ZEB2 is a protein-coding gene belonging to a very restricted family of transcription factors. ZEB2 acts mainly as a transcription repressor, is expressed in various tissues and its role is ...fundamental for the correct development of the nervous system. The best-known clinical picture associated with ZEB2 mutations is Mowat-Wilson syndrome, caused mostly by haploinsufficiency and characterized by possible multi-organ malformations, dysmorphic features, intellectual disability, and epilepsy. In this study we report the generation of IGGi004-A and IGGi005-A, iPSC clones from two patients carrying different heterozygous mutations in ZEB2, which can be used for disease modelling, pathophysiological studies and therapeutics testing.
Pallister-Killian syndrome (PKS) is a rare genetic disorder caused by mosaic tetrasomy of 12p with wide neurological involvement. Intellectual disability, developmental delay, behavioral problems, ...epilepsy, sleep disturbances, and brain malformations have been described in most individuals, with a broad phenotypic spectrum. This observational study, conducted through brain MRI scan analysis on a cohort of patients with genetically confirmed PKS, aims to systematically investigate the neuroradiological features of this syndrome and identify the possible existence of a typical pattern. Moreover, a literature review differentiating the different types of neuroimaging data was conducted for comparison with our population.
Thirty-one individuals were enrolled (17 females/14 males; age range 0.1-17.5 years old at first MRI). An experienced pediatric neuroradiologist reviewed brain MRIs, blindly to clinical data. Brain abnormalities were observed in all but one individual (compared to the 34% frequency found in the literature review). Corpus callosum abnormalities were found in 20/30 (67%) patients: 6 had callosal hypoplasia; 8 had global hypoplasia with hypoplastic splenium; 4 had only hypoplastic splenium; and 2 had a thin corpus callosum. Cerebral hypoplasia/atrophy was found in 23/31 (74%) and ventriculomegaly in 20/31 (65%). Other frequent features were the enlargement of the cisterna magna in 15/30 (50%) and polymicrogyria in 14/29 (48%). Conversely, the frequency of the latter was found to be 4% from the literature review. Notably, in our population, polymicrogyria was in the perisylvian area in all 14 cases, and it was bilateral in 10/14.
Brain abnormalities are very common in PKS and occur much more frequently than previously reported. Bilateral perisylvian polymicrogyria was a main aspect of our population. Our findings provide an additional tool for early diagnosis.Further studies to investigate the possible correlations with both genotype and phenotype may help to define the etiopathogenesis of the neurologic phenotype of this syndrome.
Mowat-Wilson Syndrome (MWS) (OMIM # 235730) is a rare disorder due to
gene defects (heterozygous mutation or deletion). The
gene is a widely expressed regulatory gene, extremely important for the ...proper prenatal development. MWS is characterized by a specific facial gestalt and multiple musculoskeletal, cardiac, gastrointestinal, and urogenital anomalies. The nervous system involvement is extensive and constitutes one of the main features in MWS, heavily affecting prognosis and life quality of affected individuals. This review aims to comprehensively organize and discuss the neurological and neurodevelopmental phenotype of MWS. First, we will describe the role of
in the formation and development of the nervous system by reviewing the preclinical studies in this regard.
regulates the neural crest cell differentiation and migration, as well as in the modulation of GABAergic transmission. This leads to different degrees of structural and functional impairment that have been explored and deepened by various authors over the years. Subsequently, the different neurological aspects of MWS (head and brain malformations, epilepsy, sleep disorders, and enteric and peripheral nervous system involvement, as well as developmental, cognitive, and behavioral features) will be faced one at a time and extensively examined from both a clinical and etiopathogenetic point of view, linking them to the
related pathways.
Pallister-Killian syndrome (PKS) is a rare genetic disorder with multi-organ involvement caused by mosaic tetrasomy of chromosome 12p. Although many caregivers report the presence of impaired sleep ...in their children, there are no clear data in the literature on this issue and no systematic study has ever been performed. With this study, we aimed to characterize the features of sleep in Pallister-Killian syndrome and identify the possible influence of clinical and demographic features. Moreover, our aim was to verify the effectiveness of conventional screening questionnaires in this particular group of patients.
We prospectively enrolled 14 patients aged 1-17 years in collaboration with PKS Kids Italia ONLUS. The Sleep Disturbance Scale for Children (SDSC) questionnaire was administered to caregivers. Then, video polysomnography (VPSG) of at least 24 h was performed and results were compared with a same-aged control group.
