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To evaluate if autism symptoms and diagnoses are more common in children with neurofibromatosis type 1 (NF1) than in typically developing children, to which levels, and to determine if co-occurring attention-deficit/hyperactivity disorder (ADHD) symptomatology accounts for this increase.We searched hospital electronic medical records (EMR) for International Classification of Diseases, 10th Revision NF1 and co-occurring diagnoses codes. We recruited a subsample of 45 children (mean age 9y 2mo; SD 2y 7mo; range 5-12y; 22 males, 23 females) and collected parental reports of autism symptomatology, adaptive behavior, and behavioral problems that were compared to those of 360 age- and sex-matched controls from the Simons Simplex Collection (SSC) with autism spectrum disorder (ASD; SSC-ASD) or typically developing (SSC-TD).The EMR search identified 968 children with NF1; 8.8% had ADHD and 2.1% had ASD co-occurring diagnoses. In the subsample, the mean autism scale score for participants with NF1 was below cut-off for significant autism symptoms. Participants with NF1 had significantly more autism and behavioral symptoms than SSC-TD participants, and significantly less than SSC-ASD participants, with one exception: ADHD symptom levels were similar to those of SSC-ASD participants. In analyses that controlled for internalizing, ADHD, and communication scores, the difference in autism symptom levels between participants with NF1 and typically developing controls disappeared almost entirely.Our results do not support an association between NF1 and autism, both at the symptom and disorder levels.Diagnoses of attention-deficit/hyperactivity disorder (ADHD) were more common in children with neurofibromatosis type 1 (NF1) than in the general child population. Diagnoses of autism spectrum disorder were no more common in children with NF1 than in the general child population. Increases in autism symptoms did not reach clinically significant thresholds. Co-occurring ADHD symptoms accounted for increased autism questionnaire scores. Adaptive behavior in participants with NF1 showed normal socialization but lower communication proficiency.Evaluar si el diagnóstico y los síntomas de autismo son más frecuentes en niños con neurofibromatosis tipo 1 (NF1) comparado a niños con desarrollo típico, cuáles son los niveles de severidad, y determinar si la sintomatología concurrente debido déficit de atención / hiperactividad (TDAH) explica la frecuencia. MÉTODO: Se realizaron búsquedas en los registros médicos electrónicos hospitalarios (EMR) para el diagnóstico de NF1 y códigos concurrentes en la Clasificación Internacional de Enfermedades, 10ma revisión. Reclutamos una submuestra de 45 niños (edad promedio 9 años 2 meses; DE 2 años 7 meses; rango 5-12 años; 22 varones y 23 mujeres). Recolectamos informes parentales acerca de la sintomatología del autismo, comportamiento adaptativo y problemas de conducta que se compararon con los de 360 niños pareados por edad y sexo provenientes de la Colección Simons Simplex (SSC) de niños con trastorno del espectro autista (SSC-ASD) o de niños con desarrollo típico (SSC-TD).La búsqueda de EMR identificó a 968 niños con NF1; 8,8% tenían TDAH y 2,1% tenían diagnósticos concurrentes de trastorno del espectro autista. En la submuestra de participantes con NF1, la media de puntaje de la escala de autismo fue inferior punto de corte. Los participantes con NF1 tuvieron significativamente más síntomas de autismo y problemas de conducta que los participantes de SSC-TD, y significativamente menos que los participantes de SSC-ASD. Hubo una excepción: los niveles de síntomas de TDAH fueron similares a los de los participantes de SSC-ASD. En los análisis que controlaron los síntomas internalizantes, el TDAH y los puntajes de comunicación, la diferencia en los niveles de síntomas de autismo entre los participantes con NF1 y los controles con desarrollo típico desaparecieron casi por completo. INTERPRETACIÓN: Nuestros resultados no respaldan una asociación entre NF1 y autismo, tanto a nivel de frecuencia de los síntomas, ni con la severidad de los mismos.Avaliar se sintomas e diagnóstico de autismo são mais comuns em crianças com neurofibromtose tipo 1 (NF1) do que em crianças com desenvolvimento típico, em quais níveis, e determinar se co-ocorrência de sintomatologia do transtorno do déficit de atenção e hiperatividade (TDAH) explica este aumento. MÉTODO: Pesquisamos registros médicos eletrônicos (RME) hospitalares quanto aos códigos diagnósticos de NF1 e diagnósticos co-ocorrentes segundo a Classificação Internacional de Doenças, 10ª revisão. Recrutamos uma sub-amostra de 45 crianças (média de idade 9a 2m; DP 2a 7m; variação 5-12a; 22 do sexo masculino, 23 do sexo feminino) e coletamos relatos parentais de sintomatologia de autismo, comportamento adaptativo, e problemas comportamentais quer foram comparados com os 360 controles pareados por sexo e idade da Simons Simplex Collection (SSC) com transtorno do espectro autista (TEA; SSC-TEA) ou desenvolvimento típico (SSC-DT).A busca em RME identificou 968 crianças com NF1; 8,8% tinha TDAH e 2,1% tinha diagnóstico concomitante de TEA. Na sub-amostra, o escore médio de autismo para os participantes com NF1 estava abaixo do ponto de corte para sintomas autistas significantes. Os participantes com NF1 tiveram significativamente mais sintomas de autismo e comportamento do que os participantes SSC-DT, e significativamente menos do que os participantes SSC-TEA, com uma exceção: os níveis de sintomas de TDAH foram similares aos participantes SSC-TEA. Na análise que controlou para escores internalizantes, TDAH e comunicação, a diferença nos níveis de sintomas autistas entre participantes com NF1 e desenvolvimento típico desapareceu quase totalmente. INTERPRETAÇÃO: Nossos resultados não suportam associação entre NF1 e autismo, mas com os sintomas e níveis de desordem.

