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Familial acute leukemia and myelodysplastic syndromes

Jane E Churpek, MD
Lucy A Godley, MD, PhD
Section Editor
Richard A Larson, MD
Deputy Editor
Alan G Rosmarin, MD


Familial forms of acute leukemia (AL) and/or myelodysplastic syndrome (MDS) have been traditionally considered rare, especially among adults affected by these malignancies. However, attention to the family history and genetic investigations of families in whom AL and/or MDS cases cluster have identified nine genes that cause inherited forms of these diseases that can present throughout the lifespan.

Here we discuss the recognized syndromes that cause a predisposition to AL and/or MDS as the main presenting feature. The many other disorders with an inherited predisposition to AL and/or MDS that have other prominent systemic manifestations, such as Down syndrome or neurofibromatosis type I, are reviewed in more detail separately, as are the inherited bone marrow failure syndromes, such as Fanconi anemia and Shwachman-Diamond syndrome, which most frequently present in childhood. (See "Down syndrome: Clinical features and diagnosis" and "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis" and "Inherited aplastic anemia in children and adolescents" and "Shwachman-Diamond syndrome".)


The incidence of the known familial AL and MDS syndromes (table 1) is not well characterized. In a study that used next-generation sequencing to determine the contribution of germline predisposition mutations in sporadic pediatric cancer, mutations that were deemed to be pathogenic or probably pathogenic were identified in 26 of 588 (4 percent) patients with pediatric leukemia [1]. However, many families in whom MDS and AL cluster test negative for mutations in all of the currently known genes, suggesting that additional causative genes remain to be identified. Because many of the genes that cause the familial AL and MDS syndromes when mutated in the germline or constitutional state are also found as somatic or acquired mutations, prior studies that sequenced these genes at diagnosis in large numbers of presumably de novo AL and MDS cases provide estimates of the maximum number of cases that could be accounted for by each inherited syndrome. Details regarding the maximum prevalence for each described entity are provided in the sections below.

Variation by race, ethnicity, and geography are not currently known. The families described in most of the familial AL and MDS syndromes appear to have their own private inherited mutations, suggesting independent events rather than a "founder" mutation occurring on an ancestral allele in a particular population.


Whom, when, and how to screen — All patients with AL and MDS should be screened at the time of initial diagnosis or referral to rule out the presence of a familial AL and MDS syndrome [2]. Similar screening is also essential during the initial pre-donation health screening evaluation for all individuals (related and unrelated) who wish to serve as an allogeneic hematopoietic cell donor for a person with a hematologic malignancy, either related or unrelated [3]. Screening consists of obtaining a careful medical and family history aimed at identifying signs and symptoms of the known familial AL and MDS syndromes. Specific information to elicit includes (figure 1):

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Literature review current through: Oct 2017. | This topic last updated: Mar 13, 2017.
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