How I diagnose and manage individuals at risk for inherited myeloid malignancies

Astute clinicians have reported familial clustering of myelodysplastic syndrome (MDS) and acute leukemia (AL; MDS/AL) for decades. These physicians often described phenotypic features that are now known to be associated with specific genetically defined hereditary myeloidmalignancy syndromes (HMMSs).Why, then, is the diagnosis of HMMS only now starting to be considered in the evaluation of the average adult patient with MDS/AL? The reasons are likely several. Historically, the HMMSs, including inherited bonemarrow (BM) failure syndromes (IBMFSs) like Fanconi anemia (FA), have often been part of a syndromewith features that are readily recognized in childhood. Thus, traditional hematology training focused on HMMS as mainly a pediatric issue. The lack of genetically defined adult-onset HMMS also limited the utility of recognizing a family history of MDS/AL for adults in most clinical scenarios. Furthermore,MDS/ALcaseswith usual onset in late adulthood seemed unlikely candidates for the discovery of novel hereditary cancer syndromes, which are expected to cause early-onset disease. Moreover, with MDS only incorporated into the National Cancer Institute’s Surveillance, Epidemiology, and End Results program in 2001 and limited literature on the yield of family cancer history in adultMDS/AL patients, the extent of clustering of adult MDS/AL cases has been underappreciated. These issues have led to a general resistance to the idea that inherited genetic factors contribute to a significant proportion of adult MDS/AL cases. This sentiment is changing as an increasing number of genetically defined HMMSs are discovered. Familial platelet disorder (FPD) with associated myeloid malignancy (FPD/acute myeloid leukemia [AML]) due to inherited mutations inRUNX1was thefirstHMMS tobe genetically defined in 1999, followed by familial AMLwithCEBPAmutation in 2004. Expanding use of next-generation sequencing (NGS) contributed to the rapid discovery of 6 additional HMMSs: familial MDS/AML with GATA2 mutation, thrombocytopenia 2 (ANKRD26), myeloid neoplasms with germ line predisposition (ATG2B/GSKIP), familial MDS/AML withmutatedDDX41, thrombocytopenia5 (ETV6), and familial aplastic anemia (AA)/MDS with SRP72 mutation. Adult-onset presentations of IBMFSs such as autosomal-dominant telomere syndromes with familial MDS/AL presentation (TERC/TERT) have also been described. Furthermore, germ line mutations in genes traditionally thought of as solid tumor predisposition genes are increasingly identified in patients with hematopoietic malignancy (HM). Recognition of HMMSs in clinical care is imperative. First, a molecular diagnosis provides a precise explanation for the conditions present within an affected individual and family, which can help patients understand their specific disorder and avoid inappropriate treatments (eg, splenectomy for misdiagnosed immune thrombocytopenia [ITP] in HMMS featuring thrombocytopenia). Second, a genetic diagnosis can help avoid the use of hematopoietic stem cells (HSCs) from an asymptomatic HMMS mutation carrier. Finally, routine clinical care now requires knowledge of HMMSs. For example, the National Comprehensive Cancer Network (NCCN) recommends surveillance for HMMSs in patients at high risk for Li-Fraumeni syndrome, and clinicians ordering genetic testing of malignant cells (eg, CEBPA for AML prognosis) will encounter reports suggesting that an identifiedmutationmay be germ line. Furthermore, the 2016 World Health Organization (WHO) classification of HMs incorporated a provisional diagnostic category for hereditary myeloid malignancies, such as AMLwith mutated RUNX1, prompting pathologists and clinicians to considerHMMSswhen rendering diagnoses. Thus, clinicianswill increasinglyneed to identify, diagnose, andmanage individuals with HMMSs. HMMSs encompass familial MDS/AL predisposition syndromes, IBMFSs, familial myeloproliferative neoplasms (MPNs), and, more broadly, traditional hereditary cancer predisposition syndromes. A review of each HMMS is beyond the scope of this article, but the featuresof each syndromeare summarized inTable1 andFigure1 and have been reviewed in detail elsewhere. In this review, we provide a practical outline for identifying and diagnosing HMMSs in hematology clinical care. We review the current evidence, or lack thereof, on how to care for individuals with known HMMS. Lastly, we