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Objective: To characterize the clinical characteristics of infants with obstructive sleep apnea (OSA), define the resolution rate of infant OSA, and identify factors associated with OSA resolution., Methods: We identified infants diagnosed with OSA via retrospective chart review at less than one year of age at a tertiary care center. We identified patient comorbidities, flexible or rigid airway evaluations, surgical procedures, and oxygen/other respiratory support administration. We identified infants as having resolved OSA based on clinical or polysomnogram resolution. We compared the frequency of comorbid diagnoses and receipt of interventions in infants with resolved versus non-resolved OSA by χ 2 analysis., Results: 83 patients were included. Prematurity was found in 35/83 (42%), hypotonia-related diagnoses in 31/83 (37%), and craniofacial abnormalities in 34/83 (41%). Resolution was observed in 61/83 (74%), either clinically or by polysomnogram, during follow up. On χ 2 analysis, surgical intervention was not associated with likelihood of resolution (73% versus 74% in those without surgical intervention, p = 0.98). Patients with airway abnormalities on flexible or rigid evaluation were less likely to have OSA resolution than those without (63% versus 100%, p = 0.010), as were patients with hypotonia-related diagnoses (58% versus 83%, p = 0.014). In patients with laryngomalacia, there was no association of supraglottoplasty with increased resolution (88% with supraglottoplasty versus 80% without, p = 1.00)., Conclusions: We identified a group of infants with OSA with diverse comorbidities. There was a high rate of resolution. This data can assist with treatment planning and family counselling for infants with OSA. A prospective clinical trial is needed to better assess consequences of OSA in this age., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Monocarboxylate transporter 8 (MCT8) deficiency is an X-linked recessive developmental disorder characterized by initially marked truncal hypotonia, later athetotic posturing, and severe intellectual disability caused by mutations in SLC16A2, which is responsible for the transport of triiodothyronine (T3) into neurons. We conducted a nationwide survey of patients with MCT8 deficiency to clarify their current status., Methods: Primary survey: In 2016-2017, we assessed the number of patients diagnosed with MCT8 deficiency from 1027 hospitals. Secondary survey: in 2017-2018, we sent case surveys to 31 hospitals (45 cases of genetic diagnosis), who responded in the primary survey. We asked for: 1) perinatal history, 2) developmental history, 3) head MRI findings, 4) neurophysiological findings, 5) thyroid function tests, and 5) genetic test findings., Results: We estimated the prevalence of MCT8 deficiency to be 1 in 1,890,000 and the incidence of MCT8 deficiency per million births to be 2.12 (95 % CI: 0.99-3.25). All patients showed severe psychomotor retardation, and none were able to walk or speak. The significantly higher value of the free T3/free T4 (fT3/fT4) ratio found in our study can be a simple and useful diagnostic biomarker (Our value 11.60 ± 4.14 vs control 3.03 ± 0.38). Initial white matter signal abnormalities on head MRI showed recovery, but somatosensory evoked potentials (SEP) showed no improvement, suggesting that the patient remained dysfunctional., Conclusion: For early diagnosis, including in mild cases, it might be important to consider the clinical course, early head MRI, SEP, and fT3/fT4 ratio., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: Previous research in autism and other neurodevelopmental disorders (NDDs) has indicated an important contribution of protein-coding (coding) de novo variants (DNVs) within specific genes. The role of de novo noncoding variation has been observable as a general increase in genetic burden but has yet to be resolved to individual functional elements. In this study, we assessed whole-genome sequencing data in 2671 families with autism (discovery cohort of 516 families, replication cohort of 2155 families). We focused on DNVs in enhancers with characterized in vivo activity in the brain and identified an excess of DNVs in an enhancer named hs737., Results: We adapted the fitDNM statistical model to work in noncoding regions and tested enhancers for excess of DNVs in families with autism. We found only one enhancer (hs737) with nominal significance in the discovery (p = 0.0172), replication (p = 2.5 × 10 -3 ), and combined dataset (p = 1.1 × 10 -4 ). Each individual with a DNV in hs737 had shared phenotypes including being male, intact cognitive function, and hypotonia or motor delay. Our in vitro assessment of the DNVs showed they all reduce enhancer activity in a neuronal cell line. By epigenomic analyses, we found that hs737 is brain-specific and targets the transcription factor gene EBF3 in human fetal brain. EBF3 is genome-wide significant for coding DNVs in NDDs (missense p = 8.12 × 10 -35 , loss-of-function p = 2.26 × 10 -13 ) and is widely expressed in the body. Through characterization of promoters bound by EBF3 in neuronal cells, we saw enrichment for binding to NDD genes (p = 7.43 × 10 -6 , OR = 1.87) involved in gene regulation. Individuals with coding DNVs have greater phenotypic severity (hypotonia, ataxia, and delayed development syndrome [HADDS]) in comparison to individuals with noncoding DNVs that have autism and hypotonia., Conclusions: In this study, we identify DNVs in the hs737 enhancer in individuals with autism. Through multiple approaches, we find hs737 targets the gene EBF3 that is genome-wide significant in NDDs. By assessment of noncoding variation and the genes they affect, we are beginning to understand their impact on gene regulatory networks in NDDs., (© 2021. The Author(s).)

Over the past decade, pathogenic variants in all members of the ASXL family of genes, ASXL1, ASXL2, and ASXL3, have been found to lead to clinically distinct but overlapping syndromes. Bohring-Opitz syndrome (BOPS) was first described as a clinical syndrome and later found to be associated with pathogenic variants in ASXL1. This syndrome is characterized by developmental delay, microcephaly, characteristic facies, hypotonia, and feeding difficulties. Subsequently, pathogenic variants in ASXL2 were found to lead to Shashi-Pena syndrome (SHAPNS) and in ASXL3 to lead to Bainbridge-Ropers syndrome (BRPS). While SHAPNS and BRPS share many core features with BOPS, there also seem to be emerging clear differences. Here, we present five cases of BOPS, one case of SHAPNS, and four cases of BRPS. By adding our cohort to the limited number of previously published patients, we review the overlapping features of ASXL-related diseases that bind them together, while focusing on the characteristics that make each neurodevelopmental syndrome unique. This will assist in diagnosis of these overlapping conditions and allow clinicians to more comprehensively counsel affected families., (© 2021 Wiley Periodicals LLC.)

