Management of a giant adrenal schwannoma.

In this case report, we present a man in his 60s who presented with an incidentally discovered right adrenal mass, which turned out to be an adrenal schwannoma. This is a very rare tumour that originates from Schwann cells and involves the peripheral nerves. The tumour was removed by open adrenalectomy, and this 15-cm adrenal schwannoma is one of the largest reported in the literature, with none >16 cm having ever been reported. This case highlights the importance of keeping an open mind about the cause of an incidentally discovered adrenal mass, which is an increasingly common way for adrenal tumours to present given the increased access to cross-sectional imaging. As well as presenting the case and the pathological basis behind adrenal schwannomas, we include a review of the literature and a general discussion about incidentally discovered adrenal masses.

Gastro-oesophageal reflux: rare presentation of Sotos syndrome in a neonate.

Sotos syndrome is a disorder characterised by distinctive facial features, excessive growth during childhood and intellectual disability. While these criteria apply to children and adults, they fall short when applied to neonates. Hyperbilirubinaemia, large for gestational age, hypotonia and seizures, along with cardiac and renal anomalies, are known to be common presentations in neonates. Reports have also added hyperinsulinaemic hypoglycaemia as a presenting feature of Sotos syndrome in neonates. Here, we report a case of Sotos syndrome in a neonate who presented in the neonatal period with recurrent apnoeic episodes with hypotonia, which were later attributed to severe gastro-oesophageal reflux.

Preimplantation Genetic Testing for Aneuploidy in In Vitro Fertilization Using Comprehensive Chromosome Screening: A Systematic Review and Meta-Analysis.

The utility of pre-implantation genetic testing (PGT-A) is controversial, with older meta-analyses demonstrating improved pregnancy outcomes, while newer trials have not shown benefit. Therefore, we performed a meta-analysis which aimed to evaluate the benefits of PGT-A using comprehensive chromosome screening (CCS) and its effects on in vitro fertilization (IVF) outcomes among randomized controlled trials (RCTs). We conducted a systematic search to identify RCTs comparing women undergoing PGT-A with CSS with women not undergoing PGT-A, from inception to December 2020. Random effects meta-analysis was utilized to calculate average odds ratios (OR) for clinical pregnancy rate (CPR), ongoing pregnancy rate (OPR), and miscarriage rate (MR). The heterogeneity of exposure was assessed using Forest plots and I2 statistics. Publication bias was evaluated using Egger's test. Among 1251 citations, seven RCTs met the inclusion criteria. Biopsies of embryos were carried out at various developmental stages, including polar body, day 3, and day 5-6 of culture. Data was analyzed as all studies and blastocyst only. Meta-analysis failed to show improvement in OPRs using PGT-A in the all ages, <35 years old and ≥35 years old age groups. There was also no significant difference in CPRs in any group. The MR decreased with the use of PGT-A (among all biopsy types and among blastocyst biopsies) in the all-ages group, but not when stratifying according to patient age <35 and ≥35 years old. More data regarding the risks and advantages of PGT-A are needed to make a final decision on the value of this intervention in clinical practice. The exact magnitude of the benefit of PGT-A selection cannot be correctly determined until multiple standardized protocol IVF PGT-A trials are conducted.

Oncological features of sporadic vs. hereditary pediatric medullary thyroid cancer.

