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Menke-Hennekam syndrome (MHS) is a relatively new genetic condition characterized by intellectual disabilities, autistic behavior, auditory defects, recurrent upper respiratory tract infections, microcephaly and short stature. Facial characteristics include short palpebral fissures, telecanthus, depressed nasal bridge, short nose, anteverted nares, short columella, and long philtrum. The genetic defect is represented by missense variants of CREBBP gene, located on exons 30 or 31. There are only around 30 cases reported by now.
The aim of the paper is to report a new case of MHS.
The case is a 3-year-old boy admitted in our department for developmental delay. The clinical examination revealed dysmorphic features; severe speech delay, mild intellectual disability, autistic behaviour.The patient had a personal history of recurrent respiratory infections, visual defect and bilateral sensorineural hearing loss. Other investigations included EEG, abdominal echography, and cerebral MRI all were normal. The genetic studies included array CGH and WES.
The array CGH was normal. WES identified a pathogenic heterozygote variant c.5600G>A in the exon 31 of CREBBP gene, confirming MHS.
Overall, the features of our patient are consistent with those reported in the previous reports, including developmental and speech delay, autistic behavior, dysmorphic features, recurrent upper way infections, sensorineural hearing loss, and visual defects. Other common features, such as growth delay and microcephaly were not present in our patient. Our case contributes to the clinical characterisation of the new syndrome. Funding: The research leading to these results has received funding from the EEA Grant 2014-2021, under the project contract No 6/2019.
Background: Copy-number variants (CNVs) of chromosome 15 have been associated with neurodevelopmental disorders like autism spectrum disorders (ASDs) and developmental delay.
We report 6 patients with autistic features and other neurodevelopmental problems carrying CNVs of chromosome 15.
Materials and methods: The probands belong to a group of patients referred to our clinic and laboratory with autism as main feature. A complete clinical evaluation was performed with focus on neurologic, psychiatric, and psychological evaluation with specific autism tests. Array-based comparative genomic hybridization (array-CGH) was performed using 180K platform (Agilent technology).
six patients investigated by array-CGH had a CNV involving chromosome 15. Four of these patients, previously reported by us (ref 1), had small duplications of 15q13.3 involving CHRNA7 and OTUD7A genes. The other two patients had large deletions of 15q21q22 and 15q24, respectively. A deletion of 15q21.2 - q22.2 was detected in one patient. The deleted region contains 62 genes and has been rarely reported in patients with neurodevelopmental disorders. A deletion of 15q24.1 - q24.2 was detected in the other patient. This region is recurrently deleted in developmentally delayed patients (ref 3).
Our data highlight that chromosome 15 is a hub for neurodevelopmental disorder and illustrates the utility of array-CGH in the investigation of patients with autism, specifically in the context of complex phenotypes. Acknowledgment: The research leading to these results has received funding from the EEA Grant 2014-2021, under the project contract No 6/2019. References: Genes (Basel). 2021 Jul 1;12(7):1025. https://www.omim.org/entry/618060 Clinical Genome Resource. https://dosage.clinicalgenome.org/clingen_region.cgi?id=ISCA-46296
15q11.2-q13.3 region is prone to genomic rearrangements leading to both deletions and duplications. A wide spectrum of neuropsychiatric conditions, such as developmental delay/intellectual disability (DD/ID), autism, attention-deficit hyperactivity disorder, schizophrenia, epilepsy was reported in association with genomic imbalances of this region.
In this paper we report on 9 children carrying 15q11.2-q13.3 duplications.
Seven boys and two girls, aged 15 months to 15 years, were included in the study. Genomic investigations were carried out by array-based comparative genomic hybridization (Agilent Technologies). In all patients the psychomotor development, dysmorphic features, neuroimaging and EEG anomalies were assessed. Psychologic and psychiatric evaluation was performed with specific tests.
The size of the duplications ranged from 9.65 Mb to 0.38 Mb. All patients presented speech delay. Autistic behavior and muscular hypotonia were detected in 8 out of 9 patients, DD/ID in 6. Two children presented epileptic seizures, in addition 4 other children had EEG anomalies. Facial dysmorphic features were observed in 5 patients. Neuroimaging studies showed anomalies in 4 children. The smallest region of overlap in our patient group harbors CHRNA7 gene, a candidate for the behavioral abnormalities.