Background: Hypotonic-hyporesponsive episodes (HHE) is one frequently reported neurologic adverse effect supposedly attributable to vaccination and immunization. Its long-term impact on neurodevelopment is not completely known., Aim: To characterize the post-pentavalent vaccine HHE events reported to the Uruguayan Ministry of Health (M of H) between 2014 and 2018. To perform neurodevelopment screening of those who were under 6 years of age at the time of evaluation., Methods: Descriptive study of the reports made to the National Farmacosurveillance System of the M of H. Neurodevelopment screening was performed using the National Guidelines for Developmental Surveillance., Results: 30 cases were studied. Most cases occurred after the first doses, were of short duration and during the first hours after vaccination, with spontaneous recovery. Median time between the event and this evaluation was 2 years and 2 months. Screening tests were normal in 15. Delay in the language area was detected in one case., Conclusions: HHE events had similar characteristics to those described in the literature, with no severe short-term complications. Despite the limitations of the present study, no delays nor deviations were found in the development of the children who were evaluated.

Background: As we move toward a polio-free world, the challenge for the polio program is to create an unrelenting focus on smaller areas where the virus is still present, where children are being repeatedly missed, where immunity levels are low, and where surveillance is weak., Objective: This article aimed to describe a possible solution to address weak surveillance systems and document the outcomes of the deployment of the Auto-Visual Acute Flaccid Paralysis Detection and Reporting (AVADAR) project., Methods: This intervention was implemented in 99 targeted high-risk districts with concerns for silent polio circulation from eight countries in Africa between August 1, 2017, and July 31, 2018. A total of 6954 persons (5390 community informants and 1564 health workers) were trained and equipped with a smartphone on which the AVADAR app was configured to allow community informants to send alerts on suspected acute flaccid paralysis (AFP) and allow health worker to use electronic checklists for investigation of such alerts. The AVADAR and Open Data Kit ONA servers were at the center of the entire process. A dashboard system and coordination teams for monitoring and supervision were put in place at all levels., Results: Overall, 96.44% (24,142/25,032) of potential AFP case alerts were investigated by surveillance personnel, yielding 1414 true AFP cases. This number (n=1414) reported through AVADAR was higher than the 238 AFP cases expected during the study period in the AVADAR districts and the 491 true AFP cases reported by the traditional surveillance system. A total of 203 out of the 1414 true AFP cases reported were from special population settings, such as refugee camps and insecure areas. There was an improvement in reporting in silent health areas in all the countries using the AVADAR system. Finally, there were 23,473 reports for other diseases, such as measles, diarrhea, and cerebrospinal meningitis, using the AVADAR platform., Conclusions: This article demonstrates the added value of AVADAR to rapidly improve surveillance sensitivity. AVADAR is capable of supporting countries to improve surveillance sensitivity within a short interval before and beyond polio-free certification., (©Johnson Muluh Ticha, Godwin Ubong Akpan, Lara MF Paige, Kamel Senouci, Andrew Stein, Patrick Briand, Jude Tuma, Daniel Rasheed Oyaole, Reuben Ngofa, Sylvester Maleghemi, Kebba Touray, Abdullahi Ahmed Salihu, Mamadou Diallo, Sisay Gashu Tegegne, Isah Mohammed Bello, Umar Kabo Idris, Omosivie Maduka, Casimir Manengu, Faisal Shuaib, Michael Galway, Pascal Mkanda. Originally published in JMIR Public Health and Surveillance (http://publichealth.jmir.org), 02.12.2020.)

Background: Acute flaccid paralysis (AFP) surveillance is an essential strategy for poliovirus eradication., Objective: This study aimed to evaluate the performance of the AFP surveillance system in Yemen from 2010 to 2015, identify components that require strengthening, and compare the indicators by year and governorates., Methods: This descriptive study was based on secondary analysis of AFP surveillance data reported during 2010-2015 from all Yemeni governorates. The World Health Organization (WHO) minimum performance standards were used to evaluate the performance of the AFP surveillance system., Results: A total of 3019 AFP cases were reported between January 2010 and December 2015. At the national level, AFP surveillance achieved WHO targets throughout the evaluating period for the nonpolio AFP rate of cases per 100,000 members of the population younger than 15 years of age, proportion of AFP cases reported within 7 days, proportion of AFP cases investigated within 48 hours of notification, proportion of AFP cases with two adequate stool specimens, and proportion of stool specimens from which nonpolio enterovirus was isolated. However, the proportion of specimens that arrived at the central level within 3 days of the first sample collection and the proportion of stool specimens with results sent from the reference laboratory within 28 days of receipt did not reach targets in 2011 and 2015, respectively., Conclusions: The AFP surveillance system in Yemen has met most of the WHO indicator levels. Nevertheless, the evaluation showed areas of weakness regarding the arrival of specimens at the central level within 3 days of the first sample collection and delays in processing of the results and submitting feedback by the laboratory. Therefore, there is a need to strengthen the follow-up of specimens submitted to the laboratory., (©Khaled Abdullah Almoayed, Ali Bin Break, Mutahar Al-Qassimi, Ali Assabri, Yousef Khader. Originally published in JMIR Public Health and Surveillance (http://publichealth.jmir.org), 06.12.2019.)