PURPOSE: No genomic data have been put forth that prove beyond a shadow of doubt that sporadic medullary thyroid cancer (MTC) occurs in infancy, childhood, and/or adolescence. METHODS: This was a retrospective comparative study of consecutive patients with MTC who had neck surgery at a tertiary center over a 30-year period. RESULTS: Included were 1252 patients with MTC (337 hereditary and 915 sporadic), of whom 107 (8.5%) were operated before the age of 18 yrs. Only 4 (3.7%) of the 107 pediatric patients, aged 14, 16, 17 and 17 years, had sporadic MTC. These 4 patients, 3 of whom had been referred for completion surgery, revealed much larger thyroid tumors (medians of 20 mm vs. 1.5-5 mm) than the 103 pediatric patients with hereditary MTC. As for extrathyroid extension and nodal metastases, the 4 patients with sporadic MTC were more comparable to the 37 carriers of highest-risk mutations, 31 (84%) of whom were index patients with de novo disease, than to the 66 carriers of high-risk, intermediate-risk, or low-risk RET mutations (25-38% vs. 0-8%, and medians of 9-9.5 vs. 0 node metastases after dissection of more (medians of 72-91.5 vs. 4.5-9) nodes). CONCLUSION: Sporadic MTC, arising rarely, if ever, below the age of 14 years, is exceptional in infancy and childhood, and infrequent in adolescence. At diagnosis, it is almost as widely metastatic as hereditary MTC of the highest-risk category which almost always, like sporadic MTC, presents as de novo disease.

The role of genomic disorders in chronic kidney failure of undetermined aetiology ≤50 years.

Background: Genomic disorders caused by copy number variations (CNVs) are prevalent in patients with kidney disease; however, their contribution to chronic kidney failure (KF) of undetermined aetiology (uKF) is unclear. We screened patients with uKF aged 50 years or younger to establish the prevalence of causative CNVs. Methods: We enrolled patients with an onset of KF ≤50 years from suspected undetermined aetiology for initial review of medical records to exclude patients with clear-cut clinical or histopathological kidney diagnoses or patients with already established genetic kidney diseases. Next, we performed single nucleotide polymorphism (SNP) array-based CNV screening. All the detected CNVs were systematically classified and evaluated as possible causes of the patient's kidney disease. Patients with CNVs not explaining the kidney phenotype were additionally screened for causal variants in 540 genes using whole-genome sequencing. Results: We enrolled 172 patients, of whom 123 underwent SNP-array. Pathogenic CNVs corresponding to known genomic disorders were identified in 12 patients (9.8%). The identified genomic disorders provided a causative kidney diagnosis in three patients, all of whom had reached KF by age 18 years. The remaining nine patients had CNVs with unclear kidney disease causality. Subsequently, whole-genome sequencing provided a causative genetic diagnosis in an additional four patients, including two diagnostic sequence variants unrelated to the detected CNVs. Conclusions: Genomic disorders were prevalent in this cohort with uKF, and causative CNVs were identified in 5 of 123 patients. Further studies combining the analysis of CNVs and sequence variants are needed to clarify the causal role of genomic disorders in kidney disease.

Microcornea, cerebellar hypoplasia and hyperlax joints-unusual combo in rare Ehlers-Danlos syndrome-musculocontractural type 1.

Ehlers-Danlos syndrome is a group of connective tissue disorders with 14 subtypes, involving joint hyperlaxity, tissue fragility, hypertensive skin and other systemic organs with an incidence of 1 in 1 000 000 worldwide. We report a middle childhood female born of second degree consanguineous marriage with limping gait with muscle weakness, with normal development and IQ. Examination revealed microcornea, distal joint laxity of fingers and wrist, hypotonia and broad-based limping gait. Fracture dislocation right hip was managed by fixation. With the atypical neuroimaging finding of cerebellar vermis hypoplasia, exome sequencing was ordered and confirmed as Ehlers-Danlos syndrome (musculocontractural type-1). Hence, genetic counselling was done and prognosis of the child was explained.

Detection of novel duplication variant in ADAMTS13 gene using chromosomal microarray analysis.

We present a case of a child with congenital thrombotic thrombocytopenic purpura found to have a compound heterozygous variant in the ADAMTS13 gene with a novel variant resulting in a large duplication of exons 9-11 of ADAMTS13 This variant was identified through additional molecular testing via a chromosomal microarray analysis. To our knowledge, this assay had not previously been utilised to identify an ADAMTS13 variant and the additional testing was possible through the involvement of a genetic counsellor.

Lactobacilli decrease the susceptibility of Salmonella Typhimurium to azithromycin.