15q duplications encompassing CHRNA7 gene were associated with different neuropsychiatric features in our patients. Our results further support the association of 15q duplications with neuropsychiatric phenotypes, with clinical heterogeneity and variable severity, which is yet to be explained. Acknowledgment: The research leading to these results has received funding from the EEA RO NO Grant 2014-2021, the project contract No 6/2019.
Brain heterotopia represent a group of rare malformations with a heterogeneous phenotype, ranging from asymptomatic to severe clinical picture (resistant epilepsy, severe developmental delay). The etiology is multifactorial, including both genetic and environmental factors.
In this paper we present our experience regarding behavior problems in patients with heterotopia.
A cohort of 16 pediatric patients with brain heterotopia, six females and ten males, with age at last follow-up ranging from 2 months to 24 years were investigated by clinical examination, electroencephalographic studies, brain imaging, and genomic tests. Specific psychological tests and psychiatric evaluation were performed in all children for behavior problems assessment.
Six individuals presented behavioral problems: autism (three patients) and hyperkinesia with attention deficit (three patients). All of them had intellectual disability or learning problems; five patients had epilepsy, with drug-resistant seizures in four cases. In two cases the behavioral problems occurred before the onset of epileptic seizures.
Behavior problems are important features in patients with brain heterotopia, making the management of these patients more difficult, especially when they occur in association with drug-resistant epilepsy. Acknowledgements: This work was supported partially by grants of the Romanian National Authority for Scientific Research and Innovation CCCDI – UEFISCDI, Projects COFUND-ERANET E-RARE 3-HETER-OMICS-2 Number 87/2019 and 88/2019 within PNCDI III.
Autism spectrum disorder (ASD) is characterized by persistent deficits in social communication and social interaction across multiple contexts and it is marked by repetitive sensory–motor behaviours and restricted interests or activities. Now recognized to occur in up to 1% of the population, the prevalence of ASD has registered a steady increase in the past two decades. Heterogeneity of presentation is a hallmark with comorbid psychiatric and medical morbidities frequently reported. Comorbidities mask and delay the diagnosis and are the cause of inadequate therapies.
In the present paper, we studied a cohort of patients with ASD, investigating the rates and types of psychiatric and medical comorbidities.
A retrospective study of psychiatric and medical comorbidities was carried out on a sample of 120 participants that met ASD criteria according to DSM-V. The patients were examined with a detailed medical history, physical examination, as well as some additional functional, imaging, laboratory and genetic investigations. The associated conditions considered were: attention deficit/hyperactivity disorder (ADHD), epilepsy, intellectual disability, gastrointestinal symptoms, ophtalmologic manifestations, infections.
Of the 120 ASD subjects referred, 25 (20.8%) received the diagnosis of epilepsy. ADHD was established in 24 cases (20%). IQ score was obtained in half of the patients, 43.3% of them presenting a severe intellectual disability (IQ<35). Respiratory disorders occured in 25% of the cases. Ophtalmological findings were observed in 9.1% of the cases. Other frequent comorbidities included motor disturbances and feeding problems.
A better understanding of comorbidities in ASD patients improves interdisciplinary collaboration, thus facilitating effective treatment programs.
X-linked mental retardation (XLMR) is a common, clinically complex and genetically heterogeneous disease arising from many mutations along the X chromosome. Although research during the past decade has identified >90 XLMR genes, many more remain uncharacterized. In XY males, duplication of any part of the X chromosome leads to functional disomy of the corresponding genes.
In this paper we present the case of a boy with a syndrome of Xq28 duplication. Methods: We present a 6 years old boy, admitted in the Department of Pediatric Psychiatry for evaluation. He presented sever mental retardation, autistic features, speech delay, hyperkinesia, and dysmorphic features (high forehead, partial palpebral ptosis, small nose, carp-shaped open mouth, micrognathia), recurrent infections. Cerebral MRI was normal. Genetic investigations, including katyotype with GTG banding and array-CGH, were performed.
Array-CGH indicated a dup(X)(q28) of less than 1.5 Mb. There were 15 duplicated genes, including MECP2 gene, which is involved in autism and mental retardation.
Duplications at Xq28 are often associated with autistic features/non-syndromic MR; alterations in MECP2 gene (duplicated in our patient) are described in Rett syndrome or as a specific phenotype. The alteration occurring at Xq28 band is responsible for the patient’s phenotype. Clinical manifestation of this child will be compared with those of other patients with the same duplication previously described to further delineate this syndrome.
