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Familial disorders of acute leukemia and myelodysplastic syndromes

Familial disorders of acute leukemia and myelodysplastic syndromes
Literature review current through: Jan 2024.
This topic last updated: May 07, 2021.

INTRODUCTION — Familial disorders of acute leukemia (AL) and myelodysplastic syndromes (MDS) may be present with AL or MDS as the principal clinical feature (ie, without other findings) or in association with other hematologic or systemic manifestations. The diagnosis of familial AL/MDS is based on detection of the causal genetic abnormality in germline tissue (ie, non-hematologic cells). The presence of the pathogenic variant (ie, mutation) in the germline distinguishes an inherited disorder from an acquired (ie, somatic) abnormality in the malignant tissue alone. It is important to identify familial AL/MDS to provide optimal management and counseling for the patient and relatives.

This topic will discuss inherited disorders in which a predisposition to AL and/or MDS is the principal presenting feature.

Disorders with an inherited predisposition to AL and/or MDS in association with other prominent systemic manifestations (eg, Down syndrome, neurofibromatosis type I) and inherited bone marrow failure syndromes (eg, Fanconi anemia, Shwachman-Diamond syndrome) are discussed separately.

(See "Down syndrome: Clinical features and diagnosis".)

(See "Transient abnormal myelopoiesis (TAM) of Down syndrome (DS)".)

(See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)

(See "Clinical manifestations and diagnosis of Fanconi anemia".)

(See "Shwachman-Diamond syndrome".)

TERMINOLOGY — Following is our preferred terminology for familial conditions.

Variant versus mutation – Variant refers to a DNA sequence that differs from the common, wild type sequence. In human genetics, the term variant is preferred over mutation, which is considered by some to be pejorative.

Variants are not necessarily deleterious; the clinical significance of gene variants is described according to a five-tier system standardized by the American College of Medical Genetics and Genomics and the Association of Molecular Pathology [1,2], as follows:

Pathogenic (P)

Likely pathogenic (LP)

Variant of uncertain significance (VUS)

Likely benign (LB)

Benign (B)

P and LP variants are deleterious variants that are commonly or colloquially referred to as mutations. However, it is important to recognize that B, LB, and VUS variants are not known to be deleterious and should not be equated with pathogenic variants. For some variants, the categorization can change over time. As examples, a VUS variant may be downgraded to LB or B or, less often, a VUS variant is upgraded to a LP or P variant as new information about its functional effects and/or segregation with a health condition are better understood.

Inherited/familial versus germline – The terms inherited and familial can be used interchangeably, but they have distinct meanings compared with the term germline:

Inherited or familial refers to a trait or an allele that is passed from a parent to child (ie, across generations).

Germline refers to an allele that is present in the germ cells of an individual, but it is not necessarily inherited from a parent. All inherited variants are germline, but not all germline variants are inherited. To illustrate the distinction, de novo DNA variants may arise spontaneously within germ cells or in the early embryo, but they are not inherited; de novo variants in SAMD9, SAMD9L, and GATA2 are examples of germline variants that are not inherited. (See 'Familial MDS/AML with mutated GATA2' below and 'Monosomy 7 and SAMD9/SAMD9L mutations' below.)

Inherited/familial versus acquired/somatic variants – Acquired or somatic refers to a variant that develops during an individual's lifetime, in contrast with an inherited/familial variant that is transmitted from a parent. Acquired variants are present in a subset of the body's cells, whereas inherited variants are present in all of the body's cells.

Disorder versus syndrome – We use the term disorder when the only recognized manifestations are hematologic (eg, leukemia, MDS, or other causes of cytopenias or qualitative disorders); we reserve the term syndrome for conditions in which non-hematologic findings (eg, skeletal or cutaneous findings) are also present.

EPIDEMIOLOGY — It is estimated that a familial (ie, inherited) acute myeloid leukemia (AML) and/or MDS (table 1) account for 30 to 50 percent of all AML/MDS cases in children, 10 to 20 percent in young adults, and 5 to 10 percent in older adults [3-11].

A study that used next-generation sequencing (NGS) of DNA in patients with pediatric cancers reported that 4 percent (26 of 588) of children with leukemia had germline variants that were considered pathogenic or probably pathogenic [3]. This likely underrepresents the true prevalence, because not all known familial AL/MDS genes were evaluated in this study and many families with clusters of hematologic cancers test negative for all currently recognized deleterious variants. Prevalence of specific disorders and syndromes is discussed in the sections below. (See 'Clinical features of inherited AL/MDS disorders' below.)

Most familial conditions appear to be associated with independently-arising deleterious variants, rather than recurrent or founder variants that occur in a particular population. Variations in prevalence according to race, ethnicity, or geography are beginning to be recognized. As an example, specific recurrent deleterious variants are found in DDX41, with p.D140fs and p.M1? common in populations of European ancestry versus p.A500fs in populations of Asian ancestry [12].

EVALUATION OF PATIENTS WITH AL OR MDS — Evaluation for a familial disorder in a patient with AL or MDS includes a screening history, focused physical examination, and diagnostic genetic testing, when indicated.

Whom and when to evaluate — Familial AL/MDS may be suspected in any child with MDS or in a child or adult when either of the following is noted:

Findings from screening history and/or physical examination – All children and adults with AL or MDS should have a screening history and physical examination at the time of initial diagnosis or referral for treatment [13]. (See 'Screening history/exam' below.)

If suggestive clinical findings emerge later in the patient's course of disease or in relatives, the screening evaluation should be repeated at that time. (See 'Screening history/exam' below.)

Suspicious laboratory or molecular/cytogenetic features – In some cases, certain laboratory findings (eg, unexplained macrocytosis) or molecular/cytogenetic features in the patient's MDS/AL can suggest the possibility of a familial disorder. (See 'Suggestive molecular/cytogenetic findings' below.)

Diagnostic genetic testing is required to confirm the diagnosis and can be performed by the clinician treating the AL/MDS or by referral to an experienced genetic counselor or specialty center. (See 'Who should perform genetic testing?' below.)

Screening history/exam — All children and adults with AL or MDS should have a screening evaluation, which includes a personal and family history and a physical examination, with special attention to features that increase the probability of an inherited disorder. Family members of individuals diagnosed with a familial disorder should also have this evaluation. Based on the high frequency of deleterious germline variants identified in patients <40 years old with MDS, all such patients should have germline genetic testing based on their age of disease onset regardless of family history or syndromic features [3-6].

Findings from the screening evaluation inform the decision to proceed with diagnostic genetic testing and/or refer the patient to a specialist for further evaluation. (See 'Diagnostic genetic testing' below and 'Referral and counseling' below.)

The screening evaluation should inquire about the presence and age of onset of the following conditions in the patient and family members, and note the presence of corresponding findings on examination (figure 1):

Prior diagnosis of a familial AL/MDS syndrome, or previous evaluation/testing for a familial syndrome (table 1).

Diagnosis of MDS in someone age 40 or younger.

Aplastic anemia, MDS, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or other hematologic malignancies in two or more relatives within two generations.

Unexplained leukopenia, anemia, and/or thrombocytopenia in two successive generations.

Patients who have had two or more cancers, including those who have a treatment-related AL or MDS that arose after treatment of a prior malignancy.

Relatives who have solid tumors that fit into a recognized cancer predisposition syndrome (eg, hereditary breast and ovarian cancer syndromes).

Recurrent or atypical infections and/or immune deficiency.

Organ system abnormalities:

Skin (eg, hyper- or hypopigmented patches, café au lait macules), mucosa (eg, oral leukoplakia), hair (premature graying), or nail abnormalities

Extensive cutaneous or anogenital warts

Primary lymphedema

Pulmonary alveolar proteinosis, idiopathic pulmonary fibrosis, or early onset emphysema

Unexplained liver cirrhosis or fibrosis

Congenital limb anomalies, especially thumb/forearm

Short stature

Deafness

Nystagmus or ataxia

Cognitive dysfunction

Findings from the screening evaluation may suggest a particular familial disorder, enabling a clinical diagnosis in some cases. For others, it can inform the testing strategy for individuals who have not previously been diagnosed with a familial disorder, as described below. (See 'Testing strategies' below.)

Suggestive molecular/cytogenetic findings — Germline abnormalities may first be detected when molecular testing is performed on a patient's AL or MDS specimen for prognostic or therapeutic purposes, as many of these panels now include genes that are known to cause inherited MDS/AL [14]. It is important for clinicians to recognize that these alleles may be present in malignant cells because they are, in fact, germline variants. Testing of the specific variant in a germline tissue source is necessary to determine if it is inherited or acquired. (See 'Diagnostic genetic testing' below.)

Examples of findings that warrant evaluation to exclude a heritable (ie, germline) abnormality (table 1) include:

Biallelic mutant CEBPA (see 'Familial AML with mutated CEBPA' below)

DDX41 mutation (see 'Familial AML with mutated DDX41' below)

GATA2 mutation (see 'Familial MDS/AML with mutated GATA2' below)

Monosomy 7 in children with AL/MDS (see "Acute myeloid leukemia in children and adolescents")

Recurrent or founder-inherited cancer susceptibility variants (eg, CHEK2 1100delC, ANKRD26 5'UTR mutations)

TP53 gene variant in a patient with low hypodiploid acute lymphoblastic leukemia (see 'Familial ALL due to TP53 mutation' below)

EVALUATION OF OTHERS — Relatives and potential stem cell donors for individuals diagnosed with an inherited disorder should be evaluated for that specific disorder.

Relatives — First-degree relatives (ie, siblings, parents, and children) of individuals diagnosed with an inherited AL/MDS disorder should be evaluated to determine if they carry the same germline variant and may, themselves, have associated health risks. In general, evaluation of relatives should be performed by a genetic counselor or clinician with expertise in these disorders, to provide optimal counseling and management. For disorders with health implications for children (eg, bleeding risk from platelet dysfunction or a substantial risk of MDS/AL in childhood), we recommend evaluation and genetic testing of at-risk children by pediatric cancer risk professionals. (See 'Referral and counseling' below.)

Evaluation of relatives should include a screening health history and physical examination and a thorough pedigree to identify other relatives who may be at risk. Pre-test and post-test genetic counseling are important for the individual (or caregivers) to understand genetic findings and the health implications. (See 'Screening history/exam' above.)

Nearly all currently recognized familial AL and MDS disorders are inherited in an autosomal dominant manner, so first-degree relatives have a 50 percent chance of inheriting the same gene variant. By contrast, inherited bone marrow failure syndromes, which may also be associated with familial AL/MDS (eg, Schwachman-Diamond syndrome, dyskeratosis congenita, Fanconi anemia), are more often inherited in an autosomal recessive manner. (See "Shwachman-Diamond syndrome" and "Dyskeratosis congenita and other telomere biology disorders" and "Clinical manifestations and diagnosis of Fanconi anemia".)

Genetic anticipation has been observed in some familial AL and MDS syndromes (ie, a child may present with symptoms earlier in life than a parent), while others are incompletely penetrant (ie, individuals carrying the familial variant may never develop syndrome-specific health problems or MDS/AL) [15-17]. Some disorders can also appear de novo and, as such, are presumably germline, but not inherited. These features can make the family history appear to lack other affected individuals, but clinical evaluation and genetic testing for the familial variant may reveal others who have not yet developed clinical symptoms or whose clinical features are present, but were not previously recognized as part of an inherited MDS/AL disorder.

Typical presentations, age of onset of clinical findings, and diagnostic testing for specific disorders are described in the sections below. (See 'Clinical features of inherited AL/MDS disorders' below.)

