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Myeloid Neoplasm With Germline Predisposition: A 2016 Update for Pathologists.

Myeloid neoplasms present primarily as sporadic diseases. Familial occurrence of myeloid neoplasms has been reported in rare pedigrees. Investigations of these pedigrees have led to identification of certain inheritable genetic mutations that predispose affected individuals to the development of myeloid neoplasm. However, approximately half of the pedigrees still lack the specific inheritable mutations, which implies that there are undiscovered genes causing diseases in these families. The diagnosis of myeloid neoplasm with genetic predisposition is difficult for a variety of reasons. First of all, the disease presentations are often heterogeneous, from overt acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) to chronic thrombocytopenia or manifestations involving other organs. Secondly, molecular testing is not widely available. Approximately half of the affected families may have gene mutations yet to be discovered. With the increasing awareness of the myeloid neoplasms with inherited genetic predisposition and growing use of next-generation sequencing, we may be able to diagnose these cases based on clinical presentation and genetic data. The diagnosis of myeloid neoplasm with genetic predisposition dictates a different approach for clinical management; therefore, these neoplasms are classified as new provisional diagnostic entities in the latest 2016 update of the World Health Organization classification of hematopoietic neoplasms. (1) In this short review, we will focus on the specific entities of this new category in the 2016 World Health Organization update and discuss the clinical and pathologic features that will help pathologists identify these rare disorders.


This category includes AML with germline CEBPA mutation and myeloid neoplasms with germline DDX41 mutation.

AML With Germline CEBPA Mutation

The CCAAT enhancer binding protein a (CEBPA) gene encodes a protein that belongs to the basic region leucine zipper family of transcription factors. The CEBPA protein contains 2 transactivation domains, TAD1 and TAD2; a basic region mediating DNA binding; and a leucine zipper region (Zip) for dimerization. CEBPA mutations are generally clustered into 2 regions. The N-terminal frameshift or nonsense mutations cause the truncation of the wild-type 42-kDa protein, leading to a mutated 30-kDa isoform that lacks the first transactivation domain (TAD1). The Cterminal in-frame insertions or deletions disrupt the basic zipper region, affecting DNA binding and dimerization.

CEBPA mutation can occur as an acquired somatic mutation in sporadic AML or as a germline mutation that is inherited across multiple generations of affected family and present in all the cells of the affected individual. Families with germline CEBPA mutations are rare and have been reported in only about 20 pedigrees. (2-13) Studies of large series of normal-karyotype AML have reported a frequency of CEBPA mutation of 8% to 13% (4,8,14); among these, 7% to 11% have germline CEBPA mutations. (4,8) The majority of the AML patients have 2 CEBPA mutations with both N-terminal frameshift mutation and C-terminal inframe mutation on different alleles. Families with germline CEBPA mutation inherit an N-terminal frameshift or nonsense mutation that predisposes to acquiring a somatic C-terminal CEBPA mutation on the other allele. (4,11)

Clinical features and family history can provide useful clues in identifying patients with germline CEBPA mutations, which are inherited in an autosomal dominant fashion and are highly penetrant. The age of onset for AML with germline CEBPA mutations is younger than that for sporadic AML. Recent clinical data from 10 affected families reported a median age for the diagnosis of AML of 24.5 years (range, 1.75-46 years). (11) In contrast, the median age at diagnosis for sporadic AML is 65 years. Morphologically, AML with mutated CEBPA often presents as AML with minimal differentiation or AML without maturation associated with normal karyotype (Figure 1, A). The blasts may show frequent Auer rods and express aberrant CD7 by flow cytometry (Figure 1, A through D). Acute myeloid leukemia patients with CEBPA mutations have a favorable clinical outcome, but recent data indicate the favorable outcome is limited to those with double mutations. (15-17) Concurrent FLT3 ITD, NPM1, or GATA2 mutations have also been reported and may indicate the heterogeneity in CEBPA-mutated AML. (8,14,18) Interestingly, individuals with germline CEBPA mutation-associated AML may recur with a different somatic CEBPA mutation, whereas in sporadic AML the CEBPA mutation appears stable throughout the disease course. (19,20) Although the recurrence is triggered by independent clones, the patients can still achieve a durable response to therapy and favorable long-term outcome. (11) Evaluation of CEBPA mutation is required for any new AML with normal karyotype, as the 2016 World Health Organization classification recognizes AML with biallelic CEBPA mutation as a distinct entity of AML with recurrent genetic abnormalities. (1) Clinical testing for the CEBPA gene is available either as a single gene assay or as part of gene panels. Because of the variations in the mutations, sequencing the entire CEBPA gene is recommended. If familial inheritance is suspected, additional testing for germline variant is recommended, which will be discussed later.

