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Medicina 2018In a wide spectrum of cases in childhood, macrocephaly does not carry a neurological risk, although a range of possibilities will have an impact on both the evolutionary...
In a wide spectrum of cases in childhood, macrocephaly does not carry a neurological risk, although a range of possibilities will have an impact on both the evolutionary and cognitive aspects of children. The previous happens in pathologies with progressive components, such as tumors or hydrocephalus, and in those cases in which the factor of the growth of the cephalic perimeter is given by structural components of the nervous system as it happens in megalocephaly. As in all other medical acts, the careful taking of the anamnesis, the appropriate neurological examination and the valuations of the neurodevelopment items can give a thorough orientation about the etiology and importance of the problem. The help of diagnostic aids as well as images will provide the other data to define the diagnosis and propose a treatment.
Topics: Child; Diagnosis, Differential; Humans; Hydrocephalus; Megalencephaly
PubMed: 30199374
DOI: No ID Found -
Frontiers in Global Women's Health 2023To compare the proportion of female and male fetuses classified as microcephalic (head circumference [HC] < 3rd percentile) and macrocephalic (>97th percentile) by...
OBJECTIVE
To compare the proportion of female and male fetuses classified as microcephalic (head circumference [HC] < 3rd percentile) and macrocephalic (>97th percentile) by commonly used sex-neutral growth curves.
METHODS
For fetuses evaluated at a single center, we retrospectively determined the percentile of the first fetal HC measurement between 16 and 0/7 and 21-6/7 weeks using the Hadlock, Intergrowth-21st, and NICHD growth curves. The association between sex and the likelihood of being classified as microcephalic or macrocephalic was evaluated with logistic regression.
RESULTS
Female fetuses ( = 3,006) were more likely than male fetuses ( = 3,186) to be classified as microcephalic using the Hadlock (0.4% male, 1.4% female; odds ratio female vs. male 3.7, 95% CI [1.9, 7.0], < 0.001), Intergrowth-21st (0.5% male, 1.6% female; odds ratio female vs. male 3.4, 95% CI [1.9, 6.1], < 0.001), and NICHD (0.3% male, 1.6% female; odds ratio female vs. male 5.6, 95% CI [2.7, 11.5], < 0.001) curves. Male fetuses were more likely than female fetuses to be classified as macrocephalic using the Intergrowth-21st (6.0% male, 1.5% female; odds ratio male vs. female 4.3, 95% CI [3.1, 6.0], < 0.001) and NICHD (4.7% male, 1.0% female; odds ratio male vs. female 5.1, 95% CI [3.4, 7.6], < 0.001) curves. Very low proportions of fetuses were classified as macrocephalic using the Hadlock curves (0.2% male, < 0.1% female; odds ratio male vs. female 6.6, 95% CI [0.8, 52.6]).
CONCLUSION
Female fetuses were more likely to be classified as microcephalic, and male fetuses were more likely to be classified as macrocephalic. Sex-specific fetal head circumference growth curves could improve interpretation of fetal head circumference measurements, potentially decreasing over- and under-diagnosis of microcephaly and macrocephaly based on sex, therefore improving guidance for clinical decisions. Additionally, the overall prevalence of atypical head size varied using three growth curves, with the NICHD and Intergrowth-21st curves fitting our population better than the Hadlock curves. The choice of fetal head circumference growth curves may substantially impact clinical care.
PubMed: 36911049
DOI: 10.3389/fgwh.2023.1080175 -
Revue Medicale de Liege Jan 2022Macrocephaly is a frequent reason for seeking advice in a pediatric neurology consultation. It is a non-specific neurological sign that can be isolated, be the sign of a...
Macrocephaly is a frequent reason for seeking advice in a pediatric neurology consultation. It is a non-specific neurological sign that can be isolated, be the sign of a serious acquired pathology or be part of a syndromic picture. Clinical history, physical examination and imaging are key elements of the diagnostic strategy. Signs of intracranial hypertension require an emergency work-up. Genetics, exome in particular, has enabled the characterization of various syndromes associating macrocephaly and neurodevelopmental delay. In this article, we propose an update of practices based on clinical signs.
Topics: Child; Humans; Megalencephaly
PubMed: 35029342
DOI: No ID Found -
Genetics in Medicine : Official Journal... Apr 2013Rare, recurrent chromosome 1q21.1 duplications have been associated with developmental delay, congenital anomalies, and macrocephaly in children. Data on adult clinical... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Rare, recurrent chromosome 1q21.1 duplications have been associated with developmental delay, congenital anomalies, and macrocephaly in children. Data on adult clinical expression would help to inform genetic counseling.
METHODS
A systematic review of 22 studies reporting 107 individuals (59 children and 48 adults) with 1q21.1 duplications was conducted. We compiled the available phenotypic data to attempt to identify the most highly associated clinical features and to determine expression in adults. We also report on seven adult cases newly identified in the studies of schizophrenia and tetralogy of Fallot at our center.