Early identification of at-risk family members enables optimal management of hematopoietic abnormalities and/or systemic manifestations and facilitates monitoring for development of a malignancy. In some cases, recognition of an underlying familial disorder can avoid misdiagnosis and/or improper treatment. As an example, individuals with inherited disorders that are associated with thrombocytopenia might erroneously be diagnosed with immune thrombocytopenia (ITP) and receive inappropriate treatment. (See 'Management' below.)

Potential stem cell donors — Transplantation with allogeneic stem cells that carry the same genetic variant as the transplant recipient can result in adverse outcomes, such as failure to engraft or donor-derived hematologic malignancies [18]. Absolute risks for these adverse outcomes in each disorder are not yet established. Thus, whenever possible, use of a donor who does not carry a deleterious variant in an inherited MDS/AL risk gene is strongly preferred; however, this decision must carefully consider the particular gene, patient situation, and alternative donor options. To facilitate this risk/benefit determination, we suggest the following:

All potential donors for allogeneic hematopoietic cell transplantation (HCT) should be evaluated for a familial AL/MDS condition by screening history and physical examination, as described above. (See 'Screening history/exam' above.)

Before donor eligibility decisions are finalized:

Related donors – Potential related donors in a family with a known familial AL/MDS disorder should be tested for the known germline variant. Allogeneic HCT presents unique pressures for related potential donors who must balance a desire to help their sick relative versus learning the results of genetic testing, which they might not otherwise favor. Genetic counseling in these situations requires special consideration and expertise.

Unrelated donors – For potential unrelated donors who have features of a familial AL/MDS disorder based on predonation clinical evaluation, we suggest referral to a provider with expertise in these disorders for additional work-up before donor eligibility decisions are finalized. (See 'Referral and counseling' below.)

Molecular testing after allogeneic stem cell transplantation – Testing for the causal variant should be performed before and serially after allogeneic HCT. If donor engraftment is >95 percent, molecular profiling should be confined to those somatic variants that were found in the recipient's malignant cells. This avoids revealing deleterious germline variants in the donor cells, as the donor is unlikely to have provided consent for revealing this information. Moreover, reporting structures do not presently exist to readily report such findings to donors, especially for unrelated and umbilical cord donors.

Some familial disorders are first recognized when an apparently healthy individual is found to have unexplained macrocytosis, thrombocytopenia, or failure to mobilize sufficient peripheral blood stem cells while undergoing evaluation as a potential stem cell donor [18,19]. Such findings should prompt evaluation for diagnosis of a familial disorder, as described below. (See 'Screening history/exam' above and 'Broader testing' below.)

DIAGNOSTIC GENETIC TESTING

Who should be tested? — Diagnostic genetic testing should be performed when:

History or physical examination of a patient with AL or MDS identifies findings suggestive of a familial disorder (see 'Screening history/exam' above)

Particular cytogenetic/molecular findings of AL/MDS cells suggest a possible familial syndrome:

Biallelic mutated CEBPA (see 'Familial AML with mutated CEBPA' below)

DDX41 mutation (see 'Familial AML with mutated DDX41' below)

GATA2/SAMD9/SAMD9L mutation or monosomy 7 in a child with AL or MDS [20,21] (see 'Familial MDS/AML with mutated GATA2' below and 'Monosomy 7 and SAMD9/SAMD9L mutations' below)

Consideration of germline testing should be given for a recognized variant of any gene known to confer risk for cancer.

A family member is diagnosed with a familial disorder or syndrome (see 'Relatives' above)

Potential related stem cell donors to an individual who is to undergo allogeneic hematopoietic stem cell transplantation (HCT) for an inherited disorder (see 'Potential stem cell donors' above)

Who should perform genetic testing? — Individuals who require genetic testing should be referred to a genetic counselor or physician trained in genetic medicine with access to specialized testing resources and experience with interpreting and managing the findings. Referral to a specialist for testing and further management is discussed below. (See 'Referral and counseling' below.)

Types of genetic testing — Two categories of genetic testing may be used to diagnose a familial AL/MDS disorder:

Gene panel/DNA sequencing – Next-generation sequencing (NGS) of DNA provides a cost-effective, broad-based approach to identifying specific gene variants. Sanger sequencing of single genes or a specific familial variant are also options.

Genomic rearrangements/deletions – Microarrays, multiplex ligation-dependent probe amplification-based (MLPA) assays, and specially designed NGS assays can detect large scale genomic rearrangements and/or deletions. It is important to pay attention to whether testing for genomic rearrangements is included in the test that you are ordering or if this must be ordered separately.

Genetic tests for familial MDS/AL-related genes via single gene assays and gene panels are available from some commercial laboratories or academic centers. The gene panels and sample requirements vary (see below) so care is necessary in choosing the best test for an individual patient [22].

The application of these techniques for diagnosing a familial AL/MDS disorder is informed by the testing strategy, as described below. (See 'Testing strategies' below.)

Specimens for genetic testing — Cultured skin fibroblasts are generally the preferred source for germline genetic testing. However, the choice of specimen may be informed by the urgency of testing, sample requirements of the reference laboratory, and the ability of a local laboratory to process particular samples; it is important to check laboratory requirements prior to sending a specimen for testing. Benefits and limitations of various tissue types are summarized in the table (table 2).

Cultured skin fibroblasts – Cultured skin fibroblasts are generally preferred for genetic testing when a hematologic malignancy involves peripheral blood or bone marrow, and in patients who have undergone allogeneic HCT. They provide a ready source of non-hematologic tissue to identify germline variants. However, use of cultured skin fibroblasts may entail additional expenses (eg, for the biopsy and culture procedures) and may require extra time for cell growth (eg, three to four weeks) prior to genetic testing. This additional time (an estimated average of eight weeks from biopsy to results) may not be acceptable if results are required urgently.

Skin fibroblasts are grown from a 3 mm punch skin biopsy or small skin ellipse (eg, from the site of the skin nick for a bone marrow biopsy). A Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory must process and culture the specimen before sending it to the reference laboratory for genetic testing. When results are required urgently, we generally submit a different tissue source (eg, direct skin punch) for immediate genetic testing while simultaneously submitting a skin biopsy specimen for culture, in the event that DNA was insufficient and/or additional confirmatory genetic testing is needed.

Other tissues that may be used for genetic testing for an inherited condition include:

Saliva and buccal swabs – Saliva or buccal swabs are readily available, inexpensive, and can provide epithelial cells as an alternative tissue source for genetic testing, but the specimen may be contaminated by malignant cells from peripheral blood, which can cloud the distinction between germline and acquired variants [23-25].

Peripheral blood – Blood specimens may be the only readily available tissue that meets requirements for urgent testing by some laboratories. If such a sample is used, the patient should be counseled that findings may require confirmation with a specimen of non-hematologic tissue.

Remission blood or bone marrow – Blood or bone marrow from patients in remission can be considered for germline testing, if they have not previously undergone allogeneic HCT. However, such testing should recognize potential confounding factors:

For some patients with a morphologic remission, acquired mutations may be detected as measurable residual disease (MRD; also referred to as minimal residual disease) [26]. (See "Acute myeloid leukemia: Induction therapy in medically fit adults".)

Healthy individuals with clonal hematopoiesis of indeterminate potential (CHIP) can have mutations that are also seen in AL/MDS (eg, TET2, DNMT3A, ASXL1). Other mutations that are associated with clonal hematopoiesis (eg, TP53) are more commonly found in patients who have been treated previously for another cancer diagnosis [27]. Assessing whether these mutations are germline versus acquired can be difficult using peripheral blood or bone marrow alone. (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis", section on 'Excluding a germline mutation'.)

Hair and nails – Hair follicles (from a "hair pluck") and nails (eg, nail clippings) are easy to obtain, but they provide only limited amounts of DNA and many laboratories do not accept these samples for clinical testing. Moreover, nail samples may contain DNA derived from monocytes; in some types of leukemia, the monocytes may be part of the malignant clone.

Testing strategies — The clinical setting determines the preferred testing strategy. Cost and/or insurance reimbursement for testing will vary by the test, laboratory, and setting.

Testing for a specific abnormality — Selective testing for a particular genetic abnormality is performed when a specific familial AL/MDS genetic abnormality has previously been diagnosed.

Settings in which selective testing may be performed include:

A patient with AL or MDS who has a relative who was previously diagnosed with a familial disorder and for whom the specific causative variant is known.

A patient has cytogenetic/molecular findings in AL/MDS cells that suggest a specific familial disorder (eg, biallelic CEBPA mutations, DDX41 mutation, GATA2 mutation or monosomy 7 in a child with AL or MDS). Distinguishing acquired mutations from germline variants is discussed separately. (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis", section on 'Excluding a germline mutation'.)

Family members who are being considered as stem cell donors for an individual who has been diagnosed with a familial disorder and for whom the causative variant is known.

Testing of a single genetic abnormality typically requires at least two to four weeks. Molecular testing for most familial AL/MDS disorders can be performed by commercial laboratories, but certain rare disorders may require referral to a specialty clinic/laboratory for testing. The tests that are required for diagnosis depend on the disorder, as described in the sections below. (See 'Clinical features of inherited AL/MDS disorders' below.)

Broader testing — Broader genetic testing is required when a specific familial AL/MDS disorder has not previously been diagnosed. The clinical presentation can inform the testing strategy. Importantly, broader testing for an as-of-yet unidentified disorder usually requires both NGS and genomic rearrangement/deletion testing, because neither approach alone can diagnose all known inherited disorders.

Clinical diagnostic criteria, which enable a diagnosis based on clinical findings alone, are not yet established for most familial AL/MDS disorders. However, in many cases, evaluation of a patient with an as-yet unidentified inherited disorder is informed by clinical findings. Initial testing should generally focus on more common disorders associated with a particular clinical presentation. As an example, in a patient with biallelic CEBPA pathologic variants in acute myeloid leukemia (AML) cells and no associated clinical findings, initial testing might initially focus on CEBPA variants. (See 'Disorders without other clinical manifestations' below.)

Broader testing typically requires investigation for more than one disorder. Because evaluation of an unknown disorder may require eight or more weeks to complete, the testing strategy depends on the urgency of the clinical situation. As an example, if allogeneic HCT for AL/MDS is planned for the near future, it may be necessary to simultaneously test for multiple possible diagnoses while concurrently testing both the patient and potential stem cell donors. Testing can generally proceed with less urgency in other clinical situations. In some cases, initially testing for a small number of disorders or even a serial (sequential) gene-by-gene approach is possible, but the advantages of these approaches can be offset by the potential for increased cost and testing fatigue by both the patient and provider.

If both NGS and genomic rearrangement/deletion testing are needed, care should be taken to ensure that both categories (ie, NGS plus genomic rearrangement/deletion testing) are ordered, since some laboratories code them as separate tests [28] (table 1). (See 'Types of genetic testing' above.)

