Inherited Predisposition to Myelodysplastic Syndrome and Acute Leukemia

Although generally thought of as pediatric conditions, inherited forms of myelodysplastic syndrome (MDS) and acute leukemia (AL) are increasingly recognized among adult patients. At present, at least nine genes, including ANKRD26, CEBPA, GATA2, PAX5, RUNX1, SRP72, TERC, TERT, and TP53, are known to cause familial MDS and/or AL syndromes. Several other promising candidate genes are emerging from ongoing research on the many pedigrees identified without a mutation in one of these already recognized genes. Clinical recognition of individuals with these syndromes is essential for optimal care of the patient and his/her at-risk family members and requires familiarity with the subtle clinical features of each syndrome and a high index of suspicion by the treating physician. Once recognized, genetic testing should be performed to identify the specific syndrome present as each can have unique aspects to their clinical care. For example, individuals with familial MDS/AL due to TERT or TERC abnormalities require monitoring of lung function and screening for head and neck and anogenital cancers, whereas individuals with platelet dysfunction due to familial platelet disorder/RUNX1 or ANKRD26 mutations require careful planning prior to surgical procedures to prevent bleeding complications. Due to significant overlap in the clinical presentation, often a multigene-based approach to genetic testing is necessary. Unique aspects of genetic testing in this population include: 1) tissue type selection as many of the genes that cause the familial MDS/AL syndromes are also somatically mutated in hematologic malignancies so results from DNA derived from peripheral blood or bone marrow in an individual with MDS or AL are difficult to interpret; and 2) urgency as allogeneic hematopoietic stem cell transplantation may be pursued quickly and requires knowledge of the specific mutation in the family to identify the optimal stem cell donor. The management of affected individuals who have not yet developed hematologic malignancies can be challenging as many may show morphologic signs of dysplasia in the bone marrow that may not truly represent overt malignancy. The decision of when to pursue allogeneic hematopoietic stem cell transplantation with curative intent is especially difficult. Ongoing research to define the specific events that trigger malignant transformation and how to optimally detect these events is underway. Practical algorithms for the clinical recognition, genetic testing, and management of individuals with these syndromes based on currently available knowledge as well as research seeking to improve the clinical care of these patients will be explored. A summary of the yield of next generation sequencing-based genetic testing strategies for familial presentations of MDS/AL will also be provided.