Bacteria are involved in numerous interactions during infection and among host-associated microbial populations. Salmonella enterica serovar Typhimurium is a foodborne pathogen of great importance as well as a model organism to study interactions within a microbial community. In this study, we found that S. Typhimurium becomes tolerant to azithromycin when co-cultured with lactobacilli strains. Similarly, acidified media, from cell-free supernatant of lactobacilli cultures for instance, also induced the tolerance of S. Typhimurium to azithromycin. The addition of membrane disruptors restored the normal sensitivity to azithromycin in acidified media, but not when lactobacilli were present. These results suggested that the acidification of the media led to modification in envelope homeostasis, but that a different mechanism promoted the tolerance to azithromycin in the presence of lactobacilli strains. To further understand how lactobacilli strains modify the sensitivity of S. Typhimurium to azithromycin, a high-throughput assay was performed using the single-gene deletion collection of the S. Typhimurium (1) in co-culture with Lacticaseibacillus rhamnosus and (2) in sterile acidic conditions (pH 5.5 media only). As expected, both screens identified genes involved in envelope homeostasis and membrane permeability. Our results also suggest that changes in the metabolism of S. Typhimurium induce the tolerance observed in the presence of L. rhamnosus. Our results thus highlight two different mechanisms by which lactobacilli induce the tolerance of S. Typhimurium to azithromycin.IMPORTANCEThis study provides valuable insights into the intricate interactions between bacteria during infections and within host-associated microbial communities. Specifically, it sheds light on the significant role of lactobacilli in inducing antibiotic tolerance in Salmonella enterica serovar Typhimurium, a critical foodborne pathogen and model organism for microbial community studies. The findings not only uncover the mechanisms underlying this antibiotic tolerance but also reveal two distinct pathways through which strains of lactobacilli might influence Salmonella's response to antibiotics. Understanding these mechanisms has the potential to enhance our knowledge of bacterial infections and may have implications for the development of strategies to combat antibiotic resistance in pathogens, such as Salmonella. Furthermore, our results underscore the necessity to explore beyond the direct antimicrobial effects of antibiotics, emphasizing the broader microbial community context.

Unlocking Glioblastoma Vulnerabilities with CRISPR-Based Genetic Screening.

Glioblastoma (GBM) is the most common malignant brain tumor in adults. Despite advancements in treatment, the prognosis for patients with GBM remains poor due to its aggressive nature and resistance to therapy. CRISPR-based genetic screening has emerged as a powerful tool for identifying genes crucial for tumor progression and treatment resistance, offering promising targets for tumor therapy. In this review, we provide an overview of the recent advancements in CRISPR-based genetic screening approaches and their applications in GBM. We highlight how these approaches have been used to uncover the genetic determinants of GBM progression and responsiveness to various therapies. Furthermore, we discuss the ongoing challenges and future directions of CRISPR-based screening methods in advancing GBM research.

Osteogenesis Imperfecta type 1: like mother, like daughter - Challenges in the perinatal management.

A third gravida with osteogenesis imperfecta (OI) type 1, in her 20s, was referred from the Medical Genetics department at 12+ weeks with a prenatal diagnosis of OI type 1 in this fetus for further management. She was wheelchair-bound and keen to continue this pregnancy. She had medical termination in her two previous pregnancies for OI in the fetuses. Ultrasound at 12+ weeks revealed a short-bent femur with sparing of the long bones of the upper limb. Serial ultrasound revealed progressive affliction of the long bones with falling growth profile and polyhydramnios. She was delivered at 36 weeks by caesarean for breech in labour under regional anaesthesia.A multidisciplinary approach, patient determination, and good partner support helped in the successful management of this pregnancy.The neonate had blue sclera, dentigerous imperfecta, bowing of the femur and relatively spared upper limbs. Growth was on the third centile. The mother says she brings the girl for follow-up every 3-6 months to give injection zoledronate. The mother confirms her girl can stand with support, crawl, and speak two-syllable words. Her daughter had to undergo femur corrective osteotomy rush nailing and hip spice application for a closed fracture of the left femur.

The psychosocial impact of prostate cancer screening for BRCA1 and BRCA2 carriers.