Examples of clinical presentations that may suggest a particular disorder include:

Initial presentation with AL/MDS and no other findings (see 'Disorders without other clinical manifestations' below)

Bone marrow failure in the patient and/or family members (see 'Inherited bone marrow failure syndromes' below and 'Familial aplastic anemia/MDS with SRP72 mutation' below)

Unexplained anemia/macrocytosis (eg, TERT/TERC); leukopenia (eg, TERC, GATA2); or thrombocytopenia/excessive bleeding in the patient or relatives (eg, RUNX1, ETV6, or ANKRD26) (see 'Inherited bone marrow failure syndromes' below and "Congenital neutropenia" and 'Syndromes featuring platelet abnormalities' below)

Monosomy 7 in a child with MDS or aplastic anemia (see 'Monosomy 7 and SAMD9/SAMD9L mutations' below and 'Familial MDS/AML with mutated GATA2' below)

Myeloproliferative neoplasms (see 'Myeloid neoplasms with germline predisposition (14q32 duplications)' below)

Acute lymphoblastic leukemia (see 'Familial ALL disorders' below)

Other cancers at an early age (eg, bone and soft tissue sarcomas, breast cancer, brain tumors, adrenocortical carcinoma) (see 'Familial ALL due to TP53 mutation' below)

Other organ system abnormalities:

Severe and/or recurrent infections (eg, atypical mycobacterial, fungal, or viral infections) or immune deficiencies (eg, monocytopenia, B lymphopenia) (see 'Familial MDS/AML with mutated GATA2' below)

Skin (eg, hyper- or hypopigmented patches or café au lait macules), mucosal (eg, oral leukoplakia), or nail disorders (see 'Inherited bone marrow failure syndromes' below and 'Familial MDS/AML with mutated GATA2' below)

Extensive cutaneous or anogenital warts (see 'Familial MDS/AML with mutated GATA2' below)

Primary lymphedema (see 'Familial MDS/AML with mutated GATA2' below)

Pulmonary alveolar proteinosis or idiopathic pulmonary fibrosis (see 'Familial MDS/AML with mutated GATA2' below and 'Inherited bone marrow failure syndromes' below)

Unexplained liver cirrhosis or fibrosis (eg, TERT/TERC) (see 'Inherited bone marrow failure syndromes' below)

Congenital limb anomalies (eg, Fanconi anemia, Diamond-Blackfan anemia, MECOM-associated syndrome) (see 'Inherited bone marrow failure syndromes' below and 'MECOM-associated syndrome' below)

Deafness (see 'Familial MDS/AML with mutated GATA2' below and 'Familial aplastic anemia/MDS with SRP72 mutation' below)

Certain inherited AL/MDS syndromes are associated with other prominent systemic manifestations (eg, Down syndrome, neurofibromatosis type I) or inherited bone marrow failure (eg, Fanconi anemia, Shwachman-Diamond syndrome); these conditions are discussed separately. (See "Down syndrome: Clinical features and diagnosis" and "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis" and "Clinical manifestations and diagnosis of Fanconi anemia" and "Shwachman-Diamond syndrome".)

MANAGEMENT — In most cases, monitoring and management of a familial AL/MDS disorder is best handled in a center that has experience with the disorder or managed locally with consultation and continued advice from such a center.

Referral and counseling — In general, referral to a cancer genetics clinic, medical geneticist, genetic counselor, or other cancer risk specialist is important for genetic counseling, confirming the diagnosis of a familial disorder, and evaluating relatives of an affected individual.

Many clinicians choose to refer a patient with AL/MDS to a specialty clinic for initial diagnostic testing based on findings from the initial screening history and examination, urgency of the clinical situation, available resources, and experience of the practitioner. Referral is also appropriate for interpretation of test results or confirmation of the diagnosis and for detailed assessment of the pedigree. The urgency of referral depends on concerns and preferences of the individual and the medical stability of the patient with AL/MDS.

Relatives of an individual with a diagnosed inherited condition should be referred to a specialist to develop a comprehensive plan for monitoring for malignancies, cytopenias, other organ system complications, and genetic counseling, if not already done.

Monitoring — The optimal schedule and nature of monitoring has not yet been established and no evidence-based guidelines are currently available. Monitoring should be individualized based on the underlying diagnosis; age; associated hematologic abnormalities (eg, cytopenias or qualitative abnormalities), syndromic features, or organ dysfunction; hematologic or other malignancies; overall health status; and preferences of the affected individual and caregiver(s).

For individuals who have not developed hematopoietic malignancies, regular complete blood counts (CBC) and physical exams should be performed. Obtaining a CBC once or twice per year is reasonable for an asymptomatic patient with no hematologic abnormalities (ie, normal CBC and blood smear) or other complications.

We generally perform a bone marrow examination at the time that an individual is diagnosed with a familial disorder to serve as a baseline. We repeat that examination if there is a significant change in blood counts or other worrisome findings. Routine surveillance bone marrows, even without changes in blood counts, should be considered for patients with conditions that confer substantial risk for MDS/AL, as cases of MDS have been identified without major changes in blood counts [29] (eg, Fanconi anemia, Shwachman-Diamond syndrome). (See 'Inherited bone marrow failure syndromes' below.)

Treatment — For a patient who has developed a familial AL or MDS, management is guided by the type of malignancy (eg, AL, MDS) and clinical or laboratory abnormalities associated with the condition. Importantly, certain conditions require distinctive management, because conventional care can be associated with excessive toxicity, unusual complications, and/or lack of efficacy (eg, inherited bone marrow failure syndromes, Li-Fraumeni syndrome). (See 'Inherited bone marrow failure syndromes' below and 'Familial ALL due to TP53 mutation' below.)

Detection of a germline pathogenic variant should prompt a discussion of the timing of an allogeneic hematopoietic cell transplantation (HCT), since chemotherapy alone (ie, without transplantation) does not remove the underlying pathogenic variant.

If allogeneic HCT is planned, potential related donors should undergo genetic testing to identify those relatives who carry the familial variant. A careful risk/benefit discussion with both donor and recipient is required to determine the optimal donor, weighing the patient's clinical situation, donor options, and specific underlying variant. Whenever possible, we prefer to utilize a donor without the familial variant. Unrelated donors from the international registries and umbilical cord units do not routinely undergo screening by family history or germline testing, but this is a practice worthy of discussion. (See 'Potential stem cell donors' above.)

Affected individuals of childbearing age should be counseled about the availability of preimplantation genetic diagnosis and procedures for pretransplant fertility preservation.

Some disorders require specific aspects of care. Examples include screening for human papillomavirus (HPV)-related malignancies, head and neck cancer, and anogenital cancer in patients with familial MDS/acute myeloid leukemia (AML) with mutated GATA2 or autosomal dominant telomere syndromes due to TERT, or TERC, or RTEL1 variants. (See 'Familial MDS/AML with mutated GATA2' below and 'Inherited bone marrow failure syndromes' below.)

CLINICAL FEATURES OF INHERITED AL/MDS DISORDERS — Clinical features of known inherited disorders of AL and MDS (table 1) are detailed in the sections that follow.

Disorders without other clinical manifestations — For the following inherited disorders, typically patients present initially with acute myeloid leukemia (AML) or MDS, because there are no other commonly associated hematologic or systemic manifestations.

Familial AML with mutated CEBPA — Familial AML with mutated CEBPA (OMIM 116897) (table 1) is associated with development of AML, but not with other malignancies or hematologic abnormalities.

Presentation – Individuals with familial AML with mutated CEBPA typically have no other hematopoietic or systemic manifestations prior to the development of AML [30,31]. AML develops between age 2 to 59 years in nearly all individuals who carry the mutation [30,32,33]. The leukemia usually features a normal karyotype, Auer rods are common, and there is aberrant expression of CD7 [30,31].

Prevalence – The prevalence is not well-defined, but indirect evidence suggests that familial AML with CEBPA mutation may account for up to 1 percent of all AML, based on the following reasoning: CEBPA mutations have been reported in 9 percent of all AML and in 15 to 18 percent of AML with normal karyotype [34-36], and germline variants were reported in 7 percent (5 of 71) [36] and 11 percent (2 of 18) [37] of patients with CEBPA mutations. (See "Acute myeloid leukemia: Risk factors and prognosis".)

Genetics – Familial AML with CEBPA mutation (OMIM 116897) is usually associated with inheritance of a single abnormal copy of CEBPA (on chromosome band 19q13.1), in which a frameshift or nonsense mutation disrupts the N-terminus of the protein [30,31]. Gene variants that disrupt the C-terminus have also been described and may be associated with a decreased penetrance compared to the nearly 100 percent penetrance of those that disrupt the N-terminus. A mutation in the second CEBPA allele is acquired at the time of progression to AML [30,37]; GATA2 mutations may also be acquired in this setting [38].

Testing – Clinical genetic testing is available as single gene next-generation sequencing (NGS) or as a component of some myeloid gene panels. Testing should include sequencing of the entire gene, which can be difficult on NGS platforms due to the GC-rich sequence of this single-exon gene. (See 'Types of genetic testing' above.)

Management – Leukemia associated with familial CEBPA mutation generally has a favorable prognosis, as does sporadic AML with biallelic CEBPA mutations [30,32,33]. However, a risk/benefit discussion is needed regarding the use and timing of allogeneic hematopoietic cell transplantation (HCT) for patients who develop AML, as only transplantation can treat the AML plus replace leukemia-prone stem cells [32]. Molecular analysis has revealed that what were initially thought to be chemotherapy-sensitive late AML relapses are, in fact, independent leukemias that arose from leukemia-prone stem cells with the germline CEBPA mutation that persisted after chemotherapy. Allogeneic HCT donors should be selected carefully to avoid a graft that carries the same gene abnormality; donor-derived AML has been reported when a relative carrying the familial mutation was unknowingly used as a stem cell donor [39]. Treatment of favorable prognosis AML is described separately. (See "Acute myeloid leukemia in children and adolescents", section on 'Treatment' and "Acute myeloid leukemia in adults: Overview", section on 'Remission induction'.)

Monitoring of individuals who carry the abnormality is described above. (See 'Management' above.)

Familial AML with mutated DDX41 — Germline mutations of DDX41 (table 1) cause an inherited disorder of myeloid malignancies that generally arise later in life. Males seem to develop malignancies more often than female carriers [40]. This disorder is typically asymptomatic, but it may be associated with cytopenias prior to development of MDS or AML.

Presentation – Affected individuals are typically asymptomatic and have no systemic manifestations, but they may have cytopenias prior to the development of a hematologic malignancy; the median age of presentation is 61 to 69 years [7,41,42].

Patients generally develop high-grade myeloid neoplasms, including MDS, AML, and chronic myelomonocytic leukemia (CMML), but lymphoid malignancies (most often lymphomas) can occur. Because the malignancies typically arise at an age that falls within the expected age of presentation for sporadic cases of these malignancies in the general population, age alone does not distinguish malignancies associated with the inherited disorder from sporadic cases. The myeloid malignancies generally have a normal karyotype and often acquire a second DDX41 mutation of the other, previously normal DDX41 allele. Solid tumors (eg, colon, gastric, pancreatic, bladder, breast cancer, melanoma) and autoimmune disorders have also been reported in some pedigrees, but a proven association with any particular cancer or other finding has not yet been defined.

Prevalence – Although the prevalence of germline DDX41 pathogenic variants is uncertain, this appears to be the most common familial MDS/AL disorder found in adults. Testing of >1000 cases of AML identified DDX41 mutations in 1.5 percent, of which half were germline variants [41]. In another study, DDX41 pathogenic variants were identified in 43 unrelated patients among 1385 individuals with MDS or AML; the variants were considered likely to be germline and causal in 33 patients (2.4 percent) [7].

Genetics – Germline mutations of DDX41, located at 5q35.3, include both missense and frameshift mutations [41]. A recurrent frameshift mutation, p.D140fs, and a recurrent missense mutation in the initiation codon, p.M1?, have both been reported in multiple independent families. Other recurrent mutations appear to be related to ancestry (eg, p.A500fs in individuals of Japanese/Korean/Asian ancestry) [12]. In about half of cases, an acquired mutation is found in the second DDX41 allele, suggesting that DDX41 can act as a tumor suppressor in myeloid cells; the most common acquired mutation is p.R525H. DDX41 is a DEAD-box helicase that can bind DNA and also act as an RNA helicase [43,44]. An increased number of mRNAs with splicing abnormalities (eg, exon skipping and/or intron retention) are present in myeloid malignancies with DDX41 mutations [41].

Disease penetrance appears to be high, but these estimates may be overestimated due to ascertainment bias, as the initial reports selected families with multiple cases of MDS and/or AL. In a given family with an inherited DDX41 variant, men and women are equally likely to inherit the mutation, but men are more often (3:1) the first in a family to be diagnosed with a hematologic malignancy, suggesting that progression to MDS/AML in this disorder may be higher in males than in females [40].

