Gut microbiome and attention deficit/hyperactivity disorder: a systematic review.

BACKROUND: This systematic review aims to examine the associations between features of gut microbiome and Attention Deficit/Hyperactivity Disorder (ADHD) risk or severity in children, adolescents and young adults. METHODS: Eligible studies were identified in PubMed and Google Scholar databases until December 31, 2020. RESULTS: The search identified a total of 1197 items, of which 11 were included in this systematic review. The findings regarding alpha, beta diversity, bacterial phyla, orders and families were inconclusive. At the genus level an increased abundance of Odoribacter (two studies) and Eggerthella (two studies) was found in ADHD; on the contrary, decreased abundance of Faecalibacterium (three studies) was noted, whereas one study suggested its inverse association with ADHD severity and hyperactivity. One study indicated that Bacteroides species also correlated with levels of hyperactivity and impulsivity. At the species level, a lower abundance of Faecalibacterium prausnitzii, but higher of Odoribacter splanchnicus and Bacteroides uniformis was reported. CONCLUSIONS: This systematic review highlights associations between gut microbiome features and ADHD. Potential mechanisms differ by microorganism and include effects on neurotransmitter production, dopamine metabolism, modulation of inflammation and neurodevelopment through the release of cytokines. IMPACT: The existence of correlations between features of gut microbiome and ADHD manifestation or its severity in children, adolescents and young adults. Associations between gut microbiome features and ADHD are highlighted. Potential mechanisms seem to differ by microorganism and include effects on neurotransmitter production, dopamine metabolism, modulation of inflammation and neurodevelopment through the release of cytokines. As correlations between gut microbiome features and ADHD seem to exist, additional studies are needed for further investigation.

A Girl with 10 Mb Distal Xp Deletion Arising from Maternal Pericentric Inversion: Clinical Data and Molecular Characterization.

BACKGROUND: Short arm deletions of the X-chromosome are challenging issues for genetic counseling due to their low penetrance in population. Female carriers of these deletions have milder phenotype than male ones, considering the intellectual ability and social skills, probably because of the X-chromosome inactivation phenomenon. CASE REPORT: A female patient with a 10Mb distal Xp deletion and an Xq duplication, showing mild intellectual disability, is described in this report. While the deletion arose from a maternal pericentric inversion, the duplication was directly transmitted from the mother who is phenotypically normal. CONCLUSION: This report underlines the usefulness of molecular cytogenetic technics in postnatal diagnosis.

Deletion of 4.4 Mb at 2q33.2q33.3 May Cause Growth Deficiency in a Patient with Mental Retardation, Facial Dysmorphic Features and Speech Delay.

A patient with a rare interstitial deletion of chromosomal band 2q33.2q33.3 is described. The clinical features resembled the 2q33.1 microdeletion syndrome (Glass syndrome), including mental retardation, facial dysmorphism, high-arched narrow palate, growth deficiency, and speech delay. The chromosomal aberration was characterized by whole genome BAC aCGH. A comparison of the current patient and Glass syndrome features revealed that this case displayed a relatively mild phenotype. Overall, it is suggested that the deleted region of 2q33 causative for Glass syndrome may be larger than initially suggested.

Complex Rearrangement Involving Three Chromosomes, Four Breakpoints and a 2.7-Mb Deletion in the 18q Segment Observed in a Girl with Mild Learning Difficulties.

Complex chromosomal rearrangements (CCRs) are balanced or unbalanced structural rearrangements involving 3 or more cytogenetic break events on 2 or more different chromosomes. Here, we report a 7-year-old girl referred to our unit because of mild dysmorphic facial features, mild learning difficulties together with very mild mental retardation. Standard cytogenetic banding analysis revealed a de novo CCR involving chromosomes 1, 2 and 18. Further molecular investigation with aCGH revealed a cryptic interstitial deletion of 2.7 Mb in 18q22.1, which does not elicit a significant clinical phenotype. FISH was performed to confirm both molecular and cytogenetic results.

An interstitial 4q31.21q31.22 microdeletion associated with developmental delay: case report and literature review.