OBJECTIVES: To report the long-term outcomes from a longitudinal psychosocial study that forms part of the 'Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted Screening in men at higher genetic risk and controls' (IMPACT) study. The IMPACT study is a multi-national study of targeted prostate cancer (PrCa) screening in individuals with a known germline pathogenic variant (GPV) in either the BReast CAncer gene 1 (BRCA1) or the BReast CAncer gene 2 (BRCA2). SUBJECTS AND METHODS: Participants enrolled in the IMPACT study were invited to complete a psychosocial questionnaire prior to each annual screening visit for a minimum of 5 years. The questionnaire included questions on sociodemographics and the following measures: Hospital Anxiety and Depression Scale, Impact of Event Scale, 36-item Short-Form Health Survey, Memorial Anxiety Scale for PrCa, Cancer Worry Scale, risk perception and knowledge. RESULTS: A total of 760 participants completed questionnaires: 207 participants with GPV in BRCA1, 265 with GPV in BRCA2 and 288 controls (non-carriers from families with a known GPV). We found no evidence of clinically concerning levels of general or cancer-specific distress or poor health-related quality of life in the cohort as a whole. Individuals in the control group had significantly less worry about PrCa compared with the carriers; however, all mean scores were low and within reported general population norms, where available. BRCA2 carriers with previously high prostate-specific antigen (PSA) levels experience a small but significant increase in PrCa anxiety (P = 0.01) and PSA-specific anxiety (P < 0.001). Cancer risk perceptions reflected information provided during genetic counselling and participants had good levels of knowledge, although this declined over time. CONCLUSION: This is the first study to report the longitudinal psychosocial impact of a targeted PrCa screening programme for BRCA1 and BRCA2 carriers. The results reassure that an annual PSA-based screening programme does not have an adverse impact on psychosocial health or health-related quality of life in these higher-risk individuals. These results are important as more PrCa screening is targeted to higher-risk groups.

A case for genetic testing: Arrhythmogenic cardiomyopathy presenting as myocarditis.

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy associated with fibrofatty tissue replacement of the ventricular tissue. The disease can cause ventricular dysfunction and arrhythmias and can increase the risk of sudden cardiac death. This cardiomyopathy can have variable clinical presentations, especially in the pediatric and young adult populations. In this report, we describe the case of an 18-year-old female with myocarditis as the initial presentation of ACM. She presented following a resuscitated cardiac arrest due to ventricular arrhythmia. On arrival, myocardial edema and delayed gadolinium enhancement were present on cardiac magnetic resonance imaging, with no ventricular changes observed, making the diagnosis consistent with myocarditis. Genetic testing revealed a pathogenic mutation in the desmoplakin gene consistent with ACM. Given the unconventional initial presentation of this patient's disease, early consideration of genetic testing may be beneficial to aid in the early diagnosis and management of ACM in young patients.

Genotype-specific development of MEN 2 constituent components in 683 RET carriers.

The age-specific development of the three constituent components of multiple endocrine neoplasia type 2 (MEN 2) is incompletely characterized for many of the >30 causative rearranged during transfection (RET) mutations, which this genetic association study aimed to specify. Included in the study were 683 carriers of heterogeneous RET germline mutations: 53 carriers with 1 highest-risk mutation (codon 918); 240 carriers with 8 different high-risk mutations (codon 634); 176 carriers with 16 different intermediate-risk mutations (codon 609, 611, 618, 620, or 630); and 214 carriers with 6 different low-risk mutations (codon 768, 790, 804, or 891).There was a strong genotype-specific development of MEN 2 constituent components, with distinct age gradients from C cell disease to node negative medullary thyroid cancer (MTC), from node negative to node positive MTC, from node positive MTC to pheochromocytoma, and from pheochromocytoma to primary hyperparathyroidism. Primary hyperparathyroidism was not observed among the 53 MEN 2B patients who carried highest-risk mutations (age range: 0.5-50 years), of whom no more than 12 (23%) and 3 (6%) carriers were older than age 30 years and 35 years, respectively. The age-specific development of MTC differed significantly between the four RET risk categories, whereas the age-specific development of pheochromocytoma differed significantly only between the two strongest RET risk categories. No significant differences were noted in the development of primary hyperparathyroidism. These findings delineate age-specific disease manifestation corridors for the three constituent components of MEN 2 by RET genotype. These corridors are useful for initial risk assessment and organ-specific surveillance of newly identified RET carriers going forward.