Myeloid Neoplasms With Germline DDX41 Mutation

DEAD-box helicase 41 (DDX41) is one of the most recently described genes that confers inherited susceptibility to myeloid neoplasm. DDX41 is located on chromosome 5q, and encodes an ATP-dependent RNA helicase involved in many aspects of RNA metabolism, such as maintaining RNA secondary structure, pre-mRNA splicing, and RNA processing. DDX41 mutation can occur as somatic mutations in sporadic AML/MDS or as a germline defect with additional acquired somatic mutations, often in a biallelic pattern. The frequency of germline DDX41 mutation is difficult to determine but may be underestimated. A recent study screened 1045 myeloid neoplasms and identified DDX41 mutation in 27 cases (2.6%), about half of which were germline mutations. (21) Lewinsohn et al (22) screened 289 families with suspected inherited hematologic malignancies and identified 9 families (3%) with heterozygous germline DDX41 mutations.

The vast majority of germline mutations occur as an Nterminal frameshift c.415_418dupGATG (p.D140Gfs*2), but other rare germline frameshift mutations or missense variants have also been reported. (21,23) The frameshift or missense mutations cause truncation or alternative translation of the protein, leading to a loss of its function. Similar to AML with biallelic CEBPA mutations, the presence of DDX41 germline mutation predisposes acquisition of additional DDX41 somatic mutation on the other allele. Detection of biallelic DDX41 mutations is strongly supportive of a predisposing germline DDX41 variant. The most common acquired somatic mutation is DDX41 c.G1574A (p.R525H), which occurs in a highly conserved C-terminal motif affecting ATP-binding site. The p.R525H mutation has also previously been reported at the time of progression to MDS or AML. (22) The p.R164W mutation is associated with a predisposition to lymphoproliferative neoplasms, particularly follicular lymphoma. (22) Deletion of the long arm of chromosome 5 involving the DDX41 locus may be functionally equivalent to the loss-of-function mutations, but is usually present in sporadic cases not associated with germline DDX41 mutations. (21) DDX41 germline mutation is considered as a founder mutation, with other additional mutations such as TP53 and RUNX1. (21)

For patients harboring the germline DDX41 mutation, there is increased risk of developing myeloid neoplasms, including MDS, AML, and chronic myeloid leukemia. In contrast to other myeloid neoplasms with germline predisposition, patients with DDX41 germline mutation have long latency to develop myeloid neoplasm, with a mean age at diagnosis of 62 years, which is similar to that of patients with sporadic AML/MDS. (22) Individuals with germline DDX41 mutation-associated myeloid neoplasm lack distinct clinical features; even the family history may not be apparent because of the late onset of the disease in affected individuals. Therefore, it is particularly difficult to identify individuals carrying this germline mutation. Patients with germline DDX41 mutations typically develop myeloid neoplasm with normal karyotype, including AML of erythroid lineage or high-grade MDS with erythroid dysplasia. The majority of carriers have normal peripheral blood counts prior to developing hematologic malignancies. In some cases, cytopenias or macrocytosis may be seen shortly before hematologic disease. Lewinsohn et al (22) reported 3 of their 9 families with DDX41 germline mutations had granulomatous immune disorder, raising the possibility of DDX41 functions in immune response and their potential link to the lymphoid malignancy in affected pedigrees.

Myeloid Neoplasms With Germline Predisposition and Preexisting Platelet Disorders

This group includes myeloid neoplasms with germline RUNX1, ANKRD26, and ETV6 mutations.

