Recognition of genetic predisposition in pediatric cancer patients: An easy-to-use selection tool

Genetic predisposition for childhood cancer is under diagnosed. Identifying these patients may lead to therapy adjustments in case of syndrome-related increased toxicity or resistant disease and syndrome-specific screening programs may lead to early detection of a further independent malignancy. Cancer surveillance might also be warranted for affected relatives and detection of a genetic mutation can allow for reproductive counseling.Here we present an easy-to-use selection tool, based on a systematic review of pediatric cancer predisposing syndromes, to identify patients who may benefit from genetic counseling. The selection tool involves five questions concerning family history, the type of malignancy, multiple primary malignancies, specific features and excessive toxicity, which results in the selection of those patients that may benefit from referral to a clinical geneticist

The Results of CHD7 Analysis in Clinically Well-Characterized Patients with Kallmann Syndrome

Item does not contain fulltextCONTEXT: Kallmann syndrome (KS) and CHARGE syndrome are rare heritable disorders in which anosmia and hypogonadotropic hypogonadism co-occur. KS is genetically heterogeneous, and there are at least eight genes involved in its pathogenesis, whereas CHARGE syndrome is caused by autosomal dominant mutations in only one gene, the CHD7 gene. Two independent studies showed that CHD7 mutations can also be found in a minority of KS patients. OBJECTIVE: We aimed to investigate whether CHD7 mutations can give rise to isolated KS or whether additional features of CHARGE syndrome always occur. DESIGN: We performed CHD7 analysis in a cohort of 36 clinically well-characterized Dutch patients with KS but without mutations in KAL1 and with known status for the KS genes with incomplete penetrance, FGFR1, PROK2, PROKR2, and FGF8. RESULTS: We identified three heterozygous CHD7 mutations. The CHD7-positive patients were carefully reexamined and were all found to have additional features of CHARGE syndrome. CONCLUSION: The yield of CHD7 analysis in patients with isolated KS seems very low but increases when additional CHARGE features are present. Therefore, we recommend performing CHD7 analysis in KS patients who have at least two additional CHARGE features or semicircular canal anomalies. Identifying a CHD7 mutation has important clinical implications for the surveillance and genetic counseling of patients

Clinical and Molecular Characteristics and Outcome of Cystic Partially Differentiated Nephroblastoma and Cystic Nephroma: A Narrative Review of the Literature

In children presenting with a predominantly cystic renal tumor, the most likely diagnoses include cystic partially differentiated nephroblastoma (CPDN) and cystic nephroma (CN). Both entities are rare and limited information on the clinical and molecular characteristics, treatment, and outcome is available since large cohort studies are lacking. We performed an extensive literature review, in which we identified 113 CPDN and 167 CN. The median age at presentation for CPDN and CN was 12 months (range: 3 weeks–4 years) and 16 months (prenatal diagnosis–16 years), respectively. No patients presented with metastatic disease. Bilateral disease occurred in both entities. Surgery was the main treatment for both. Two/113 CPDN patients and 26/167 CN patients had previous, concomitant, or subsequent other tumors. Unlike CPDN, CN was strongly associated with somatic (n = 27/29) and germline (n = 12/12) DICER1-mutations. Four CPDN patients and one CN patient relapsed. Death was reported in six/103 patients with CPDN and six/118 CN patients, none directly due to disease. In conclusion, children with CPDN and CN are young, do not present with metastases, and have an excellent outcome. Awareness of concomitant or subsequent tumors and genetic testing is important. International registration of cystic renal tumor cohorts is required to enable a better understanding of clinical and genetic characteristics

The Study of Education Effect on Knowledge of, and Attitudes Toward Electroconvulsive Therapy Among Iranian Nurses and Patients’ Relatives in a Psychiatric Hospital, 2009-2010

AbstractElectroconvulsive therapy (ECT) is a cost effective method in the treatment of some psychiatric disorders. Although, service users such as health providers and nurses, also patients and their relatives may refuse ECT when indicated, due to the myths and little or lack of knowledge about the procedure. The knowledge of and attitudes toward ECT among nurses, may reflect on patients and influence treatment choice. For doing this procedure relatives informed consent is necessary, so their knowledge of and attitude toward ECT is important for getting informed consent and following treatment sessions. Objective: This research was conducted as a quasi-experimental study to measure knowledge of and attitudes toward ECT in 2 groups: relatives and nursing. Also, to study the effect of education on knowledge of and attitudes toward ECT in 2 groups. Methods: In this research the pre and post test self – administered questionnaires were completed by 46 relatives and 46 nurses before and after education about ECT. Results: Nurses in this research received a mean score of X=34.97 knowledge before education and X=39.78 after education (t=2.02, p<0.05), and a mean score of X=33.41 attitude before education and, X=42.82 after education (t=-14.25, p<0.001). Relatives received a mean score of X=23.41 knowledge before education and X=30.15 after education (t=-12.44, p<0.001), and a mean score of X=33.39 attitude before education and, X=41.13 after education (t=-9.10, p<0.001). The differences between the 2 means among two groups were found to be statistically significant. Conclusion: Education given to nurses and relatives about ECT increased their knowledge of, and improved their attitudes toward ECT. For this reason it is recommended that continuing education about ECT process should be planned and given at regular intervals

Paediatric metanephric tumours: a clinicopathological and molecular characterisation