Genetic screening of liver cancer: State of the art.

Liver cancer, primarily hepatocellular carcinoma, remains a global health challenge with rising incidence and limited therapeutic options. Genetic factors play a pivotal role in the development and progression of liver cancer. This state-of-the-art paper provides a comprehensive review of the current landscape of genetic screening strategies for liver cancer. We discuss the genetic underpinnings of liver cancer, emphasizing the critical role of risk-associated genetic variants, somatic mutations, and epigenetic alterations. We also explore the intricate interplay between environmental factors and genetics, highlighting how genetic screening can aid in risk stratification and early detection via using liquid biopsy, and advancements in high-throughput sequencing technologies. By synthesizing the latest research findings, we aim to provide a comprehensive overview of the state-of-the-art genetic screening methods for liver cancer, shedding light on their potential to revolutionize early detection, risk assessment, and targeted therapies in the fight against this devastating disease.

Update on the practice of premarital screening for sickle cell traits in Africa: a systematic review and meta-analysis.

BACKGROUND: Screening for sickle cell traits before marriage or producing children is one of the outstanding preventive measures for sickle cell disease (SCD).The disease is a collection of inherited blood disorders that impact millions globally, with a predominant 75% occurrence in the sub-Saharan region. With increasing burden of SCD on the continent amidst a cost effective prevention method, no study has systematically reviewed or presented meta-analytic uptake or practice of premarital sickle cell trait screening. METHODS: This review systematically explored the uptake or practice of premarital genotype screening in Africa. We searched PubMed and Scopus databases for African studies on premarital screening for sickle cell traits. RESULTS: Our results indicate that the pooled uptake of premarital sickle cell trait screening in Africa is 47.82% (95% CI: [46.53-49.11]; I2: 98.95% [98.74-99.13]). Our review observed, a significant relationship between the awareness of sickle cell disease and the uptake of genotype screening; F(1, 13) = 12.04, p = 0.004). The model explained approximately 48.08% of the variation in genotype screening (R² = 0.4808) and predicted a 0.729 increase in the likelihood of genotype screening uptake for every unit rise in sickle cell disease awareness (ß = 0.729, p = 0.004). Additionally, Pearson correlation (r = 0.6934) indicated a moderately strong positive correlation between the two variables. CONCLUSION: With over 75% of the global burden of sickle cell disease domiciled in Africa, the continent cannot overlook the cost of hemoglobinopathies. The uptake of sickle cell traits screening is suboptimal across the continent. To achieve the mandate of sustainable development goal number (3); to end preventable deaths of newborns and children under 5 years of age by 2030, there is need to intensify campaigns on premarital genetic screening through education and other health promotion tools.

Genetic Screening-Emerging Issues.

In many countries, some form of genetic screening is offered to all or part of the population, either in the form of well-organized screening programs or in a less formalized way. Screening can be offered at different phases of life, such as preconception, prenatal, neonatal and later in life. Screening should only be offered if the advantages outweigh the disadvantages. Technical innovations in testing and treatment are driving changes in the field of prenatal and neonatal screening, where many jurisdictions have organized population-based screening programs. As a result, a greater number and wider range of conditions are being added to the programs, which can benefit couples' reproductive autonomy (preconception and prenatal screening) and improve early diagnosis to prevent irreversible health damage in children (neonatal screening) and in adults (cancer and cascade screening). While many developments in screening are technology-driven, citizens may also express a demand for innovation in screening, as was the case with non-invasive prenatal testing. Relatively new emerging issues for genetic screening, especially if testing is performed using DNA sequencing, relate to organization, data storage and interpretation, benefit-harm ratio and distributive justice, information provision and follow-up, all connected to acceptability in current healthcare systems.

