Page 44 - Haematologica August 2018

J. Donadieu et al.
coloration and/or culture in 14 of 16 patients). Mycobacterial infection was suspected if the tissue sample demonstrated granu- loma, and/or clinical symptoms were cured by antimycobacterial drugs (2 out of 16 patients).
Immunoglobulin levels were analyzed according to the patient's age.18 Age at first symptom was defined by the age at the first clin- ical pathological manifestation among the following list: myelodysplastic syndromes (MDS) or acute leukemia (AL), any severe and potentially life-threatening infection, lymphoedema, pulmonary proteinosis, or profuse human papillomavirus (HPV) infection. A GATA2 mutation carrier was considered asympto- matic if no clinical and/or biological symptoms were described at the last follow-up visit. Siblings or parents of probands were con- sidered as carriers of the familial GATA2 mutation if they present- ed with one of the typical manifestations of the GATA2 deficien- cy, even in the absence of genetic testing.
Hematologic features
Blood counts were recorded at baseline if available, at any peri- od following a hematologic complication, and after HSCT (if applicable). Bone marrow studies were performed in the event of blood count abnormality. Hematologic malignancies were classi- fied according to the 2008 World Health Organization (WHO) classification.19,20 MDS was classified according to the revised ver- sion of the International Prognostic Scoring System (IPSS)21 and juvenile myelo-monocytic leukemia (JMML) was classified according to the 2016 WHO classification.22
Statistical analysis
Stata® software (v.13) was used for all the statistical analyses. Lower and upper interquartile and median values express the dis- tribution of quantitative variables. Differences between groups of patients were analyzed using Fisher’s exact test if the event was discrete and Wilcoxon’s test for quantitative variables. Survival was compared between the groups of subjects using the log-rank test, and Cox's model was used for the multivariate analysis. As we performed repeated tests, P<0.01 was considered significant, unless otherwise stated. For survival, the end points were death, MDS or AL; the time-period started at birth until an event or the day of last news. We also analyzed survival after onset of a clonal event. The time period started from the first clonal event (MDS or AL) until death or the day of last news. The Kaplan-Meier method was used to estimate survival rates. The cut-off date was 30th September 2016.
Results
Early onset of severe infections and/or hematologic diseases in GATA2 deficiency
Forty males and 39 females from 53 families with a het- erozygous germline GATA2 mutation are herein reported (Table 1 and Online Supplementary Table S1), including 14 previously described patients,11 whose clinical and biolog- ical data have been up-dated. The patients were enrolled in France (n=72) and Belgium (n=7). Median age at the last follow up was 24.5 years old (range, 3.9-73). The probabil- ity of remaining symptom-free was 38% at the age of 20 (95%CI: 27-48.7%) and 8% at the age of 40 (95%CI: 3.3- 15%) (Figure 1A). All patients except 5 were symptomatic at the time of the last follow up. These 5 individuals were first-degree relatives of symptomatic patients with a GATA2 mutation (Online Supplementary Table S2). Median age at onset of the first clinical symptom was 18.6 years (range, 0-61) (Figure 1A and Online Supplementary Table
S1). Initial manifestations were a hematologic malignancy in 19 patients (26%), a severe bacterial infection in 17 (23%), profuse warts or HPV in 15 (20%), lymphoedema in 7 (9.4%), or a mycobacterial infectious disease in 6 (8.1%). Blood counts of patients with opportunistic infec- tions (HPV, mycobacteria, mycosis, the JC virus) were sys- tematically abnormal (monocytopenia, neutropenia, pan- cytopenia, severe anemia).
Additional clinical features in GATA2 deficiency
Outside hematologic and infectious clinical presenta- tions, erythema nodosum/panniculitis (4 patients), mental retardation (1 patient), transient ischemic cerebral palsy (1 patient), and progressive multifocal leukoencephalopathy linked to the JC virus (PML, 1 patient) were the initial symptoms in 7 patients.
Over the course of the disease, 9 patients had systemic inflammatory manifestations with panniculitis, vasculitis, Sweet's syndrome, lupus-like disease or granulomatous disease mimicking sarcoidosis. Of note, auto-immune markers were present in 12 patients, which may be an underestimation because they were not sought for in all patients (Table 1).
Chronic lymphoedema was noted in 12 patients (15%). Vascular and/or thrombotic complications were observed in 7 patients: 2 patients presented with transient cerebral palsy, one patient presented with splenic-vein thrombosis after a splenectomy and mycobacteriosis, one patient pre- sented with 3 deep-vein thromboses in a context of AL,
Table 1. Clinical and biological presentation of GATA2 deficient patients.
Diagnostic features
Hematologic features
Recurrent infections
(viral, mycobacterial, fungal)
Warts
Lymphoedema Pulmonary features
Vascular features
Deafness
Autoimmune features
Other features
Incidence in our survey
70% (55/79) 19% (15/79) 1.3% (1/79) 2.5% (2/79) 1.3% (1/79)
49% (24/49) 100% (38/38) 7.8% (3/38)
40% (32/79) 3.8% (3/79)
15% (12/79)
3.8% (3/79) 56% (44/79)
9% (7/79)
1.3% (1/79)
11% (9/79)
5% (4/79) 6.3% (5/79) 1.3% (1/79)
Clinical and biological aspects
MDS
AML
ALL
Aplastic anemia Juvenile myelomonocytic leukemia
Monocytopenia B lymphopenia NK lymphopenia
HPV-related (genital and cutaneous) Oncogenesis
Pulmonary alveolar proteinosis Recurrent bacterial infections
Thrombosis, myocardial
infarction
Panniculitis, erythema nodosum, vasculatis, lupus-like and sarcoidosis-like syndrome, Sweet's syndrome
Urinary-system malformation Premature labor, miscarriage Hypothyroidism
1280
MDS: myelodysplastic syndromes; AML: acute myeloid leukemia; ALL: acute lym- phoblastic leukemia; NK: natural killer cell; HPV: human papillomavirus.
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