Testing – When testing adults for a familial disorder, it is important to choose an MDS/AL gene panel that includes DDX41, because not all commercial familial gene panels include this gene [22].

Management – Treatment of hematologic malignancies associated with germline variants of DDX41 is similar to that of other adverse prognosis AML and MDS [7,41]. We generally pursue allogeneic HCT for medically-eligible patients who develop AML, both to treat the AML and to replace the leukemia-prone stem cells. (See "Acute myeloid leukemia in adults: Overview", section on 'Remission induction' and "Overview of the treatment of myelodysplastic syndromes".)

Monitoring of individuals who carry the abnormality is described above. (See 'Management' above.)

Familial AML with mutated MBD4 — Germline mutation of MBD4 is an exceedingly rare disorder that is associated with AML, but no other hematologic or other systemic abnormalities are known [45].

Presentation – No associated hematologic or systemic abnormalities (other than DNMT3A-related clonal hematopoiesis and AML) have been reported [45].

Prevalence – Only three individuals with germline mutation of MBD4 have been reported [45]. Monoallelic MBD4 mutations have been observed in 0.8 percent of patients in The Cancer Genome Atlas (TCGA).

Genetics – Individuals with germline MBD4 mutations were identified because their AML DNA had an unusually high burden of C>T mutations that was discovered as a result of large-scale DNA sequencing [45]. Homozygous germline deletion of MBD4 was found in one patient, while compound heterozygous MBD4 mutations were found in two sisters who developed AML four years apart (one of whom developed AML after serving as the first sister’s stem cell donor). All three cases also had either an IDH1 or IDH2 mutation (all of which arose from C>T transition mutations) or had multiple independent, acquired, biallelic DNMT3A mutations, suggesting a propensity to DNMT3A-mutated clonal hematopoiesis.

MBD4 is a glycosylase involved in an initial step of base excision repair of DNA. Modified 5-methylcytosine (m5C) bases in CG dinucleotides may undergo spontaneous deamination, which results in mispaired thymine bases. If the DNA repair machinery, which includes thymine DNA glycosylate (TDG) and MBD4, fails to remove an unpaired thymine, a C>T transition mutation will occur at this position.

Testing – The three known cases were identified by research-based, large-scale sequencing of leukemia DNA that detected a high mutational burden. Standard acquired mutation panels in use for MDS/AML clinical testing may not be designed for the detection of this signature.

Management – Management is uncertain. It remains to be determined whether this DNA repair defect increases risk for other cancers.

Syndromes featuring platelet abnormalities

Presentations associated with platelet abnormalities — In the following syndromes, chronic thrombocytopenia and/or a bleeding propensity may present before the development of AL or MDS. A subtle clinical presentation or lack of awareness of prior platelet counts in the patient or family members can mask this finding and, in many cases, has been labeled as another platelet disorder (eg, immune thrombocytopenia). The combination of thrombocytopenia with normal platelet size and a family history of AL or MDS may help to differentiate the following syndromes from other inherited causes of thrombocytopenia [46,47]. (See "Causes of thrombocytopenia in children".)

Familial platelet disorder with propensity to myeloid malignancies (FPD) — Familial platelet disorder with propensity to myeloid malignancies (OMIM 601399) (table 1), which is caused by pathogenic variants of RUNX1, is associated with variable degrees of thrombocytopenia, a functional platelet defect, and increased risk for hematologic malignancies.

Presentation – Individuals with FPD can display widely variable clinical phenotypes, even within a single family. The classic presentation is longstanding mild to moderate thrombocytopenia, a mild bleeding propensity (with an aspirin-like functional platelet defect), and an increased lifetime risk of developing MDS, AML, and T cell acute lymphoblastic leukemia (ALL) [48,49]. However, some individuals have a normal platelet count and no bleeding propensity, while others have variable quantitative and qualitative platelet abnormalities and develop a hematologic malignancy at early age. Factors that contribute to this clinical heterogeneity are uncertain.

The lifetime risk of AL or MDS is estimated to be 35 to 40 percent, with an average age of onset of a malignancy of 33 years (range: 6 to 76 years) [48,50-56]. The phenotypes of MDS, AML, and T cell ALL in FPD vary widely [48,50-56]. A diverse array of acquired cytogenetic and molecular genetic abnormalities have been observed in FPD-associated malignancies and they likely contribute to the heterogeneous phenotype. Acquired mutations or loss of the previously normal copy of RUNX1 are common, but appear not to be required for development of the malignancy [56].

Prevalence – FPD is thought to be most common disorder among familial syndromes associated with functional platelet defects, but the prevalence is not well-defined. RUNX1 mutations have been identified in 10 to 33 percent of de novo MDS and AML cases [57-60], but the proportion of RUNX1 variants that are germline, rather than acquired, is uncertain.  

Genetics – FPD is an autosomal dominant syndrome caused by a monoallelic mutation of RUNX1 (chromosome band 21q22) [49]. Pathogenic variants are most often frameshift or nonsense mutations or small deletions that cause premature truncation of the protein; missense mutations in the DNA binding domain and large genomic rearrangements have also been reported [61].

Testing – Clinical genetic testing should include sequencing of the entire gene and testing for large rearrangements. (See 'Types of genetic testing' above.)

Management

Bleeding propensity – Unless there is clinical bleeding, affected individuals do not require specific treatment for thrombocytopenia and platelet dysfunction. Agents that inhibit platelet function should be avoided in those who exhibit a bleeding tendency; site-specific measures to control bleeding (eg, topical agents and pressure for nosebleeds) should be utilized. Platelet transfusions should be on-hand prior to major surgery or childbirth and utilized should major bleeding occur, if bleeding at the site would cause significant morbidity, or if patient's history suggests a high likelihood of bleeding. HLA-matched platelets should be considered to avoid alloimmunization, given the lifelong duration of thrombocytopenia in these individuals. (See "Perioperative blood management: Strategies to minimize transfusions".)

Monitoring for development of a hematologic malignancy – No clinical or laboratory marker is known to predict when a patient with FPD will develop an overt malignancy. Somatic genetic testing of peripheral blood is likely to identify clonal hematopoiesis that may or may not reflect overt malignancy in the bone marrow. In one small study, clonal hematopoiesis developed in most asymptomatic carriers of germline RUNX1 mutations (cumulative risk >80 percent by age 50 years) [9]. Another study identified mutations in CDC25C in 7 of 13 individuals with FPD; in the two patients with hematologic malignancies, additional mutations were present in the CDC25C-mutated leukemic clones, suggesting that this may be an early event in progression to malignancy [62].

The US National Institutes of Health is conducting a natural history study of FPD to inform evidence-based guidelines for monitoring and managing patients with FPD (https://clinicaltrials.gov/ct2/show/NCT03854318). The study seeks to better characterize the phenotype of FPD, establish the prevalence of progression to MDS/AML, and identify biomarkers of progression. A patient advocacy group (https://www.runx1-fpd.org) is available to explore research opportunities and to connect individuals with one another and with expert clinicians.

Treatment of hematologic malignancies – Treatment of hematologic malignancies should be based on the optimal therapy for that specific malignancy. We generally suggest allogeneic HCT because of the underlying propensity to hematologic complications and further malignancies. HCT donors who carry the mutation should not be utilized as stem cell donors due to a failure to engraft and because donor-derived leukemias have been reported [63].

Thrombocytopenia 2 (THC2; germline ANKRD26 mutations) — Thrombocytopenia 2 (THC2; OMIM 188000) (table 1) is an autosomal dominant disorder caused by ANKRD26 mutations, which presents with moderate thrombocytopenia (with or without a mild bleeding propensity), dysmegakaryopoiesis, and development of hematologic malignancies in adulthood.

Presentation – THC2 is an autosomal dominant disorder that typically presents with moderate thrombocytopenia with or without a mild bleeding propensity. Laboratory findings in 78 individuals from 21 affected families included an average platelet count of 48,000/microL (range 7 to 176,000/microL), normal platelet volume, pale platelets (due to decreased platelet alpha-granule content), decreased platelet surface glycoprotein Ia (GPIa), elevated thrombopoietin levels, and variable in vitro platelet aggregation defects [64]. Affected individuals with THC2 have an increased risk of developing MDS, AL, and chronic myeloid leukemia (CML), with onset typically between age 30 and 70 years [65].

Bone marrow morphology often shows evidence of dysmegakaryopoiesis with hypolobated micromegakaryocytes [64,66]. This morphology can be a diagnostic challenge for hematopathologists, as the unilineage dysplasia may be sufficient to warrant a diagnosis of MDS. However, dysmegakaryopoiesis alone without evidence of dysplasia in other lineages or additional acquired cytogenetic or molecular genetic changes diagnostic of MDS could be solely due to the underlying inherited ANKRD26 mutation.

Prevalence – The prevalence of this inherited disorder is not known. Screening of 215 individuals enrolled on an inherited thrombocytopenia registry identified THC2 in 23 cases (11 percent) [65]. Affected individuals were from several different countries of origin.

Genetics – THC2 is caused by inheritance of monoallelic pathogenic variants in ANKRD26 (chromosome band 10p12) [67]. Most are clustered in the 5' untranslated region (UTR) of the gene, but a missense mutation in exon 3 has been reported [64,68]. The 5' UTR mutations disrupt the ability of the RUNX1 and FLI1 transcription factors to downregulate ANKRD26 in megakaryocytes, causing excess MAPK signaling [69]. Interestingly, attenuating this signaling through the use of a MEK inhibitor reversed in vitro proplatelet formation defects in megakaryocytes derived from a patient with THC2 [69].

Testing – Clinical testing is available as a component of NGS testing at a limited number of academic centers and commercial laboratories in the United States. Affected patients and family members should be referred to a specialized center for diagnostic testing and management. (See 'Referral and counseling' above.)

Management – Thrombocytopenia and the mild bleeding tendency in individuals with THC2 should be managed as individuals with FPD with propensity to myeloid malignancies, described above. (See 'Familial platelet disorder with propensity to myeloid malignancies (FPD)' above.)

Treatment for hematologic malignancies is based on the optimal therapy for that specific malignancy. If allogeneic HCT will be pursued, potential donors who carry the ANKRD26 variant should be excluded.

Thrombocytopenia 5 (THC5; germline ETV6 mutations) — Thrombocytopenia 5 (THC5; OMIM 616216) (table 1) is an autosomal dominant syndrome caused by inheritance of monoallelic mutations of the ETV6 gene, and typically presents with moderate thrombocytopenia with or without a mild bleeding propensity, hypolobulated megakaryocytes, and is associated with hematologic and other malignancies.

Presentation – Patients with THC5 can present as early as infancy, with variable degrees of thrombocytopenia, normal-sized platelets, and a tendency to mild or moderate bleeding. Bone marrow examination reveals small hypolobulated megakaryocytes and mild dyserythropoiesis. MDS, AML, CMML, B lymphoblastic leukemia, multiple myeloma, and early onset colorectal cancer have been reported in a small number of affected individuals [70-72].

Prevalence – Neither the prevalence of the syndrome nor the frequency of development of an associated malignancy is well-defined. One study of 4405 cases of ALL in children found germline ETV6 variants in 0.8 percent. ALL in carriers of the germline mutation were diagnosed at an older age (10 versus 5 years) and more often had a hyperdiploid karyotype (64 versus 27 percent) [73].

Genetics – THC5 is an autosomal dominant syndrome caused by inheritance of monoallelic pathogenic variants of ETV6 (chromosome band 12p13). Germline ETV6 variants are usually missense mutations, but frameshift mutations have been identified. Mutations may disrupt nuclear localization or DNA binding of the ETV6 protein, resulting in reduced expression of platelet-associated genes [74].

