Diagnosis -- MDS with Unilineage Dysplasia

FINAL DIAGNOSIS

MDS with unilineage dysplasia

Preceded by congenital thrombocytopenia and constitutional chromosome 21q22/RUNX1 deletion.

Although the etiology is similar to familial platelet disorder with propensity to myeloid malignancy, it is hard to classify this case as familial or inherited since there is no family history of MDS/AML or platelet dysfunction. Instead, this case is better characterized as a sporadic case of germline RUNX1 deletion.

Mild monocytosis and mild macrocytic anemia were seen on peripheral blood examination.

Bone marrow examination showed a cellular marrow with trilineage hematopoiesis. Prominent megakaryocytic dysplasia was noted. The megakaryocytes were abnormally small with decreased nuclear lobation. Other hematopoietic lineages did not show significant dyspoiesis. Blast percentage was high normal, as noted on manual differential count (4.7%).

Flow cytometric analysis of bone marrow aspirate showed moderate numbers of polytypic B-cells and heterogenous T-cells, a few NK cells and hematogones (that represented about 8% of the total analyzed cells). Many granulocytes and a few monocytes were also identified. The immature cells (CD45-dim/low SSC) included CD34 positive blasts that lacked myeloid antigen expression and likely represented early CD34+ hematogones (about 3% of the total cells); and CD117 positive early myeloid progenitors/blasts which comprised about 1% of the total analyzed cells. No immunophenotypically aberrant myeloid or monocytic populations were identified.

DISCUSSION

Myeloid neoplasms with germline predisposition are a recently recognized category in the 2017 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. These include:

• Myeloid neoplasms with germline predisposition without a pre-existing disorder or organ dysfunction
• Myeloid neoplasms with germline predisposition and pre-existing platelet disorders
• Myeloid neoplasms with germline predisposition associated with other organ dysfunction
• Myeloid neoplasms with germline predisposition associated with inherited bone marrow failure syndromes and telomere biology disorders

Of these, germline RUNX1 mutations/deletions are included in the category of myeloid neoplasms with pre-existing platelet disorders. Other germline mutations implicated in similar syndromes include ANKRD26 and ETV6. These disorders may also be referred to as familial platelet disorders with predisposition to AML.

RUNX1 spans 261 kb on chromosome band 21q22. It encodes 3 major isoforms in temporal and tissue specific patterns. The larger isoforms contain two major functional protein domains. The Runt-homology domain (RHD) acts as both a DNA binding domain and CBFB interaction domain. The transactivation domain (TAD) interacts with co-activator or co-repressor proteins to activate or suppress the transcription of target genes. Thus, RUNX1 forms a heterodimeric transcription factor by binding to core binding factor beta (CBFB) protein and is required for normal hematopoiesis.

Clinical presentation of patients with RUNX1 abnormalities is variable and is influenced by the type of mutation or deletion effecting the gene. Patients may present (as in our case) with bleeding tendency early in life. Platelet counts may be normal or mildly reduced. Platelet morphology is classically described as normal. Concurrent platelet dysfunction may occur in the form of dense granule storage pool defect or impaired platelet aggregation with collagen and epinephrine.

A second hit mutation is thought to lead to development of a hematopoietic neoplasm at a young age in patients with germline RUNX1 abnormalities. The most commonly reported neoplasms include MDS and AML. The median age for development of MDS/AML in cases with RUNX1 gene defects is 33 years. Like some other genetic disorders, familial platelet disorder with RUNX1 mutations may show the phenomenon of anticipation. Anticipation refers to progressively earlier presentation of a genetic disease with each succeeding generation. Hence, patients should be closely followed from a young age. The typical morphology of AML occurring in conjunction with this syndrome has been described as AML with or without maturation. Auer rods are often seen. Other neoplasms which may occur include CMML, T-ALL and in rare cases, B-cell neoplasms.

REFERENCES

1. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC. Lyon, France: 2017.
2. Almazni I, Chudakou P, Dawson-Meadows A, et al. A novel RUNX1 exon 3 - 7 deletion causing a familial platelet disorder. Platelets 2021: 1369-1635.
3. Chisholm KM, Denton C, Keel S, et al. Bone Marrow Morphology Associated with Germline RUNX1 Mutations in Patients with Familial Platelet Disorder with Associated Myeloid Malignancy. Pediatric and Developmental Pathology. 2019;22(4):315-328.
4. Sood R, Kamikubo Y, Liu P. Role of RUNX1 in hematological malignancies. Blood 2017;129(15):2070-2082.

Contributed by Shikha Malhotra, MD, Grant Bullock, MD, Svetlana Yatsenko, MD, Melanie Babcock, MD, Marie DeFrances, MD, PhD, and Eric Carlsen, MD