The 4q deletion syndrome phenotype consists of growth failure and developmental delay, minor craniofacial dysmorphism, digital anomalies, and cardiac and skeletal defects. We have identified an inversion (inv(1)(q25.2q31.1)) and an interstitial deletion in a boy with developmental delay using array-comparative genomic hybridization. This de novo deletion is located at 4q31.21q31.22 (145,963,820- 147,044,764), its size is 0.9-1.1 Mb, and it contains 7 genes (ABCE1, OTUD4, SMAD1, MMAA, C4orf51, ZNF827, and ANAPC10) as well as 5 retrotransposon-derived pseudogenes. Bioinformatic analysis revealed that while small copy number variations seem to have no impact on the phenotype, larger deletions or duplications in the deleted region are associated with developmental delay. Additionally, we found a higher coverage in transposable element sequences in the 4q31.21q31.22 region compared to that of the expected repeat density when regarding any random genome region. Transposable elements might have contributed to the reshaping of the genome architecture and, most importantly, we identified 3 L1PA family members in the breakpoint regions, suggesting their possible contribution in the mechanism underlying the appearance of this deletion. In conclusion, this is one of the smallest deletions reported associated with developmental delay, and we discuss the possible role of genomic features having an impact on the phenotype.

Predictors of severity and outcome of global developmental delay without definitive etiologic yield: a prospective observational study.

BACKGROUND: Although several determinants of global developmental delay (GDD) have been recognized, a significant number of children remain without definitive etiologic diagnosis. The objective of this study was to assess the effect of various prenatal and perinatal factors on the severity and outcome of developmental delay without definitive etiologic yield. METHODS: From March 2008 to February 2010, 142 children with developmental quotient (DQ) <70 and without definitive etiologic diagnosis, were included. Prenatal and perinatal risk factors known to be associated with disordered neonatal brain function were identified. Participants underwent a thorough investigation, an individualized habilitation plan was recommended, and the children were followed-up regularly for a period of 2 < years. The effect of prenatal and perinatal risk factors on the severity and outcome of GDD was assessed by regression analysis. RESULTS: The mean age at enrolment was 31 ± 12 < months, and the mean DQ 52.2 ± 11.4. Prematurity and intrauterine growth restriction (IUGR) were found to be independently associated with lower DQ values. The mean DQ after the 2-year follow-up was 62.5 ± 12.7, and the DQ difference from the enrollment 10.4 ± 8.9 (median 10; range-10 to 42). DQ improvement (defined as a DQ difference?≥?median) was noted in 52.8% of the children. IUGR, low socio-economic status, and poor compliance to habilitation plan were found to be independently associated with poorer developmental outcomes. CONCLUSIONS: Prematurity and IUGR were found to be significantly and independently related to the severity of GDD in cases without definitive etiologic yield. Poorer 2-year developmental outcome was associated with IUGR, low socioeconomic status and non compliance to habilitation plan. Prematurity was a significant determinant of the outcome only in association with the above mentioned factors.

Giftedness and Neurodevelopmental Disorders in Children and Adolescents: A Systematic Review.

OBJECTIVE: Throughout the years, several myths have arisen suggesting that children diagnosed with neurodevelopmental disorders possess unusually high abilities in specific domains, depending on the disorder. On the other hand, special skills and talents in children with neurodevelopmental disorders are most commonly overshadowed by their difficulties and overlooked. The purpose of this systematic review is to examine the association between giftedness and neurodevelopmental disorders. METHODS: The related articles published in PubMed, Google Scholar, PsycINFO, and Embase up to December 31, 2020, as well as their reference lists, were reviewed systematically. RESULTS: A total of 6069 studies were scanned, and 32 of them (9904 subjects) were deemed eligible for this systematic review. Studies have supported associations between autism spectrum disorders and music ability. Contradictory results have been published regarding associations between giftedness, attention-deficit/hyperactivity disorder, and specific learning disorders. Diagnostic methods seemed to modify associations between giftedness and neurodevelopmental disorders. CONCLUSION: The dearth of the available evidence is prominent. More research is needed to investigate the field of dual exceptionality. Longitudinal studies are needed, addressing methodological challenges pertaining to variability in the definition of giftedness.

Postpartum depression and ADHD in the offspring: Systematic review and meta-analysis.

