Case Presentation. Pei Lin, M. D.

Transcription

1 Case Presentation Pei Lin, M. D.

2 History A 26 yr man reports a history of numerous skin and upper respiratory infections as a child, including lymphadenitis and meningitis. In March 2013 during a preoperative evaluation to debride MRSA of the right shoulder, CBC showed WBC 2.2 k/ul and platelet count 120K/uL. In June 5, 2013, seen for gingivitis and sinusitis WBC 1.84 k/ul, Hgb 12.5 g/dl, Platelet count 165.

3 History He was referred to a local hematologist BM biopsy showed hypocellular marrow, moderate myeloid hypoplasia and some dysmegakaryopoesis, no increased blasts. After a possible diagnosis of myelodysplasia was made, the patient did not go for further evaluations due to lack of medical insurance.

4 History & PE Hydroceletomy surgery right testis, 2012 Genital warts Migraine 2006 Meningitis 2015 Arthralgia, back pain and joint swelling Mother: Rheumatoid arthritis, lupus, Sister: Psoriasis, father: None

5 PB (2017) WBC 1.3K/uL ( ) Hgb 11.5gm/dL ( ) Platelet 184K/uL ( ) Neutrophil 52.0% Lymphocyte 44.8% Monocyte 2.4% Eosinophil 0.8% Neutrophil Abs 0.65K/uL L ( ) Lymphocyte Abs 0.56K/uL L ( ) Monocyte Abs 0.03K/uL L ( ) Eosinophil

6 Bone Marrow osteoclast-like megs CD61

7 BMA

8 SSC-A CD123 APC-A HLA-DR CD34 PerCP-Cy5-5-A SSC-A CD123 APC-A HLA-DR FITC-A CD34 PerCP-Cy5-5-A The patient % Blast 01= 1.41% 1.45% % 97.30% 0.98% % % % % CD34 PerCP-Cy5-5-A 0.82% % HLA-DR FITC-A pdc 18.38% % HLADR= CD10 PE-Cy7-A Normal control 10 5 Hematogones 74.23% 24.43% % 10 5 MFI= CD117 PE-A 67.41% % CD34 PerCP-Cy5-5-A % HLA-DR FITC-A 79.97% HLADR= CD MFI= CD117 PE-A

9 SSC-A SSC-A Our Patient 63 year old woman Mono= 4.7% Mono= 0.6% CD64 PE-A CD64 PE-A

10 SSC LAM PE-A The Patient CD19 gate= 1.7% CD KAP FITC-A

11 CD56 PE-A CD57 FITC-A SSC-A CD3 PE-Cy7-A CD3 PE-Cy7-A 54.98% 45.02% 48.34% 51.66% % % CD3= 30.0% % CD4 PerCP-Cy5-5-A 14.74% 3.83% CD8 APC-A CD3 PE-Cy7-A 3.87% 10 5 NK cells CD3 PE-Cy7-A CD8 APC-A

12 Ancillary tests Karyotype: 46,XY FISH: trisomy 8 in 6% of analyzed cells Negative for -7/7q, del5q or 17p

13 The most likely diagnosis is A: Aplastic anemia B: Severe congenital neutropenia C: Primary immune deficiency associated cytopenia D: Myelodysplastic syndrome E: Familial MDS (myeloid neoplasms with germline predisposition)

14 VAF: 49%

15 Diagnosis Myelodysplastic syndrome with multilineage dysplatia associated with GATA2 mutation (GATA2 deficiency)

16 What s next What test should be done next? Skin fibroblasts to test for germline GATA2 mutation Bucal swap to test for germline GATA2 mutation Screen family members for GATA2 mutation, and possible SCT donor Search for matched unrelated SCT donor

17 Skin Punch biopsy p.arg396trp (CGG>TGG): c.1186 C>T in exon 6 of the GATA2 gene Missense mutation

18 Diagnosis Myelodysplastic syndrome with multilineage dysplatia associated with germline GATA2 mutation (GATA2 deficiency) SCT planned for December 2018

19 GATA2 is essential for Hematopoiesis Transcription Factor on 3q21 GATA2 is expressed in hematopoietic and nonhematopoietic embryonic stem cells bind the DNA sequence (A/T)GATA(A/G) through two zinc finger (ZnF) domains Crit Rev Oncol Hematol Apr;82(1):1-17.

