aqueductal obstruction, cysts, and encephaloceles had worse clinical outcomes than those with other forms of developmental hydrocephalus. Overall, 53% of surgically treated patients experienced at least 1 shunt failure, but hydrocephalus associated with posterior fossa crowding required fewer shunt revisions. We conclude that each subtype of developmental hydrocephalus is associated with distinct clinical characteristics, syndromology, and outcomes, suggesting differences in underlying mechanisms.

Maternal and infant factors associated with infancy-onset hydrocephalus in Washington State.

OBJECTIVE: Hydrocephalus, a complex condition characterized by progressive accumulation of cerebrospinal fluid within the ventricular system of the brain, affects ∼ 6 in 10,000 infants and is heterogeneous in nature. Previous investigations of risk factors have not considered etiologic heterogeneity. METHODS: We conducted a case-control study of 1748 children with hydrocephalus identified through birth certificate check boxes and ICD-9 codes of linked hospital discharge records through the first year of life. Control infants were identified from birth records (N = 19,700), frequency matched to cases by year of birth. Three mutually exclusive, nonexhaustive subgroups were identified: hydrocephalus associated with a neural tube defect (n = 332); prenatal-onset hydrocephalus (n = 402); and hydrocephalus associated with intracranial hemorrhage (n = 446). Within each group, we examined associations with maternal age, race/ethnicity, parity, diabetes and hypertension, and infant sex and gestation. We used logistic regression to calculate odds ratios and 95% confidence intervals. RESULTS: Asian ethnicity was independently associated with an inverse risk of all subtypes of hydrocephalus (hydrocephalus associated with a neural tube defect: odds ratio, 0.44; 95% confidence interval, 0.23 to 0.84; prenatal-onset hydrocephalus: odds ratio, 0.47; 95% confidence interval, 0.27 to 0.83; hydrocephalus associated with intracranial hemorrhage: odds ratio, 0.59; 95% confidence interval, 0.33 to 1.07) compared with whites. Pre-existing diabetes was associated to varying degrees with all three subtypes (hydrocephalus associated with a neural tube defect: odds ratio, 1.94; 95% confidence interval, 0.61 to 6.17; prenatal-onset hydrocephalus: odds ratio, 5.20; 95% confidence interval, 2.60 to 10.40; hydrocephalus associated with intracranial hemorrhage: odds ratio, 5.26; 95% confidence intervals, 2.85 to 9.69). Hypertension had a positive association with hydrocephalus associated with intracranial hemorrhage (odds ratio, 1.91; 95% confidence interval, 1.46 to 2.52) but an inverse association with hydrocephalus associated with a neural tube defect (odds ratio, 0.59; 95% confidence interval, 0.36 to 0.98). Gestation ≤ 30 weeks was associated with all three subgroups, most notably hydrocephalus associated with intracranial hemorrhage (odds ratio, 443.56; 95% confidence intervals, 326.34 to 602.87); nearly two-thirds (64%) of hydrocephalus associated with intracranial hemorrhage infants were born ≤ 30 weeks. Male gender was independently associated only with hydrocephalus associated with intracranial hemorrhage (odds ratio, 1.82; 95% confidence interval, 1.40 to 2.39). No associations were observed with advanced or young maternal age or with parity. CONCLUSIONS: The different risk profiles seen among these three subgroups support the biologically heterogeneous nature of infantile hydrocephalus. Future research should take specific etiologic subtypes into account.

Infantile hydrocephalus: a review of epidemiology, classification and causes.

Hydrocephalus is a common but complex condition caused by physical or functional obstruction of CSF flow that leads to progressive ventricular dilatation. Though hydrocephalus was recently estimated to affect 1.1 in 1000 infants, there have been few systematic assessments of the causes of hydrocephalus in this age group, which makes it a challenging condition to approach as a scientist or as a clinician. Here, we review contemporary literature on the epidemiology, classification and pathogenesis of infantile hydrocephalus. We describe the major environmental and genetic causes of hydrocephalus, with the goal of providing a framework to assess infants with hydrocephalus and guide future research.

Persistent figure-eight and side-to-side head shaking is a marker for rhombencephalosynapsis.

BACKGROUND: Head-shaking stereotypies have been described in patients with neurological impairment. We noted an unusual preponderance of head shaking in patients with rhombencephalosynapsis (RES). We sought to delineate the movements further and determine whether oculomotor and vestibular testing could reveal their cause. METHODS: Information was collected from direct observation, video review and parental questionnaire from 59 patients with RES. Oculomotor and vestibular testing was performed in 4 children. RESULTS: Of 59 patients, 50 had persistent head shaking that was often observed years before RES was recognized. Three affected children demonstrated abnormal central vestibular processing. CONCLUSIONS: Head-shaking is common in RES. These characteristic movements may provide input to a defective vestibular system or may represent a motor pattern that is usually suppressed by vestibular feedback. Persistent head shaking should alert clinicians to the possible presence of a congenital hindbrain abnormality that affects the vestibulocerebellum, particularly RES.