Purpose: Intellectual disability (ID) results from a heterogeneous group of disorders and affects 1% to 2% of children. ID frequently occurs in association with other clinical features such as seizures or malformations. We suspected that strabismus might also be unusually frequent in this population and that it might be associated with ID groups affecting motor control., Methods: We reviewed phenotypic descriptors, extracted from medical records, for a heterogeneous series of 222 probands with ID who had been enrolled in a study of clinical application of exome sequencing. We estimated the frequency of strabismus and other common clinical features and explored statistical associations between them. Data from Population Data British Columbia and Online Mendelian Inheritance in Man were also examined for confirmation of our observations., Results: Strabismus had a higher prevalence among probands with ID than in the general population (odds ratio = 5.46). Moreover, probands with both ID and strabismus were more likely to have problems affecting motor control than those with ID and no strabismus (odds ratio = 2.84). Hypotonia was one of the most common motor control subgroups affecting the ID probands, and a frequent co-occurrence of strabismus and hypotonia was also observed (odds ratio = 2.51) and supported by related gene literature review. There was no evidence for associations between strabismus and other frequent clinical features., Conclusion: Strabismus is a frequent feature in individuals with ID. The frequent co-occurrence of strabismus and motor control phenotypes, in particular hypotonia, suggests that a common cerebellar mechanism or pathway may underlie these phenotypes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To identify the proportion of patients previously diagnosed with apparent life-threatening events (ALTE) who would meet criteria for brief resolved unexplained events (BRUE) and to identify rates of adverse outcomes in subgroups: ALTE not meeting criteria for BRUE, lower-risk BRUE, and higher-risk ALTE., Methods: We performed a secondary analysis of a single-center prospective registry of patients diagnosed with ALTE in a tertiary care emergency department from March 1, 1997 to October 31, 2007. We identified the proportion of patients meeting criteria for BRUE, and the proportion of patients with BRUE meeting lower-risk criteria. We assessed outcomes of patients in subgroups., Results: Seven hundred and sixty-two patients were included. Adverse outcomes included recurrent ALTE (n = 49), aspiration (n = 9), trauma (n = 8), and death (n = 4). Three hundred and twenty-six of 762 (42.8%) met criteria for BRUE. Seventy of 326 (21.5%) met criteria for lower-risk BRUE. Adverse outcomes occurred in 40 of 436 (9.2%) with ALTE not meeting criteria for BRUE, 2 of 70 (2.9%) with lower-risk BRUE, and 23 of 256 (9.0%) with higher-risk BRUE. Of 4 patients who died, 1 had an ALTE not meeting criteria for BRUE and 3 had non-lower-risk BRUE. The BRUE risk criteria identified all BRUE patients that died or had substantial morbidity as higher-risk., Conclusions: Less than half of patients with ALTE meet criteria for BRUE. Of those who do, one-fifth is lower-risk. In this series, the risk-stratification in the BRUE criteria identified those patients at highest risk of adverse outcomes. Further research is required to risk-stratify patients with BRUE., (Copyright © 2019 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Objectives: Isolated REM sleep without atonia (iRSWA) is regarded as prodromal phase of REM sleep behavior disorder (RBD) and synucleinopathies. Other factors, however, have also been described to cause RSWA, including sleep apnea, antidepressants use and narcolepsy. We investigated the frequency of RSWA and its different etiologies., Methods: We investigated RSWA in patients that underwent a clinical video polysomnography. In iRSWA subjects, we examined polysomnography indication and two markers of prodromal Parkinson's disease: excessive daytime sleepiness and depressive symptoms, with a case-control design., Results: Of the 864 included polysomnographies, 188 were positive for RSWA (21.8%), 17 for RBD (2.0%) and 48 for iRSWA (5.6%). Mean Epworth Sleepiness Scale scores were 9.8 ± 4.8 (iRSWA subjects) and 7.5 ± 4.9 (controls), p = 0.014. Mean Beck Depression Inventory-II scores were 11.3 ± 7.9 (iRSWA subjects) and 9.5 ± 8.4 (controls), p = 0.229. Excessive daytime sleepiness was more often the polysomnography indication in the iRSWA group (p = 0.006)., Conclusions: RSWA is a frequent finding in the context of antidepressant use or synucleinopathies. iRSWA subjects reported increased excessive daytime sleepiness and more often had excessive daytime sleepiness as polysomnography indication., Significance: Our study provides evidence for high frequency of RSWA, underscoring the need for longitudinal studies in iRSWA patients, with interest for conversion to synucleinopathies., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

In Greece, data for human parechoviruses (HPeVs) are scarce and our aim was to conduct a large scale study to determine for the first time their occurrence. Under the spectrum of surveillance, we retrospectively screened stool specimens obtained from 71 children with acute flaccid paralysis (AFP) symptoms and from 311 individuals in high-risk population groups such as children living in bad sanitation conditions for HPeVs presence by rRT-PCR targeting the 5' UTR. All positive samples were then genotyped by targeting the HPeVs VP1 region. Totally, 15/311 (5%) stool samples from children living in bad sanitation conditions and 4/71 (6%) from the non polio AFP children were positive for HPeVs. Sequencing analysis revealed that genotypes HPeV1 (n = 4/15), HPeV5 (n = 2/15), and HPeV6 (n = 2/15) were circulating among Roma children population whereas HPeV1 (n = 1/4) and HPeV5 (n = 1/4) were circulating in children with AFP-like symptoms. We did not obtain a seasonality motive among HPeV1 or HPeV5 genotypes whereas HPeV6 was detected only in July. Phylogenetic analysis showed that Greek HPeVs strains are clustered together with HPeV strains circulating in other European countries during the same period. We describe the presence of HPeVs in Greece, and we enforce that their diagnosis should be considered in children with neurological outcome such as non-polio AFP.

Purpose: Identifying and characterizing novel causes of autosomal recessive intellectual disability based on systematic clinical and genetic evaluation, followed by functional experiments., Methods: Clinical examinations, genome-wide positional mapping, and sequencing were followed by quantitative polymerase chain reaction and western blot of the protein SVBP and its interaction partners. We then knocked down the gene in rat primary hippocampal neurons and evaluated the consequences on synapses., Results: We identified a founder, homozygous stop-gain variant in SVBP (c.82C>T; p.[Gln28*]) in four affected individuals from two independent families with intellectual disability, microcephaly, ataxia, and muscular hypotonia. SVBP encodes a small chaperone protein that transports and stabilizes two angiogenesis regulators, VASH1 and VASH2. The altered protein is unstable and nonfunctional since transfected HeLa cells with mutant SVBP did not reveal evidence for immunoreactive SVBP protein fragments and cotransfection with VASH1 showed a severe reduction of VASH1 in medium and cell lysate. Knocking down Svbp in rat primary hippocampal neurons led to a significant decrease in the number of excitatory synapses., Conclusion: SVBP is not only involved in angiogenesis, but also has vital functions in the central nervous system. Biallelic loss-of-function variants in SVBP lead to intellectual disability.