Myeloid Neoplasms With Germline RUNX1 Mutation

Runt-related transcription factor 1 (RUNX1) is located on chromosome 21q22 and encodes a subunit of the corebinding factor complex. A variety of RUNX1 mutations have been described, including frameshift or nonsense mutations or deletion throughout the gene as well as missense point mutations clustering within the highly conserved RUNT homology domain (RHD) and transactivation domain (TAD). RUNX1 mutations are frequent in myeloid neoplasm and have been reported in 10% to 33% of de novo AML and MDS. (24-27) However, the prevalence of germline RUNX1 mutation is unknown; there are fewer than 70 pedigrees reported in the literature. (28) Germline RUNX1 mutations generally cluster to the N-terminal region, resulting in disruption of DNA binding, and are less frequent in the C-terminal region, which maintains DNA binding but lacks the functional transactivation domain. Rare cases reporting intragenic deletion of RUNX1 gene or duplication of the chromosome 21 carrying the RUNX1 -deleted or mutated allele may have similar phenotype. (29-31) A recent study indicated that familial platelet disorder should be suspected in AML cases with a RUNX1 biallelic mutation or with a single RUNX1 mutation with a variant allele frequency more than 50%, which could indicate trisomy 21 with a duplication of the mutated chromosome or loss of heterozygosity. (32)

RUNX1 germline mutation is reported in families with platelet disorder that was previously called familial platelet disorder with propensity to myeloid malignancies. These patients are characterized by lifelong history of mild to moderate thrombocytopenia, mild bleeding tendency, and an increased lifetime risk of developing MDS or AML. The familial platelet disorder is inherited in an autosomal dominant fashion. There is also mild platelet aggregation defect with collagen and epinephrine, similar to abnormalities caused by aspirin. Therefore, in case of surgery, bleeding can be out of proportion for the platelet count because of impaired platelet function. However, neither the complete blood cell count nor the platelet function test would be a sensitive screening test to identify patients with germline RUNX1 mutation. Carriers of germline RUNX1 mutations have an increased lifetime risk (35%-40%) of developing MDS or acute leukemia, with an average age at diagnosis of 33 years (range, 6-76 years). (33,34) However, there is clinical heterogeneity in the degree of platelet disorder as well as the varying risks of developing MDS and AML manifested with a large range of prevalence of myeloid malignancy among affected families. (34) In addition to myeloid neoplasm, development of T-lymphoblastic leukemia/lymphoma has also been reported in the context of familial platelet disorder with RUNXl mutation. (31,33,35) Acute myeloid leukemia secondary to familial platelet disorder has a high frequency of biallelic alteration in the RUNXl gene, indicating acquisition of additional genetic events involving the other nonmutated RUNXl cooperative genes during progression to AML. (32,33,36) There is no clear association of RUNXl mutational status with morphologic subtype of AML. Cytogenetic analyses have reported trisomy 21, monosomy 5, and 5q deletion in AML in the context of familial platelet disorder. (31,33) Given the small number of pedigrees reported in the literature and the heterogeneity of the genetic and clinical features, there are very limited data regarding the prognosis and outcome of AML developed in the context of familial platelet disorder with RUNXl germline mutation.

Myeloid Neoplasms With Germline ANKD26 Mutation

Ankyrin repeat domain 26 (ANKD26)-related thrombocytopenia is a rare inherited form of autosomal dominant thrombocytopenia. ANKRD26 mutations are identified in 23 of 215 individuals (11%) in the inherited thrombocytopenia registry. (37) Patients with ANKD26-related thrombocytopenia, previously called thrombocytopenia 2, are characterized by moderate thrombocytopenia with normal platelet size, no or very mild spontaneous bleeding, and predisposition to developing myeloid neoplasm. An analysis of 78 affected individuals from 21 families with ANKRD26 mutations reported isolated thrombocytopenia with a mean platelet count of 48 000/[micro]L and normal hemoglobin and leukocyte counts. (38) The platelets had normal size, which differentiated this group of patients from those with other forms of inherited thrombocytopenias. (37,38) Platelets may appear pale because of reduced platelet granule contents. Electronic microscopy has demonstrated borderline low mean dense granules per platelet, decreased [alpha] granules, and an increased canalicular network pattern in most of the affected individuals. (39) No consistent in vitro platelet aggregation abnormalities to collagen, ADP, or ristocetin stimulation are observed. Bone marrow biopsies show increased reticulin fibrosis and increased numbers of dysplastic megakaryocytes, including micromegakaryocytes and/or hypolobated megakaryocytes. (37,38,40) The presence of megakaryocytic dysplasia may pose a diagnostic challenge to differentiation of thrombocytopenia in the setting of germline ANKRD26 mutation versus MDS.

