A novel pathogenic variant of the FH gene in a family with hereditary leiomyomatosis and renal cell carcinoma

Hereditary leiomyomatosis and renal cell carcinoma caused by loss-of-function germline variants of the FH gene can develop into aggressive renal cell carcinoma (RCC). We report the case of a 27-year-old man who died of RCC. Genetic testing revealed a novel pathogenic variant of FH, NM_000143.3:c.1013_1014del (p.Ile338Serfs*3), that was also identified in healthy siblings. Identification of genetic causes in the proband helped us to provide relatives with precise genetic counseling and appropriate surveillance programs.

Mental Health of Siblings of Children with Rare Congenital Surgical Diseases during the COVID-19 Pandemic

Introduction The COVID-19 pandemic has affected every aspect of our society, particularly vulnerable groups, such as families with children suffering from rare diseases. However, the psychosocial influences of COVID-19 on the healthy siblings of children with rare diseases have not been investigated yet. Thus, the study aimed to evaluate the mental health of healthy siblings of children with rare congenital surgical diseases during the COVID-19 pandemic. Material and methods Siblings of children with rare congenital surgical diseases were investigated cross-sectionally between April 2020 and April 2021. Data on mental health were collected using the parent-version of the Strengths and Difficulties Questionnaire (SDQ). Results Out of 104 families, 81 (77.88%) participated in the survey. Healthy siblings presented with comparable levels of emotional and behavioral difficulties compared with population norms before the COVID-19 pandemic. Compared with studies that surveyed child and adolescent mental health during the COVID-19 pandemic, parents of siblings in this study reported a significantly lower impairment rate. Psychosocial and disease-specific risk factors of the respective outcomes in healthy siblings were identified through regression analysis models. Conclusion In general, health-care professionals should be aware of the possibility of siblings' mental health being at risk. Therefore, screening for psychosocial deficits may be essential in preventing psychiatric disorders in this population, especially during pandemics. Trial registration ClinicalTrials.gov: NCT04382820 (registered April 8, 2020)

Can the Imbalance Between Neurotrophic and Apoptotic Proteins be the "Beware the Ides of March" for Unaffected Relatives of Schizophrenia Patients?

Schizophrenia (SZ) is a mental disorder with a strong genetic basis as well as epigenetic aspects. Siblings of patients with SZ can share certain endophenotypes with the patients, suggesting that the siblings may be important for distinguishing between trait and state markers. In the current study, we aimed to characterize the balance between pro-BDNF/mature BDNF and its receptors p75NTR/TrkB, which is tpa-BDNF pathways proteins and thought to play a role in synaptic pruning as a possible endophenotype of schizophrenia. Forty drug-naïve patients with first-episode psychosis (FEP) matched for age, gender and level of education, 40 unaffected siblings (UAS) of patients with FEP and 67 healthy controls (HC) were included in the study. Blood samples were collected from all participants to determine BDNF, pro-BDNF, TrkB and p75NTR, PAI1, tPA, ACTH and cortisol levels. We showed that levels of proteins of the tPA-BDNF pathway, pro-BDNF/m-BDNF and p75NTR/TrkB ratios could successfully differentiateFEP and their siblings from the HCs by using ROC analysis. Plasma levels of m-BDNF were found to be the lowest in the healthy siblings and highest in the healthy control group with statistically significant differences between all 3 groups. The plasma levels of pro-BDNF in the healthy control group were similar to the FEP patients, the same in the healthy siblings of the FEP patients. Our data Support the hypothesis that imbalance between neurotrophic and apoptotic proteins might occur in SZ, and this imbalance could be an endophenotype of the disease.