Purpose: Brachial plexus birth palsy (BPBP) is common; however, the current incidence is unknown and more than 50% of infants with BPBP have no known risk factors. The purpose of this study was to determine the current incidence of BPBP, assess known risk factors, and evaluate hypotonia as a new risk factor, as well as estimate the length of stay (LOS) and direct costs of children with an associated BPBP injury., Methods: Data from the 1997 to 2012 Kids' Inpatient Database data sets were evaluated to identify patients with a BPBP injury and various risk factors. Evaluation of LOS data and direct costs was also performed. Multivariable logistic regression analysis was utilized to assess the association of BPBP with its known and previously undescribed risk factors., Results: The incidence of BPBP has steadily decreased from 1997 to 2012, with an incidence of 0.9 ± 0.01 per 1,000 live births recorded in 2012. Shoulder dystocia is the number 1 risk factor for the development of a BPBP injury. Hypotonia is a newly recognized risk factor for the development of BPBP. Fifty-five percent of infants with BPBP have no known perinatal risk factors. The initial hospital LOS is approximately 20% longer for children with a BPBP injury and the hospital stay direct costs are approximately 40% higher., Conclusions: The incidence of BPBP is decreasing over time. Shoulder dystocia continues to be the most common risk factor for sustaining a BPBP injury. Children with a BPBP injury have longer LOSs and hospital direct costs compared with children without a BPBP injury., Type of Study/level of Evidence: Prognostic II., (Copyright © 2019 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Background: Musculoskeletal complications of Down syndrome (DS) are common but infrequently reported. The combination of ligamentous laxity and low muscle tone contributes to increased risk of a number of musculoskeletal disorders and a delay in acquisition of motor milestones. The primary aim of this study was to describe musculoskeletal anomalies reported in a national cohort of children with DS., Methods: This was an observational study. Children with DS, aged 0-21 years, were invited to attend a musculoskeletal assessment clinic conducted by a paediatric physician. Relevant musculoskeletal history and clinical findings were documented., Results: Over an 18-month period, 503 children with DS were examined (56% male). The median age was 8.1 years (0.6-19.2). Pes planus was almost universal, occurring in 91% of the cohort. A range of other musculoskeletal anomalies were observed, with inflammatory arthritis (7%) and scoliosis (4.8%) occurring most frequently after pes planus. Delay in ambulation was common; the median age to walk was 28 months (12-84)., Conclusion: Children with DS are at increased risk of a number of potentially debilitating musculoskeletal problems. These conditions can present in variable manners or be completely asymptomatic. Pes planus is common; therefore, early consideration of orthotics and lifelong appropriate supportive footwear should be considered. Delayed ambulation is frequently noted. A significant proportion of children with DS have arthritis; however, despite a high prevalence, it is often missed, leading to delayed diagnosis. An annual musculoskeletal assessment for all children with DS could potentially enable early detection of problems, allowing for timely multidisciplinary team intervention and better clinical outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: Human parechoviruses (HPeV) are responsible for fever without a source (FWS), sepsis-like illness and encephalitis in neonates and children under 3 months of age. Short-term outcome is generally good, but there is great concern about medium and long- term outcome of infants after HPeV infection. The aim of this study is to assess the medium-term outcome in infants following HPeV infection without encephalitis., Methods: Patients who suffered HPeV infection involving cerebrospinal fluid were evaluated twice using Ages and Stages Questionnaire-3 (ASQ-3). The first evaluation was conducted at least one year after the infection and the second one year later., Results: Sixteen patients were evaluated in the first assessment, and three of them presented mild alterations in motor function domains. Moreover, hypotonia was observed in the neurologic exam in one case, and hemiparesis in another case. In the second assessment fifteen patients were included, and only the patient with hemiparesis continued presenting gross motor disfunction, with complete recovery of the remaining patients., Interpretation: We have observed a good medium-term prognosis in infants after HPeV infections, with improvement of mild motor alterations after at-home intervention. Infants who suffer HPeV infection without encephalitis seem to have a better prognosis than those with encephalitis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: Children with autism spectrum disorder (ASD) have a high prevalence of co-occurring medical conditions, including speech, sleep, and gastrointestinal disorders (constipation and feeding difficulties); developmental delay; attention deficit/hyperactivity disorder; hypotonia; epilepsy; anxiety; disruptive behavior; pica; and eczema. Less is known about whether these commonly coexist in the same children. We sought to determine clinically meaningful, statistically significant associations among co-occurring medical conditions in children with ASD that could lead to better understanding, identification, and treatment of these disorders., Methods: We studied 2114 children with ASD aged 17 months to 5years and 1221 children aged 6 to 17years at 15 Autism Speaks Autism Treatment Network Registry sites. Clinician-reported diagnoses and problems were grouped into 12 core conditions. We determined the observed prevalence (O) of co-occurring conditions and the estimated expected prevalence (E) across the network, adjusting for sitevariability in the prevalence of individual conditions. Pvalues were calculated using a Cochran-Mantel-Haenszel test stratified by site. We identified pairs of conditions co-occurring more frequently than expected (O/E >1) and less frequently than expected (O/E <1) and highlighted statisticallysignificant differences., Results: Among the 66 condition pairs for each age group, we confirmed previously identified associations, such as sleep disorders and anxiety symptoms, in older children. We found some associations not previously described, including feeding with sleep disorders (younger children only), constipation with sleep disorders, feeding with speech disorders, and constipation with speech disorders., Conclusions: We have identified new associations among co-occurring medical conditions in children with ASD, offering the potential to examine common pathways., (Copyright © 2018 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

During 2018, the United Kingdom experienced an increase in reports of cases of acute flaccid paralysis (AFP). As at 21 January 2019, 40 cases had been identified with a peak in October 2018. The increase was temporally associated with an upsurge in enterovirus (EV) D68 activity. Enterovirus was detected in 15 cases, mainly from respiratory tract samples; nine were typed as EV-D68. A national task force has been established and investigations are ongoing.

