Hypothalamic hamartoma surgery in a setting with limited resources.

BACKGROUND: Three years ago (in 2020), we at the epilepsy center in Shiraz, Iran, started an endeavor to initiate a surgical program for patients with hypothalamic hamartoma (HH). We discussed that although minimally invasive techniques are desired, they are not available in the nation. We decided to proceed with open disconnection and resection surgery techniques. The current manuscript presents the results of the HH surgery program at our center as a case series. METHODS: This study included all patients with a diagnosis of HH who were referred to Shiraz Epilepsy Center with drug-resistant epilepsy and who underwent HH surgery from October 2020 to January 2023 at our epilepsy center, Namazi Hospital, Shiraz, Iran. RESULTS: Seven patients were included. All patients had gelastic seizures. Four patients (57%) underwent total resection of HH, and the lesions were disconnected and partially resected in three other patients (43%). Three patients (43%) became seizure-free after surgery, and three patients (43%) had more than 50% reduction in their seizure frequencies. Three patients (43%) had no post-operative complications. Only one patient (14.3%) suffered from a permanent postoperative complication (right hemiparesis). The mortality rate was zero. Five parents (71%) were satisfied with the surgery outcomes. CONCLUSION: Hypothalamic hamartoma surgery is feasible even in centers with limited resources if a close collaboration exists between the epileptology and neurosurgery teams. Careful planning based on the expertise of the team members and the available resources is required to foster success.

Deletion of 15q11.2(BP1-BP2) region: further evidence for lack of phenotypic specificity in a pediatric population.

Microdeletion of the BP1-BP2 region at 15q11.2 is a recurrent copy number variant (CNV) frequently found in patients undergoing chromosomal microarray (CMA). Genetic counselling regarding this CNV is challenging due to the wide range of phenotypic presentation in reported patients and lack of general population-based data. As one of the most common reasons for CMA is childhood developmental delay, clinicians need to be cognizant of the inherent ascertainment bias in the literature. We performed a detailed medical record review for 55 patients with this 15q11.2 microdeletion and report the clinical features of the 35 patients for whom information was available. We compared our results to the recent report by Cafferkey et al. in this journal. Our conclusion is that the phenotypic spectrum is too broad and non-specific to constitute a bona fide "syndrome" and that further research must be done to delineate the contribution of this CNV to phenotype.

Constitutional Chromothripsis on Chromosome 2: A Rare Case with Severe Presentation.

Chromothripsis is characterized by shattering and subsequent reassembly of chromosomes by DNA repair processes, which can give rise to a variety of congenital abnormalities and cancer. Constitutional chromothripsis is a rare occurrence, reported in children presenting with a wide range of birth defects. We present a case of a female child born with multiple major congenital abnormalities including severe microcephaly, ocular dysgenesis, heart defect, and imperforate anus. Chromosomal microarray and mate pair sequencing identified a complex chromosomal rearrangement involving the terminal end of the long arm of chromosome 2, with two duplications (located at 2p25.3-p25.1 and 2q35-q37.2 regions) and two deletions (located at 2q37.2-q37.3 and 2q37.3 regions) along with structural changes including inverted segments. A review of the literature for complex rearrangements on chromosome 2 revealed overlapping features; however, our patient had a significantly more severe phenotype which resulted in early death at the age of 2 years. Breakpoints analysis did not reveal the involvement of any candidate genes. We concluded that the complexity of the genomic rearrangement and the combined dosage/structural effect of these copy number variants are likely explanations for the severe presentation in our patient.

A Prenatal Presentation of CDK13-Related Disorder with a Novel Pathogenic Variant.

Cyclin-dependent kinase 13 (CDK13) is a member of the cyclin-dependent serine/threonine protein kinase family. Members of this family are well known for their essential roles as master switches in cell cycle control. CDK13-related disorder is a newly described genetic condition with characteristic clinical features including mild to severe intellectual disability, developmental delay, neonatal hypotonia, a variety of facial dysmorphism, behavioral problems, congenital heart defects, and structural brain abnormalities. We report a case of prenatal diagnosis of CDK13-related disorder. Detection of cystic hygroma with thickened nuchal fold led to prenatal genetic investigation, which identified a novel de novo likely pathogenic variant in the CDK13 gene (c.900C > G, p.Tyr300∗). Pregnancy was terminated and autopsy was performed. To our best knowledge, this is the first reported case of prenatal presentation of this condition with a detailed phenotypic description of the affected fetus.

New presentation of CLIFAHDD syndrome with a novel variant in NALCN gene: A report of a rare case.

Key Clinical Message: Congenital Contractures of Limbs and Face, Hypotonia, and Developmental Delay (CLIFAHDD) syndrome is a recently described type of distal arthrogryposis which unlike other subtypes is associated with developmental delay and various neurologic presentation. Epilepsy and ataxia have been reported. We add paroxysmal dyskinesia to the clinical spectrum. Understanding the molecular mechanism can help developing targeted therapy in future. Abstract: This study resulted in identification of a novel variant in NALCN gene leading to autosomal dominant CLIFAHDD syndrome. Our patient presented with a form of nonepileptic paroxysmal dyskinesia. This is a new phenotype that has not been described previously.

Detection of driver engagement in secondary tasks from observed naturalistic driving behavior.

