Early Diagnostic Signs and the Natural History of Typical Findings in Cohen Syndrome.

OBJECTIVE: To describe the clinical presentation and long-term clinical features of a molecularly confirmed cohort with Cohen syndrome. STUDY DESIGN: Twelve patients with Cohen syndrome aged 0.2-13.9 years from 8 families with a median follow-up of 7 years were enrolled to the study. Genetic analyses were made by VPS13B and whole-exome sequencing analyses. RESULTS: Biallelic VPS13B variants, including 3 nonsense, 1 frameshift, and 1 splice-site variant, and a multiexon deletion were detected. Prader-Willi syndrome-like features such as hypotonia, small hands, round face with full cheeks, almond-shaped eyes, and micrognathia were observed in all infantile patients. Beginning from age 4 years, it was noticed that the face gradually elongated and became oval. The typical facial features of Cohen syndrome such as a long face, beak-shaped nose, and open-mouth appearance with prominent upper central incisors became evident at age 9. Other Cohen syndrome features including retinopathy (11/11), neutropenia (11/12), truncal obesity (5/12), and myopia (5/11) were detected at the median ages of 7.8, 7, 7.5, and 5 years, respectively. Eleven patients aged older than 5 years at their last examination had severe speech delay. CONCLUSIONS: A differential diagnosis of Cohen syndrome in the infancy should be made with Prader-Willi syndrome, and that the typical facial features for Cohen syndrome is prominent at age 9 years, when retinopathy, neutropenia, and truncal obesity become evident. Moreover, adding the severe speech delay to the diagnostic criteria should be considered.

Two novel pathogenic variants in MED13L: one familial and one isolated case.

BACKGROUND: Genetic variants involving the MED13L gene can lead to an autosomal dominant syndrome characterised by intellectual disability/developmental delay and facial dysmorphism. METHODS: We investigated two cases (one familial and one isolated) of intellectual disability with speech delay and dysmorphic facial features by whole-exome sequencing analyses. Further, we performed a literature review about clinical and molecular aspects of MED13L gene and syndrome. RESULTS: Two MED13L variants have been identified [MED13L(NM_015335.5):c.4417C>T and MED13L(NM_015335.5):c.2318delC] and were classified as pathogenic according to the ACMG (American College of Medical Genetics and Genomics) guidelines. One of the variants was present in sibs. CONCLUSIONS: The two pathogenic variants identified have not been previously reported. Importantly, this is the first report of a familial case of MED13L nonsense mutation. Although the parents of the affected children were no longer available for analysis, their apparently normal phenotypes were surmised from familial verbal descriptions corresponding to normal mental behaviour and phenotype. In this situation, the familial component of mutation transmission might be caused by gonadal mosaicism of a MED13L mutation in a gonad from either the father or the mother. The case reports and the literature review presented in this manuscript can be useful for genetic counselling.

Comparison of anxiety and child-care education characteristics of mothers who have children with or without speech delays / Comparação da ansiedade e características da educação infantil em mães com filhos com ou sem atrasos na fala

Abstract Introduction: Speech delay in a child could be the cause and/or result of the emotional disorder. The child rearing attitude that the parents have accepted could have both positive and negative effects on the personality of the child. Objective: The current study aimed to investigate the sociodemographic features and the mothers' anxiety of children with speech delay. Methods: One hundred five mothers with children aged between 3 and 6 years with speech delays were included in the patient group, and 105 mothers who have children aged between 3 and 6 years with normal speech and language development were included in the control group. An information form questionnaire including demographic characteristics, the Family Life and Childrearing Attitude Scale (PARI - Parental Attitude Research Instrument) and Beck anxiety scale were requested from all mothers in the patient and the control groups. Results: In the current study, there was a significant difference between the groups in terms of gender (p = 0.001). According to Parental Attitude Research Instrument, the mean of mothers of the children with speech delays was higher than the mean of mothers of normal children in terms of the answers to overprotective mother aspect (p < 0.01). The mothers of children with speech delays had more overprotective motherhood attitudes; however, the difference in terms of the answers to the aspects of democratic attitude and provision of equality, refusal to be a housewife, husband-wife conflict, and suppression and discipline were not statistically significant. The Beck anxiety scale, a significant difference was detected between the two groups (p < 0.01). It was found that the mothers of children with speech delays had more severe levels of anxiety. Conclusion: The social structure of the family, the attitudes and the behaviors of the mother, and the anxiety levels of the mothers have important effects on child development. Thus, it is necessary to perform further studies related to speech delays, in which many factors play a role in the etiology.

