SummaryBackgroundThe Sustainable Development Goals (SDGs) mandate systematic monitoring of the health and wellbeing of all children to achieve optimal early childhood development. However, global epidemiological data on children with developmental disabilities are scarce. The Global Burden of Diseases, Injuries, and Risk Factors Study 2016 provides a comprehensive assessment of prevalence and years lived with disability (YLDs) for development disabilities among children younger than 5 years in 195 countries and territories from 1990 to 2016.MethodsWe estimated prevalence and YLDs for epilepsy, intellectual disability, hearing loss, vision loss, autism spectrum disorder, and attention deficit hyperactivity disorder. YLDs were estimated as the product of the prevalence estimate and the disability weight for each mutually exclusive disorder, corrected for comorbidity. We used DisMod-MR 2.1, a Bayesian meta-regression tool, on a pool of primary data derived from systematic reviews of the literature, health surveys, hospital and claims databases, cohort studies, and disease-specific registries.FindingsGlobally, 52·9 million (95% uncertainty interval [UI] 48·7–57·3; or 8·4% [7·7–9·1]) children younger than 5 years (54% males) had developmental disabilities in 2016 compared with 53·0 million (49·0–57·1; or 8·9% [8·2–9·5]) in 1990. About 95% of these children lived in low-income and middle-income countries. YLDs among these children increased from 3·8 million (95% UI 2·8–4·9) in 1990 to 3·9 million (2·9–5·2) in 2016. These disabilities accounted for 13·3% of the 29·3 million YLDs for all health conditions among children younger than 5 years in 2016. Vision loss was the most prevalent disability, followed by hearing loss, intellectual disability, and autism spectrum disorder. However, intellectual disability was the largest contributor to YLDs in both 1990 and 2016. Although the prevalence of developmental disabilities among children younger than 5 years decreased in all countries (except for North America) between 1990 and 2016, the number of children with developmental disabilities increased significantly in sub-Saharan Africa (71·3%) and in North Africa and the Middle East (7·6%). South Asia had the highest prevalence of children with developmental disabilities in 2016 and North America had the lowest.InterpretationThe global burden of developmental disabilities has not significantly improved since 1990, suggesting inadequate global attention on the developmental potential of children who survived childhood as a result of child survival programmes, particularly in sub-Saharan Africa and south Asia. The SDGs provide a framework for policy and action to address the needs of children with or at risk of developmental disabilities, particularly in resource-poor countries.FundingThe Bill & Melinda Gates Foundation.

BackgroundPontocerebellar hypoplasia (PCH) represents a group of neurodegenerative disorders with prenatal onset. Eight subtypes have been described thus far (PCH1-8) based on clinical and genetic features. Common characteristics include hypoplasia and atrophy of the cerebellum, variable pontine atrophy, and severe mental and motor impairments. PCH1 is distinctly characterized by the combination with degeneration of spinal motor neurons. Recently, mutations in the exosome component 3 gene (EXOSC3) have been identified in approximately half of the patients with PCH subtype 1.MethodsWe selected a cohort of 99 PCH patients (90 families) tested negative for mutations in the TSEN genes, RARS2, VRK1 and CASK. Patients in this cohort were referred with a tentative diagnose PCH type 1, 2, 4, 7 or unclassified PCH. Genetic analysis of the EXOSC3 gene was performed using Sanger sequencing. Clinical data, MR images and autopsy reports of patients positive for EXOSC3 mutations were analyzed.ResultsEXOSC3 mutations were found in twelve families with PCH subtype 1, and were not found in patients with other PCH subtypes. Identified mutations included a large deletion, nonsense and missense mutations. Examination of clinical data reveals a prolonged disease course in patients with a homozygous p.D132A mutation. MRI shows variable pontine hypoplasia in EXOSC3 mediated PCH, where the pons is largely preserved in patients with a homozygous p.D132A mutation, but attenuated in patients with other mutations. Additionally, bilateral cerebellar cysts were found in patients compound heterozygous for a p.D132A mutation and a nonsense allele.ConclusionsEXOSC3 mediated PCH shows clear genotype-phenotype correlations. A homozygous p.D132A mutation leads to PCH with possible survival into early puberty, and preservation of the pons. Compound heterozygosity for a p.D132A mutation and a nonsense or p.Y109N allele, a homozygous p.G31A mutation or a p.G135E mutation causes a more rapidly progressive course leading to death in infancy and attenuation of the ventral pons.Our findings imply a clear correlation between genetic mutation and clinical outcome in EXOSC3 mediated PCH, including variable involvement of the pons.