BACKGROUND: Postpartum depression (PPD) is a disorder that has a severe impact on a woman's mental state and mood after birth. Research has shown that postnatal levels of family adversity and maternal psychopathology are associated with Attention Deficit Hyperactivity Disorder (ADHD). This paper is intended to examine the association among maternal PPD and the risk of ADHD in the offspring. METHODS: Keyword search was conducted for PsycINFO, PubMed, Google Scholar, and Embase up to Feb 28, 2021; studies in English were deemed eligible. Random-effects meta-analysis and meta-regression analysis took place. Subgroup analyses by study design, geographical region, level of adjustment and study setting were performed. RESULTS: Nine cohort studies and two case-control studies published from 2003 to 2019 were included in the qualitative synthesis; among them, eight studies were synthesized in the meta-analysis. Overall, maternal PPD was associated with an increased risk of ADHD in the offspring (pooled relative risk, RR = 1.69, 95%CI: 1.27-2.26). Significant associations were noted in the subsets of cohort studies, studies implementing multivariate analyses and registry-based surveys. LIMITATIONS: Overall, a larger number of studies of the field are needed. Data collection relied on self-report and attrition bias limited the validity of eligible studies. Studies from developing countries were underrepresented. There was significant publication bias (p = 0.035, Egger's test). CONCLUSIONS: The relationship between PPD and ADHD in children was found to be significant in this systematic review and meta-analysis and reveals the need for further investigation in various geographical regions.

Partial deletion of chromosome 6p causing developmental delay and mild dysmorphisms in a child: molecular and developmental investigation and literature search.

BACKGROUND: The interstitial 6p22.3 deletions concern rare chromosomal events affecting numerous aspects of both physical and mental development. The syndrome is characterized by partial deletion of chromosome 6, which may arise in a number of ways. CASE PRESENTATION: We report a 2.8-year old boy presenting with developmental delay and mild dysmorphisms. High-resolution oligonucleotide microarray analysis revealed with high precision a 2.5 Mb interstitial 6p deletion in the 6p22.3 region which encompasses 13 genes. CONCLUSIONS: Identification and in-depth analysis of cases presenting with mild features of the syndrome will sharpen our understanding of the genetic spectrum of the 6p22.3 deletion.

Cyberbullying and Obesity in Adolescents: Prevalence and Associations in Seven European Countries of the EU NET ADB Survey.

BACKGROUND: overweight and obese individuals may often face aggressive messages or comments on the internet. This study attempts to evaluate the association between cyberbullying victimization and overweight/obesity in adolescents participating in the European Network for Addictive Behavior (EU NET ADB) survey. METHODS: a school-based cross-sectional study of adolescents aged 14-17.9 years was conducted (n = 8785) within the EU NET ADB survey, including data from seven European countries (Germany, Greece, Iceland, the Netherlands, Romania, Poland, Spain). Complex samples and univariate and multivariate logistic regression analyses were performed. RESULTS: overall, overweight adolescents were more likely to have been cyberbullied compared to their normal weight peers (adjusted OR (Odds ratio) = 1.20, CI (confidence intervals): 1.01-1.42); this association was pronounced in Germany (adjusted OR = 1.58, CI: 1.11-2.25). In Iceland, obese adolescents reported cyberbullying victimization more frequently compared to their normal weight peers (adjusted OR = 2.87, 95% CI: 1.00-8.19). No significant associations with cyberbullying victimization were identified either for obese or overweight adolescents in Greece, Spain, Romania, Poland, and the Netherlands. CONCLUSIONS: this study reveals an overall association between cyberbullying victimization and overweight on the basis of a sizable, representative sample of adolescent population from seven European countries. Country-specific differences might reflect differential behavioral perceptions, but also normalization aspects.

Adolescent Perspectives About Online Hate Speech: Qualitative Analysis in the SELMA Project.

OBJECTIVE: This paper aims to study the views, perceptions and representations of online hate speech among adolescents in the Greek cohort of the SELMA Project. METHODS: Qualitative research was conducted in focus groups of 36 Greek adolescents and the data were processed through thematic analysis method. RESULTS: The majority was unfamiliar with the term "hate speech" and confused it with cyberbullying. The target characteristics of hate, ethnicity, race, gender, religion, physical weakness, disability, sexual orientation, and appearance emerged. Regarding people involved in hate speech, perpetrators in both hate speech and bullying were described to share common characteristics. The emphasis was placed on the victims' resilience, as well as their socialization, as protective behaviors. Participants stressed the value of the right to freedom of speech, although there was no agreement on its limits. Additionally, it was highlighted that awareness of what is right and wrong is mostly taught by parents, while the role of education was also important. An important finding was that the majority of teenagers were optimistic, supporting the belief that it is possible to find a realistic solution. CONCLUSION: The findings support the need for prevention strategies in the school environment, so that adolescents will be able to recognize and potentially combat hate speech in the online and offline worlds.

