Management and outcomes of obstructive sleep apnea in infants.

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 χ2 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 χ2 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.

A nationwide survey of monocarboxylate transporter 8 deficiency in Japan: Its incidence, clinical course, MRI and laboratory findings.

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.

Coding and noncoding variants in EBF3 are involved in HADDS and simplex autism.

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.

[Characterization of hypotonia-hyporesponsiveness after pentavalent vaccine and neurodevelopmental screening in children under 6 years of age, 2013-2018, Uruguay]. / Caracterización de la hipotonía-hiporrespuesta post vacuna pentavalente y tamizaje del neurodesarrollo en niños bajo 6 años de edad, 2013-2018, Uruguay.

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.

Caracterización de la hipotonía-hiporrespuesta post vacuna pentavalente y tamizaje del neurodesarrollo en niños bajo 6 años de edad, 2013-2018, Uruguay / Characterization of hypotonia-hyporesponsiveness after pentavalent vaccine and neurodevelopmental screening in children under 6 years of age, 2013-2018, Uruguay

INTRODUCCIÓN: La hipotonía-hiporrespuesta (HHR) es uno de los efectos adversos supuestamente atribuibles a la vacunación e inmunización de tipo neurológico más notificados. El impacto a largo plazo a nivel del neurodesarrollo no es completamente conocida. OBJETIVO: Caracterizar los eventos de HHR post vacuna pentavalente notificados entre 2014 y 2018 al Ministerio de Salud Pública (MSP) de Uruguay. Realizar el tamizaje del neurodesarrollo de los que al momento de la evaluación tenían menos de 6 años de edad. METODOLOGÍA: Estudio descriptivo de las notificaciones al Sistema Nacional de Farmacovigilancia del MSP. Se realizó el tamizaje del neurodesarrollo con la Guía Nacional para la Vigilancia del Desarrollo. RESULTADOS: 30 casos, la mayoría de breve duración, en las primeras horas post primera dosis y con recuperación espontánea. Requirieron hospitalización 29. Se realizó el tamizaje del neurodesarrollo en 16. La media de tiempo entre el evento y esta evaluación fue 2 años y 2 meses. Fue normal la prueba de tamizaje en 15. En uno se detectó un retraso del lenguaje. CONCLUSIONES: Los episodios de HHR se presentaron con características similares a las descritas en la bibliografía. A pesar de las limitaciones del estudio, no se encontraron retrasos ni desvíos del desarrollo en los niños evaluados.

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.

Understanding the phenotypic spectrum of ASXL-related disease: Ten cases and a review of the literature.

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.

Outcomes of the Deployment of the Auto-Visual Acute Flaccid Paralysis Detection and Reporting (AVADAR) System for Strengthening Polio Surveillance in Africa From 2017 to 2018: Evaluation Study.

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.

The Acute Flaccid Paralysis (AFP) Surveillance System in Yemen, 2010-2015: Descriptive Study Based on Secondary Data Analysis.

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.

Strabismus in Children With Intellectual Disability: Part of a Broader Motor Control Phenotype?

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.

Brief Resolved Unexplained Events: Analysis of an Apparent Life Threatening Event Database.

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.

Frequency and characteristic features of REM sleep without atonia.

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 ±â€¯4.8 (iRSWA subjects) and 7.5 ±â€¯4.9 (controls), p = 0.014. Mean Beck Depression Inventory-II scores were 11.3 ±â€¯7.9 (iRSWA subjects) and 9.5 ±â€¯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.

A 5-year study of human parechoviruses in children living in bad sanitation conditions and non-polio acute flaccid paralysis children from Greece.

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.

Neurodevelopment medium-term outcome after parechovirus infection.

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.

An increase in reports of acute flaccid paralysis (AFP) in the United Kingdom, 1 January 2018-21 January 2019: early findings.

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.

Loss of function of SVBP leads to autosomal recessive intellectual disability, microcephaly, ataxia, and hypotonia.

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.

Assessment of Current Epidemiology and Risk Factors Surrounding Brachial Plexus Birth Palsy.

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.

Identifying Associations Among Co-Occurring Medical Conditions in Children With Autism Spectrum Disorders.

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.

Clinical variability in inherited glycosylphosphatidylinositol deficiency disorders.

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.

Musculoskeletal anomalies in children with Down syndrome: an observational study.

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.