Resumo Introdução: O atraso da fala em uma criança pode ser a causa e/ou o resultado de distúrbio emocional. As atitudes tomadas pelos pais na educação da criança podem ter efeitos positivos e negativos sobre a personalidade infantil. Objetivo: Investigar as características sociodemográficas e a ansiedade das mães de crianças com atraso na fala. Método: Foram incluídas no grupo de pacientes 105 mães com crianças entre 3 e 6 anos de idade e atrasos na fala e no grupo controle 105 mães com crianças na mesma faixa etária e desenvolvimento normal da fala e da linguagem. Foi solicitado às mães de ambos os grupos o preenchimento de informações em um formulário, incluindo características demográficas, o instrumento Family Life and Child Rearing Attitude Scale (PARI - Parental Attitude Research Instrument) e o inventário de ansiedade Beck. Resultados: No estudo atual, houve diferença significativa entre os grupos em relação ao gênero (p = 0,001). De acordo com o instrumento Parental Attitude Research Instrument, a média das mães das crianças com atrasos na fala foi maior do que a média das mães de crianças normais em relação às respostas sobre superproteção materna (p < 0,01). As mães de crianças com atrasos na fala apresentaram mais atitudes de proteção materna excessiva; no entanto, a diferença das respostas sobre atitudes democráticas e igualitarismo, recusa do papel de dona de casa, conflito marital e disciplina rígida não foram estatisticamente significantes. No inventário de ansiedade de Beck foi encontrada uma diferença significativa entre os dois grupos (p < 0,01). Verificou-se que as mães de crianças com atrasos na fala apresentavam níveis mais graves de ansiedade. Conclusão: A estrutura social da família, as atitudes, o comportamento e os níveis de ansiedade das mães têm efeitos importantes no desenvolvimento da criança. Conclui-se, portanto, a necessidade de realizar estudos adicionais relacionados aos atrasos na fala, nos quais diversos fatores desempenham um papel etiológico.

Comparison of anxiety and child-care education characteristics of mothers who have children with or without speech delays.

INTRODUCTION: Speech delay in a child could be the cause and/or result of the emotional disorder. The child rearing attitude that the parents have accepted could have both positive and negative effects on the personality of the child. OBJECTIVE: The current study aimed to investigate the sociodemographic features and the mothers' anxiety of children with speech delay. METHODS: One hundred five mothers with children aged between 3 and 6 years with speech delays were included in the patient group, and 105 mothers who have children aged between 3 and 6 years with normal speech and language development were included in the control group. An information form questionnaire including demographic characteristics, the Family Life and Childrearing Attitude Scale (PARI - Parental Attitude Research Instrument) and Beck anxiety scale were requested from all mothers in the patient and the control groups. RESULTS: In the current study, there was a significant difference between the groups in terms of gender (p=0.001). According to Parental Attitude Research Instrument, the mean of mothers of the children with speech delays was higher than the mean of mothers of normal children in terms of the answers to overprotective mother aspect (p<0.01). The mothers of children with speech delays had more overprotective motherhood attitudes; however, the difference in terms of the answers to the aspects of democratic attitude and provision of equality, refusal to be a housewife, husband-wife conflict, and suppression and discipline were not statistically significant. The Beck anxiety scale, a significant difference was detected between the two groups (p<0.01). It was found that the mothers of children with speech delays had more severe levels of anxiety. CONCLUSION: The social structure of the family, the attitudes and the behaviors of the mother, and the anxiety levels of the mothers have important effects on child development. Thus, it is necessary to perform further studies related to speech delays, in which many factors play a role in the etiology.