It is estimated that 0.5% of all mammalian proteins have a glycosylphosphatidylinositol (GPI)-anchor. GPI-anchored proteins (GPI-APs) play key roles, particularly in embryogenesis, neurogenesis, immune response and signal transduction. Due to their involvement in many pathways and developmental events, defects in the genes involved in their synthesis and processing can result in a variety of genetic disorders for which affected individuals display a wide spectrum of features. We compiled the clinical characteristics of 202 individuals with mutations in the GPI biosynthesis and processing pathway through a review of the literature. This review has allowed us to compare the characteristics and the severity of the phenotypes associated with different genes as well as highlight features that are prominent for each. Certain combinations, such as seizures with aplastic/hypoplastic nails or abnormal alkaline phosphatase levels suggest an inherited GPI deficiency, and our review of all clinical findings may orient the management of inherited GPI deficiencies., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Nigeria is the only country in Africa that is yet to be certified as polio free. Surveillance for acute flaccid paralysis (AFP) is the foundation of the polio eradication initiative since it provides information to alert both health managers and clinician that timely actions should be initiated to interrupt transmission of the polio virus. The strategy also provides evidence for the absence of wild poliovirus. This evaluation was performed to assess key quality indicators defined by the polio eradication program and thus to identify gaps to allow planning for corrective measures to achieve a polio-free situation in Bauchi state and in Nigeria at large. We conducted a cross-sectional descriptive study which involved a desk review of documents to authenticate the correctness and completeness of data, and a review of documented evidence for the quality of AFP surveillance. We interviewed Local Government Authority (LGA) surveillance officers and clinicians from focal and non-focal sites, along with caregivers of children with AFP and community leaders. The data were entered and analyzed in a Microsoft Excel spreadsheet., Methods: We conducted a cross-sectional study of the AFP surveillance and documentation in eighteen of the twenty Local Government Areas (LGAs) of Bauchi State. We assessed the knowledge of the clinician at focal and non-focal sites on case definition of AFP, the number and method of stool specimen collection to investigate a case and types of training received for AFP surveillance. We verified AFP case investigations for the last three years: The caregivers (mothers) were interviewed to authenticate the reported information of AFP cases, the method used for stool specimen collection and feedbacks. Community leaders' knowledge on AFP surveillance was also assessed. Data was entered and analyzed in excel spread sheet., Results: Of the 18 LGA Disease Surveillance and Notification Officers (DSNOs), only 2 (11%) and 5 (28%) had reports of polio outbreak investigations and supervisory visits at the lower levels, respectively. Furthermore, only 6 (33%) and 7 (39%) of the DSNOs had minutes of meetings and surveillance work plans, respectively. Of the 31 AFP cases investigated, only 39, 26, 23, and 23% had correct and complete information for the birth day, birth month, date of onset of paralysis, and date of investigation, respectively. Seventy-one percent of the clinicians at the AFP focal sites knew the correct definition for AFP compared with only 30% at the non-focal sites. Of the 38 caregivers (mothers), 16 (42%) did not remember the day or month the AFP investigation was conducted. However, 95% gave a correct number of stool samples collected and 40% mentioned that the samples were collected 24 h apart. Feedback was not given to 26 (68%) of the caregivers. The majority (79%) of the community leaders knew how to recognize a case of AFP and knew that the stool was the specimen required for the investigation, but 21% did not know to whom they should report a case of AFP in their community., Conclusion: This study revealed a gap in the quality indicators for polio eradication in the state, especially regarding knowledge and documentation for AFP surveillance at the operational level. Regular training of the DSNOs and focal persons, regular sensitization of clinicians, community education, supplies of reporting tools, and ensuring their judicious use will improve AFP surveillance in the state.

Background: Nigeria has made remarkable progress in its current efforts to interrupt wild poliovirus transmission despite the re-emergence of wild poliovirus in 2016. The gains made in Nigeria have been achieved through concerted efforts by governments at all levels, traditional leaders, health workers, caregivers, and development partners. The efforts have involved an elaborate plan, coordination, and effective implementation of routine immunization services, supplemental immunization activities, and acute flaccid paralysis (AFP) surveillance., Methods: We conducted the following activities to strengthen AFP surveillance in Kaduna state: a monetary reward for all AFP cases reported by health workers or community informants and verified as "true" AFP by a World Health Organization (WHO) cluster coordinator; training and sensitization of surveillance officers, clinicians, and community informants; recruitment of more personnel and expansion of the surveillance network; and the involvement of special populations (nomadic, hard-to-reach, and border communities) and caregivers in stool sample collection. The paired t test was used to evaluate the impact of the different initiatives implemented in Kaduna state to intensify AFP surveillance in 2016., Results: There was increased annualized non-polio AFP rate (ANPAFPR) in 21 out of 23 Local Government Areas (LGAs) of Kaduna state 6 months after implementation of different initiatives to intensify AFP surveillance. The AFP reported by the special population increased in 15 out of 23 LGAs. Statistical analyses of mean scores of ANPAFPR before and after the interventions using the paired t test revealed a significant difference in mean scores: mean = 19.7 (standard deviation (SD) = 16.1) per 100,000 < 15 years old in July-December 2015, compared with 38.0 (SD = 21.6) per 100,000 < 15 years old in January-June 2016 (p < 0.05). Likewise, analysis of silent wards using the paired t test showed a significant difference in mean scores: mean = 4.0 (SD = 2.1) in July-December 2015 compared with 2.4 (SD = 1.8) in January-June 2016 (p < 0.05)., Conclusion: The different initiatives implemented in 23 LGAs of Kaduna state to intensify AFP surveillance may be responsible for the significant improvement in the AFP surveillance performance indicators in 2016.

Background: Eradication of polio requires that the acute flaccid paralysis (AFP) surveillance system is sensitive enough to detect all cases of AFP, and that such cases are promptly reported and investigated by disease surveillance personnel. When individuals, particularly community informants, are unaware of how to properly detect AFP cases or of the appropriate reporting process, they are unable to provide important feedback to the surveillance network within a country., Methods: We tested a new SMS-based smartphone application (App) that enhances the detection and reporting of AFP cases to improve the quality of AFP surveillance. Nicknamed Auto-Visual AFP Detection and Reporting (AVADAR), the App creates a scenario where the AFP surveillance network is not dependent on a limited number of priority reporting sites. Being installed on the smartphones of multiple health workers (HWs) and community health informants (CHIs) makes the App an integral part of the detection and reporting system., Results: Results from two phases of tests conducted in Nigeria point to the effectiveness of the App in the surveillance of AFP., Conclusion: We posit that appropriate use of the App can soon bring about a worldwide eradication of poliomyelitis.

In August 2018, CDC noted an increased number of reports of patients having symptoms clinically compatible with acute flaccid myelitis (AFM), a rare condition characterized by rapid onset of flaccid weakness in one or more limbs and spinal cord gray matter lesions, compared with August 2017. Since 2014, CDC has conducted surveillance for AFM using a standardized case definition (1,2). An Epi-X* notice was issued on August 23, 2018, to increase clinician awareness and provide guidance for case reporting., Competing Interests: All authors have completed and submitted the ICMJE form for disclosure of potential conflicts of interest. W. Allan Nix reports U.S. Patent Numbers 7,714,122 and 8,048,630, and U.S. Provisional Patent Application Serial Number 62/171,657. No other potential conflicts of interest were disclosed.