Mutations are heterozygous single-nucleotide substitutions clustered in a highly conserved sequence within the 50 untranslated region of ANKRD26, which is the binding site for RUNX1 and friend leukemia integration 1 transcription factor (FLI1). (41,42) Accumulating evidence indicates that the 50 untranslated region mutations cause ANKRD26 overexpression because of defective inhibitory regulation of RUNX1 and FLI1, and this leads to disruption of the thrombopoietin/myeloproliferative leukemia virus oncogene pathway, which is important for platelet formation by megakaryocytes. (41,43) Mutations in the ANKRD26 coding region are less common but also induce ANKRD26 overexpression through a mechanism independent of RUNX1/FLI1 interaction. (43)

The incidence of myeloid neoplasm in ANKD26 related individuals is higher, with an estimated 24-fold increased risk for developing AML compared with the general population. (37) In a study of 118 subjects affected by ANKD26 mutation, 10 (8.4%) developed myeloid neoplasm, including 4 AML, 4 MdS, and 2 chronic myeloid leukemia. (37) Therefore, recognition of this insidious form of inherited thrombocytopenia and its associated risk for myeloid neoplasm is important, as these cases may be inappropriately managed as idiopathic thrombocytopenia purpura and treated with steroids or splenectomy.

Myeloid Neoplasms With Germline ETV6 Mutation

ETV6-related thrombocytopenia is another autosomal dominant familial thrombocytopenia, previously referred to as thrombocytopenia 5. The ETV6 gene is located on the short arm of chromosome 12 and consists of 3 functional domains: an N-terminal pointed domain, which is involved in protein-protein interactions; a central regulatory domain, which promotes DNA binding; and a C-terminal DNAbinding domain. ETV6 mutations are mostly clustered in the DNA-binding and central domains, which abrogates the ETV6 nuclear localization and results in reduced expression of ETV6 and other platelet-associated genes. (44,45)

Germline ETV6 mutations have recently been reported as a rare form of inherited thrombocytopenia with predisposition to hematologic malignancy. (44,46-48) Melazzini et al (45) screened 130 families with inherited thrombocytopenia of unknown etiology and identified ETV6 mutations in 7 pedigrees (5%). The affected individuals have variable degrees of thrombocytopenia and mild to moderate bleeding tendencies, some with erythroid macrocytosis but no anemia. Bone marrow biopsies reveal small, hypolobulated megakaryocytes and mild dyserythropoesis. (44) There is no consistent defect in platelet aggregation or activation; platelet spreading appears reduced on fibrinogen but not on collagen and von Willebrand factor. (45) Similar to RUNX1-and AKND26-affected pedigrees, ETV6-related thrombocytopenia is also characterized by normal-sized platelets, (44,45) but electric microscopy shows occasional elongated platelet a granules in affected individuals. (44) There is no unique clinical or pathological feature that could raise the suspicion of germline ETV6-related thrombocytopenia, although there are studies (44,45) suggesting macrocytosis is present in 22% (4 of 18) to 45% (10 of 22) of the patients. However, it was also noted that macrocytosis was not consistent in the same patient and may have limited utility as a clue to this condition. (44,45) Individuals carrying germline ETV6 mutations have increased risks for hematologic malignancies, including AML, MDS, B-lymphoblastic leukemia, chronic myelomonocytic leukemia, and plasma cell myeloma. (44-48) Given the increasing awareness of germline mutations with predisposition to hematologic malignancies, it is recommended that patients with autosomal dominant familial thrombocytopenia and normal platelet size be tested for mutations in ETV6, RUNX1, and ANKRD26.


This category includes myeloid neoplasms with germline GATA2 mutation, bone marrow failure syndromes, telomere biology disorders, Down syndrome or juvenile myelomonocytic leukemia associated with neurofibromatosis, and Noonan syndrome or Noonan syndrome-like disorders. We will focus on the first 3 entities in more detail.