Cognitive and psychosocial development of HIV pediatric patients receiving highly active anti-retroviral therapy: a case-control study.

BACKGROUND: The psychosocial development of pediatric HIV patients has not been extensively evaluated. The study objectives were to evaluate whether emotional and social functions are differentially associated with HIV-related complications. METHODS: A matched case-control study design was conducted. The case group (n = 20) consisted of vertically infected children with HIV (aged 3-18 years) receiving HAART in Greece. Each case was matched with two randomly selected healthy controls from a school-based population. CNS imaging and clinical findings were used to identify patients with HIV-related neuroimaging abnormalities. The Wechsler Intelligence Scale III and Griffiths Mental Abilities Scales were applied to assess cognitive abilities. The age specific Strengths and Difficulties Questionnaire was used to evaluate emotional adjustment and social skills. The Fisher's exact test, student's t-test, and Wilcoxon rank sum test were used to compare categorical, continuous, and ordinal scores, respectively, of the above scales between groups. RESULTS: HIV patients without neuroimaging abnormalities did not differ from patients with neuroimaging abnormalities with respect to either age at HAART initiation (p = 0.306) or months of HAART treatment (p = 0.964). While HIV patients without neuroimaging abnormalities had similar cognitive development with their healthy peers, patients with neuroimaging abnormalities had lower mean General (p = 0.027) and Practical (p = 0.042) Intelligence Quotient scores. HIV patients without neuroimaging abnormalities had an increased likelihood of both Abnormal Emotional Symptoms (p = 0.047) and Hyperactivity scores (p = 0.0009). In contrast, HIV patients with neuroimaging abnormalities had an increased likelihood of presenting with Abnormal Peer Problems (p = 0.033). CONCLUSIONS: HIV patients without neuroimaging abnormalities are more likely to experience maladjustment with respect to their emotional and activity spheres, while HIV patients with neuroimaging abnormalities are more likely to present with compromised social skills. Due to the limited sample size and age distribution of the study population, further studies should investigate the psychosocial development of pediatric HIV patients following the disclosure of their condition.

Autism Spectrum Disorders in Greece: Nationwide Prevalence in 10-11 Year-Old Children and Regional Disparities.

Autism spectrum disorders (ASD) constitute a public health concern with increasing prevalence worldwide. We aimed to estimate prevalence and age at diagnosis in Greece, where no large-scale prevalence study has ever been conducted. Aggregate data were collected on ASD diagnoses by gender and calendar year of diagnosis up to 2019, for children born in 2008 and 2009, from the Centers for Educational and Counseling Support, which evaluate children to receive special educational support in school. Coverage was 87.1% of centers and 88.1% of schoolchildren born in 2008-9. ASD prevalence overall was 1.15% (1.83% males, 0.44% females; ratio 4.14:1), ranging from 0.59% to 1.50% in Greece's 13 regions. In five regions, prevalence differed significantly between centers. Overall, only 3.8% of diagnoses were made before the fourth year after birth and 42.7% before the sixth year, with considerable variation between regions. Approximate mean age at diagnosis was six years and one month, and about three months earlier for girls than for boys. Our results provide evidence-based information to guide service planning and development at national and regional levels. Particular attention should be paid to smoothing out inequalities regarding service accessibility and provision. Emphasis should be given to earlier identification and diagnosis of ASD.

17p13.1 Microduplication Syndrome in a Child, Familial Short Stature, and Growth Hormone Deficiency: A Case Report and Review of the Literature.

To date, 6 cases of 17p13.1 microduplications have been described in the literature. Intellectual disability is the core feature, together with minor facial dysmorphisms and obesity. We describe the first case of a young patient with a maternally inherited microduplication in 17p13.1 presenting with growth hormone deficiency. The boy was addressed to the endocrine division for growth retardation (weight and height <3rd percentile). Besides minor facial dysmorphisms, physical and neurological examinations were normal except for motor dyspraxia. Basic blood tests and endocrinological investigations were normal, but IGF1 levels were low for his age. Growth hormone deficiency was confirmed. Hypothalamic pituitary MRI was normal. His karyotype was 46XY. Array-CGH analysis detected a 422-kb copy number gain in the spanning region 17p13.1 inherited from his mother. Although familial short stature is considered a "normal" variation of growth retardation, hormonal and genetic investigation is essential in the etiological diagnosis.