Background: A hypotonic hyporesponsive episode (HHE) is a well-described adverse event following immunisation (AEFI) in young children. There is limited data regarding recurrence post re-vaccination., Method: A retrospective analysis of HHEs reported to two tertiary paediatric hospitals in Australia: The Royal Children's Hospital, Melbourne [2006-11] and the Children's Hospital Westmead, Sydney [1997-2014]. HHE definition level of confidence was allocated according to Brighton Collaboration (BC) criteria and defined immediate if within 30 min post vaccination. The Australian Immunisation Register (AIR) was utilised to document current immunisation status., Results: 235 HHE cases (135 Melbourne, 100 Sydney) were identified: 47% were female and 67% (157/235) occurred following the routine dose one vaccines at 6-8 weeks of age. Median time following immunisation was 120 min (range 1 min to 14 days) An immediate HHE occurred in 43% (102/235) and by BC criteria, 74% (173/235) were level 1 (definite). Subsequent vaccines were administered under supervision in hospital in 37% overall (86/235); 43% (58/135) in Melbourne and 28% (28/100) in Sydney. HHE recurrence rate was 3% (7/235) [95% confidence interval 1-6%]. AIR records were available in 94% (221/235). At a median age of 3.1 years, 84% (186/221) were up-to-date with recommended vaccines., Conclusion: This study highlights the importance of specialist immunization clinics in supporting the National Immunisation Program, through follow-up and management of serious adverse events following immunization., (Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.)

Aims: We sought to determine if some unclassified renal cell carcinomas (RCCs) in children and young adults that are characterised by predominantly eosinophilic cytoplasm are related to the recently described succinate dehydrogenase (SDH)-deficient RCC, fumarate hydratase (FH)-deficient RCC or eosinophilic solid and cystic (ESC) RCC., Methods and Results: We reviewed 33 unclassified RCCs with predominantly eosinophilic cytoplasm in patients aged 35 years or younger. Immunohistochemistry (IHC) for SDHB, FH and CK20 (a marker of ESC) was performed in all cases. IHC for 2-succinocysteine (2SC) was performed on RCC with loss of FH labelling. Four RCC (12%) (median age 18 years) demonstrated loss of FH labelling as well as aberrant 2SC labelling, and were thus classified as FH-deficient RCCs. Importantly, none of these cases demonstrated the characteristic macronucleoli typical of FH-deficient RCC. Eight RCC (24%) (median age 20.5 years) demonstrated loss of SDHB and were reclassified as SDH-deficient RCCs. Importantly, only four of eight SDH-deficient RCC demonstrated the characteristic cytoplasmic vacuoles and inclusions of typical SDH-deficient RCC. Ten RCC (30%) (median age 27 years) were reclassified as ESC RCCs. Four of 10 ESC RCC were multifocal (one bilateral), four of 10 ESC RCC occurred in males and one patient presented with liver and lung metastases, all not described previously in ESC. Eleven RCC (33%) remained unclassified., Conclusions: Pathologists should have a low threshold for performing FH, SDHB and CK20 IHC when confronted with unclassified eosinophilic RCC or 'oncocytoma' in young patients., (© 2017 John Wiley & Sons Ltd.)

Background: Acute flaccid myelitis (AFM) is an acute flaccid paralysis syndrome with spinal motor neuron involvement of unknown etiology. We investigated the characteristics and prognostic factors of AFM clusters coincident with an enterovirus D68 (EV-D68) outbreak in Japan during autumn 2015., Methods: An AFM case series study was conducted following a nationwide survey from August to December 2015. Radiographic and neurophysiologic data were subjected to centralized review, and virology studies were conducted for available specimens., Results: Fifty-nine AFM cases (58 definite, 1 probable) were identified, including 55 children and 4 adults (median age, 4.4 years). The AFM epidemic curve showed strong temporal correlation with EV-D68 detection from pathogen surveillance, but not with other pathogens. EV-D68 was detected in 9 patients: 5 in nasopharyngeal, 2 in stool, 1 in cerebrospinal fluid (adult case), and 1 in tracheal aspiration, nasopharyngeal, and serum samples (a pediatric case with preceding steroid usage). Cases exhibited heterogeneous paralysis patterns from 1- to 4-limb involvement, but all definite cases had longitudinal spinal gray matter lesions on magnetic resonance imaging (median, 20 spinal segments). Cerebrospinal fluid pleocytosis was observed in 50 of 59 cases (85%), and 8 of 29 (28%) were positive for antiganglioside antibodies, as frequently observed in Guillain-Barré syndrome. Fifty-two patients showed variable residual weakness at follow-up. Good prognostic factors included a pretreatment manual muscle strength test unit score >3, normal F-wave persistence, and EV-D68-negative status., Conclusions: EV-D68 may be one of the causative agents for AFM, while host susceptibility factors such as immune response could contribute to AFM development., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Pityriasis rosea (PR) is a self-limiting exanthematous disease associated with human herpesvirus (HHV)-6 and/or HHV-7 reactivation. In pregnant women, PR may be associated with pregnancy complications., Objective: To determine relevant risk factors in the development of negative pregnancy outcome in PR., Methods: Between 2005 and 2017 at the Department of Dermatology, University of Genoa, we recruited 76 women who developed PR during pregnancy. In 60 patients without known risk factors for intrauterine fetal death (30 with pregnancy complications and 30 without) we analyzed the pregnancy week of PR onset, presence of enanthem and of constitutional symptoms, PR body surface area involvement, age, and in 50 patients (20 with pregnancy complications and 30 without), the viral load of HHV-6 and HHV-7 (copies/mL)., Results: In logistic regression analysis, early onset of PR (p = 0.0017) and enanthem (p = 0.0392) proved to be significantly associated with pregnancy complications. HHV-6 viral load (copies/mL) (p < 0.0001), constitutional symptoms (p < 0.001), and PR body surface area involvement (p < 0.004) were also significantly associated with pregnancy complications., Conclusion: The onset of PR before week 15 and enanthem may be considered major risk factors that should alarm the dermatologist. Constitutional symptoms and involvement of > 50% of the body area may be considered minor risk factors., (© 2018 S. Karger AG, Basel.)