To characterize metanephric tumours in children, we performed a literature review investigating paediatric metanephric adenomas (MA), metanephric stromal tumours (MST) and metanephric adenofibromas (MAF). Including two patients from our own institution (MA, MAF), 110 individual cases (41 MA, 20 MAF, 49 MST) were identified. Additionally, fifteen composite tumours were identified, with areas of MA/MAF and Wilms tumour (WT) or papillary carcinoma. No distinct clinical or radiological features could be defined. In pure metanephric tumours, histologically proven distant metastases were reported once (MA), relapse was reported once (MST) and one tumour-related death occurred (MST). Somatic BRAF-V600E mutations were tested in 15 cases, and identified in 3/6 MA, 3/3 MAF, and 6/6 MST. In our institution the MA harboured a somatic KRAS-G12R mutation. Overall, paediatric metanephric tumours are difficult to discriminate from other renal tumours at presentation, behave relatively benign, and the occurrence of composite tumours warrants analysis of underlying (genetic) pathways

Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation

Noonan syndrome (NS) is characterized by short stature, facial dysmorphisms and congenital heart defects. PTPN11 mutations are the most common cause of NS. Patients with NS have a predisposition for leukemia and certain solid tumors. Data on the incidence of malignancies in NS are lacking. Our objective was to estimate the cancer risk and spectrum in patients with NS carrying a PTPN11 mutation. In addition, we have investigated whether specific PTPN11 mutations result in an increased malignancy risk. We have performed a cohort study among 297 Dutch NS patients with a PTPN11 mutation (mean age 18 years). The cancer histories were collected from the referral forms for DNA diagnostics, and by consulting the Dutch national registry of pathology and the Netherlands Cancer Registry. The reported frequencies of cancer among NS patients were compared with the expected frequencies using population-based incidence rates. In total, 12 patients with NS developed a malignancy, providing a cumulative risk for developing cancer of 23% (95% confidence interval (CI), 8–38%) up to age 55 years, which represents a 3.5-fold (95% CI, 2.0–5.9) increased risk compared with that in the general population. Hematological malignancies occurred most frequently. Two malignancies, not previously observed in NS, were found: a malignant mastocytosis and malignant epithelioid angiosarcoma. No correlation was found between specific PTPN11 mutations and cancer occurrence. In conclusion, this study provides first evidence of an increased risk of cancer in patients with NS and a PTPN11 mutation, compared with that in the general population. Our data do not warrant specific cancer surveillance

No Pathogenic DICER1 Gene Variants in a Cohort Study of 28 Children With Congenital Pulmonary Airway Malformation

Background: Distinguishing congenital pulmonary airway malformations (CPAMs) from pleuropulmonary blastoma (PPB) can be challenging. Previously diagnosed patients with CPAM may have been misdiagnosed and we may have missed DICER1-associated PPBs, a diagnosis with important clinical implications for patients and their families. To gain insight in potential misdiagnoses, we systematically assessed somatic DICER1 gene mutation status in an unselected, retrospective cohort of patients with a CPAM diagnosis. Methods: In the Amsterdam University Medical Center (the Netherlands), it has been standard policy to resect CPAM lesions. We included all consecutive cases of children (age 0–18 years) with a diagnosis of CPAM between 2007 and 2017 at this center. Clinical and radiographic features were reviewed, and DICER1 gene sequencing was performed on DNA retrieved from CPAM tissue samples. Results: Twenty-eight patients with a surgically removed CPAM were included. CPAM type 1 and type 2 were the most common subtypes (n = 12 and n = 13). For 21 patients a chest CT scan was available for reassessment by two pediatric radiologists. In 9 patients (9/21, 43%) the CPAM subtype scored by the radiologists did not correspond with the subtype given at pathology assessment. No pathogenic mutations and no copy number variations of the DICER1 gene were found in the DNA extracted from CPAM tissue (0/28). Conclusions: Our findings suggest that the initial CPAM diagnoses were correct. These findings should be validated through larger studies to draw conclusions regarding whether systematic DICER1 genetic testing is required in children with a pathological confirmed diagnosis of CPAM or not. Level of Evidence: Level IV

Ribosomal protein gene RPL9 variants can differentially impair ribosome function and cellular metabolism

Variants in ribosomal protein (RP) genes drive Diamond-Blackfan anemia (DBA), a bone marrow failure syndrome that can also predispose individuals to cancer. Inherited and sporadic RP gene variants are also linked to a variety of phenotypes, including malignancy, in individuals with no anemia. Here we report an individual diagnosed with DBA carrying a variant in the 5'UTR of RPL9 (uL6). Additionally, we report two individuals from a family with multiple cancer incidences carrying a RPL9 missense variant. Analysis of cells from these individuals reveals that despite the variants both driving pre-rRNA processing defects and 80S monosome reduction, the downstream effects are remarkably different. Cells carrying the 5'UTR variant stabilize TP53 and impair the growth and differentiation of erythroid cells. In contrast, ribosomes incorporating the missense variant erroneously read through UAG and UGA stop codons of mRNAs. Metabolic profiles of cells carrying the 5'UTR variant reveal an increased metabolism of amino acids and a switch from glycolysis to gluconeogenesis while those of cells carrying the missense variant reveal a depletion of nucleotide pools. These findings indicate that variants in the same RP gene can drive similar ribosome biogenesis defects yet still have markedly different downstream consequences and clinical impacts