Autism spectrum disorder, anxiety and severe depression in a male patient with deletion and duplication in the 21q22.3 region: A case report.

In this report, a patient carrying a 650 kb deletion and a 759 kb duplication of chromosomal 21q22.3 region was described. Facial dysmorphic features, hypotonia, short stature, learning impairment, autism spectrum disorder, anxiety and depression were observed clinical characteristics. Mentioned copy number variants were the shortest in length reported so far. The current study hypothesized that the presence of a susceptibility locus for autism spectrum disorder associated with depression and anxiety may be located in a 200 kb region between the PCNT and PRMT2 genes. The current study aimed to provide insight into the human genome morbidity map of chromosome 21.

Long-term follow-up of a child with Klinefelter syndrome and achondroplasia from infancy to 16 years.

BACKGROUND: Achondroplasia (ACH), an autosomal dominant skeletal dysplasia, occurs in approximately 1:20,000 births. On the other hand, 47,XXY aneuploidy (Klinefelter syndrome [KS]) is the most common sex chromosome disorder, with a prevalence of approximately 1:600 males. To the best of our knowledge, only five cases of patients presenting both ACH and KS have been reported to date in the international literature. However, none of these cases has been longitudinally followed during the entire childhood. CASE PRESENTATION: We report a male patient with ACH and KS, diagnosed in early infancy because of his typical phenotype of ACH. The diagnosis was confirmed by molecular analysis revealing a de novo heterozygous 1138 G-to-A mutation of the FGFR3 gene. During his first assessment, a karyotype was performed, which also revealed coexistence of KS. He was followed by our pediatric endocrinology team until the age of 16 years, then he was gradually transferred to adult endocrine care. CONCLUSIONS: This is the first reported case with both conditions that was diagnosed in infancy and was longitudinally followed by a pediatric endocrinology team regularly, from infancy to late adolescence. With a typical phenotype of ACH, it is striking and noteworthy that he did not develop the classical endocrine complications of a child with KS, neither did he necessitate testosterone supplementation during his pubertal development, due to his normal virilization and testosterone levels.

Partial monosomy 8p and trisomy 16q in two children with developmental delay detected by array comparative genomic hybridization.

Two cases of liveborn unrelated children with developmental delay and overlapping unbalanced translocations der(8)t(8;16)(p23.2;q23.3) and der (8)t(8;16)(p23.1;q23.1), leading to partial monosomy 8p and partial trisomy 16q, are reported in the present study. The first patient was a 10­year­old boy with mild developmental delay and minor congenital anomalies (borderline microcephaly, clinodactyly, hypertelorism, epicanthus, mild systolic murmur and kidney reflux). The second patient was a 3 year­old girl with developmental delay, gross motor milestone delay and dysmorphic features. Array­comparative genomic hybridization analysis revealed that partial chromosome 8p monosomy extended from 8p23.2 to 8pter (4.8 Mb) in Patient 1 and from 8p23.1 to 8pter (9.5 Mb) in Patient 2, and partial chromosome 16 trisomy extended from 16q23.3 to 16qter (5.6 Mb) in Patient 1 and from 16q23.1 to 16qter (11.7 Mb) in Patient 2. The mechanism of appearance of the rearrangement in association with the genes involved and the architecture of the region is discussed.

Two years of growth hormone treatment in the first growth hormone deficient patient with cerebrofaciothoracic dysplasia.

We recently reported two siblings, a sister and a brother, with intrauterine growth retardation, microcephaly, short stature, mental retardation, facial dysmorphism and multiple costovertebral malformations. These features fit most with the diagnosis of cerebrofaciothoracic dysplasia, or Pascual-Castroviejo syndrome. The second sibling, our index patient, presented also with cleft palate and growth hormone (GH) deficiency, suggesting that endocrinological assessment should be performed in short patients with this syndrome, especially if midline defects are present. We present the results of 2 years GH treatment of this first GH deficient patient with cerebrofaciothoracic syndrome and compare the results to those observed in other genetic syndromes with GH deficiency.