Purpose: To investigate the prevalence of eyelid laxity and quantify eyelid measurements in normal and keratoconic eyes and the correlations of these findings with ophthalmic parameters and disease severity in patients with keratoconus (KC)., Methods: In a prospective case-control study, prevalence of eyelid laxity and eyelid measurements were evaluated in 53 patients with KC and the same number of matched healthy controls. The eyelid measurements were compared between the groups, as well as mean keratometry (K), central and thinnest corneal thickness (CCT and TCT), astigmatism, manifest refraction spherical equivalent (MRSE), best spectacle-corrected visual acuity (BCVA), and severity of KC according to the Keratoconus Severity Score., Results: Prevalence of eyelid laxity was 71.7% (38 patients) in patients with KC and 20.8% (11 patients) in normal participants (p<0.001, odds ratio 9.673 [95% confidence interval 3.959 to 23.631]). Comparison of the eyelid measurements in the patients with KC with and without eyelid laxity revealed significantly higher measurements of anterior eyelid distraction test, Hertel exophthalmometry measurements, lateral canthal angle to orbital rim and tendon movement, palpebral fissure width, retraction test (lower eyelid), and vertical lid pull (upper eyelid) in patients with KC with eyelid laxity (p<0.05). No significant difference was found regarding mean K, CCT, TCT, astigmatism, MRSE, or BCVA values of the patients with KC with and without eyelid laxity (p>0.05). Moreover, severity of KC was not associated with the presence of eyelid laxity or eyelid measurements (p>0.05)., Conclusions: Higher prevalence and greater eyelid laxity were found in patients with KC compared to healthy participants. However, eyelid laxity was not associated with severity of KC.

Acute flaccid paralysis (AFP) surveillance is a key strategy used by the Global Polio Eradication Initiative (GPEI) to measure progress towards reaching the global eradication goal. Supported by a global polio laboratory network, AFP surveillance is conducted in 179 of 194 WHO member states. Active surveillance visits to priority health facilities are used to assure all children <15 years with AFP are detected, followed by stool specimen collection and testing for poliovirus in WHO-accredited polio laboratories. The quality of AFP surveillance is regularly monitored with standardized surveillance quality indicators. In highest risk countries and areas, the sensitivity of AFP surveillance is enhanced by environmental surveillance (testing of sewage samples). Genetic sequencing of detected poliovirus isolates yields programmatically important information on polio transmission pathways. AFP surveillance is one of the most valuable assets of the GPEI, with the potential to serve as a platform to build integrated disease surveillance systems. Continued support to maintain AFP surveillance systems will be essential, to reliably monitor the completion of global polio eradication, and to assure that a key resource for building surveillance capacity is transitioned post-eradication to support other health priorities., (© The Author 2017. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Prader Willi syndrome, resulting from the partial deletion or lack of expression of a region of genes on the paternal chromosome 15, has a number of phenotypic features which predispose affected patients to ventilatory problems. These include generalised hypotonia, abnormal arousal and ventilatory responses to hypoxia and hypercapnia, scoliosis and frequently, obesity. The spectrum of the resulting respiratory complications thus runs from sleep disordered breathing, to aspiration and respiratory functional impairment. While the use of growth hormone, in conjunction with multidisciplinary clinical management, is currently the cornerstone of clinical care of these patients, concerns have been raised following reports of sudden death shortly after growth hormone initiation. This review summarizes the respiratory complications commonly seen and draws together the published literature on the impact of growth hormone in relation to various respiratory parameters, aiming to provide the reader with the necessary information to manage these patients as safely as possible., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Routine mass immunization programs have contributed greatly to the control of infectious diseases and to the improvement of the health of populations. Over the last decades, the rise of antivaccination movements has threatened the advances made in this field to the point that vaccination coverage rates have decreased and outbreaks of vaccine-preventable diseases have resurfaced. One of the critical points of the immunization debate revolves around the level of risk attributable to vaccination, namely the possibility of experiencing serious and possibly irreversible adverse events. Unfortunately, the knowledge about adverse events, especially rare ones, is usually incomplete at best and the attribution of a causal relationship with vaccinations is subject to significant uncertainties. The aim of this paper is to provide a narrative review of seven rare or very rare adverse events: hypotonic hyporesponsive episode, multiple sclerosis, apnea in preterm newborns, Guillain-Barré syndrome, vasculitides, arthritis/ arthralgia, immune thrombocytopenic purpura. We have selected these adverse events based on our experience of questions asked by health care workers involved in vaccination services. Information on the chosen adverse events was retrieved from Medline using appropriate search terms. The review is in the form of questions and answers for each adverse event, with a view to providing useful and actionable concepts while not ignoring the uncertainties that remain. We also highlight in the conclusion possible future improvements to adverse event detection and assessment that could help identify individuals at higher risk against the probable future backdrop of ever-greater abandonment of compulsory vaccination policies.