Testing – NGS testing for ETV6 variants is available at certain academic institutions and commercial laboratories. Testing should include sequencing and testing for large deletions of the entire gene [75].

Management – Management for THC5-associated malignancies is based on the optimal therapy for that specific cancer. Monitoring of patients and testing and monitoring of family members should be performed by a specialized center. (See 'Referral and counseling' above.)

Syndromes featuring other organ system manifestations

Familial MDS/AML with mutated GATA2 — The syndrome of GATA2 mutations (OMIM 137295) (table 1) has a heterogeneous presentation and may be associated with MDS, AL, aplastic anemia, congenital neutropenia, or other hematologic abnormalities. It is among the more common inherited AL/MDS disorders, especially in children and young adults with MDS.

Presentation – Some individuals present without any hematopoietic or organ system manifestations prior to the development of MDS or AML, while others have distinctive syndromic presentations or phenotypes that overlap these syndromes [76-79].

Syndromic presentations:

-Emberger syndrome, which features primary lymphedema, sensorineural deafness, cutaneous warts, and a low CD4/CD8 T cell ratio along with MDS/AL predisposition [80].

-MonoMAC or DCML syndrome, in which affected individuals have dendritic cell, monocyte, and B/NK cell deficiencies, develop atypical mycobacterial or other infections, pulmonary alveolar proteinosis, and MDS/AL predisposition [81,82].

Other presentations:

-Hematologic parameters may be normal prior to the development of a hematologic malignancy, or they may reveal monocytopenia, lymphopenia (most commonly, B cells, but also NK and CD4 T cells), or less frequently neutropenia [76,78,83]. Cytopenias may progress over time in asymptomatic individuals [84]. MDS/AML develops in approximately 70 percent of affected individuals with a median age of onset of 29 years (range 0.4 to 78 years) and most often features a hypocellular bone marrow, dysplastic megakaryocytes, and increased reticulin fibrosis [78,85]. The karyotype is frequently abnormal, commonly with trisomy 8 or monosomy 7 [76-78,86]. Mutations of ASXL1 are frequently acquired at the time of malignant progression, being observed in 14 of 42 individuals (33 percent) with a germline GATA2 pathogenic variant and hematologic malignancy [87]. As in sporadic disease, pathogenic variants of ASXL1 portended a poor prognosis in carriers of germline GATA2 mutations [87,88].

In a series of 57 patients with germline GATA2 mutations who were identified through recruitment of subjects with primary immunodeficiency, inherited bone marrow failure, or atypical mycobacterial infections, the initial clinical presentation was ≤20 years (5 months to 78 years) and was most often due to infections (64 percent; viral [32 percent], disseminated mycobacterial [28 percent], invasive fungal [4 percent]) followed by MDS/AML (21 percent) and lymphedema (9 percent) [78]. The presence of symptoms was associated with adverse prognosis; only 67 percent survive 20 years after initial symptom onset [78,79]. (See "NK cell deficiency syndromes: Clinical manifestations and diagnosis", section on 'Autosomal dominant GATA2 deficiency' and "Mendelian susceptibility to mycobacterial diseases: Specific defects", section on 'GATA2 deficiency (MonoMAC syndrome)'.)

Prevalence – An international series identified germline GATA2 mutations in 7 percent of primary pediatric MDS [77]. Among small series of familial MDS/AML cases, GATA2 mutations were identified in 4 of 12 (33 percent) [76] and 4 of 27 (15 percent) [10] families. Among children and adolescents with primary MDS and monosomy 7, the prevalence of germline GATA2 mutations was 37 percent overall and varied with age (7 percent for those <6 years; 48 percent for age 6 to <12 years; 72 percent for age 12 to 19 years) [77]. Those with GATA2 mutation were more likely to present at an older age (median 12 versus 10 years), have advanced disease at the time of presentation (46 versus 18 percent), and have a positive family history (29 versus 2 percent). Signs and symptoms of Emberger syndrome or MonoMac syndrome were identified in half of the patients with GATA2 mutations, including deafness (9 percent), lymphedema/hydrocele (23 percent), and immunodeficiency (39 percent).

Genetics – These disorders are caused by monoallelic mutations in GATA2 (chromosome band 3q21.3) [76]. Missense mutations (predominantly in the second zinc finger domain), truncating frameshift or nonsense mutations, large genomic rearrangements, and mutations within a conserved enhancer element within intron 5 have been reported [78]. Synonymous mutations that affect gene splicing have also been identified [89].

Testing – Clinical genetic testing should include NGS of the full gene (including the conserved intron 5 enhancer region, which may not be included on all commercial laboratory tests that interrogate this gene) and testing for large rearrangements. If testing is being done due to MDS or aplastic anemia in a child with monosomy 7, testing for germline mutations in SAMD9/SAMD9L should be performed as well. (See 'Types of genetic testing' above.)

Management

Monitoring – Early identification of individuals with GATA2 deficiency allows screening for and management of any associated organ system manifestations. A multidisciplinary care team, including hematology, infectious disease, pulmonary, and vascular specialists, may be needed to manage multiple affected organ systems. Given the susceptibility to human papillomavirus (HPV)-related and atypical mycobacterial infections in these individuals, one group has recommended early HPV vaccination and azithromycin prophylaxis for all [78].

The high incidence of MDS/AML in this disorder warrants close monitoring. Peripheral blood should be regularly monitored for worsening immunodeficiency (based on monocyte count, lymphocyte subsets, and quantitative immunoglobulins) and changes suggestive of progression to MDS or AML. A baseline bone marrow examination with cytogenetic analysis is strongly recommended, and there should be a low threshold to repeat this if new blood count abnormalities develop.

Allogeneic HCT has been used to treat several manifestations of this disorder, including hematologic malignancies, recurrent severe infections, and pulmonary alveolar proteinosis [78,90] and is the subject of an ongoing clinical trial (NCT01861106). HLA-matched relatives who carry the germline pathogenic variant should be avoided. The optimal timing for allogeneic HCT should be individualized; specific conditioning regimens have been evaluated for individuals with GATA2 mutations [91]. Notably, infections and pulmonary abnormalities (eg, pulmonary hypertension, pulmonary alveolar proteinosis) resolved in some patients following transplantation.

Monosomy 7 and SAMD9/SAMD9L mutations — Together, inherited mutations of SAMD9 or SAMD9L are a common cause of MDS diagnosed in children, especially in pediatric bone marrow failure/MDS with monosomy 7 [4,92].

Presentation – Clinically, this syndrome may present as marrow failure, MDS alone, and/or a wide variety of somatic abnormalities. Homozygous deletions of SAMD9 result in normophosphatemic familial tumoral calcinosis (OMIM 610455) and deposition of calcified tumors, whereas heterozygous mutations (OMIM 617053) cause MIRAGE syndrome: adrenal hypoplasia, myelodysplasia with monosomy 7, growth retardation, genital phenotypes, and enteropathy [93]. Heterozygous mutations in SAMD9L (OMIM 159550, OMIM 611170) cause ataxia, pancytopenia, and monosomy 7 MDS [94].

Prevalence – Mutations of SAMD9 or SAMD9L are a common cause of MDS diagnosed in children, and they account for nearly 20 percent of pediatric cases of bone marrow failure/MDS with monosomy 7 [4,92].

GeneticsSAMD9 and SAMD9L result from a gene duplication event on chromosome band 7q21.2 [95,96]. Both normal proteins have an inhibitory effect on hematopoiesis. Germline mutations in children are gain-of-function mutations that confer additional growth-restriction; with time, the chromosome 7 that includes the mutated SAMD9/SAMD9L alleles may be lost, leading to monosomy 7 with retention of the wild-type allele. This corrects the growth inhibitory effect of the germline mutation, but it may contribute to progression to MDS. In other patients, additional truncating mutations of the variant SAMD9/SAMD9L alleles occur upstream from the germline mutation on the same allele or a genetic reversion event with uniparental disomy of the wild-type allele has been seen, with both of these causing in vivo correction of the bone marrow abnormalities.

Testing – The tissue that is tested for this syndrome should be non-hematopoietic. In genetic testing of MDS with monosomy 7, the germline variant is often lost with the missing copy of chromosome 7, while the normal wild-type chromosome 7 is retained; in such cases, the germline variant may be found at a lower than expected allelic ratio (ie, lower than the 40 to 60 percent expected for a germline variant) or not at all. In contrast to MDS cells, the expected variant allele frequencies would be found in cultured skin fibroblasts.

Management – Clinical management is best handled by a multidisciplinary team familiar with these syndromes because individuals with constitutional SAMD9/SAMD9L mutations typically have complex clinical presentations (eg, MIRAGE syndrome, ataxia pancytopenia). (See 'Referral and counseling' above.)

Familial aplastic anemia/MDS with SRP72 mutation — Familial aplastic anemia (AA)/MDS with SRP72 mutation (OMIM 602122) (table 1) is a rare, autosomal dominant cause of familial MDS.

Presentation – Only two pedigrees with this familial autosomal dominant AA/MDS disorder have been reported [97]. Pancytopenia was observed in childhood in affected individuals in one pedigree and MDS developed in adulthood in both families. None of the six affected individuals required treatment for the pancytopenia or MDS at the time of the initial report, despite reported disease duration of several years. Congenital nerve deafness was observed in affected individuals in one pedigree, but not the other.

Prevalence – Only two pedigrees have been reported [97].

Genetics – One family carried a frameshift truncating mutation and the other a missense mutation in SRP72, a gene whose protein product is a part of the signal recognition peptide complex that controls intracellular protein trafficking [97].

Testing – NGS testing is available as part of familial bone marrow failure and/or leukemia gene panels at some academic centers and commercial laboratories.

Management – Management is best handled by a specialized center. (See 'Referral and counseling' above.)

Myeloid neoplasms with germline predisposition (14q32 duplications) — Myeloid neoplasms with germline predisposition (14q32 duplications) is a rare disorder that may present with thrombocythemia and/or adult onset of a myeloproliferative neoplasm (MPN) or AML.

Presentation – The disorder has been reported in four families from the French West Indies, one from North America, and one from Australia [98-100]. Two-thirds of affected individuals initially presented with essential thrombocythemia, of whom half progressed to myelofibrosis or AML. MDS, including the refractory anemia with ring sideroblasts (RARS)-T subtype, CMML, CML, and atypical CML have also been reported in carriers of this genomic duplication.

The MPNs in these individuals exhibited acquired mutations that resemble those in sporadic MPNs (ie, 68 percent with JAK2 V617F, 18 percent with CALR mutations, and 9 percent with MPL mutations). Some AMLs had a complex karyotype and acquisition of somatic mutations accompanied progression to myelofibrosis or AML (TET2 in 38 percent, IDH2 in 19 percent, IDH1 in 10 percent, and ASXL1 in 5 percent).

Prevalence – The syndrome was reported in four families from the French West Indies, one from North America, and one from Australia [98-100].

Genetics – In the families from the French West Indies, germline duplication of a 700 kb region of 14q32.2 was associated with overexpression of ATG2B and GSKIP (which are located within the amplicon); in the Australian and North American families, duplications in the 14q32 region did not include ATG2B and GSKIP. TCL1A is the only gene shared in 14q32 duplications across all families (table 1) [98]. The penetrance of development of malignancy in these families is very high (estimated at >80 percent).

Testing – Clinical testing for duplication of 14q32 can be obtained at specialized commercial and academic laboratories. Diagnosis is best handled by a specialized center. (See 'Referral and counseling' above.)

Management – Management is best handled by a specialized center. (See 'Referral and counseling' above.)