Clinical, cytogenetic, and molecular characterization of six patients with ring chromosomes 22, including one with concomitant 22q11.2 deletion.

We report here on six patients with a ring chromosome 22 and the range of cytogenetic and phenotypic features presented by them. Genomic analysis was carried out using classical and molecular cytogenetics, MLPA (Multiplex Ligation-dependent Probe Amplification) and genome-wide SNP-array analysis. The ring was found in all patients, but Patient 6 displayed constitutional mosaicism with a normal cell line. Five patients had deletions in the ring chromosome 22, and in four of them the breakpoints--unique for each patient--could be identified by genome-wide SNP-array analysis. One patient presented with a 22q11.2 deletion concomitant with the deletion caused by the ring formation. Common phenotypic features included autism, speech delay and seizures, as previously reported for individuals with r(22) and/or 22q13.3 deletions. Investigation of the genes within the deletions revealed multiple genes related to development of the central nervous system, psychomotor delay, severe language impairment, hypotonia, and autistic symptoms. There was no clear correlation between the severity of clinical features and the size of the deleted segment. This study underscores the variability in ring structure and clinical presentation of the r(22) and adds information to the limited literature on this rare disorder.

Toxoplasmose congênita: evolução da função auditiva e da linguagem emcrianças diagnosticadas e tratadas precocemente / Congenital toxoplasmosis: auditory and language outcomes inearly diagnosed and treated children

A cross-sectional study included all children diagnosed with congenital toxoplasmosis, through the Minas Gerais State Neonatal Screening Program, from September 2006 to March 2007. All children received early treatment, initiated before the age of 2.5 months, and were periodically assisted by a team of specialists including pediatricians, ophthalmologists and speech-language therapists and audiologists. Hearing function was evaluated with the following procedures: tympanometry, transient evoked otoacoustic emissions, distortion product otoacoustic emissions, behavioral observation audiometry, and brainstem auditory evoked potentials. Hearing function and sensitivity was estimated and audiological results were classified as normal, conductive hearing loss, sensory-neural hearing loss and central dysfunction. Language performance was assessed and classified as normal or abnormal, according to test results. The following variables were studied: audiological results, neurological and ophthalmological conditions, language performance and presence of risk indicator for hearing loss other than congenital toxoplasmosis. Univariate analysis was conducted using the chi-square or Fisher?s Exact test. Results: From September 2006 to March 2007, 106 children were diagnosed with congenital toxoplasmosis through the neonatal screening program, and were included in the study. Data analysis showed normal hearing in 60 children (56.6%), while 13 children (12.3%) had conductive hearing loss, four children (3.8%) had sensory-neural hearing loss and 29 children (27.4%) presented central hearing dysfunction. There was association between hearing problems and language deficits. The comparison between children with additional risks for hearing loss other than toxoplasmosis and children who only presented toxoplasmosis as a risk factor showed no differences. This finding suggests that audiological problems were due to congenital toxoplasmosis alone.

Um estudo transversal descritivo incluiu todas as crianças diagnosticadas com toxoplasmose congênita (TC) pelo Prog. Est. de Tria. Neonatal de MG entre set. 2006 e mar. de 2007. Todas as crianças foram submetidas ao protocolo de tratamento com pirimetamina e sulfadiazina iniciado antes dos 2,5 meses de idade e com duração de 12 meses, tendo realizado acompanhamento pediátrico, oftalmológico e fonoaudiológico periódico. Para avaliar a audição foram usados, como instrumentos diagnósticos, medidas de imitância acústica, emissões otoacústicas evocadas por estímulo transiente e produto de distorção, potencial evocado auditivo de tronco encefálico e observação do comportamento auditivo. Foi avaliada a acuidade auditiva e as alterações auditivas foram classificadas em condutivas, neurossensoriais e retrococleares. O desempenho de ling. foi avaliado usando-se um instrumento de aval. do desenvolvimento da ling., e os resultados foram classificados como normais ou alterados. As seguintes variáveis foram estudadas: resultados audiológicos, condições neurológicas e oftalmológicas, linguagem e presença de fator de risco para perda auditiva além da TC. Foi realizada análise univariada pelo qui-quadrado ou teste exato de Fisher. Resultados: entre set. 2006 e mar. 2007, 106 crianças foram diagnos. com TC pelo programa de triagem neonatal, sendo incluídas no estudo. A análise dos dados mostrou que 60 crianças apresentavam audição normal (56,6%) e 46 crianças apresentavam audição alterada, sendo 13 crianças (12,3%) com alteração condutiva, 4 (3,8%) com perda auditiva neurossensorial e 29 (27,4%) com comprometimento retrococlear. Houve associação entre presença de alteração auditiva e déficit de linguagem. A comparação entre crianças que apresentavam outro fator de risco além da TC e crianças que apresentavam somente a toxoplasmose como fator de risco para alteração auditiva não mostrou diferenças.