Background: During late summer/fall 2014, pediatric cases of acute flaccid myelitis (AFM) occurred in the United States, coincident with a national outbreak of enterovirus D68 (EV-D68)-associated severe respiratory illness., Methods: Clinicians and health departments reported standardized clinical, epidemiologic, and radiologic information on AFM cases to the Centers for Disease Control and Prevention (CDC), and submitted biological samples for testing. Cases were ≤21 years old, with acute onset of limb weakness 1 August-31 December 2014 and spinal magnetic resonance imaging (MRI) showing lesions predominantly restricted to gray matter., Results: From August through December 2014, 120 AFM cases were reported from 34 states. Median age was 7.1 years (interquartile range, 4.8-12.1 years); 59% were male. Most experienced respiratory (81%) or febrile (64%) illness before limb weakness onset. MRI abnormalities were predominantly in the cervical spinal cord (103/118). All but 1 case was hospitalized; none died. Cerebrospinal fluid (CSF) pleocytosis (>5 white blood cells/µL) was common (81%). At CDC, 1 CSF specimen was positive for EV-D68 and Epstein-Barr virus by real-time polymerase chain reaction, although the specimen had >3000 red blood cells/µL. The most common virus detected in upper respiratory tract specimens was EV-D68 (from 20%, and 47% with specimen collected ≤7 days from respiratory illness/fever onset). Continued surveillance in 2015 identified 16 AFM cases reported from 13 states., Conclusions: Epidemiologic data suggest this AFM cluster was likely associated with the large outbreak of EV-D68-associated respiratory illness, although direct laboratory evidence linking AFM with EV-D68 remains inconclusive. Continued surveillance will help define the incidence, epidemiology, and etiology of AFM., (Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Aim: To describe the distribution of impairments among persons with cerebral palsy (CP) in a large Australian cohort., Method: Records of persons on the Australian Cerebral Palsy Register (ACPR) (n=3466) born from 1996 to 2005 were reviewed to extract year of birth, sex, CP subtype, Gross Motor Function Classification System (GMFCS) level, and impairments in vision, hearing, speech, intellect, and epilepsy. The distributions of GMFCS levels and CP subtype were plotted, and the proportions of each level of impairment were tabulated and presented as stacked graphs within the GMFCS and CP subtype distributions., Results: The proportions of persons with CP with each associated impairment increased with increasing GMFCS level. Compared with other spastic CP subtypes, individuals with spastic quadriplegia had higher frequencies of all associated impairments. Other than epilepsy, which was most prevalent in persons with spastic quadriplegia (53%), all impairments were most frequent in non-spastic CP subtypes. Hearing impairment was recorded for 21% of persons with dyskinesia whereas the hypotonic subtype had the highest prevalence of visual impairment (57%), intellectual impairment (90%), and speech impairment (95%)., Interpretation: Distributions of associated impairments across all GMFCS levels and CP subtypes in a large cohort are presented in formats suitable for clinical use and discussion with families., (© 2016 The Authors. Developmental Medicine & Child Neurology © 2016 Mac Keith Press.)

Protein phosphatase 2A (PP2A) is a heterotrimeric protein serine/threonine phosphatase and is involved in a broad range of cellular processes. PPP2R5D is a regulatory B subunit of PP2A and plays an important role in regulating key neuronal and developmental regulation processes such as PI3K/AKT and glycogen synthase kinase 3 beta (GSK3β)-mediated cell growth, chromatin remodeling, and gene transcriptional regulation. Using whole-exome sequencing (WES), we identified four de novo variants in PPP2R5D in a total of seven unrelated individuals with intellectual disability (ID) and other shared clinical characteristics, including autism spectrum disorder, macrocephaly, hypotonia, seizures, and dysmorphic features. Among the four variants, two have been previously reported and two are novel. All four amino acids are highly conserved among the PP2A subunit family, and all change a negatively charged acidic glutamic acid (E) to a positively charged basic lysine (K) and are predicted to disrupt the PP2A subunit binding and impair the dephosphorylation capacity. Our data provides further support for PPP2R5D as a genetic cause of ID.

Importance: There has been limited surveillance for acute flaccid paralysis in North America since the regional eradication of poliovirus. In 2012, the California Department of Public Health received several reports of acute flaccid paralysis cases of unknown etiology., Objective: To quantify disease incidence and identify potential etiologies of acute flaccid paralysis cases with evidence of spinal motor neuron injury., Design, Setting, and Participants: Case series of acute flaccid paralysis in patients with radiological or neurophysiological findings suggestive of spinal motor neuron involvement reported to the California Department of Public Health with symptom onset between June 2012 and July 2015. Patients meeting diagnostic criteria for other acute flaccid paralysis etiologies were excluded. Cerebrospinal fluid, serum samples, nasopharyngeal swab specimens, and stool specimens were submitted to the state laboratory for infectious agent testing., Main Outcomes and Measures: Case incidence and infectious agent association., Results: Fifty-nine cases were identified. Median age was 9 years (interquartile range [IQR], 4-14 years; 50 of the cases were younger than 21 years). Symptoms that preceded or were concurrent included respiratory or gastrointestinal illness (n = 54), fever (n = 47), and limb myalgia (n = 41). Fifty-six patients had T2 hyperintensity of spinal gray matter on magnetic resonance imaging and 43 patients had cerebrospinal fluid pleocytosis. During the course of the initial hospitalization, 42 patients received intravenous steroids; 43, intravenous immunoglobulin; and 13, plasma exchange; or a combination of these treatments. Among 45 patients with follow-up data, 38 had persistent weakness at a median follow-up of 9 months (IQR, 3-12 months). Two patients, both immunocompromised adults, died within 60 days of symptom onset. Enteroviruses were the most frequently detected pathogen in either nasopharynx swab specimens, stool specimens, serum samples (15 of 45 patients tested). No pathogens were isolated from the cerebrospinal fluid. The incidence of reported cases was significantly higher during a national enterovirus D68 outbreak occurring from August 2014 through January 2015 (0.16 cases per 100,000 person-years) compared with other monitoring periods (0.028 cases per 100,000 person-years; P <.001)., Conclusions and Relevance: In this series of patients identified in California from June 2012 through July 2015, clinical manifestations indicated a rare but distinct syndrome of acute flaccid paralysis with evidence of spinal motor neuron involvement. The etiology remains undetermined, most patients were children and young adults, and motor weakness was prolonged.

Background: 'Profound intellectual and multiple disability' (PIMD) is defined as a profound cognitive disability with severe sensory and motor impairments. The aim of this study was to evaluate the respiratory morbidity in children with PIMD and investigate possible risk factors., Methods: In 10 specialized facilities for daily care of patients with PIMD, children underwent a standardized clinical assessment evaluating respiratory and motor function. Additional medical information was obtained., Results: One hundred and twenty seven children aged 2-21 years were tested (median age 12 years; IQR 8-16). 72% had epilepsy, 42% were gastrostomy fed. The median number of lower airway infection per years was four (IQR 1-4). While 68% of patient had no hospital admissions for respiratory disease, 12% of patients were admitted three times or more. Chronic antibiotic therapy was prescribed to nine patients (7%), and 19 patients (15%) were chronically treated with mucolytics, inhaled corticosteroids and/or bronchodilators. Chest physiotherapy was given daily to 26 patients (22%). Gastroesophageal reflux, swallowing problem and aspiration increased the risk for hospital admissions. Additionally risk factors were the severity of disability, axial hypotonia, presence of epilepsy, scoliosis, limited shoulder movement, paradoxical breathing and absence of a spontaneous cough reflex., Conclusion: The overall respiratory morbidity in our sample of children with PIMD was lower than anticipated. While a subgroup of children are prone to recurrent severe airway problems, the majority of children did not experience severe airway infections., (© 2014 Wiley Periodicals, Inc.)