Distracted driving has long been acknowledged as one of the leading causes of death or injury in roadway crashes. The focus of past research has been mainly on the impact of different causes of distraction on driving behavior. However, only a few studies attempted to address how some driving behavior attributes could be linked to the cause of distraction. In essence, this study takes advantage of the rich SHRP 2 Naturalistic Driving Study (NDS) database to develop a model for detecting the likelihood of a driver's involvement in secondary tasks from distinctive attributes of driving behavior. Five performance attributes, namely speed, longitudinal acceleration, lateral acceleration, yaw rate, and throttle position were used to describe the driving behavior. A model was developed for each of three selected secondary tasks: calling, texting, and passenger interaction. The models were developed using a supervised feed-forward Artificial Neural Network (ANN) architecture to account for the effect of inherent nonlinearity in the relationships between driving behavior and secondary tasks. The results show that the developed ANN models were able to detect the drivers' involvement in calling, texting, and passenger interaction with an overall accuracy of 99.5%, 98.1%, and 99.8%, respectively. These results show that the selected driving performance attributes were effective in detecting the associated secondary tasks with driving behavior. The results are very promising and the developed models could potentially be applied in crash investigations to resolve legal disputes in traffic accidents.

Diagnostic value of immunohistochemistry staining of Bcl-2, CD34, CD20 and CD3 for distinction between discoid lupus erythematosus and lichen planus in the skin.

BACKGROUND: Cluster of differentiation (CD) markers is a classification system for monoclonal antibodies against cell surface molecules on leukocytes and antigens from other cells. AIMS: The aim of this study is to evaluate immunohistochemical markers in patients with discoid lupus erythematosus (DLE) and lichen planus (LP) and correlation of these markers in two groups and with the normal group in the West of Iran. SETTINGS AND DESIGN: Analytical cross-sectional study. MATERIALS AND METHODS: This study was performed on paraffin blocks of DLE and LP patients with normal group (21, 21 and 16 cases, respectively) between 2009 and 2012. Formalin-fixed, paraffin-embedded tissue sections from each DLE, LP, and normal skin biopsy specimen were cut into 4-µ thick sections and mounted on glass slides. Initial sections were stained with hematoxylin and eosin. Primary antihuman antibodies against CD3, CD20, CD34, and Bcl-2 were applied. Positive control samples for CD3, CD20, and Bcl-2 were received from lymph nodes and for CD34 from dermal microvessels. STATISTICAL ANALYSIS USED: SPSS version 19 (SPSS, Inc., Chicago, USA) and Microsoft Excel 2007. RESULTS: The mean staining for four markers was more significant in DLE and LP groups compared to normal group and for CD34 and CD3 was more significant in LP groups versus DLE group. CONCLUSIONS: CD3+, CD34+, Bcl-2+, and CD20+ cells are significantly higher in DLE and LP lesional skins versus normal skin. In addition, there were higher expressions of CD3 and CD34 in LP lesional skin versus DLE lesional skin.

Whole Genome Sequencing Expands Diagnostic Utility and Improves Clinical Management in Pediatric Medicine.

The standard of care for first-tier clinical investigation of the etiology of congenital malformations and neurodevelopmental disorders is chromosome microarray analysis (CMA) for copy number variations (CNVs), often followed by gene(s)-specific sequencing searching for smaller insertion-deletions (indels) and single nucleotide variant (SNV) mutations. Whole genome sequencing (WGS) has the potential to capture all classes of genetic variation in one experiment; however, the diagnostic yield for mutation detection of WGS compared to CMA, and other tests, needs to be established. In a prospective study we utilized WGS and comprehensive medical annotation to assess 100 patients referred to a paediatric genetics service and compared the diagnostic yield versus standard genetic testing. WGS identified genetic variants meeting clinical diagnostic criteria in 34% of cases, representing a 4-fold increase in diagnostic rate over CMA (8%) (p-value = 1.42e-05) alone and >2-fold increase in CMA plus targeted gene sequencing (13%) (p-value = 0.0009). WGS identified all rare clinically significant CNVs that were detected by CMA. In 26 patients, WGS revealed indel and missense mutations presenting in a dominant (63%) or a recessive (37%) manner. We found four subjects with mutations in at least two genes associated with distinct genetic disorders, including two cases harboring a pathogenic CNV and SNV. When considering medically actionable secondary findings in addition to primary WGS findings, 38% of patients would benefit from genetic counseling. Clinical implementation of WGS as a primary test will provide a higher diagnostic yield than conventional genetic testing and potentially reduce the time required to reach a genetic diagnosis.

CHD2 haploinsufficiency is associated with developmental delay, intellectual disability, epilepsy and neurobehavioural problems.

BACKGROUND: The chromodomain helicase DNA binding domain (CHD) proteins modulate gene expression via their ability to remodel chromatin structure and influence histone acetylation. Recent studies have shown that CHD2 protein plays a critical role in embryonic development, tumor suppression and survival. Like other genes encoding members of the CHD family, pathogenic mutations in the CHD2 gene are expected to be implicated in human disease. In fact, there is emerging evidence suggesting that CHD2 might contribute to a broad spectrum of neurodevelopmental disorders. Despite growing evidence, a description of the full phenotypic spectrum of this condition is lacking. METHODS: We conducted a multicentre study to identify and characterise the clinical features associated with haploinsufficiency of CHD2. Patients with deletions of this gene were identified from among broadly ascertained clinical cohorts undergoing genomic microarray analysis for developmental delay, congenital anomalies and/or autism spectrum disorder. RESULTS: Detailed clinical assessments by clinical geneticists showed recurrent clinical symptoms, including developmental delay, intellectual disability, epilepsy, behavioural problems and autism-like features without characteristic facial gestalt or brain malformations observed on magnetic resonance imaging scans. Parental analysis showed that the deletions affecting CHD2 were de novo in all four patients, and analysis of high-resolution microarray data derived from 26,826 unaffected controls showed no deletions of this gene. CONCLUSIONS: The results of this study, in addition to our review of the literature, support a causative role of CHD2 haploinsufficiency in developmental delay, intellectual disability, epilepsy and behavioural problems, with phenotypic variability between individuals.