GATA2 Haploinsufficiency: An immuno-viro-hemato-

endocrino-pulmono-gastroentero-dermato-

oncologic diseaseSteven M. Holland, MD

Laboratory of Clinical Infectious DiseasesNational Institute of Allergy and Infectious Diseases

National Institutes of Healthsmh@nih.gov

Myelodysplasia

lymphedema

warts

fungus

Acute leukemia

NTM

AA

GATA2

It’s Alveolar

proteinosis

Blindmen

It’sAplastic Anemia

Elephant

It’sNK Deficiency

It’s C. difficile

It’sM. kansasii

It’sEBV

GATA2 Deficiency5 names, one disease

MonoMACDCML

Emberger syndromeFamilial MDS/AML

Classical NK cell Deficiency

GATA2 DeficiencyIt’s also

Pediatric neutropeniaPediatric MDS (especially tri8, mono7)

AMLALL

CMML

5 New Things about GATA2 DeficiencySevere EBV Infection

Severe Mycobacterium kansasii infection

Common Lung Abnormalities (not PAP)

Severe C. difficile infection

GATA2 Deficiency Imitation

1992: 41 yo Woman Refractory MAC Infection

EBV+ Smooth Muscle TumorM. avium

E F G

I

L

EBV

26 yo man

EBEREBERCD3 CD3

Cohen JI et al, CID in press

20 yo Cantonese Woman with Hydroa Vacciniforme and HLH

Cohen JI, et al. CID, in press

R398W

Treatment Steroids HSCT HSCT None HLH94/HSCT HSCT HSCT

General GATA2 patient EBV viral load 117 copies/ml

Revised List for EBV Susceptibility,Chronic Active EBV, EBV malignancies

SH2D1BIRC4ITKMAGT1CD27PRF1PIK3CDCORO1AMST1/STK4

GATA2

NEJM 1989;320:1731

GATA2 c.1025_1026insGCCG p.A342GfsX41

23 yo Woman, Anemia, Fever for 5 months, Steroid therapy

Mycobacterium kansasii

The most like MTB of all the nontuberculous mycobacteria (NTM)

(can give + Quantiferon test)

Caused 2.5% of disseminated NTM in AIDS

Up to 7% of the disseminated NTM in hairy cell leukemia

53 yo womanMultifocal MK abscesses over skin

Spontaneously draining sternal notch

Mycobacterium kansasii: >15% of GATA2

Severe M. kansasii in GATA2

Highest rate of MK known

Abscess formation, especially in mediastinum

Prolonged course

All treatable (so far, some with IFNγ)

Drainage before HSCT not necessary

23 yo Woman, Anemia, Fever for 5 months, Steroid therapy

PULMONARY ALVEOLAR PROTEINOSIS

E F

Pulmonary Alveolar

Proteinosis

GATA2: Subpleural Blebs and Emphysema

Subpleural Blebs and Emphysema30% of patients

Begins early in life

At tissue junctions: interlobar, apical

Can lead to emphysematous changes

Etiology? Not apparently infectious

JPGN 2015;60: 486–492

IBD with C. diff All IBD in children

Lower odds of colectomy

9/23/2015

10/3/2015

10/21/2015

11/6/2015

Why are we discussing this common hospital acquired infection?

4/70 GATA2 patients seen here have had severeC. difficile colitis (6%)

14 yo boy: C. diff after MAC therapy-colectomy17 yo girl: C. diff after abx, ICU with chest tubes

59 yo woman: fatal C. diff colitis28 yo woman: C. diff in MK therapy-colectomy

(in comparison at NIH, 0 in CGD, ~1 in STAT3)

Abt et al, Cell Host & Microbe 2015

C. difficile infection in GATA2

Can be very severe, even in childhood

Severe edema bowel wall

Recurrent

Mouse model underway

Myelodysplasia

lymphedema

warts

fungus

Acute leukemia

NTM

AA

GATA2

It’s Alveolar

proteinosis

Blindmen

It’sAplastic Anemia

Elephant

It’sNK Deficiency

It’s C. difficile

It’sM. kansasii

It’sEBV

20 yo woman neutropenia, anemia, fungal infection

7 yo “CVID”19 yo fever, neutropenia, invasive fungal

sinusitisE. coli sepsis, shock, ventilation

NIH transfer:Fusarium proliferatum sinusitisNeutrophils 0 cells/µlMonocytes 1 cells/µlNK cells 32 cells/µlB cells 0 cells/µl

Clinical Course

Persistent fever, neutropeniaClinically Consistent with GATA2 deficiency but no mutation foundSuccessful haploidentical HSCT from 17 yo sister(busulfan, cylclophosphamide, 200cGy, post-Cy)Bacteremia, ventilation, but complete recovery

Clinical Course

Persistent fever, neutropeniaClinically Consistent with GATA2 deficiency but no mutation foundSuccessful haploidentical HSCT from 17 yo sister(busulfan, cylclophosphamide, 200cGy, post-Cy)Bacteremia, ventilation, but complete recovery

But where was her problem in GATA2?

Homozygous Null CECR1 (ADA2 deficiency)

Homozygous Null CECR1 (ADA2 deficiency)

Q268X

March 2014

Hsu et al, JACI, in press

Circ

ulat

ing

ADA2

Myelodysplasia

lymphedema

warts

fungus

Acute leukemia

mycobacteria

AA

GATA2?

It’s Alveolar proteinosis

Blindmen

It’sAplastic Anemia

Elephant?

It’sNK Deficiency

It’s C. difficile

It’sM. kansasii

5 New Things about GATA2 DeficiencySevere EBV Infection

Severe Mycobacterium kansasii infection

Common Lung Abnormalities (not PAP)

Severe C. difficile infection

GATA2 Deficiency Imitation

GATA2 HaploinsufficiencyIt started complex and remains complex

We are still learning about its phenotypesIt does seem to have exquisite susceptibilities

(M. kansasii, C. difficile, so far, no TB)

It is not the only disease that can have similar features

AcknowledgementsAmy P. Hsu

Elizabeth SampaioLauren SanchezMichael Spinner

Kathy CalvoDiane ArthurMark Raffeld

Stefania PittalugaLi Ding

Lisa McReynoldsSmita PatelJosh Milner

Liana FalconeKen Olivier

Blanche AlterNeelam Giri

Inga HoffmanTom FleisherGulbu Uzel

Christa ZerbeAlexandra FreemanSergio Rosenzweig

Janine DaubLisa Barnhart

Reggie ClaypoolCathleen Frein

Vickey AndersonMaria L. TurnerEmery BresnickKirby Johnson

Danielle TownsleyNeal YoungEmily Mace

Jordan OrangeJennifer Cuellar-Rodriguez

Dennis Hickstein