Clostridioides Difficile Carriage Rate Increases during Pediatric ALL Treatment

Background Clostridioides difficile infection (CDI) is frequent in pediatric patients with acute lymphoblastic leukemia (ALL). Studies have shown upwards of 20% positivity rate in CDI testing among pediatric oncology patients, and up to several percent in pediatric ALL patients in the first 180 days of diagnosis. Antibiotic usage has been variably linked to CDI positivity in these populations. As CDI testing is usually done in symptomatic patients, the question of C. difficile carriage versus CDI has not been addressed. We and others have shown that microbiome is altered in pediatric ALL patients and survivors. We conducted a longitudinal stool microbiome study in pediatric ALL patients and tested the hypothesis that alteration of the microbiome during ALL treatment promotes C. difficile carriage. Methods Children with ALL were prospectively recruited on a rolling basis and stool samples were collected at diagnosis (Dx) and at the end of induction (EOI), consolidation (EOC), interim maintenance I (IMI), delayed intensification (DI), interim maintenance II (IMII), as well as approximately 3 months and 6 months into maintenance (M3, M6). Stool samples from healthy siblings were used as controls. TaqMan-based quantitative-PCR (qPCR) was performed on DNA extracted from stool samples to detect C. diff 16S rRNA, tcdA, (Toxin A) and tcdB (Toxin B) genes . Samples positive or either tcdA or tcdB, or both, were designated positive for toxigenic C. difficile. 16S rRNA hypervariable region V4 was sequenced and analyzed for microbiome diversity and relative abundance of microbiota. Results 32 ALL patients age 3 months-19 years were included. The diagnoses were 12 standard risk and 14 high risk pre-B ALL, 5 T-ALL, and 1 relapsed pre-B ALL. Stool samples were collected from 18 healthy siblings. The numbers of samples tested at each treatment phase were: 29 Dx, 24 EOI, 23 EOC, 25 IMI, 21 DI, 6 IMII, 14 M3, 7 M6. No patient had symptoms suggestive of CDI, and no patient was clinically tested or treated for CDI. Total number of stool samples tested was 149, of which 43 (29%) were positive for toxigenic C. difficile (Figure 1). At diagnosis, 2/29 (7%) patients were positive, compared to 2/18 (11%) in healthy siblings. At EOI, positivity rate increased to 17%, then up to 40% - 52% at EOC, IMI, and DI. C. difficile positivity were lower around 30% at M3 and M6, although few patients reached maintenance to contribute samples for analysis. Twenty-five patients (78%) were positive at some phase. Longitudinal analysis of individual patients showed that C. difficile positivity was intermittent through treatment phases; only 3 patients remained persistently positive. Seven patients (22%) were never positive. Multivariate analysis showed that EOC, IMI, and DI treatment phases were significant risk factors for C. difficile carriage. Neither the number of antibiotics nor the number of antibiotic courses administered was significant. Leukemia risk stratification (high risk versus standard risk) also did not correlate with C. difficile positivity. Microbiome analysis showed statistically significant differences in relative abundance of certain taxa between C. diff positive and negative samples at the class, order, and family levels (Figure 2). Examples include depletion of the class Verrucomicrobiae, which contains protective Akkermansia, and depletion of the common taxa Bifidobacteriaceae and Ruminococcaceae. Conclusion Longitudinal PCR testing of toxigenic C. difficile in pediatric ALL patients demonstrated increased C. difficile prevalence further into treatment phases. C. difficile carriage correlated significantly with depletion of several bacterial taxa, as microbiome diversity decreased overall with successive treatment phases. Our data lend support to the hypothesis that altered microbiome in ALL treatment allows permissibility for C. difficile carriage. In addition, no C. difficile positive patient had symptoms of CDI, therefore, caution must be taken in clinical testing, as there is a high asymptomatic carriage rate. Further longitudinal testing during maintenance and off-therapy is needed to see if C. difficile carriage rate returns to baseline and correlates with recovery of gut microbiome. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Gut Microbiota Diversity and Composition Are Altered during Therapy in Pediatric Acute Lymphoblastic Leukemia Patients

Background Childhood acute lymphoblastic leukemia (ALL) has a very high cure rate, however, long-term survivors are at increased risk of chronic medical illnesses that are likely in part microbiome mediated. Previous studies comparing microbiota of pediatric ALL survivors to healthy siblings showed altered composition in survivors. Longitudinal microbiome changes through treatment leading to these alterations are unknown. Methods Children with ALL were enrolled and stool samples were collected at diagnosis and at the end of induction, consolidation, interim maintenance I, delayed intensification, interim maintenance II, as well as approximately 3 months and 6 months into maintenance. Stool samples from healthy siblings were used as controls. Clinical data were collected. DNA was extracted from stool samples and 16S rRNA was sequenced for analysis of hypervariable region V4. Differences in alpha and beta diversities and relative abundance of taxa were calculated between phases and with sibling controls. Results 35 ALL patients age 3 months-19 years were included. The diagnoses were 14 standard risk pre-B ALL, 14 high risk pre-B ALL, 6 T-ALL, and 1 relapsed pre-B ALL. Stool samples were sequenced from 19 healthy siblings. Statistically significant differences in alpha diversity (Shannon) were found between healthy siblings and ALL patients during the more intense chemotherapy phases before low dose maintenance (Figure 1A). Beta diversity (Bray-Curtis), was significantly different between microbiota of ALL patients at diagnosis and their siblings, as well as between ALL patients at diagnosis and at each of the subsequent treatment phases (Figure 1B). Longitudinal comparison using multivariate analysis showed that leukemia risk group (high risk vs standard risk) and antibiotic treatment were significant factors in beta diversity changes. The relative abundance of microbes showed that with treatment, ALL patients exhibit a significant decrease in the phylum Verrucomicrobiota, driven by the genus Akkermansia, which is beneficial to health and is associated with protection against obesity and other chronic inflammatory diseases (Figure 2). Proteobacteria and Fusobacteria, which include proinflammatory species, were increased. Conclusion Pediatric ALL patients have decreased diversity of gut microbes at diagnosis and during treatment. The types of gut microbes harbored in ALL patients are already different than their siblings at diagnosis and continue to change during treatment, but may begin to recover in low dose maintenance therapy. Taxa considered to be beneficial are depleted, while more pathogenic microbes become prominent. Microbiota changes are likely influenced by intensity of chemotherapy and antibiotic exposure. Continued longitudinal follow up is needed to determine whether these changes correlate with adverse long term health outcomes. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Self-reported experiences of siblings of children with life-threatening conditions: A scoping review

Sibling relationships are one of the most long-lasting and influential relationships in a human’s life. Living with a child who has a life-threatening condition changes healthy siblings’ experience. This scoping review summarized and mapped research examining healthy siblings’ experience of living with a child with a life-threatening condition to identify knowledge gaps and provide direction for future research. Studies were identified through five electronic databases. Of the 34 included studies, 17 used qualitative methods, four gathered data longitudinally and 24 focused on children with cancer. Four broad themes of sibling experience were identified across studies: family functioning, psychological well-being, social well-being, and coping. Siblings experienced challenges and difficulties over the course of the child’s illness. Future research should incorporate longitudinal designs to better understand the trajectory of siblings’ experiences and focus on a wider variety of life-threatening conditions.