Myeloid Neoplasms With Germline GATA2 Mutation

GATA2 is a transcription factor that binds to specific DNA motifs through 2 zinc finger domains and regulates gene expression. The germline GATA2 mutations are often truncating mutations, resulting in the loss of second zinc finger domain (ZF2), or missense mutations in ZF2 or the noncoding regulatory region, resulting in haplo-insufficiency of GATA2. (49-52) Germline GATA2 mutation is associated with a broad spectrum of phenotypes, encompassing hematologic disease such as AML and MDS; infection characterized by viral, mycobacterial, and fungal infection; immunodeficiency with monocytopenia; B- and NK-cell lymphocytopenia; skin conditions with warts and panniculitis; pulmonary disorder; and vascular/lymphatic dysfunction. (52,53) These features can be variably present and provide clinical clues, but may also be absent. GATA2 mutation can be seen in sporadic AML with normal cytogenetics and biallelic CEBPA mutations, in which the GATA2 mutation is considered as an acquired mutation. (54,55) More recently, GATA2 mutation has been identified as one of the germline mutations that confer predisposition to myeloid neoplasm. Germline testing is recommended in patients with any deleterious GATA2 mutation. The overall frequency of germline GATA2 mutation is not well studied. Wlodarski et al (56) recently studied 508 children and adolescents from the European Working Group of MDS in Childhood and reported that germline GATA2 mutations were present in 28 of 426 primary MDS cases (7%) and in 13 of 85 (15%) with advanced disease. Myeloid neoplasms with germline GATA2 mutations demonstrate clinical heterogeneity. Spinner et al (52) studied a large series of 57 patients with GATA2 deficiency and reported 50% were asymptomatic by age 20 years, 25% by age 30 years, and 16% by age 40 years. The median age for newly diagnosed AML/MDS associated with germline GATA2 mutation is younger than that for sporadic cases, but the age onset could be variable even among affected family members. The affected individual may or may not have precedent hematologic disorder. Cases described in the literature have different morphologic subtypes (Figure 2, A and B) and variable cytogenetic abnormalities, including monosomy 7, trisomy 8, and trisomy 21. (49,56) Acquired somatic ASXL1 mutation was reported present in 14 of 48 patients with GATA2 mutations (29%) and was associated with transformation to proliferative chronic myelomonocytic leukemia. (57) In adult AML, cases with germline GATA2 mutations appear to be more aggressive and warrant early allogeneic stem cell transplant. However, in children and adolescents, GATA2 mutational status does not appear to negatively affect the outcome of MDS. The decision of transplant should be guided by the known risk factors of the disease, such as cytogenetic evolution and severity of cytopenias. (56)

Myeloid Neoplasm Associated With Inherited Bone Marrow Failure Syndromes and Telomere Biology Disorders

Inherited bone marrow failure syndromes are a group of diseases characterized by cytopenia with associated genetic alterations and increased risks for cancers. These entities include dyskeratosis congenita, Diamond-Blackfan anemia, Fanconi anemia, Shwachman-Diamond syndrome, and severe congenital neutropenia. The risk for developing MDS and/or AML is significantly increased in the setting of bone marrow failure syndromes. Figure 3, A through D, is an example of a case of MDS with excess blasts arising in the setting of Fanconi anemia. Identifying these individuals is important, as additional genetic counseling and testing may be offered, and unique considerations, such as stem cell transplant, may be given in clinical practice. Individuals with inherited bone marrow failure syndromes are often diagnosed in adolescence or young adulthood. Occasionally, a definitive diagnosis may be delayed to adulthood. These disorders are often diagnosed based on clinical features of developmental abnormalities. For example, Fanconi anemia is associated with congenital limb anomalies such as short stature, microphthalmia, bone deformities, skin hyperpigmentation, and other organ anomalies. Dyskeratosis congenita is characterized by the mucocutaneous triad of abnormal skin pigmentation, nail dystrophy, and mucosal leukoplakia, and by very short telomeres. A detailed description of the molecular and clinical features of this broad category of bone marrow failure syndrome is beyond the scope of this review. Many genes impairing the DNA repair signaling pathway have been discovered associated with Fanconi anemia. Several genes responsible for dyskeratosis congenita have been identified, including mutations associated with telomere disorders such as telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC). However, the molecular mechanism of increased risks of developing myeloid neoplasm in patients with inherited bone marrow failure syndromes remains elusive. Genetic testing for relevant genes is becoming available for patients with clinical suspicion of bone marrow failure syndrome.