Inherited bone marrow failure syndromes — Inherited bone marrow failure syndromes (IBMFS) include Fanconi anemia (FA); telomere syndromes (TS), such as dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), Shwachman-Diamond syndrome (SDS); and others. IBMFS are most often diagnosed in childhood due to early onset bone marrow failure or from work-up of the systemic manifestations (eg, limb anomalies in FA, pancreatic dysfunction in SDS); a hematologic malignancy is the first manifestation for a subset of patients [101].

Early diagnosis and syndrome-specific management are important to decrease morbidity, because patients with FA and TS are at increased risk of toxicity from standard chemotherapy regimens, especially in the transplant setting [102-104]. Clinical characteristics, pathophysiology, genetics, and management of the IBMFS, including the increased risk for toxicity with chemotherapy and transplantation, are discussed separately. (See "Clinical manifestations and diagnosis of Fanconi anemia" and "Shwachman-Diamond syndrome".)

These syndromes can have subtle presentations that delay the diagnosis until the patient presents with AL or MDS [101,105-110]. As examples:

Fanconi anemia – Approximately 40 percent of affected individuals lack physical anomalies and are also less likely to develop early onset bone marrow failure; 13 percent of patients with low congenital abnormality scores developed marrow failure by age 10 versus 84 percent with high congenital abnormality scores [111]. As a result, these individuals have a higher likelihood of developing a malignancy (eg, MDS, AML, other early onset solid tumors, especially squamous cell carcinomas). (See "Clinical manifestations and diagnosis of Fanconi anemia".)

Telomere syndromes – These syndromes are caused by abnormalities in the maintenance of telomeres. Familial clustering of hematologic disorders, including cytopenias, AA, MDS, or AML may be the first clinical manifestations in some pedigrees affected by DC or other short telomere syndromes. The classical presentation of DC features the diagnostic triad of oral leukoplakia, reticular skin pigmentation, and nail dystrophy, and is most often due to pathogenic variants of DKC1 (OMIM 127550) [112]. Other systemic manifestations include pulmonary fibrosis, early graying of the hair, liver fibrosis/cirrhosis, and early onset squamous cell carcinomas of the head and neck or anogenital regions [19,105,113].

Pathogenic variants in a subset of telomere associated genes, such as TERT (OMIM 613989 and 187270), TERC (OMIM 127550 and 602322), RTEL1 (OMIM 615190 and 608833), TINF2 (OMIM 613990 and 604319), and PARN (OMIM 616353 and 604212) can cause autosomal dominant TS with incomplete penetrance, disease heterogeneity within a single family, and may lack oral and integumentary findings [105,113]. When a family presents with a familial pattern of AL or MDS, or an individual with AA, MDS, or leukemia has a relative with unexplained (even subtle) cytopenias with or without macrocytosis, it is important to specifically inquire about a personal or family history of other manifestations of TS. Together, germline variants in telomere-associated genes are the second most frequent pathogenic variants that underlie familial MDS/AL; only DDX41 appears to be more common [114]. (See "Dyskeratosis congenita and other telomere biology disorders".)

Severe congenital neutropenia – Congenital neutropenia syndromes (eg, ELANE variants, Kostmann syndrome) occasionally present with AML and/or MDS as the initial clinical finding. (See "Congenital neutropenia", section on 'Severe congenital neutropenia'.)

MECOM-associated syndrome — MECOM-associated syndromes (OMIM 165215 and 616738) manifest a range of hematologic and systemic manifestations.

The phenotype of MECOM-associated syndromes can range from isolated radioulnar synostosis without hematopoietic defects to severe bone marrow failure with normal skeletal development. MECOM-associated syndrome was first described in the context of amegakaryocytic thrombocytopenia-2, but congenital variants in the MECOM/EVI1 complex on chromosome 3q26.2 have been associated with hematologic defects (eg, B cell deficiency, bone marrow failure, MDS) and various systemic manifestations (eg, radiosynostosis, clinodactyly, presenile hearing loss, cardiac/renal malformations) [115-120]. A range of genetic variants have been observed, including gene deletions and point mutations. The combination of radioulnar synostosis and B cell deficiency has been associated with mutations in the C-terminal zinc finger.

Familial ALL disorders

Presentations associated with familial ALL — Familial presentations of ALL are rare. Inherited pathogenic variants of ETV6, PAX5, and TP53 have been identified as the cause of a familial clustering of ALL without other hematologic or associated organ system manifestations. Other pathogenic variants (eg, SH2B3, IKZF1) are known to cause familial ALL in association with other hematologic, immune, or somatic abnormalities. Inherited ALL disorders are generally associated with B cell ALL. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children".)

Familial ALL, with or without thrombocytopenia or thrombocytopenia alone, has been reported in families with germline pathogenic variants of ETV6 [73]. (See 'Thrombocytopenia 5 (THC5; germline ETV6 mutations)' above.)

Familial ALL due to TP53 mutation — Li-Fraumeni syndrome (OMIM 151623) (table 1) is an inherited autosomal dominant disorder associated with germline variants of TP53 and a wide range of malignancies that appear at an early age and susceptibility to radiation-associated second malignancies. TP53 mutations account for rare familial leukemia cases. (See "Li-Fraumeni syndrome".)

Germline variants of TP53 (chromosome band 17p13) are most commonly associated with breast cancer, sarcomas, malignant brain tumors, and adrenal cortical carcinomas, which are considered the core tumors of Li-Fraumeni syndrome [121,122]. Leukemias were seen in only 5 percent of individuals with germline variants of TP53. A germline variant of TP53 was associated with an autosomal dominant pattern of inheritance of hematologic malignancies in a single pedigree, including three cases of pediatric ALL among a total of five cases of leukemia [123]. Detection of low hypodiploid ALL should prompt evaluation for a germline variant of TP53 [122]. Clinical genetic testing should include NGS of the complete gene and testing for large rearrangements.

Management of ALL in this setting should be informed by the clinical, pathologic, and molecular features of the leukemia. However, radiation therapy should be avoided unless it is required for cure, to prevent the risk of radiation-induced malignancies [124].

Familial B cell ALL due to PAX5 mutation — Germline variants in PAX5 (OMIM 615545) (table 1) (chromosome band 9p13) have been associated with B cell ALL, but no other hematologic or organ system manifestations were reported.

Germline variants in PAX5 segregated in an autosomal dominant inheritance pattern with development of B cell ALL in three separate pedigrees [125,126]. Despite widely different ethnic backgrounds, all carried the same pathogenic variant (c.547G>A; which results in substitution of a serine for a glycine at position 183 of the protein); chromosome 9p deletions with retention of the mutated PAX5 allele were present in leukemia cells from all individuals who developed ALL [125,126]. The disorder is variably expressed (incompletely penetrant), as each pedigree contains individuals who carry the pathogenic variant but have not yet developed ALL. NGS testing is available commercially by single gene sequencing or on hereditary leukemia NGS panels.

ALL in association with other abnormalities

SH2B3 – Homozygous germline pathogenic variants of SH2B3 (OMIM 605093) (table 1) were identified in two siblings who presented with developmental delay, autoimmunity, and chronic hepatitis; one patient developed precursor B cell ALL [127]. Clinical findings would be expected to follow an autosomal recessive pattern of inheritance. SH2B3 plays important roles in the regulation of lymphoid proliferation and hematopoietic stem cell homeostasis.

IKZF1 – Heterozygous variants in IKZF1 (IKAROS transcription factor, which has a critical role in hematopoiesis) were associated with B cell ALL in the setting of an autosomal dominant form of common variable immune deficiency (CVID) with age-associated loss of serum immunoglobulins and B cells [128].

Germline IKZF1 variants are associated with T cell, B cell, and myeloid immunodeficiency states and an increased risk of ALL (OMIM 613067 and 603023); the immunodeficiency may be subtle and remain undiagnosed until adulthood [129-134]. One study identified germline IKZF1 pathogenic variants in 0.9 percent of 4963 children with ALL; nearly all occurred in cases of B cell ALL, of which 8 of 21 had high hyperdiploidy. IKZF1 mutations have also been identified in sporadic cases of ALL; notably, BCR-ABL1 positive and CRLF2-rearranged ALL was observed in carriers of germline IKZF1 variants, which mirrors the association of acquired mutations in IKZF1 with BCR-ABL1 positive or Ph-like ALL [132]. (See "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma", section on 'Molecular features'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute myeloid leukemia" and "Society guideline links: Bone marrow failure syndromes".)

SUMMARY

Familial disorders of acute leukemia (AL) and myelodysplastic syndromes (MDS) may be associated with up to 30 to 50 percent of all cases of acute myeloid leukemia (AML)/MDS in children, 10 to 20 percent in young adults, and 5 to 10 percent in older adults. (See 'Epidemiology' above.)

Evaluation of patients with suspected AL/MDS – A familial disorder may be suspected in any child with MDS or when a child or an adult with AL or MDS has:

Positive findings from a screening history and physical examination. (See 'Screening history/exam' above.)

Certain laboratory or molecular/cytogenetic features of the AL/MDS. (See 'Suggestive molecular/cytogenetic findings' above.)

Evaluation of others – First-degree relatives of a patient with a diagnosed familial AL/MDS and potential related allogeneic transplant donors should be evaluated. (See 'Evaluation of others' above.)

Diagnostic genetic testing

Diagnostic genetic testing should be performed when there are positive findings from the screening evaluation or when certain molecular/cytogenetic features are detected in the AL/MDS cells (eg, biallelic mutation of CEBPA, mutation of DDX41 or GATA2, monosomy 7 in a child with AL or MDS). (See 'Who should be tested?' above.)

Diagnostic testing, which is available from some commercial laboratories and academic centers, is often best performed by a specialized center that has access to testing resources/techniques and has experience with interpreting and managing the findings. (See 'Who should perform genetic testing?' above.)

In most cases, genetic testing requires techniques that provide comprehensive sequencing as well as detection of large scale genomic rearrangements/deletions; exceptions are informed by the clinical setting and specific disorder. (See 'Types of genetic testing' above.)

Cultured skin fibroblasts are generally the preferred source for germline genetic testing, but other specimens may be acceptable in certain settings, as discussed above. (See 'Specimens for genetic testing' above.)

A decision to test for a single genetic abnormality (eg, a specific mutation has previously been detected in the individual or a relative) versus broader genetic testing (eg, a specific familial disorder and/or mutation has not previously been diagnosed) is discussed above. (See 'Testing strategies' above.)

Management

Referral to a cancer risk specialist (eg, cancer genetics clinic, medical geneticist, genetic counselor) may be useful for establishing/confirming the diagnosis and for genetic counseling of individuals who carry the mutation, whether or not a hematologic malignancy has been diagnosed. (See 'Referral and counseling' above.)

The schedule and nature of monitoring should be individualized, based on the underlying diagnosis; age; overall health status; associated hematologic abnormalities (eg, cytopenias or qualitative abnormalities), syndromic features, or organ dysfunction; hematologic or other malignancies; and preferences of the affected individual and caregiver(s). (See 'Monitoring' above.)

For a patient with AL or MDS associated with a familial disorder, management is guided by the type of malignancy (eg, AL, MDS) and associated clinical or laboratory abnormalities. Importantly, certain disorders require distinctive management because conventional care can be associated with excessive toxicity, unusual complications, and/or lack of efficacy (eg, inherited bone marrow failure syndromes, Li-Fraumeni syndrome). (See 'Treatment' above.)

Specific disorders – Familial AL/MDS disorders vary widely in prevalence, clinical manifestations (eg, associated malignancies and somatic abnormalities), molecular basis, pattern of transmission, penetrance, and age at presentation (table 1). Some disorders have no known clinical manifestations beyond AL/MDS, whereas other syndromes are associated with protean hematologic findings and/or abnormalities in other organ systems. Specific disorders are described in the sections above. (See 'Clinical features of inherited AL/MDS disorders' above.)