RESULTS
Five cases were ascertained as controls, 32 as relatives of probands, and 70 as having clinical features: autism spectrum disorder (n = 15), congenital heart disease (n = 12), schizophrenia (n = 10), or other, mostly developmental, features (n = 33). The 1q21.1 duplication was significantly enriched in the cohorts with schizophrenia (P = 0.0155) and tetralogy of Fallot (P = 0.0040) at our center as compared with controls. There was a paucity of clinical data for adults; the most common features, other than those used for ascertainment, included macrocephaly and abnormalities of possible connective tissue origin (e.g., carpal tunnel syndrome).
CONCLUSION
Further data are needed to characterize lifetime expression of 1q21.1 duplications. These initial results, however, suggest that anticipatory care should include attention to later-onset conditions such as schizophrenia.
Topics: Adolescent; Adult; Anticipation, Genetic; Child; Child, Preschool; Chromosome Duplication; Chromosomes, Human, Pair 1; Female; Genetic Counseling; Humans; Infant; Male; Middle Aged; Phenotype
PubMed: 23018752
DOI: 10.1038/gim.2012.129 -
Neurobiology of Disease Aug 2023Lesional epilepsy is a common and severe disease commonly associated with malformations of cortical development, including focal cortical dysplasia and... (Review)
Review
Lesional epilepsy is a common and severe disease commonly associated with malformations of cortical development, including focal cortical dysplasia and hemimegalencephaly. Recent advances in sequencing and variant calling technologies have identified several genetic causes, including both short/single nucleotide and structural somatic variation. In this review, we aim to provide a comprehensive overview of the methodological advancements in this field while highlighting the unresolved technological and computational challenges that persist, including ultra-low variant allele fractions in bulk tissue, low availability of paired control samples, spatial variability of mutational burden within the lesion, and the issue of false-positive calls and validation procedures. Information from genetic testing in focal epilepsy may be integrated into clinical care to inform histopathological diagnosis, postoperative prognosis, and candidate precision therapies.
Topics: Humans; Brain; Mosaicism; Mutation; Epilepsy; Hemimegalencephaly; Malformations of Cortical Development
PubMed: 37343892
DOI: 10.1016/j.nbd.2023.106208 -
International Journal of Molecular... May 2021Pathogenic copy number variations (CNVs) contribute to the etiology of neurodevelopmental/neuropsychiatric disorders (NDs). Increased CNV burden has been found to be... (Review)
Review
Pathogenic copy number variations (CNVs) contribute to the etiology of neurodevelopmental/neuropsychiatric disorders (NDs). Increased CNV burden has been found to be critically involved in NDs compared with controls in clinical studies. The 1q21.1 CNVs, rare and large chromosomal microduplications and microdeletions, are detected in many patients with NDs. Phenotypes of duplication and deletion appear at the two ends of the spectrum. Microdeletions are predominant in individuals with schizophrenia (SCZ) and microcephaly, whereas microduplications are predominant in individuals with autism spectrum disorder (ASD) and macrocephaly. However, its complexity hinders the discovery of molecular pathways and phenotypic networks. In this review, we summarize the recent genome-wide association studies (GWASs) that have identified candidate genes positively correlated with 1q21.1 CNVs, which are likely to contribute to abnormal phenotypes in carriers. We discuss the clinical data implicated in the 1q21.1 genetic structure that is strongly associated with neurodevelopmental dysfunctions like cognitive impairment and reduced synaptic plasticity. We further present variations reported in the phenotypic severity, genomic penetrance and inheritance.
Topics: Abnormalities, Multiple; Autism Spectrum Disorder; Chromosome Deletion; Chromosome Duplication; Chromosomes, Human, Pair 1; DNA Copy Number Variations; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Megalencephaly; Mental Disorders; Microcephaly; Neurodegenerative Diseases; Neurodevelopmental Disorders; Schizophrenia
PubMed: 34071723
DOI: 10.3390/ijms22115811 -
Science Advances Mar 2023Pathogenic variants in , a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM 617788). Given...
Pathogenic variants in , a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest ( = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in -related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.
Topics: Animals; Humans; Mice; Haploinsufficiency; Megalencephaly; Methyltransferases; Mice, Knockout; Neurodevelopmental Disorders; Phenotype
PubMed: 36897941
DOI: 10.1126/sciadv.ade1463 -
American Journal of Human Genetics Jan 2014The proper development of neuronal circuits during neuromorphogenesis and neuronal-network formation is critically dependent on a coordinated and intricate series of...