Mutations in telomerase complex result in abnormal telomere maintenance and are reported to have increased risks for MDS/AML. Telomere disorders with germline TERC and TERT mutations have an autosomal dominant inheritance pattern with variable clinical presentations. The TERT and TERC mutation carriers may present with essentially normal complete blood cell count with only subtle abnormalities, such as elevated mean corpuscular volume or thrombocytopenia, before developing bone marrow failure. (58,59) Some patients may have idiopathic pulmonary fibrosis or liver fibrosis. (58,59) The co-occurrence of aplastic anemia and idiopathic pulmonary fibrosis is considered quite predictive for germline telomerase gene mutation. (60) Bone marrow biopsy may show moderately increased reticulin fibrosis, notable myeloid dysplasia, and megakaryocytic lineages characterized by predominantly small, hypolobated, dysplastic-appearing forms. (40) The affected families may have anticipation with progressive shortening of the telomeres in passing generations and show worsening phenotype. (58) In addition to predisposition to MDS/AML, the telomere disorders may be associated with a variety of solid tumors, including squamous cell carcinoma and stomach, lung, esophageal, and colon cancers. (61)


Recognizing individuals or families with germline predisposition to myeloid neoplasm has significant clinical importance. So far, there is no consensus on screening germline mutations in newly diagnosed AML and MDS in clinical practice; however, guidelines and algorithms have been proposed to screen and identify patients with germline predisposition. It is crucial to start from a complete evaluation of patients' personal and family history of cancer and systemic symptoms. The clinical symptoms of these entities are diverse and rapidly expanding (Table 1). It is important to maintain a high suspicion index in clinical practice to allow further genetic counseling. Germline testing is recommended in families with 2 or more cases of MDS/AML or unexplained cytopenias, or in individuals or families with MDS/AML with specific organ-system manifestations associated with germline predisposition. (62) With the increasing use of next-generation sequencing in newly diagnosed myeloid neoplasm, pathologists may first identify mutations associated with both the sporadic and inherited forms of myeloid neoplasm. Clinicians should be informed of the potential inherited genetic predisposition. Additional testing on germline tissue should be obtained for clarification. Germline analysis is imperative in any newly diagnosed myeloid neoplasm with biallelic CEBPA, a deleterious GATA2 mutation, or a deleterious RUNX1 mutation. (62) Indications for prompt genetic counseling and germline analysis in any newly diagnosed myeloid neoplasm are summarized in Table 2.

Gene panel-based genetic testing is most cost-effective in identifying most of the causative genes in myeloid neoplasm with germline predisposition, and is becoming available in a few medical centers. The presence of a germline variant is confirmed by identifying the heterozygous status of genes of interest in nonhematopoietic tissue or in multiple generations of the affected families. Molecular testing performed on blood or bone marrow during active AML is not helpful in determine the germline mutational status. Molecular testing on uninvolved tissue such as skin biopsy, buccal swab/saliva, or cultured mesenchymal cells is required. Caution is advised that the uninvolved tissue may contain hematopoietic cells, such as lymphocytes carrying the somatic mutations. Testing of blood or bone marrow during complete remission from AML may also be used to detect germline variants, as residual leukemic cells are negligible in these samples. Typically, for patients carrying germline mutations, the current recommendation is to have a baseline bone marrow biopsy with cytogenetic analysis, followed by complete blood cell count and clinical examinations at regular intervals. (63) Hematopoietic stem cell transplantation is a treatment option often offered to AML patients. When patients carrying germline mutation develop AML or MDS, unrelated-donor allogeneic stem cell transplant is recommended. If an allogeneic stem cell transplant is considered among family members, proper genetic testing should be performed.

Myeloid neoplasm with germline predisposition is a rapidly evolving area, with an increasing number of genes identified and more being discovered. It is important for pathologists to be familiar with the common entities and maintain awareness in approaching patients with clinical, morphologic, and molecular features suspicious for these entities. A more systemic laboratory approach in the diagnosis and screening of these germline predisposition syndromes is needed and may transform the way we view and manage these patients and families.


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Juehua Gao, MD, PhD; Shunyou Gong, MD, PhD; Yi-Hua Chen, MD

Accepted for publication July 18, 2017.

Published online January 26, 2018.