  1. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17:405.
  2. Rivera-Muñoz EA, Milko LV, Harrison SM, et al. ClinGen Variant Curation Expert Panel experiences and standardized processes for disease and gene-level specification of the ACMG/AMP guidelines for sequence variant interpretation. Hum Mutat 2018; 39:1614.
  3. Zhang J, Walsh MF, Wu G, et al. Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med 2015; 373:2336.
  4. Schwartz JR, Ma J, Lamprecht T, et al. The genomic landscape of pediatric myelodysplastic syndromes. Nat Commun 2017; 8:1557.
  5. Keel SB, Scott A, Sanchez-Bonilla M, et al. Genetic features of myelodysplastic syndrome and aplastic anemia in pediatric and young adult patients. Haematologica 2016; 101:1343.
  6. Feurstein S, Churpek JE, Walsh T, et al. Germline variants drive myelodysplastic syndrome in young adults. Leukemia 2021; 35:2439.
  7. Sébert M, Passet M, Raimbault A, et al. Germline DDX41 mutations define a significant entity within adult MDS/AML patients. Blood 2019; 134:1441.
  8. Bottomly D, Long N, Yang F, et al. Framework to Identify and Prioritize Candidate Inherited Myeloid Malignancy Germline Variants Leveraging the BEAT AML Cohort [Abstract]. Blood (ASH Annual Meeting Abstracts) 2019; 134:1407.
  9. Churpek JE, Pyrtel K, Kanchi KL, et al. Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia. Blood 2015; 126:2484.
  10. Holme H, Hossain U, Kirwan M, et al. Marked genetic heterogeneity in familial myelodysplasia/acute myeloid leukaemia. Br J Haematol 2012; 158:242.
  11. DiNardo CD, Bannon SA, Routbort M, et al. Evaluation of Patients and Families With Concern for Predispositions to Hematologic Malignancies Within the Hereditary Hematologic Malignancy Clinic (HHMC). Clin Lymphoma Myeloma Leuk 2016; 16:417.
  12. Cheah JJC, Hahn CN, Hiwase DK, et al. Myeloid neoplasms with germline DDX41 mutation. Int J Hematol 2017; 106:163.
  13. Churpek JE, Lorenz R, Nedumgottil S, et al. Proposal for the clinical detection and management of patients and their family members with familial myelodysplastic syndrome/acute leukemia predisposition syndromes. Leuk Lymphoma 2013; 54:28.
  14. Kraft IL, Godley LA. Identifying potential germline variants from sequencing hematopoietic malignancies. Blood 2020; 136:2498.
  15. Horwitz M, Goode EL, Jarvik GP. Anticipation in familial leukemia. Am J Hum Genet 1996; 59:990.
  16. Savage SA, Bertuch AA. The genetics and clinical manifestations of telomere biology disorders. Genet Med 2010; 12:753.
  17. Tegg EM, Thomson RJ, Stankovich JM, et al. Anticipation in familial hematologic malignancies. Blood 2011; 117:1308.
  18. Churpek JE, Nickels E, Marquez R, et al. Identifying familial myelodysplastic/acute leukemia predisposition syndromes through hematopoietic stem cell transplantation donors with thrombocytopenia. Blood 2012; 120:5247.
  19. Fogarty PF, Yamaguchi H, Wiestner A, et al. Late presentation of dyskeratosis congenita as apparently acquired aplastic anaemia due to mutations in telomerase RNA. Lancet 2003; 362:1628.
  20. Davidsson J, Puschmann A, Tedgård U, et al. SAMD9 and SAMD9L in inherited predisposition to ataxia, pancytopenia, and myeloid malignancies. Leukemia 2018; 32:1106.
  21. Wlodarski MW, Sahoo SS, Niemeyer CM. Monosomy 7 in Pediatric Myelodysplastic Syndromes. Hematol Oncol Clin North Am 2018; 32:729.
  22. Roloff GW, Godley LA, Drazer MW. Assessment of technical heterogeneity among diagnostic tests to detect germline risk variants for hematopoietic malignancies. Genet Med 2021; 23:211.
  23. Ewalt M, Galili NG, Mumtaz M, et al. DNMT3a mutations in high-risk myelodysplastic syndrome parallel those found in acute myeloid leukemia. Blood Cancer J 2011; 1:e9.
  24. Rasi S, Bruscaggin A, Rinaldi A, et al. Saliva is a reliable and practical source of germline DNA for genome-wide studies in chronic lymphocytic leukemia. Leuk Res 2011; 35:1419.
  25. Heinrichs S, Li C, Look AT. SNP array analysis in hematologic malignancies: avoiding false discoveries. Blood 2010; 115:4157.
  26. Ding L, Ley TJ, Larson DE, et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 2012; 481:506.
  27. Coombs CC, Zehir A, Devlin SM, et al. Therapy-Related Clonal Hematopoiesis in Patients with Non-hematologic Cancers Is Common and Associated with Adverse Clinical Outcomes. Cell Stem Cell 2017; 21:374.
  28. https://www.genetests.org/ (Accessed on September 23, 2014).
  29. Myers KC, Furutani E, Weller E, et al. Clinical features and outcomes of patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia: a multicentre, retrospective, cohort study. Lancet Haematol 2020; 7:e238.
  30. Owen C, Barnett M, Fitzgibbon J. Familial myelodysplasia and acute myeloid leukaemia--a review. Br J Haematol 2008; 140:123.
  31. Smith ML, Cavenagh JD, Lister TA, Fitzgibbon J. Mutation of CEBPA in familial acute myeloid leukemia. N Engl J Med 2004; 351:2403.
  32. Stelljes M, Corbacioglu A, Schlenk RF, et al. Allogeneic stem cell transplant to eliminate germline mutations in the gene for CCAAT-enhancer-binding protein α from hematopoietic cells in a family with AML. Leukemia 2011; 25:1209.
  33. Tawana K, Wang J, Renneville A, et al. Disease evolution and outcomes in familial AML with germline CEBPA mutations. Blood 2015; 126:1214.
  34. Pabst T, Eyholzer M, Fos J, Mueller BU. Heterogeneity within AML with CEBPA mutations; only CEBPA double mutations, but not single CEBPA mutations are associated with favourable prognosis. Br J Cancer 2009; 100:1343.
  35. Preudhomme C, Sagot C, Boissel N, et al. Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA). Blood 2002; 100:2717.
  36. Taskesen E, Bullinger L, Corbacioglu A, et al. Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity. Blood 2011; 117:2469.
  37. Pabst T, Eyholzer M, Haefliger S, et al. Somatic CEBPA mutations are a frequent second event in families with germline CEBPA mutations and familial acute myeloid leukemia. J Clin Oncol 2008; 26:5088.
  38. Green CL, Tawana K, Hills RK, et al. GATA2 mutations in sporadic and familial acute myeloid leukaemia patients with CEBPA mutations. Br J Haematol 2013; 161:701.
  39. Xiao H, Shi J, Luo Y, et al. First report of multiple CEBPA mutations contributing to donor origin of leukemia relapse after allogeneic hematopoietic stem cell transplantation. Blood 2011; 117:5257.
  40. Quesada AE, Routbort MJ, DiNardo CD, et al. DDX41 mutations in myeloid neoplasms are associated with male gender, TP53 mutations and high-risk disease. Am J Hematol 2019; 94:757.
  41. Polprasert C, Schulze I, Sekeres MA, et al. Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms. Cancer Cell 2015; 27:658.
  42. Lewinsohn M, Brown AL, Weinel LM, et al. Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies. Blood 2016; 127:1017.
  43. Zhang Z, Yuan B, Bao M, et al. The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells. Nat Immunol 2011; 12:959.
  44. Parvatiyar K, Zhang Z, Teles RM, et al. The helicase DDX41 recognizes the bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response. Nat Immunol 2012; 13:1155.
  45. Sanders MA, Chew E, Flensburg C, et al. MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML. Blood 2018; 132:1526.
  46. Noris P, Pecci A. Hereditary thrombocytopenias: a growing list of disorders. Hematology Am Soc Hematol Educ Program 2017; 2017:385.
  47. Downes K, Megy K, Duarte D, et al. Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders. Blood 2019; 134:2082.
  48. Owen CJ, Toze CL, Koochin A, et al. Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy. Blood 2008; 112:4639.
  49. Song WJ, Sullivan MG, Legare RD, et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet 1999; 23:166.
  50. Arepally G, Rebbeck TR, Song W, et al. Evidence for genetic homogeneity in a familial platelet disorder with predisposition to acute myelogenous leukemia (FPD/AML). Blood 1998; 92:2600.
  51. Béri-Dexheimer M, Latger-Cannard V, Philippe C, et al. Clinical phenotype of germline RUNX1 haploinsufficiency: from point mutations to large genomic deletions. Eur J Hum Genet 2008; 16:1014.
  52. Buijs A, Poddighe P, van Wijk R, et al. A novel CBFA2 single-nucleotide mutation in familial platelet disorder with propensity to develop myeloid malignancies. Blood 2001; 98:2856.
  53. Churpek JE, Garcia JS, Madzo J, et al. Identification and molecular characterization of a novel 3&#x2032; mutation in RUNX1 in a family with familial platelet disorder. Leuk Lymphoma 2010; 51:1931.
  54. Kirito K, Sakoe K, Shinoda D, et al. A novel RUNX1 mutation in familial platelet disorder with propensity to develop myeloid malignancies. Haematologica 2008; 93:155.
  55. Michaud J, Wu F, Osato M, et al. In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis. Blood 2002; 99:1364.
  56. Preudhomme C, Renneville A, Bourdon V, et al. High frequency of RUNX1 biallelic alteration in acute myeloid leukemia secondary to familial platelet disorder. Blood 2009; 113:5583.
  57. Cancer Genome Atlas Research Network, Ley TJ, Miller C, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013; 368:2059.
  58. Chen CY, Lin LI, Tang JL, et al. RUNX1 gene mutation in primary myelodysplastic syndrome--the mutation can be detected early at diagnosis or acquired during disease progression and is associated with poor outcome. Br J Haematol 2007; 139:405.
  59. Tang JL, Hou HA, Chen CY, et al. AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations. Blood 2009; 114:5352.
  60. Schnittger S, Dicker F, Kern W, et al. RUNX1 mutations are frequent in de novo AML with noncomplex karyotype and confer an unfavorable prognosis. Blood 2011; 117:2348.
  61. Nickels EM, Soodalter J, Churpek JE, Godley LA. Recognizing familial myeloid leukemia in adults. Ther Adv Hematol 2013; 4:254.
  62. Yoshimi A, Toya T, Kawazu M, et al. Recurrent CDC25C mutations drive malignant transformation in FPD/AML. Nat Commun 2014; 5:4770.
  63. Liew E, Owen C. Familial myelodysplastic syndromes: a review of the literature. Haematologica 2011; 96:1536.
  64. Noris P, Perrotta S, Seri M, et al. Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families. Blood 2011; 117:6673.
  65. Noris P, Favier R, Alessi MC, et al. ANKRD26-related thrombocytopenia and myeloid malignancies. Blood 2013; 122:1987.
  66. Marquez R, Hantel A, Lorenz R, et al. A new family with a germline ANKRD26 mutation and predisposition to myeloid malignancies. Leuk Lymphoma 2014; 55:2945.
  67. Pippucci T, Savoia A, Perrotta S, et al. Mutations in the 5' UTR of ANKRD26, the ankirin repeat domain 26 gene, cause an autosomal-dominant form of inherited thrombocytopenia, THC2. Am J Hum Genet 2011; 88:115.