SHANK3 encodes for a scaffolding protein that links neurotransmitter receptors to the cytoskeleton and is enriched in postsynaptic densities of excitatory synapses. Deletions or mutations in one copy of the SHANK3 gene cause Phelan-McDermid syndrome, also called 22q13.3 deletion syndrome, a neurodevelopmental disorder with common features including global developmental delay, absent to severely impaired language, autistic behavior, and minor dysmorphic features. By whole exome sequencing, we identified two de novo novel variants including one frameshift pathogenic variant and one missense variant of unknown significance in a 14-year-old boy with delayed motor milestones, delayed language acquisition, autism, intellectual disability, ataxia, progressively worsening spasticity of the lower extremities, dysmorphic features, short stature, microcephaly, failure to thrive, chronic constipation, intrauterine growth restriction, and bilateral inguinal hernias. Both changes are within the CpG island in exon 21, separated by a 375 bp sequence. Next generation sequencing of PCR products revealed that the two variants are most frequently associated with each other. Sanger sequencing of the cloned PCR products further confirmed that both changes were on a single allele. The clinical presentation in this individual is consistent with other patients with a truncating mutation in exon 21, suggesting that the missense change contributes none or minimally to the phenotypes. This is the first report of two de novo mutations in one SHANK3 allele.

To assess the frequency of cytogenetic abnormalities in children with autism spectrum disorders (ASDs), routine G-banded cytogenetic analyses and FISH studies to rule out 15q11.2 and 17p11.2 duplications were performed on 49 children with ASDs. Blood samples were further studied using a complete set of subtelomeric FISH probes. Routine chromosome study showed that one child had a small duplication of chromosome 5: 46,XY,dup(5)(p?14.2p?15.1). Another child had an interstitial duplication of the Prader-Willi and Angelman syndrome critical region of chromosome 15, detected by FISH analysis. The detection of these two cases underscores the importance of obtaining routine chromosome and 15q11-q13 FISH analyses in children with ASDs. No instance of 17p11.2 duplication was observed. Subtelomeric analysis did not reveal abnormalities in any of the subjects.

About 1% of individuals with autism or types of pervasive developmental disorder have a duplication of the 15q11-q13 region. These abnormalities can be detected by routine G-banded chromosome study, showing an extra marker chromosome, or demonstrated by fluorescence in situ hybridization (FISH) analysis, revealing an interstitial duplication. We report here the molecular, cytogenetic, clinical and neuropsychiatric evaluations of a family in whom 3 of 4 siblings inherited an interstitial duplication of 15q11-q13. This duplication was inherited from their mother who also had a maternally derived duplication. Affected family members had apraxia of speech, phonological awareness deficits, developmental language disorder, dyslexia, as well as limb apraxia but did not have any dysmorphic clinical features. The observations in this family suggest that the phenotypic manifestations of proximal 15q duplications may also involve language-based learning disabilities.

We report on a 34-year-old developmentally disabled man referred to our clinic for evaluation of possible Prader-Willi syndrome on the basis of obesity and voracious appetite. Cytogenetic and molecular analysis revealed a 47, XYY karyotype and the presence of a trinucleotide repeat expansion resulting in fragile X syndrome. To our knowledge, this is the first report of concurrence of XYY and fragile X syndrome in the medical literature. Review of sex chromosome abnormalities associated with fragile X syndrome and phenotypic considerations are presented.