Advancements and Applications of Preimplantation Genetic Testing in In Vitro Fertilization: A Comprehensive Review.

Preimplantation genetic testing (PGT) has become an integral component of assisted reproductive technology (ART), offering couples the opportunity to screen embryos for genetic abnormalities before implantation during in vitro fertilization (IVF). This comprehensive review explores the advancements and applications of PGT in IVF, covering its various types, technological developments, clinical applications, efficacy, challenges, regulatory aspects, and future directions. The evolution of PGT techniques, including next-generation sequencing (NGS) and comparative genomic hybridization (CGH), has significantly enhanced the accuracy and reliability of genetic testing in embryos. PGT holds profound implications for the future of ART by improving IVF success rates, reducing the incidence of genetic disorders, and mitigating the emotional and financial burdens associated with failed pregnancies and genetic diseases. Recommendations for clinicians, researchers, and policymakers include staying updated on the latest PGT techniques and guidelines, exploring innovative technologies, establishing clear regulatory frameworks, and fostering collaboration to maximize the potential benefits of PGT in assisted reproduction. Overall, this review provides valuable insights into the current state of PGT and its implications for the field of reproductive medicine.

Prevalence threshold and positive predictive value of noninvasive prenatal testing.

OBJECTIVE: Noninvasive prenatal testing (NIPT) has increased the number of conditions that can be screened. However, the prevalence of conditions assessed by NIPT has remained stable. The "prevalence threshold," a novel epidemiological concept, uses a test's sensitivity and specificity to determine the prevalence below which a test's positive predictive value declines most sharply relative to disease prevalence. In this article, we calculated the prevalence threshold for common conditions assessed through NIPT and compared the value with the actual prevalence of each condition to best ascertain the reliability of NIPT results. METHODS: Six databases and PubMed were searched from January 2010 to March 2023 for sensitivity and specificity parameters of common conditions tested through NIPT. Using an equation previously derived by the authors of the current paper, the prevalence threshold for each condition was calculated. The theoretical number of test iterations required to reach the prevalence threshold was also reported. RESULTS: None of the conditions tested through the NIPT had a prevalence rate that met or exceeded the calculated prevalence threshold. Trisomy 21 had the greatest concordance between the prevalence rate and the prevalence threshold. In contrast, Angelman, Cri-du-chat, and Prader-Willi syndromes had the most significant discordance. Apart from trisomy 21 and XXY, all remaining conditions required more than one test iteration to reach their respective prevalence threshold. CONCLUSION: We conclude that at the current prevalence levels, the positive predictive value of NIPT remains low, with the prevalence of disease levels significantly lower than the prevalence threshold for each condition tested.

An evaluation of the cost-effectiveness of population genetic screening for familial hypercholesterolemia in US patients.

BACKGROUND AND AIMS: Familial hypercholesterolemia is an underdiagnosed genetic metabolic condition limiting the clearance of low-density lipoprotein cholesterol and increasing lifetime risk of cardiovascular disease. Population genetic screening in unselected individuals could quickly identify cases of familial hypercholesterolemia and enable early prevention, but the economic impact of widespread screening on patients has not been studied. METHODS: We assessed the cost-effectiveness of population genetic screening for familial hypercholesterolemia in 20 and 35-year-old adults in the United States from the perspective of patients. We developed a decision tree Markov hybrid model to examine diagnoses, cardiovascular disease, cardiac events, quality of life, and costs under population genetic screening compared to family-based cascade testing. RESULTS: While population genetic screening increased diagnoses and reduced incidence of cardiovascular disease, population genetic screening was not cost-effective compared to cascade testing at current levels of willingness to pay. Lower genetic testing costs, combined screening with other genetic conditions, and support to maintain lipid-lowering therapy use over time could improve the cost-effectiveness of population genetic screening. CONCLUSIONS: Future research is needed to examine how cost-sharing strategies may affect the cost-effectiveness of screening to patients and how families and providers experience the clinical and economic outcomes of population screening.