The proper development of neuronal circuits during neuromorphogenesis and neuronal-network formation is critically dependent on a coordinated and intricate series of molecular and cellular cues and responses. Although the cortical actin cytoskeleton is known to play a key role in neuromorphogenesis, relatively little is known about the specific molecules important for this process. Using linkage analysis and whole-exome sequencing on samples from families from the Amish community of Ohio, we have demonstrated that mutations in KPTN, encoding kaptin, cause a syndrome typified by macrocephaly, neurodevelopmental delay, and seizures. Our immunofluorescence analyses in primary neuronal cell cultures showed that endogenous and GFP-tagged kaptin associates with dynamic actin cytoskeletal structures and that this association is lost upon introduction of the identified mutations. Taken together, our studies have identified kaptin alterations responsible for macrocephaly and neurodevelopmental delay and define kaptin as a molecule crucial for normal human neuromorphogenesis.
Topics: Actin Cytoskeleton; Amino Acid Sequence; Developmental Disabilities; Female; Fluorescent Antibody Technique; Genetic Linkage; Humans; Male; Megalencephaly; Microfilament Proteins; Molecular Sequence Data; Mutation; Pedigree; Seizures
PubMed: 24239382
DOI: 10.1016/j.ajhg.2013.10.001 -
American Journal of Medical Genetics.... Dec 2019EML1 encodes the protein Echinoderm microtubule-associated protein-like 1 or EMAP-1 that binds to the microtubule complex. Mutations in this gene resulting in complex... (Review)
Review
EML1 encodes the protein Echinoderm microtubule-associated protein-like 1 or EMAP-1 that binds to the microtubule complex. Mutations in this gene resulting in complex brain malformations have only recently been published with limited clinical descriptions. We provide further clinical and imaging details on three previously published families, and describe two novel unrelated individuals with a homozygous partial EML1 deletion and a homozygous missense variant c.760G>A, p.(Val254Met), respectively. From review of the clinical and imaging data of eight individuals from five families with biallelic EML1 variants, a very consistent imaging phenotype emerges. The clinical syndrome is characterized by mainly neurological features including severe developmental delay, drug-resistant seizures and visual impairment. On brain imaging there is megalencephaly with a characteristic ribbon-like subcortical heterotopia combined with partial or complete callosal agenesis and an overlying polymicrogyria-like cortical malformation. Several of its features can be recognized on prenatal imaging especially the abnormaly formed lateral ventricles, hydrocephalus (in half of the cases) and suspicion of a neuronal migration disorder. In conclusion, biallelic EML1 disease-causing variants cause a highly specific pattern of congenital brain malformations, severe developmental delay, seizures and visual impairment.
Topics: Brain; Humans; Malformations of Cortical Development, Group II; Microtubule-Associated Proteins; Mutation, Missense; Sequence Deletion
PubMed: 31710781
DOI: 10.1002/ajmg.c.31751 -
Translational Psychiatry Oct 2022CHD8, a major autism gene, functions in chromatin remodelling and has various roles involving several biological pathways. Therefore, unsurprisingly, previous studies...
CHD8, a major autism gene, functions in chromatin remodelling and has various roles involving several biological pathways. Therefore, unsurprisingly, previous studies have shown that intellectual developmental disorder with autism and macrocephaly (IDDAM), the syndrome caused by pathogenic variants in CHD8, consists of a broad range of phenotypic abnormalities. We collected and reviewed 106 individuals with IDDAM, including 36 individuals not previously published, thus enabling thorough genotype-phenotype analyses, involving the CHD8 mutation spectrum, characterization of the CHD8 DNA methylation episignature, and the systematic analysis of phenotypes collected in Human Phenotype Ontology (HPO). We identified 29 unique nonsense, 25 frameshift, 24 missense, and 12 splice site variants. Furthermore, two unique inframe deletions, one larger deletion (exons 26-28), and one translocation were observed. Methylation analysis was performed for 13 patients, 11 of which showed the previously established episignature for IDDAM (85%) associated with CHD8 haploinsufficiency, one analysis was inconclusive, and one showing a possible gain-of-function signature instead of the expected haploinsufficiency signature was observed. Consistent with previous studies, phenotypical abnormalities affected multiple organ systems. Many neurological abnormalities, like intellectual disability (68%) and hypotonia (29%) were observed, as well as a wide variety of behavioural abnormalities (88%). Most frequently observed behavioural problems included autism spectrum disorder (76%), short attention span (32%), abnormal social behaviour (31%), sleep disturbance (29%) and impaired social interactions (28%). Furthermore, abnormalities in the digestive (53%), musculoskeletal (79%) and genitourinary systems (18%) were noted. Although no significant difference in severity was observed between males and females, individuals with a missense variant were less severely affected. Our study provides an extensive review of all phenotypic abnormalities in patients with IDDAM and provides clinical recommendations, which will be of significant value to individuals with a pathogenic variant in CHD8, their families, and clinicians as it gives a more refined insight into the clinical and molecular spectrum of IDDAM, which is essential for accurate care and counselling.
Topics: Autism Spectrum Disorder; Autistic Disorder; DNA-Binding Proteins; Female; Genetic Association Studies; Humans; Intellectual Disability; Male; Megalencephaly; Phenotype; Transcription Factors
PubMed: 36182950
DOI: 10.1038/s41398-022-02189-1