👤 Mahmoud Y Issa

Spinal osteochondromas develop from aberrant endochondral ossification of the vertebrae, which originate from the sclerotome of the paraxial mesoderm. These tumors typically involve the posterior elements, such as the spinous process, lamina, or pedicles. Spinal osteochondromas are rare, constituting less than 2% of all osteochondromas and under 4% of spinal tumors. A 7-year-old boy came to the clinic with a lump at the back of the neck and difficulty moving his head, which was diagnosed as osteochondroma at the fifth cervical vertebra (C5). The child also had a history of multiple hereditary exostoses affecting other parts of the body. Spinal osteochondromas account for a small percentage of cases, with the cervical spine being the most frequently affected. Diagnosis relies on computed tomography for precise visualization, aiding in preoperative planning. The etiology involves genetic mutations in EXT1 and EXT2, with additional mechanical factors possibly contributing to cervical spine involvement. This case contributes valuable insights into pediatric spinal osteochondromas, underscoring the need for timely diagnosis to prevent complications. Osteochondromas are considered the most common benign tumors. However, spinal osteochondromas are very rare, particularly in pediatric patients. This case underscores the importance of recognizing osteochondroma as a differential diagnosis for neck masses in children. Early diagnosis and surgical intervention can prevent complications and recurrence, highlighting the clinical significance of this rare condition. This report also emphasizes the necessity of vigilant postoperative follow-up to ensure complete recovery and monitor for potential complications. Show less

Dried blood spot sampling offers a scalable strategy to close diagnostic gaps and improve global surveillance for cardiovascular-kidney-metabolic syndrome. However, assay performance and the extent of validity vary widely between biomarkers used in cardiovascular-kidney-metabolic health assessment under different settings and have not been well described. To fill this gap, we conducted a systematic search of the literature and a narrative synthesis through April 2024 and included reports with laboratory or field validation measuring biomarkers that can be used in cardiovascular-kidney-metabolic health assessment. We categorized assays into categories based on laboratory validation: excellent performance (r>0.95 with gold standard methods and coefficients of variation <5%), very good performance (r>0.90 and coefficients of variation <10%), reasonable performance (r>0.80 and coefficients of variation <15%), and poor performance (r<0.80 or coefficients of variation >15%). The extent of validation was determined by the total number of field validation studies with strong agreement. Hemoglobin A1c has strong laboratory and field validation and should be considered for expansion into clinical testing in low-resource settings. Traditional lipid biomarkers showed poor performance in field validation studies, but apoB (apolipoprotein B), creatinine, cystatin C, and NT-proBNP (N-terminal prohormone of brain natriuretic peptide) showed promising initial laboratory validation results and deserve greater attention in field validation studies. High-sensitivity C-reactive protein has strong laboratory and field validation but has limited clinical utility. Dried blood spot assays have been developed for biomarkers that offer mechanistic insights including inflammatory and vascular injury markers, fatty acids, malondialdehyde, asymmetric dimethylarginine, trimethylamine N-oxide, carnitines, and omics. Show less

Childhood-onset thoracic aortic dilatation (TAD) is a heterogenous group of genetic conditions the inheritance of which is largely dominant. To our knowledge, the influence of consanguinity on childhood-onset TAD has not been addressed systematically. We aim to study a cohort of children with TAD in our highly consanguineous population. Children with TAD were consecutively recruited. Based on the likelihood of a founder mutation, genetic test was categorized to either targeted gene testing or multi-gene sequencing, followed by genetic screening of first-degree relatives. Clinical data and outcome were reviewed. Thirty-three children, from 20 families, had childhood-onset TAD. Genetic test was positive in 20 children, from 13 families, providing a yield of 65 % (13/20). The median age of onset of TAD was 4.5 years. Eight variants were detected in 4 genes (FBN1, EFEMP2, ACTA2, KANSL1) with a homozygous EFEMP2 variant found in 6 families (46.2 %). Surgical intervention was required in 14 (70 %) cases (13 with EFEMP2, 1 with FBN1 variants) at a median age of 3.5 years. All patients are alive (ages range:3-31 years). Our work illustrates the impact of consanguinity on the genetics of childhood-onset TAD elucidating severe presentation of recessively inherited form. Our data underscores the importance of genetic screening and early recognition of TAD to achieve excellent outcome. Show less

To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3 million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 common variant loci for SND, DCD and PM, respectively. Four well-known loci (SCN5A/SCN10A, CCDC141, TBX20 and CAMK2D) were shared for SND and DCD, while others were more specific for SND or DCD. SND and DCD showed a moderate genetic correlation (r Show less

NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the "NALCN channelosome", consisting of multiple proteins including UNC80 and UNC79. The predominant neuronal expression pattern and its function suggest an important role in neuronal function and disease. So far, biallelic NALCN and UNC80 variants have been described in a small number of individuals leading to infantile hypotonia, psychomotor retardation, and characteristic facies 1 (IHPRF1, OMIM 615419) and 2 (IHPRF2, OMIM 616801), respectively. Heterozygous de novo NALCN missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD, OMIM 616266) with some clinical overlap. In this study, we present detailed clinical information of 16 novel individuals with biallelic NALCN variants, 1 individual with a heterozygous de novo NALCN missense variant and an interesting clinical phenotype without contractures, and 12 individuals with biallelic UNC80 variants. We report for the first time a missense NALCN variant located in the predicted S6 pore-forming unit inherited in an autosomal-recessive manner leading to mild IHPRF1. We show evidence of clinical variability, especially among IHPRF1-affected individuals, and discuss differences between the IHPRF1- and IHPRF2 phenotypes. In summary, we provide a comprehensive overview of IHPRF1 and IHPRF2 phenotypes based on the largest cohort of individuals reported so far and provide additional insights into the clinical phenotypes of these neurodevelopmental diseases to help improve counseling of affected families. Show less

Menopause is associated with changes in lipid levels resulting in increased risk of atherosclerosis and cardiovascular events. Hormone therapy (HT) and atorvastatin have been used to improve lipid profile in postmenopausal women. Effects of HT, atorvastatin and APOE polymorphisms on serum lipids and APOE and LXRA expression were evaluated in 87 hypercholesterolemic postmenopausal women, randomly selected for treatment with atorvastatin (AT, n=17), estrogen or estrogen plus progestagen (HT, n=34) and estrogen or estrogen plus progestagen associated with atorvastatin (HT+AT, n=36). RNA was extracted from peripheral blood mononuclear cells (PBMC) and mRNA expression was measured by TaqMan(®) PCR. APOE ɛ2/ɛ3/ɛ4 genotyping was performed using PCR-RFLP. Total cholesterol (TC), LDL-c and apoB were reduced after each treatment (p<0.001). Triglycerides, VLDL-c and apoAI were reduced only after atorvastatin (p<0.05), whereas triglycerides and VLDL-c were increased after HT (p=0.01). HT women had lower reduction on TC, LDL-c and apoB than AT and HT+AT groups (p<0.05). APOE mRNA expression was reduced after atorvastatin treatment (p=0.03). Although LXRA gene expression was not modified by atorvastatin, it was correlated with APOE mRNA before and after treatments. Basal APOE mRNA expression was not influenced by gene polymorphisms, however the reduction on APOE expression was more pronounced in ɛ3ɛ3 than in ɛ3ɛ4 carriers. Atorvastatin down-regulates APOE mRNA expression and it is modified by APOE genotypes in PBMC from postmenopausal women. Show less