From the Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Juehua Gao, MD, PhD, Department of Pathology, Northwestern University Feinberg School of Medicine, 251 E Huron St, Feinberg 7-209A, Chicago, IL 60611 (email:

Caption: Figure 1. An example of acute myeloid leukemia with biallelic CEBPA mutations. A, Bone marrow aspirate smears reveal increased blasts with frequent Auer rods. B, Bone marrow core biopsy contains hypercellular bone marrow replaced by sheets of blasts. C, Next-generation sequencing identified the presence of both N-terminal frameshift mutation (CEBPA c.68_78delCGCACGCGCCC, p.Pro23fs; variant allele fraction 47%) and Cterminal in-frame deletion (CEBPA c.914_916delAGC, p.Gln305del; variant allele fraction 32%) D, Flow cytometric analysis reveals blasts with aberrant CD7 expression (Wright-Giemsa, original magnification X1000 [A]; hematoxylin-eosin, original magnification X600 [B]).

Caption: Figure 2. An example of acute myeloid leukemia in a patient with germline GATA2 mutation (GATA2 c.1123C>T, p.L375V) (courtesy Katherine Calvo, MD, National Institutes of Health). A, Bone marrow aspirate smear shows numerous blasts with folded nuclei and moderate amount of cytoplasm. Flow cytometry analysis indicates the blasts are CD34~, CD117~, CD13~, CD33+, CD14~, CD64+, CD56+, HLA-DR+, and CD123+, consistent with monoblasts. B, Bone marrow core is replaced by sheet of blasts with folded nuclei and dispersed chromatin (Wright-Giemsa, original magnification X1000 [A]; hematoxylin-eosin, original magnification X600 [B]).

Caption: Figure 3. An example of myelodysplastic syndrome with excess blasts (MDS, RAEB2) arising in the setting of Fanconi anemia with biallelic mutations in FANCA. A, Peripheral blood smear reveals pancytopenia. B, Bone marrow aspirate smears show increased blasts (inset arrow) and dysplastic megakaryocytes with hypolobated nuclei or separate nuclear lobes. C, Bone marrow core biopsy is hypercellular with increased blasts. D, A CD34 immunohistochemical stain confirms increased number of blasts, comprising ~10% of the bone marrow cellularity (Wright-Giemsa, original magnifications X600 [A] and X1000 [B and B inset]; hematoxylin-eosin, original magnification X400 [C]; peroxidase, original magnification X400 [D]).
Table 1. World Health Organization Classification of
Myeloid Neoplasms With Germline Predisposition

       Category            Causative Genes        Pattern of

Myeloid neoplasms with germline predisposition
without a preexisting disorder or organ dysfunction

  AML with germline     CEBPA (2)                AD
  CEBPA mutation

  Myeloid neoplasms     DDX41 (21,23)            AD
  with germline DDX41

Myeloid neoplasms with germline predisposition
and preexisting platelet disorders

  Myeloid neoplasms     RUNX1 (31,33)            AD
  with germline RUNX1

  Myeloid neoplasms     ANKRD26 (37,38,42)       AD
  with germline
  ANKRD26 mutation

  Myeloid neoplasms     ETV6 (47,48)             AD
  with germline ETV6

Myeloid neoplasms with germline predisposition
and other organ dysfunction

  Myeloid neoplasms     GATA2 (49,50)            AD
  with germline
  GATA2 mutation

Myeloid neoplasm associated with inherited bone
marrow failure syndromes and telomere biology

  Fanconi anemia        FANCA, FANCC, FANCG,     AR, XL
                        FANC1/BRCA2 (64,65)

  Dyskeratosis          DKC1, (66) NOP10,        XL, AR, AD
  congenita             NPH2, TCAB1, C16orf57,
                        RTEL1, (67,68) TERC,
                        TERT, TINF2 (69)

  Telomere biology      TERT, TERC (70)          AD, AR (TERT)

       Category                Germline Genetic Alterations

Myeloid neoplasms with germline predisposition
without a preexisting disorder or organ dysfunction

  AML with germline     N-terminal frameshift or
  CEBPA mutation        nonsense mutation

  Myeloid neoplasms     Majority p.D140Gfs*2
  with germline DDX41

Myeloid neoplasms with germline predisposition
and preexisting platelet disorders

  Myeloid neoplasms     Frameshift, nonsense mutations, or
  with germline RUNX1   deletion cluster to RUNX1 N-terminal
  mutation              region and less frequently C-terminal

  Myeloid neoplasms     Single-nucleotide substitutions in 5'
  with germline         untranslated region
  ANKRD26 mutation

