Hannah M. Tully

Rhombencephalosynapsis: a hindbrain malformation associated with incomplete separation of midbrain and forebrain, hydrocephalus and a broad spectrum of severity

Rhombencephalosynapsis is a midline brain malformation characterized by missing cerebellar vermis with apparent fusion of the cerebellar hemispheres. Rhombencephalosynapsis can be seen in isolation or together with other central nervous system and extra-central nervous system malformations. Gómez-López-Hernández syndrome combines rhombencephalosynapsis with parietal/temporal alopecia and sometimes trigeminal anaesthesia, towering skull shape and dysmorphic features. Rhombencephalosynapsis can also be seen in patients with features of vertebral anomalies, anal atresia, cardiovascular anomalies, trachea-oesophageal fistula, renal anomalies, limb defects (VACTERL) association. Based on a comprehensive evaluation of neuroimaging findings in 42 patients with rhombencephalosynapsis, we propose a spectrum of severity, ranging from mild (the partial absence of nodulus, anterior and posterior vermis), to moderate (the absence of posterior vermis with some anterior vermis and nodulus present), to severe (the absence of posterior and anterior vermis with some nodulus present), to complete (the absence of the entire vermis including nodulus). We demonstrate that the severity of rhombencephalosynapsis correlates with fusion of the tonsils, as well as midbrain abnormalities including aqueductal stenosis and midline fusion of the tectum. Rhombencephalosynapsis is also associated with multiple forebrain abnormalities including absent olfactory bulbs, dysgenesis of the corpus callosum, absent septum pellucidum and, in rare patients, atypical forms of holoprosencephaly. The frequent association between rhombencephalosynapsis and aqueductal stenosis prompted us to evaluate brain magnetic resonance images in other patients with aqueductal stenosis at our institution, and remarkably, we identified rhombencephalosynapsis in 9%. Strikingly, subjects with more severe rhombencephalosynapsis have more severely abnormal neurodevelopmental outcome, as do subjects with holoprosencephaly and patients with VACTERL features. In summary, our data provide improved diagnostic and prognostic information, and support disruption of dorsal-ventral patterning as a mechanism underlying rhombencephalosynapsis.

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.

Novel mutations in ATP1A3 associated with catastrophic early life epilepsy, episodic prolonged apnea, and postnatal microcephaly

Mutations of ATP1A3 have been associated with rapid onset dystonia‐parkinsonism and more recently with alternating hemiplegia of childhood. Here we report one child with catastrophic early life epilepsy and shortened survival, and another with epilepsy, episodic prolonged apnea, postnatal microcephaly, and severe developmental disability. Novel heterozygous mutations (p.Gly358Val and p.Ile363Asn) were identified in ATP1A3 in these children.

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.

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

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.

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.

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.

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.

Bi-allelic mutations of CCDC88C are a rare cause of severe congenital hydrocephalus

Congenital or infantile hydrocephalus is caused by genetic and non‐genetic factors and is highly heterogeneous in etiology. In recent studies, a limited number of genetic causes of hydrocephalus have been identified. To date, recessive mutations in the CCDC88C gene have been identified as a cause of non‐syndromic congenital hydrocephalus in three reported families. Here, we report the fourth known family with two affected individuals with congenital hydrocephalus due to a homozygous mutation in the CCDC88C gene identified by whole exome sequencing. Our two newly described children, as well as the previously published ones, all shared several features including severe infantile‐onset hydrocephalus, mild to severe intellectual delay, varying degrees of motor delay, and infantile onset seizures. All identified homozygous mutations in CCDC88C abolish the PDZ binding site necessary for proper CCDC88C protein function in the Wnt signaling pathway. Our report further establishes CCDC88C as one of the few known recessive causes of severe prenatal‐onset hydrocephalus. Recognition of this syndrome has important diagnostic and genetic implications for families identified in the future.

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.