20 2011

21 PAP: Pulmonary alveolar proteinosis NTM: non-tb type mycobacterial infection MonoMAC syndrome Modified from Hsu AP, et al. GATA2 deficiency. Curr Opin Allergy Clin Immunol Feb;15(1):104-9.

22 GATA2 mutations Null Regulator Missense Credit: NIAID

23 Mechanisms Deletions, missense, nonsense, frameshift, splice site changes Most occur in the 2 zinc fingers, leading to a nonfunctional protein unable to bind DNA or other TF partners. Intronic regulatory elements (intron 5 enhancer lead to reduced transcription of the cis allele)

24 Clinical features of GATA2 deficiency Stroke and Thrombosis Infection HPV EBV MAC Lymphedema, Hearing loss (Emberger syndrome) Pulmonary alveolar proteinosis Autoimmune hepatitis Rheumatologic symptoms: erythema nodosum, panniculitis, or arthralgias Miscarriage/preterm labor Autism Cytopenia (MDS/AML) Modified from Michael A. Spinner et al. Blood 2014;123:

25 Clinical, pathologic, and Imaging of GATA2 deficiency. mycobacteria infection PAP alveolar space with lipoproteinaceous Panniculitis/EN Brain infarct EBV+ spindle cell lesion Michael A. Spinner et al. Blood 2014;123:

26 GATA2 deficiency in Pediatric MDS Associated with -7 (41% ), trisomy 8 (15%), and trisomy 1q. GATA2 deficiency accounts for 7% of primary pediatric MDS and 15% of children with advanced MDS In pediatric patients with MDS and -7, 37% have germline GATA2 mutations In adolescents with MDS and -7, 72% have germline GATA2 mutations GATA2 deficiency likely the most common underlying genetic defect predisposing to pediatric MDS.

27 Associated mutations Myeloid neoplasms (MNs) of any type eventually develop in up to 75% of patients (MDS, AML, CMML, rarely ALL) Average age of onset for MNs is 12 to 35 years old, median: 19.7 year SETBP1, ASXL1, STAG2, RUNX1, CBL, EZH2, NRAS, JAK3, and PTPN11 CMML with ASXL1

28 Key features Typical onset in early adulthood, variable presentation Cytopenias of monocytes, B cells, and NK cells, Unusual infection: disseminated non-tuberculous mycobacterial (NTM) and other opportunistic infections (HPV) A high risk of developing MDS and AML Poor survival once MDS/AML arises Allogeneic stem cell transplantation (allo-sct)

29 Diagnostic Clues Peripheral blood Dendritic cell, NK, B-Cell cytopenia Monocytopenia Neutropenia Bone marrow Hypocellular for age Megakaryocytic atypia/dysplasia Flow cytometry: absence or very few monocytes, B-cell precursors, B-cells, dendritic cells, NK-cells; inverted CD4:CD8 ratios

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31 Types of inherited cytopenia Type Genetics Mechanism Fanconi anemia AR DNA repair Dykeratosis congenita XL, AD, AR Telomere maintenance Shhwachman-Diamond syndrome Diamond-Blackfan anemia Congenital dyserythropietic anemia AR AD, or XL in GATA1 related AR (I and II, AD (IIIand IV) Risosomal assembly Risosomal biogenesis Unfolded protein response TF Severe congenital neutropenia ELANE mutation Familial platelet disorder with myeloid malignancy RUNX1 AD AD Unfolded protein response HSC diff GATA2 deficiency AD HSC diff

32 Take home message GATA2 deficiency has a broad spectrum of phenotype including MonoMAC, MDS/AML, pulmonary disease and vascular/lymphatic dysfunction Diagnostic clues include cytopenia (monopenia, lack of HG), hypocellular marrow and dysmegs Early screening and family counseling are essential SCT is curative