  68. Al Daama SA, Housawi YH, Dridi W, et al. A missense mutation in ANKRD26 segregates with thrombocytopenia. Blood 2013; 122:461.
  69. Bluteau D, Balduini A, Balayn N, et al. Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation. J Clin Invest 2014; 124:580.
  70. Noetzli L, Lo RW, Lee-Sherick AB, et al. Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nat Genet 2015; 47:535.
  71. Zhang MY, Churpek JE, Keel SB, et al. Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy. Nat Genet 2015; 47:180.
  72. Topka S, Vijai J, Walsh MF, et al. Germline ETV6 Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia. PLoS Genet 2015; 11:e1005262.
  73. Moriyama T, Metzger ML, Wu G, et al. Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia: a systematic genetic study. Lancet Oncol 2015; 16:1659.
  74. Nishii R, Baskin-Doerfler R, Yang W, et al. Molecular basis of ETV6-mediated predisposition to childhood acute lymphoblastic leukemia. Blood 2021; 137:364.
  75. Rampersaud E, Ziegler DS, Iacobucci I, et al. Germline deletion of ETV6 in familial acute lymphoblastic leukemia. Blood Adv 2019; 3:1039.
  76. Hahn CN, Chong CE, Carmichael CL, et al. Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat Genet 2011; 43:1012.
  77. Wlodarski MW, Hirabayashi S, Pastor V, et al. Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. Blood 2016; 127:1387.
  78. Spinner MA, Sanchez LA, Hsu AP, et al. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood 2014; 123:809.
  79. Ishida H, Imai K, Honma K, et al. GATA-2 anomaly and clinical phenotype of a sporadic case of lymphedema, dendritic cell, monocyte, B- and NK-cell (DCML) deficiency, and myelodysplasia. Eur J Pediatr 2012; 171:1273.
  80. Ostergaard P, Simpson MA, Connell FC, et al. Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nat Genet 2011; 43:929.
  81. Dickinson RE, Griffin H, Bigley V, et al. Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency. Blood 2011; 118:2656.
  82. Hsu AP, Sampaio EP, Khan J, et al. Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood 2011; 118:2653.
  83. Pasquet M, Bellanné-Chantelot C, Tavitian S, et al. High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia. Blood 2013; 121:822.
  84. Dickinson RE, Milne P, Jardine L, et al. The evolution of cellular deficiency in GATA2 mutation. Blood 2014; 123:863.
  85. Micol JB, Abdel-Wahab O. Collaborating constitutive and somatic genetic events in myeloid malignancies: ASXL1 mutations in patients with germline GATA2 mutations. Haematologica 2014; 99:201.
  86. Fisher KE, Hsu AP, Williams CL, et al. Somatic mutations in children with GATA2-associated myelodysplastic syndrome who lack other features of GATA2 deficiency. Blood Adv 2017; 1:443.
  87. West RR, Hsu AP, Holland SM, et al. Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation. Haematologica 2014; 99:276.
  88. Bödör C, Renneville A, Smith M, et al. Germ-line GATA2 p.THR354MET mutation in familial myelodysplastic syndrome with acquired monosomy 7 and ASXL1 mutation demonstrating rapid onset and poor survival. Haematologica 2012; 97:890.
  89. Wehr C, Grotius K, Casadei S, et al. A novel disease-causing synonymous exonic mutation in GATA2 affecting RNA splicing. Blood 2018; 132:1211.
  90. Cuellar-Rodriguez J, Gea-Banacloche J, Freeman AF, et al. Successful allogeneic hematopoietic stem cell transplantation for GATA2 deficiency. Blood 2011; 118:3715.
  91. Parta M, Shah NN, Baird K, et al. Allogeneic Hematopoietic Stem Cell Transplantation for GATA2 Deficiency Using a Busulfan-Based Regimen. Biol Blood Marrow Transplant 2018; 24:1250.
  92. Bluteau O, Sebert M, Leblanc T, et al. A landscape of germ line mutations in a cohort of inherited bone marrow failure patients. Blood 2018; 131:717.
  93. Narumi S, Amano N, Ishii T, et al. SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7. Nat Genet 2016; 48:792.
  94. Chen DH, Below JE, Shimamura A, et al. Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L. Am J Hum Genet 2016; 98:1146.
  95. Thomas ME 3rd, Abdelhamed S, Hiltenbrand R, et al. Pediatric MDS and bone marrow failure-associated germline mutations in SAMD9 and SAMD9L impair multiple pathways in primary hematopoietic cells. Leukemia 2021; 35:3232.
  96. Yoshida M, Tanase-Nakao K, Shima H, et al. Prevalence of germline GATA2 and SAMD9/9L variants in paediatric haematological disorders with monosomy 7. Br J Haematol 2020; 191:835.
  97. Kirwan M, Walne AJ, Plagnol V, et al. Exome sequencing identifies autosomal-dominant SRP72 mutations associated with familial aplasia and myelodysplasia. Am J Hum Genet 2012; 90:888.
  98. Saliba J, Saint-Martin C, Di Stefano A, et al. Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies. Nat Genet 2015; 47:1131.
  99. Babushok DV, Stanley NL, Morrissette JJD, et al. Germline duplication of ATG2B and GSKIP genes is not required for the familial myeloid malignancy syndrome associated with the duplication of chromosome 14q32. Leukemia 2018; 32:2720.
  100. Hahn CN, Wee A, Babic M, et al. Duplication on Chromosome 14q Identified in Familial Predisposition to Myeloid Malignancies and Myeloproliferative Neoplasms [Abstract]. Blood (ASH Annual Meeting Abstracts) 2017; 130:492.
  101. Shimamura A, Alter BP. Pathophysiology and management of inherited bone marrow failure syndromes. Blood Rev 2010; 24:101.
  102. Dietz AC, Orchard PJ, Baker KS, et al. Disease-specific hematopoietic cell transplantation: nonmyeloablative conditioning regimen for dyskeratosis congenita. Bone Marrow Transplant 2011; 46:98.
  103. Nishio N, Takahashi Y, Ohashi H, et al. Reduced-intensity conditioning for alternative donor hematopoietic stem cell transplantation in patients with dyskeratosis congenita. Pediatr Transplant 2011; 15:161.
  104. Ayas M, Nassar A, Hamidieh AA, et al. Reduced intensity conditioning is effective for hematopoietic SCT in dyskeratosis congenita-related BM failure. Bone Marrow Transplant 2013; 48:1168.
  105. Dokal I, Vulliamy T. Inherited bone marrow failure syndromes. Haematologica 2010; 95:1236.
  106. Alter BP, Giri N, Savage SA, et al. Malignancies and survival patterns in the National Cancer Institute inherited bone marrow failure syndromes cohort study. Br J Haematol 2010; 150:179.
  107. Dror Y, Donadieu J, Koglmeier J, et al. Draft consensus guidelines for diagnosis and treatment of Shwachman-Diamond syndrome. Ann N Y Acad Sci 2011; 1242:40.
  108. Kutler DI, Singh B, Satagopan J, et al. A 20-year perspective on the International Fanconi Anemia Registry (IFAR). Blood 2003; 101:1249.
  109. Rosenberg PS, Greene MH, Alter BP. Cancer incidence in persons with Fanconi anemia. Blood 2003; 101:822.
  110. Savage SA, Dokal I, Armanios M, et al. Dyskeratosis congenita: the first NIH clinical research workshop. Pediatr Blood Cancer 2009; 53:520.
  111. Rosenberg PS, Alter BP, Ebell W. Cancer risks in Fanconi anemia: findings from the German Fanconi Anemia Registry. Haematologica 2008; 93:511.
  112. Heiss NS, Knight SW, Vulliamy TJ, et al. X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat Genet 1998; 19:32.
  113. Ballew BJ, Savage SA. Updates on the biology and management of dyskeratosis congenita and related telomere biology disorders. Expert Rev Hematol 2013; 6:327.
  114. Feurstein S, Adegunsoye A, Mojsilovic D, et al. Telomere biology disorder prevalence and phenotypes in adults with familial hematologic and/or pulmonary presentations. Blood Adv 2020; 4:4873.
  115. Nielsen M, Vermont CL, Aten E, et al. Deletion of the 3q26 region including the EVI1 and MDS1 genes in a neonate with congenital thrombocytopenia and subsequent aplastic anaemia. J Med Genet 2012; 49:598.
  116. Niihori T, Ouchi-Uchiyama M, Sasahara Y, et al. Mutations in MECOM, Encoding Oncoprotein EVI1, Cause Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia. Am J Hum Genet 2015; 97:848.
  117. Bouman A, Knegt L, Gröschel S, et al. Congenital thrombocytopenia in a neonate with an interstitial microdeletion of 3q26.2q26.31. Am J Med Genet A 2016; 170A:504.
  118. Lord SV, Jimenez JE, Kroeger ZA, et al. A MECOM variant in an African American child with radioulnar synostosis and thrombocytopenia. Clin Dysmorphol 2018; 27:9.
  119. Ripperger T, Hofmann W, Koch JC, et al. MDS1 and EVI1 complex locus (MECOM): a novel candidate gene for hereditary hematological malignancies. Haematologica 2018; 103:e55.
  120. Germeshausen M, Ancliff P, Estrada J, et al. MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia. Blood Adv 2018; 2:586.
  121. Gonzalez KD, Noltner KA, Buzin CH, et al. Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol 2009; 27:1250.
  122. Comeaux EQ, Mullighan CG. TP53 Mutations in Hypodiploid Acute Lymphoblastic Leukemia. Cold Spring Harb Perspect Med 2017; 7.
  123. Powell BC, Jiang L, Muzny DM, et al. Identification of TP53 as an acute lymphocytic leukemia susceptibility gene through exome sequencing. Pediatr Blood Cancer 2013; 60:E1.
  124. Heymann S, Delaloge S, Rahal A, et al. Radio-induced malignancies after breast cancer postoperative radiotherapy in patients with Li-Fraumeni syndrome. Radiat Oncol 2010; 5:104.
  125. Auer F, Rüschendorf F, Gombert M, et al. Inherited susceptibility to pre B-ALL caused by germline transmission of PAX5 c.547G>A. Leukemia 2014; 28:1136.
  126. Shah S, Schrader KA, Waanders E, et al. A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia. Nat Genet 2013; 45:1226.
  127. Perez-Garcia A, Ambesi-Impiombato A, Hadler M, et al. Genetic loss of SH2B3 in acute lymphoblastic leukemia. Blood 2013; 122:2425.
  128. Kuehn HS, Boisson B, Cunningham-Rundles C, et al. Loss of B Cells in Patients with Heterozygous Mutations in IKAROS. N Engl J Med 2016; 374:1032.
  129. Hoshino A, Okada S, Yoshida K, et al. Abnormal hematopoiesis and autoimmunity in human subjects with germline IKZF1 mutations. J Allergy Clin Immunol 2017; 140:223.
  130. Yoshida N, Sakaguchi H, Muramatsu H, et al. Germline IKAROS mutation associated with primary immunodeficiency that progressed to T-cell acute lymphoblastic leukemia. Leukemia 2017; 31:1221.
  131. Lopes BA, Barbosa TC, Souza BKS, et al. IKZF1 Gene in Childhood B-cell Precursor Acute Lymphoblastic Leukemia: Interplay between Genetic Susceptibility and Somatic Abnormalities. Cancer Prev Res (Phila) 2017; 10:738.
  132. Churchman ML, Qian M, Te Kronnie G, et al. Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia. Cancer Cell 2018; 33:937.
  133. Germline IKZF1 Variants Predispose Children to Developing B-ALL. Cancer Discov 2018; 8:675.
  134. Boutboul D, Kuehn HS, Van de Wyngaert Z, et al. Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency. J Clin Invest 2018; 128:3071.
Topic 93183 Version 20.0

References

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