Overview of the Clinical Features of Li-Fraumeni Syndrome and the Current European ERN GENTURIS Guideline.

Patients with a tumour-risk syndrome have a significantly increased risk of developing cancer during their lifetime. A positive family history of tumour disease or an unusually early age of onset may be indicative of a tumour risk syndrome. With the diagnosis of a tumour risk syndrome it is possible to recommend a risk-adapted tumour surveillance programme for the patient and (asymptomatic) family members at risk.

Proportion of children with cancer that have an indication for genetic counseling and testing based on the cancer type irrespective of other features.

In children with cancer, specific clinical features such as physical anomalies, occurrence of cancer in young relatives, specific cancer histologies, and unique mutation/methylation signatures may indicate the presence of an underlying cancer predisposition syndrome (CPS). The proportion of children with a cancer type suggesting a CPS among all children with cancer is unknown. To determine the proportion of children with cancer types suggesting an underlying CPS among children with cancer.

Mutational Spectrum of Fanconi Anemia Associated Myeloid Neoplasms.

Individuals with Fanconi anemia (FA) have a high risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), yet the secondary somatic mutations lending to these malignancies remain to be further elucidated. We employed a next-generation sequencing myeloid neoplasia gene panel to determine the mutational spectrum of FA-related MDS/AML. Ten of 16 patients showed missense, nonsense, insertion or duplication mutations in 13 genes.

Androgen therapy in Fanconi anemia: A retrospective analysis of 30 years in Germany.

A substantial number of individuals with Fanconi anemia (FA) develop bone marrow failure and are treated with androgen therapy in order to increase blood counts. The authors retrospectively identified 70 patients who received androgen therapy any time between July 1976 and September 2014. Among these patients, 37 had medical records for analysis.

Genetic predisposition to acute lymphoblastic leukemia: Overview on behalf of the I-BFM ALL Host Genetic Variation Working Group.

Environmental causes of childhood acute lymphoblastic leukemia (ALL) remain largely undiscovered. In contrast, multiple germline ALL risk variants have been identified in the recent years. Apart from the low-risk common ALL risk alleles identified through genome wide association studies, rare germline mutations that cause cancer prone syndromes have been found to be associated with an increased risk of developing ALL.

Germline KRAS mutations cause aberrant biochemical and physical properties leading to developmental disorders.

The KRAS gene is the most common locus for somatic gain-of-function mutations in human cancer. Germline KRAS mutations were shown recently to be associated with developmental disorders, including Noonan syndrome (NS), cardio-facio-cutaneous syndrome (CFCS), and Costello syndrome (CS). The molecular basis of this broad phenotypic variability has in part remained elusive so far.

Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination.

Immunoglobulin (Ig) class switch recombination (CSR) deficiencies are rare primary immunodeficiencies characterized by the lack of switched isotype (IgG/IgA/IgE) production. In some cases, CSR deficiencies can be associated with abnormal somatic hypermutation. Analysis of CSR deficiencies has helped reveal the key functions of CSR-triggering molecules, i.

Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia: molecular classification and treatment options.

Myelodysplastic syndromes (MDS) and the mixed myelodysplastic/myeloproliferative disorder juvenile myelomonocytic leukaemia (JMML) are rare haematopoietic stem cell diseases in children. While MDS-initiating events remain largely obscure, a growing body of clinical, genetic and laboratory evidence suggests that JMML is, at least in part, caused by aberrant signal transduction resulting from mutations of components of the RAS signalling pathway. To date, haematopoietic stem cell transplantation cures more than half of children diagnosed with MDS or JMML.

Lethal proliferation of erythroid precursors in a neonate with a germline PTPN11 mutation.

We report a neonate with hypertrophic cardiomyopathy and lethal myeloproliferative disorder with excessively proliferating immature erythroid precursors infiltrating non-hematopoietic organs. Mutational analysis uncovered a germline mutation in the Noonan syndrome/LEOPARD syndrome (NS/LS) gene PTPN11. In conclusion, this case report suggests that congenital myeloproliferative disorders in association with germline PTPN11 mutations may affect the erythroid lineage.

Pediatric myelodysplastic syndromes.

A new classification of myelodysplastic and myeloproliferative diseases in childhood has greatly facilitated the diagnosis of these uncommon disorders. Because hematopoietic stem cell transplantation (HSCT) can cure more than half of the affected children, palliative treatment strategies often applied in adult myelodysplastic syndrome (MDS) are of little importance in pediatric MDS. Unraveling some of the underlying genetic factors predisposing to MDS at a young age may give important insights into leukemogenesis in the elderly.