Seizures in juvenile Huntington's disease: frequency and characterization in a multicenter cohort.

Little is known about the epilepsy that often occurs in the juvenile form of Huntington's disease (HD), but is absent from the adult-onset form. The primary aim of this study was to characterize the seizures in juvenile HD (JHD) subjects with regard to frequency, semiology, defining EEG characteristics, and response to antiepileptic agents. A multicenter, retrospective cohort was identified by database query and/or chart review. Data on age of HD onset, primary HD manifestations, number of CAG repeats, the presence or absence of seizures, seizure type(s), antiepileptic drugs used, subjects' response to antiepileptic drugs (AEDs), and EEG results were assembled, where available. Ninety subjects with genetically confirmed JHD were included. Seizures were present in 38% of subjects and were more likely to occur with younger ages of HD onset. Generalized tonic-clonic seizures were the most common seizure type, followed by tonic, myoclonic, and staring spells. Multiple seizure types commonly occurred within the same individual. Data on EEG findings and AED usage are presented. Seizure risk in JHD increases with younger age of HD onset. Our ability to draw firm conclusions about defining EEG characteristics and response to AEDs was limited by the retrospective nature of the study. Future prospective studies are required.

Beyond Gómez-López-Hernández syndrome: recurring phenotypic themes in rhombencephalosynapsis.

Rhombencephalosynapsis (RES) is an uncommon cerebellar malformation characterized by fusion of the hemispheres without an intervening vermis. Frequently described in association with Gómez-López-Hernández syndrome, RES also occurs in conjunction with VACTERL features and with holoprosencephaly (HPE). We sought to determine the full phenotypic spectrum of RES in a large cohort of patients. Information was obtained through database review, patient questionnaire, radiographic, and morphologic assessment, and statistical analysis. We assessed 53 patients. Thirty-three had alopecia, 3 had trigeminal anesthesia, 14 had VACTERL features, and 2 had HPE with aventriculy. Specific craniofacial features were seen throughout the cohort, but were more common in patients with alopecia. We noted substantial overlap between groups. We conclude that although some distinct subgroups can be delineated, the overlapping features seen in our cohort suggest an underlying spectrum of RES-associated malformations rather than a collection of discrete syndromes.

Ligand substitution, pH dependent deoxygenation, and linkage isomerization reactions of the 2,2'-bipyridinetetranitroruthenate dianion.

The reaction of the [Ru(bpy)(NO(2))(4)](2-) (bpy = 2,2'-bipyridine) ion in aqueous solutions produces two different nitrosyl complexes, depending on the pH of the solution. At acidic pH, complex cis,cis-Ru(bpy)(NO(2))(2)(ONO)(NO) was isolated. At neutral or basic pH, [Ru(bpy)(NO(2))(4)](2-) reacts to give cis,trans-Ru(bpy)(NO(2))(2)(NO)(OH). Both new complexes were fully characterized by elemental analysis and UV-vis, IR, (1)H NMR, and (15)N NMR spectroscopy. A single-crystal X-ray structure of cis,trans-Ru(bpy)(NO(2))(2)(NO)(OH) was also obtained. cis,cis-Ru(bpy)(NO(2))(2)(ONO)(NO) isomerizes in acetone or water solution to give a mixture of the trans,cis-Ru(bpy)(NO(2))(2)(ONO)(NO) and cis,cis-Ru(bpy)(ONO)(2)(NO(2))(NO) linkage isomers as determined by (1)H and (15)N NMR spectroscopy. A single-crystal X-ray structure of a solid solution of cis,cis-Ru(bpy)(ONO)(2)(NO(2))(NO)/trans,cis-Ru(bpy)(NO(2))(2)(ONO)(NO) was also obtained. This pair of isomers is the first crystallographically characterized compound with nitro, nitrito, and nitrosyl ligands. The kinetic studies of the Ru-NO(2) --> Ru-NO conversion reactions of [Ru(bpy)(NO(2))(4)](2)(-) in buffered solutions from pH 3 to pH 9 complement previous studies of the reverse reaction. The reactions are first order in [Ru(bpy)(NO(2))(4)](2-). At high pH, the reaction is independent of the concentration of H(+) while, at low pH, the reaction is first order in the concentration of H(+). The rate determining step of the high pH reaction involves breakage of the Ru-NO(2) bond while, at low pH, the mechanism involves a rapid reversible protonation of a NO(2) ligand followed by the rate determining loss of hydroxide to produce a nitrosyl ligand.