BACKGROUND: Estimates of children and adolescents with disabilities worldwide are needed to inform global intervention under the disability-inclusive provisions of the Sustainable Development Goals. We sought to update the most widely reported estimate of 93 million children ,15 years with disabilities from the Global Burden of Disease Study 2004. METHODS: We analyzed Global Burden of Disease Study 2017 data on the prevalence of childhood epilepsy, intellectual disability, and vision or hearing loss and on years lived with disability (YLD) derived from systematic reviews, health surveys, hospital and claims databases, cohort studies, and disease-specific registries. Point estimates of the prevalence and YLD and the 95% uncertainty intervals (UIs) around the estimates were assessed. RESULTS: Globally, 291.2 million (11.2%) of the 2.6 billion children and adolescents (95% UI: 249.9-335.4 million) were estimated to have 1 of the 4 specified disabilities in 2017. The prevalence of these disabilities increased with age from 6.1% among children aged ,1 year to 13.9% among adolescents aged 15 to 19 years. A total of 275.2 million (94.5%) lived in lowand middle-income countries, predominantly in South Asia and sub-Saharan Africa. The top 10 countries accounted for 62.3% of all children and adolescents with disabilities. These disabilities accounted for 28.9 million YLD or 19.9% of the overall 145.3 million (95% UI: 106.9-189.7) YLD from all causes among children and adolescents. CONCLUSIONS: The number of children and adolescents with these 4 disabilities is far higher than the 2004 estimate, increases from infancy to adolescence, and accounts for a substantial proportion of all-cause YLD. WHAT'S KNOWN ON THIS SUBJECT: The World Disability Report 2011 indicated that at least 93 million (∼5.1%) children ,15 years old had a moderate-to-severe disability and 13 million (0.7%) had a severe disability on the basis of the Global Burden of Disease Study 2004. WHAT THIS STUDY ADDS: More than 291 million children aged ,20 years had epilepsy and intellectual and sensory disabilities in 2017. The top 10 countries accounted for 62% of the children with these disabilities, and 95% lived in low and middle income countries.

Juvenile polyps are present in a number of Mendelian disorders, sometimes in association only with gastrointestinal cancer [juvenile polyposis syndrome (JPS)] and sometimes as part of known syndromes (Cowden, Gorlin and Banayan-Zonana) in association with developmental abnormalities, dysmorphic features or extra-intestinal tumours. Recently, a gene for JPS was mapped to 18q21.1 and the candidate gene DPC4 (SMAD4) was shown to carry frameshift mutations in some JPS families. We have analysed eight JPS families for linkage to DPC4. Overall, there was no evidence for linkage to DPC4; linkage could be excluded in two of the eight pedigrees and was unlikely in two others. We then tested these eight families and a further 13 familial and sporadic JPS cases for germline mutations in DPC4. Just one germline DPC4 mutation was found (in a familial JPS patient from a pedigree unsuitable for linkage analysis). Like all three previously reported germline mutations, this variant occurred towards the C-terminus of the DPC4 protein. However, our patient's mutation is a missense change (R361C); somatic missense mutations in DPC4 have been reported previously in tumours. We therefore confirm DPC4 as a cause of JPS, but show that there is considerable remaining, uncharacterized genetic heterogeneity in this disease.

Accelerating progress on early childhood development for children under 5 years with disabilities by 2030The Global Research on Developmental Disabilities Collaborators*The likelihood of a newborn child dying before their fifth birthday (under-5 mortality rate) is universally acknowledged as a reflection of the social, economic, health, and environmental conditions in which children (and the rest of society) live, but little is known about the likelihood of a newborn child having a lifelong disability before their fifth birthday if he or she survives. Available data show that globally the likelihood of a child having a disability before their fifth birthday was ten times higher than the likelihood of dying ( 377•2 vs 38•2 per 1000 livebirths) in 2019. However, disability funding declined by 11•4% between 2007 and 2016, and only 2% of the estimated US$79•1 billion invested in early childhood development during this period was spent on disabilities. This funding pattern has not improved since 2016. This paper highlights the urgent need to prioritise early childhood development for the beneficiaries of global child survival initiatives who have lifelong disabilities, especially in low-income and middle-income countries, as envisioned by the Sustainable Development Goals agenda. This endeavour would entail disability-focused programming and monitoring approaches, economic analysis of interventions services, and substantial funding to redress the present inequalities among this cohort of children by 2030.