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 MonoMAC syndrome

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 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

27 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.

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

33 Synopsis of cytopenias in PID. Conceptual overview, excluding primary defects of phagocyte number or function, inherited non-pid bone marrow failure syndromes, and disorders of isolated lymphopenia (without other cytopenia). *Includes hypomorphic mutations... Markus G. Seidel Blood 2014;124:

34 Clinical presentation: Warts, fungal infections, lymphedema, pulmonary alveolar proteinosis, aplastic anemia, MDS and AML Clinical features suggestive of GATA2 deficiency: persistent warts, lymphedema, pulmonary alveolar proteinosis or disseminated, and/or unusual infections.

35 GATA2 is expressed in hematopoietic progenitors and in nonhematopoietic embryonic stem cells (MIM: ) Heterozygous pathogenic variants in the GATA2 gene complex congenital immunodeficiency, which predisposes to infection and myeloid malignancy (Spinner et al., 2014). This includes autosomal dominant monocytopenia and mycobacterial infection (MonoMAC) syndrome, NK-cell deficiency, and primary lymphedema with myelodysplasia, also known as Emberger syndrome (Hsu et al., 2011; Hsu et al., 2013; Ostergaard et al., 2011; Seo et al., 2016). Additional features of Emberger syndrome can include sensorineural deafness, generalized warts, and facial dysmorphism (Mansour et al., 2010). Multiple variant types deep intronic variants from a highly conserved region within intron 4 (Stenson et al., 2014; Hsu et al., 2013; Wlodarski et al., 2016).

36 Annals of Hematology (2018) 97:

37 GATA2 p.r396w: p.arg396trp (CGG>TGG): c.1186 C>T in exon 6 in the GATA2 gene (NM_ ). The R396W variant in the GATA2 gene has been reported previously in two individuals with monocytopenia and mycobacterial infection (MonoMAC) syndrome (Hsu et al., 2011; Camargo et al., 2013). In addition, a different missense substitution at this position (R396Q) has been reported in association with MonoMAC syndrome (Hsu et al., 2011). The R396W variant is not observed in large population cohorts (Lek et al., 2016). The R396W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret R396W as a likely pathogenic

38 Diagnostic Clues Radiologic Crazy paving on chest CT Subpleural blebs Paraseptal emphysema Ground glass opacities Splenomegaly

39 GATA2 deficiency GATA2 encodes a zinc finger TF necessary for normal hematopoiesis located on chromosome 3q21.2. Heterozygous germline mutations in GATA2 leading haploinsufficiency DCML deficiency (dendritic cell, moncytes, B, and NK deficiency) MonoMAC Familial MDS/AML Emberger syndrome (MDS with lymphedema). Autosomal-dominant disorders

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41 a family with three affected individuals in two generations with severe congenital deafness in addition to lower limb lymphedema of childhood onset and hematological abnormalities (two with pancytopenia and one with AML). One member of the same family had isolated deafness and another had isolated lymphedema of the left lower limb (onset at 26 years). The latter, a female first cousin, once removed, at the age of 48 developed cirrhosis of the liver, mitral valve sclerosis, and cerebellar atrophy. Autosomal dominant inheritance with variable penetrance was suggested.

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