A total of 92% of patients had abnormal SDSC scores, extremely high in the "disorder of initiating and maintaining sleep" (DIMS) and "sleep breathing disorders" (SBD) subscales. VPSG showed a significantly impaired macrostructure in PKS patients, with a higher Arousal Index (
< 0.00001) and percentage of time spent in N3 (
< 0.00001), and reduced Sleep Efficiency (
= 0.0006). After dividing both PKS and controls into two groups based on median age, some peculiarities emerged: the younger group had higher Awakenings Index (
= 0.0207) and percentage of time spent in N1 (
= 0.015) while the older group showed higher time in bed (TIB) (
= 0.0485), compared with controls. Due to poor compliance, the Apnea-Hypopnea Index (AHI) was evaluated only for 10 PKS children, being significantly increased (
= 0.0427) compared with controls. SBD subscale scores in SDSC were significantly related to AHI values in VPSG (
= 0.0099).
This study constitutes the first attempt to describe the sleep pattern in PKS. Despite small numbers due to the rarity of the syndrome, our VPSG results confirm the high prevalence of sleep disorders (SDs) in these patients. It is therefore essential to investigate and treat them. The SDSC scale is a good screening tool for early detection also in these patients, with particular sensitivity in detecting breathing disorders.
Mowat-Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene. It is characterized by moderate-severe intellectual disability, ...epilepsy, Hirschsprung disease and multiple organ malformations of which congenital heart defects and urogenital anomalies are the most frequent ones. To date, a clear description of the physical development of MWS patients does not exist. The aim of this study is to provide up-to-date growth charts specific for infants and children with MWS. Charts for males and females aged from 0 to 16 years were generated using a total of 2865 measurements from 99 MWS patients of different ancestries. All data were collected through extensive collaborations with the Italian MWS association (AIMW) and the MWS Foundation. The GAMLSS package for the R statistical computing software was used to model the growth charts. Height, weight, body mass index (BMI) and head circumference were compared to those from standard international growth charts for healthy children. In newborns, weight and length were distributed as in the general population, while head circumference was slightly smaller, with an average below the 30th centile. Up to the age of 7 years, weight and height distribution was shifted to slightly lower values than in the general population; after that, the difference increased further, with 50% of the affected children below the 5th centile of the general population. BMI distribution was similar to that of non-affected children until the age of 7 years, at which point values in MWS children increased with a less steep slope, particularly in males. Microcephaly was sometimes present at birth, but in most cases it developed gradually during infancy; many children had a small head circumference, between the 3rd and the 10th centile, rather than being truly microcephalic (at least 2 SD below the mean). Most patients were of slender build. These charts contribute to the understanding of the natural history of MWS and should assist pediatricians and other caregivers in providing optimal care to MWS individuals who show problems related to physical growth. This is the first study on growth in patients with MWS.
Developmental delay and intellectual disability are two pivotal elements of the phenotype of Pallister-Killian Syndrome (PKS). Our study aims to define the cognitive, adaptive, behavioral, and ...sensory profile of these patients and to evaluate possible correlations between the different aspects investigated and with the main clinical and demographic variables.
Individuals of any age with genetically confirmed PKS were recruited. Those ≤ 42 months were administered the Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III), and those > 42 months the Vineland Adaptive Behavior Scales-Second Edition (Vineland-II). Stereotyped behaviors (Stereotypy Severity Scale, SSS) and aggressive behaviors (Behavior Problems Inventory-Short Version, BPIs) were assessed in all subjects > 1 year; sensory profile (Child Sensory Profile 2, C-SP2) in all aged 2-18 years.
Twenty-two subjects were enrolled (11 F/11 M; age 9 months to 28 years). All subjects ≤ 42 months had psychomotor developmental delay. Of the subjects > 42 months, 15 had low IQ deviation, and 1 in the normal range. Stereotypies were frequent (median SSS-total score 25/68). Lower Vineland-II values corresponded to greater intensity and frequency of stereotypies (
= 0.004 and
= 0.003), and self-injurious behaviors (
= 0.002 and
= 0.002). Patients with severe low vision had greater interference of stereotypies (
= 0.027), and frequency and severity of aggressive behaviors (
= 0.026;
= 0.032). The C-SP2, while not homogeneous across subjects, showed prevalence of low registration and sensory seeking profiles and hypersensitivity to tactile and auditory stimuli. Lower Vineland-II scores correlated with higher Registration scores (
= 0.041), while stereotypies were more frequent and severe in case of high auditory sensitivity (
= 0.019;
= 0.007). Finally, greater sleep impairment correlated with stereotypies and self-injurious behaviors, and lower Vineland-II scores.
