mds arising in a 13- year-old with runx1 · 2020-04-15 · karen m. chisholm, md, phd. department...
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![Page 1: MDS arising in a 13- year-old with RUNX1 · 2020-04-15 · Karen M. Chisholm, MD, PhD. Department of Laboratories, Seattle Children’s Hospital, Seattle, WA. Case SH2017-0039. MDS](https://reader033.vdocuments.net/reader033/viewer/2022050608/5fafbd1dc6b8717c74584cca/html5/thumbnails/1.jpg)
Karen M. Chisholm, MD, PhD
Department of Laboratories, Seattle Children’s Hospital, Seattle, WA
Case SH2017-0039MDS arising in a 13-year-old with RUNX1familial platelet disorder
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• 13 year old boy– Age 11
• Thrombocytopenia (68 K/µL) in the setting of a chronic idiopathic elevation of CK and myopathy of unclear etiology
• CBC also showed neutropenia without anemia– Thrombocytopenia could be tracked back to
the newborn period (29-90 K/µL)– No history of excessive bleeding– Adopted at 4 months of age (no available
family history)
Clinical History
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• Bone marrow aspirates and biopsies at ages 11 and 12– Mildly hypocellular marrow with
megakaryocytic hypoplasia and dysplasia– Cytogenetics at age 11:
46,XY,?del(13)(q14q22)[2]/46,XY[18]– Cytogenetics at age 12:
46,XY,?del(13)(q14q21)[1]/46,XY[21]– FISH at both time points did not identify any
abnormalities at 13q
Clinical History, continued
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Bone marrow aspirate at age 11
Small megakaryocytes with hypolobated nuclei
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Bone marrow aspirate at age 11
Small megakaryocytes with hypolobated nuclei, high nuclear-to-cytoplasmic ratios, and/or separate nuclear lobes
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Bone marrow aspirate at age 12
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• Presented at age 13 for annual routine bone marrow surveillance biopsy
• CBC– WBC 3.1 K/µL
• ANC 899 /µL– Platelets 65 K/µL– Hemoglobin 12.4 g/dL
Clinical History, continued
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Smaller megakaryocytes with eccentric hypolobated nuclei and/or separate nuclear lobes
Bone marrow aspirate at age 13
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Bone marrow biopsy at age 13
Normocellular to mildly hypocellular marrow
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Bone marrow aspirate at age 14
Smaller megakaryocytes with eccentric hypolobated nuclei, high nuclear-to-cytoplasmic ratios, and/or separate nuclear lobes Pelger-Huet-like neutrophils
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Bone marrow biopsy at age 14
Mildly hypocellular marrow
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Bone marrow aspirate at age 15
Megakaryocytes with separate nuclear lobes and/or small size
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Bone marrow biopsy at age 15
Hypocellular marrow
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Flow cytometry at ages 13, 14, and 15
• No increase in blasts• No abnormal populations
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Cytogenetics at ages 13, 14, and 15
46,XY,del(5)(q21q3?1)[4]/46,XY[16]
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FISH
Red = EGR1 (5q31.2)Green = D5630/D5S2064
(5p15.31)
Age 14 – del(5q) = 8%Age 15 – del(5q) = 14%
FISH negative for monosomy 7/del(7q), trisomy 8, del(20q)
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• Normal breakage studies of blood and fibroblasts to rule out Fanconi anemia
• Mildly abnormal telomere length analysis but not consistent with dyskeratosis congenita
• Normal Fragile X testing• Normal comparative genomic hybridization
(CGH) microarray• No pathogenic GATA2 mutations• No SBDS mutations (Shwachman-Diamond)
Molecular findings
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• RUNX1 sequencing performed after the bone marrow at age 14– STOP mutation at Y189 (c.567C>G)
Molecular findings
RHD = Runt Homology Domain - heterodimerizes with CBFβ to mediate DNA binding
TAD = transcriptional activation domain
1 77 204 269 438 480
RHD TADN C
RUNX1c isoform
Y189X
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Myelodysplastic syndrome with multilineage dysplasia with germline RUNX1 mutation
Final Panel Diagnosis
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• Underwent mismatched unrelated double cord blood transplant 4 months after last bone marrow (3.5 months after the identification of the RUNX1 mutation)
• Now 3 years from transplant and doing well
Clinical Management
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Thank you!
Final Panel Diagnosis: Myelodysplastic syndrome with
multilineage dysplasia with germline RUNX1 mutation