  Myeloid neoplasms     Frameshift, missense, and nonsense
  with germline ETV6    mutations in the DNA-binding and central
  mutation              domains

Myeloid neoplasms with germline predisposition
and other organ dysfunction

  Myeloid neoplasms     Truncating or missense
  with germline         mutations in second zinc finger domain,
  GATA2 mutation        or mutations in the noncoding regulatory

Myeloid neoplasm associated with inherited bone
marrow failure syndromes and telomere biology

  Fanconi anemia        Null mutations as results of frameshift,
                        stop codon, and large deletions;altered
                        protein mutations as results of missense,
                        in-frame deletions, or C-terminus
                        truncation mutations

  Dyskeratosis          Large and small deletions, insertions,
  congenita             and missense mutations throughout the
                        coding regions

  Telomere biology      Large and small deletions, insertions,
  disorder              and missense mutations throughout the
                        coding regions

Abbreviations: AD, autosomal dominant;AML, acute myeloid
syndrome; NK, natural killer; XL, X linked.

Table 1. Extended

Acquired Genetic         Clinical Features      Pathologic Features
Alterations During

Somatic C-terminal     AML with double         AML M1 or M2
CEBPA mutation on      CEBPA mutations         morphology;aberrant
the other allele       is associated with      CD7 expression;normal
                       good prognosis          karyotype; CEBPA
                                               biallelic mutation

p.R525H                Long latency, with      Normal-karyotype AML
                       disease onset in        often erythroleukemia
                       older adults similar    or high-grade MDS
                       to sporadic MDS/AML

A second somatic       History of              Thrombocytopenia with
RUNX1 mutation,        thrombocytopenia of     normal platelet
deletion or            variable degree with    size;aspirin-like
chromosome 21          or without bleeding     platelet dysfunction
aberration             tendency, development
                       of acute leukemia in
                       the context of
                       familial platelet

Unknown                Moderate                Thrombocytopenia with
                       thrombocytopenia, no    normal platelet
                       or very mild            size;
                       spontaneous bleeding    dysmegakaryopoiesis

Unknown                Variable degree of      Thrombocytopenia with
                       thrombocytopenia,       normal platelet
                       bleeding tendencies,    size; megakaryocytic
                       some with erythroid     dysplasia; increased
                       macrocytosis but no     bone marrow reticulin
                       anemia                  fibrosis

Somatic ASXL1          Neutropenia,            Different morphologic
mutation in 29%        monocytopenia, B/NK/    subtypes and variable
of patients with       dendritic cell          cytogenetic
germline GATA2         deficiencies,           abnormalities,
mutation (57)          atypical infections,    including monosomy 7,
                       lymphedema              trisomy 8, and
                                               trisomy 21

Unknown;biallelic      Progressive bone        AML/MDS is often
mutations may have     marrow failure during   preceded by a
increased risks        childhood, congenital   hypoplastic/aplastic
                       abnormalities,          phase; chromosomal
                       increased risk for      breakage analysis or
                       AML/MDS, solid tumors   molecular genetic
                       arise in adulthood      testing for relevant
                                               genes if clinical
                                               features are

Unknown                Nail dystrophy,         Telomere length
                       abnormal skin           testing and molecular
                       pigmentation, oral      genetic testing for
                       leukoplakia,            relevant genes if
                       pulmonary fibrosis,     clinical features are
                       bone marrow failure     suspicious

Unknown                Bone marrow failure,    Increased bone marrow
                       predisposition to       reticulin fibrosis,
                       AML/MDS, and a          dysplasia in myeloid
                       variety of solid        and megakaryocytic
                       tumors                  lineages

Table 2. Indications to Prompt Genetic Counseling
and Germline Testing

Family history

  Family history of myeloid neoplasm
  Early onset of hematologic malignancy
  Multiple close relatives with cancer

Personal history

  History of bleeding episodes or preexisting platelet
  Lymphedema/monocytopenia/atypical infection
  Skin pigmentation/nail abnormalities
  Leukopenia/pulmonary fibrosis
  Bone marrow failure syndrome

Somatic mutations detected in myeloid neoplasm

  Biallelic CEBPA
  Deleterious GATA2 mutation
  Deleterious RUNX1 mutation
  Frameshift DDX41 mutation
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Author:Gao, Juehua; Gong, Shunyou; Chen, Yi-Hua
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Report
Date:Jan 1, 2019
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