Landau-Kleffner syndrome without seizures: would speech delay justify the treatment with antiepileptic drugs?: [review] / Síndrome de Landau-Kleffner sem crises: atraso na aquisição da fala justifica o tratamento com drogas epilépticas?: [revisão]

INTRODUCTION: Landau-Kleffner Syndrome is a rare epileptic syndrome characterized by the association of receptive aphasia, epileptic seizures, behavioral disorders and electroencephalographic changes with discharges at the temporal lobe unilaterally or bilaterally. Seizures are not essential for diagnosis. CASE REPORT: J. V. S. S., 3 y/o male, with delay in acquirement of speech, psychomotor agitation and sleep disorder (sleeplessness). Attempt to communicate was established by gestures and pointing at things. His behavior characterized by agitation, restlessness, aggressiveness and difficulty to establish social contact with other children by the same age. MRI was normal and the EEG showed sharp-wave discharges in the left medial and posterior temporal regions. After three months of treatment with carbamazepine the child returned to an evaluation, presenting substantial improvement at speech, speaking simple words and with meaningful improvement on both behavioral and sleep patterns, as well as, social interaction. DISCUSSION: Expression and reception speech disorders are relatively common in children with different epileptic syndromes, particularly in Landau-Kleffner syndrome. Epileptiform discharges can occur in people without epilepsy and use to be called subclinical discharges. What would be the impact of subclinical discharges on this population remains uncertain at the present time. We reviewed these interactions in the light of a representative case, showing favorable outcome following introduction of an antiepileptic drug.

INTRODUÇÃO: Síndrome de Landau-Kleffner é uma síndrome epiléptica rara caracterizada pela associação de afasia de recepção, crises epilépticas, distúrbios do comportamento e alterações eletrencefalográficas com descargas nos lobos temporais unilaterais ou bilaterais. Crises convulsivas não são essenciais para o diagnóstico. RELATO DO CASO: J.V.S.S., masculino, três anos de idade, com atraso na aquisição da fala, agitação psicomotora e distúrbio do sono. Ele usava gestos e apontava para os objetos tentando se comunicar. Seu comportamento era muito agitado, impaciente, períodos de agressividade e muita dificuldade em estabelecer contato social com outras crianças da mesma idade. RNM foi normal e o EEG mostrou descargas de ondas agudas nas regiões temporais média e posterior esquerda. Após três meses de tratamento com carbamazepina a criança retornou para reavaliação, apresentando importante melhora da fala, falando palavras simples, melhora do comportamento e do padrão de sono e da interação social. DISCUSSÃO: Alterações na linguagem de recepção e de expressão são relativamente comuns em crianças com diferentes síndromes epilépticas, particularmente na síndrome de Landau-Kleffner. Descargas epileptiformes podem ocorrer em pessoas sem epilepsia sendo denominadas descargas subclínicas. Qual o impacto das descargas subclínicas para estas pessoas é incerto até o momento. Relatamos o caso de um menino com descargas epileptiformes no EEG, sem história de crises convulsivas e excelente evolução clínica após tratamento com droga antiepiléptica.