Mental retardation (MR) is the most common developmental disability, affecting 2–3% of the general population. A major challenge in both clinical practice and research in the field of MR is to identify the underlying causes: genetic, chromosomal and environmental factors that have an influence on a person's development and behavior.
We present the results of our study regarding genetic abnormalities associated with mental retardation in children.
A total of 180 children were studied using a diagnostic protocol based on dysmorphologic and clinical assessment. A disease, familial and personal history were noted. All patients were evaluated by clinical and paraclinical exams (including dysmorphological features, psychological tests, neurological features, neuroimagistic studies). Genetic investigations included a karyotype with GTG banding, FISH and array-CGH.
A specific causes for the mental handicap was identified in 80 children (44%).
These included a chromosomal abnormality in 32 cases (17%), microdeletion syndromes in 25 children (14%), recognizable syndromes in 23 (13%). Array CGH identified a 22q11 deletion in a girl with unusual phenotype for DiGeorge syndrome, a Xp21 duplication in a girl with severe phenotype (including sever mental retardation, epilepsy, dysmorphic features, genital anomalies, glaucoma, dental anomalies), and a 4p14 deletion in a girl with moderate mental retardation, dysmorphic features, diparesis, congenital heard malformation.
While clinical diagnosis and conventional techniques form the mainstay of investigation of children with mental retardation, array CGH proved important diagnostic tool. Acknowledgments: National Research Program PN II, Project 42–130, CAPACITATI 29/2007–2009 Project; CNCSIS, Project 1203
(Micro)deletion/(Micro)duplication syndromes in one of the most common cause of intellectual disability in children, often in association with a sever phenotype. Introducing of new genetic techniques of molecular diagnosis, like array-CGH, allowed identification of new microdeletion/microduplication syndromes. This paper presents our experience regarding diagnosis and management of children with (micro)deletion/(micro)duplication syndromes.
Material and methods:
250 children with mental retardation, selected using a diagnostic protocol based on personal and familial history, general and neurological examination, dysmorphologic and psychological assessment, specific paraclinical tests, were included in our study. in 130 children genetic investigations, including karyotype with GTG banding, FISH and array-CGH, were performed.
44 (micro)deletion/(micro)duplication syndromes were diagnosed: 16 cases with Williams syndrome, 10 cases with Angelman syndrome, 3 cases with Prader-Willi syndrome, 2 cases with Wolf-Hirschorn syndrome, 3 cases with cri-du-chat syndrome, and one from the following syndromes: DiGeorge, 1q deletion, 3p deletion, 3q duplication, 4p deletion, 8p deletion, 9p deletion, 12p duplication, Xp duplication, Xq duplication. the management of these children included physical therapy, speech therapy, behavioral therapy, the therapy of associated conditions (epilepsy, malformation etc.).
An early diagnosis of (micro)deletion/(micro)duplication syndromes is very important for a proper management of these conditions. New molecular genetics tests are useful for identification of some new or very rare anomalies.
Angelman syndrome (AS) is a neurogenetic disorder caused by various 15q11–q13 abnormalities, characterized by severe mental retardation, speech delay, ataxia, happy disposition. in this paper we present our experience regarding the management of children with AS.
Material and methods:
Our study included 9 children (5 boys and 4 girls) with AS, all with interstitial deletion of 15q11–13, with aged ranged between 6 months and 12 years. in all children we noted: clinical phenotype, epilepsy history (seizures onset, type of seizures, response to antiepileptic drugs), psychomotor development. all children have been followed up regarding epileptic seizures control and psychomotor development.
All patients presented the typical clinical pictures. the most frequent seizures were partial seizures, followed by atonic seizures and atypical absences. the EEG exhibited the characteristic AS pattern. Valproate was preferentially used anticonvulsant, in some cases in association with clonazepam, lamotrigine or levetiracetam. Corticotherapy was used in four cases, with good results; also, improvement of EEG abnormalities and a slight psychomotor amelioration was noted. 8 children are seizures free in present. all children made physical therapy and cognitive stimulation.
In our patients, the treatment of epileptic seizures was effective. Valproate was most effective, but association of other antiepileptic drugs was necessary in many cases. Corticotherapy had good effect, not only in controlling seizures, but also in improvement of psychomotor delay and EEG abnormalities. Physical therapy and cognitive stimulation were useful tools for the improvement of psychomotor development.
CNCSIS 1203 project, PN II 42–130 project.
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