The present study provides a further step in the investigation of the etiopathogenesis of the syndrome. Furthermore, these aspects could guide rehabilitation therapy through the identification of targeted protocols.
Abstract Background Although the posterior reversible encephalopathy syndrome (PRES) is considered to have a benign clinical outcome, the presentation of PRES can be associated with life-threatening ...complications such as severe cerebral hemorrhage, cerebellar herniation and refractory status epilepticus (SE). The aim of this paper is to report incidence, clinical features and outcome of life-threatening complications related to PRES in children. Methods Patients who suffered from life-threatening complications were retrospectively identified from a group composed by 27 consecutive children diagnosed with PRES in our hospital between 2000 and 2012. The clinical, radiological and EEG features and the outcome of these patients were evaluated and compared to the characteristics of patients with no complications. Results Five patients (18%) presented life-threatening complications: 2 cerebral hemorrhages with mass effect and midline shift (1 massive intraparenchymal hemorrhage and 1 subdural hemorrhage and intraparenchymal hemorrhage), 2 transforaminal cerebellar herniations and 1 refractory SE. Two children died because of complications and 2 children required urgent neurosurgical intervention. The infratentorial involvement at onset of PRES and the observation of focal neurological deficits other than visual disturbances were significantly more frequent in children with life-threatening complications ( p < 0.01). Conclusions PRES is associated with a non-negligible incidence of life-threatening complications. A careful clinical, neuroradiological and EEG monitoring is necessary in order to improve the outcome especially in the case of focal neurological deficits and infratentorial involvement.
Therapy-related neurotoxicity greatly affects possibility of survival and quality of life of pediatric patients treated for cancer. Central nervous system (CNS) involvement is heterogeneous, varying ...from very mild and transient symptoms to extremely severe and debilitating, or even lethal syndromes. In this review, we will discuss the broad scenario of CNS complications and toxicities occurring during the treatment of pediatric patients receiving both chemotherapies and hematopoietic stem cell transplantation. Different types of complications are reviewed ranging from therapy related to cerebrovascular with a specific focus on neuroradiologic and clinical features.
KCNB1-associated encephalopathy is characterized by intellectual disability (ID), autism spectrum disorder and epilepsy. Specific treatments are still lacking. We describe a 12-year-old boy with ...severe ID and treatment-resistant seizures due to a pathogenic KCNB1 variant. His EEG showed a CSWS pattern. Aged 11, he started treatment with highly purified cannabidiol (CBD) and has been seizure free for 18 months, with significant EEG and social skills improvements. This suggests CBD may benefit CSWS, likely due to its anti-inflammatory properties. Some preclinical studies also indicate CBDs interact with voltage-gated channels, leading us to speculate its possible role for treating KCNB1 related encephalopathy.
Narcolepsy type 1 (NT1) is a rare central disorder of hypersomnolence characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, hallucinations, and fragmented nocturnal sleep usually ...arising in adolescence or young adulthood. Recently, the childhood NT1 diagnoses have increased for improved disease awareness and for several cases occurring after the H1N1 pandemic influenza or vaccination. As in adults, the occurrence of NT1 in individuals with a genetic predisposition of the immune system (e.g., human leukocyte antigen, HLA-DQB1*0602) together with the role of environmental triggers (e.g., H1N1 influenza virus, streptococcus β hemolyticus) further supports the autoimmune pathogenesis. Children with NT1 close to disease onset show a peculiar cataplexy phenotype characterized by persistent hypotonia with prominent facial involvement (cataplectic facies) and by a complex mosaic of hyperkinetic movement abnormalities that increase during emotional stimulation. This phenotype progressively vanishes along the disease course leading to the typical picture of cataplexy (i.e., muscle weakness exclusively evoked by strong emotions). This possibly explains in part the misdiagnoses and diagnostic delay. Childhood NT1 also shows behavioral abnormalities and psychiatric disorders, encompassing depressive feelings, hyperactive/aggressive behavior, up to psychotic features. The association with obesity and precocious puberty strikingly suggests that NT1 arising in prepubertal children may reflect a wide hypothalamic derangement secondary to hypocretin neuronal loss. The complexity of the childhood NT1 phenotype claims a multidisciplinary assessment and management, taking behavioral and endocrinological features into account. NT1 indeed is a lifelong disorder with a devastating impact on quality of life, especially when arising across developmental age, and targeted school programs, medicolegal and psychological supports are essential for patients care. Controlled studies are mandatory to assess safety and efficacy of the current symptomatic off-label medications on which also relies the treatment for children with NT1, and hopefully future pathogenetic evidences will pave the way to better disease prevention and therapies to modify the disease course.
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