Natural history of GATA2 deficiency in a survey of 79 French and Belgian patients

Abstract

Heterozygous germline GATA2 mutations strongly predispose to leukemia, immunodeficiency, and/or lymphoedema. We describe a series of 79 patients (53 families) diagnosed since 2011, made up of all patients in France and Belgium, with a follow up of 2249 patients/years. Median age at first clinical symptoms was 18.6 years (range, 0-61 years). Severe infectious diseases (mycobacteria, fungus, and human papilloma virus) and hematologic malignancies were the most common first manifestations. The probability of remaining symptom-free was 8% at 40 years old. Among the 53 probands, 24 had missense mutations including 4 recurrent alleles, 21 had nonsense or frameshift mutations, 4 had a whole-gene deletion, 2 had splice defects, and 2 patients had complex mutations. There were significantly more cases of leukemia in patients with missense mutations (n=14 of 34) than in patients with nonsense or frameshift mutations (n=2 of 28). We also identify new features of the disease: acute lymphoblastic leukemia, juvenile myelomonocytic leukemia, fatal progressive multifocal leukoencephalopathy related to the JC virus, and immune/inflammatory diseases. A revised International Prognostic Scoring System (IPSS) score allowed a distinction to be made between a stable disease and hematologic transformation. Chemotherapy is of limited efficacy, and has a high toxicity with severe infectious complications. As the mortality rate is high in our cohort (up to 35% at the age of 40), hematopoietic stem cell transplantation (HSCT) remains the best choice of treatment to avoid severe infectious and/or hematologic complications. The timing of HSCT remains difficult to determine, but the earlier it is performed, the better the outcome.

Figure 1.

Onset of disease, hematologic and infectious complications. (A) Kaplan Meier curves are shown for the onset of disease in 74 symptomatic patients with a GATA2 mutation. (B) Occurrence of myelodysplastic leukemia (MDS) / acute leukemia (AL).(C-F) Rate in mycobacterial, human papillomavirus (HPV), bacterial and mycotic infections. Confidence intervals of 95% are shaded gray.

Figure 2.

Hematologic features of the 79 patients. (A) Hematologic malignancies among the 79 patients. Progression to acute myeloid leukemia (AML) from myelodysplastic syndromes (MDS) is indicated. (B) Karyotypes availables for 66 out of 79 GATA2-deficient patients. ^*4 patients with monosomy 7 also had trisomy 8. (C) Hematologic complications and the outcome of patients older than the age of 40. JMML: juvenile myelomonocytic leukemia; CMML: chronic myelomonocytic leukemia; LEMP: leukoencephalomyelopathy; HSCT: hematopoietic stem cell transplantation.

Figure 3.

Clinical, radiographic, and cytological features of GATA2 syndrome. (A) Cutaneous warts on the hands of a woman with myelodysplastic syndromes (MDS). (B) Hand rheumatism (C) Bilateral lymphoedema post-hematopoietic stem cell transplantation. (D) Acute respiratory distress syndrome in a H1N1 infection. (E) Osteomyelitis at presentation. (F) Progressive multifocal leukoencephalopathy in a 43-year old man. (G) Pulmonary alveolar proteinosis in a woman with MDS and warts. (H) Disseminated mycobacteriosis. (I and J) Bone marrow smears of pedigree 46. (I) Dysgranulopoiesis and blasts in a woman with MDS evolving to acute myeloid leukemia. (J) Dyserythropoiesis and dysgranulopoiesis in her son with MDS. (K) Macrophage activation secondary to flu infection.

Figure 4.

Survival in 79 patients. (A) Kaplan-Meier curves showing overall survival of the whole cohort. (B) Survival after a clonal event. (C) Overall survival was studied after hematopoietic stem cell transplantation (HSCT) depending on the age (years) at transplantation (P>0.05). (D) Overall survival of patients with myelodysplastic syndromes (MDS) and/or acute leukemia (AL) was plotted according to the revised International Prognostic Scoring System (IPSS-R) score at the time of the diagnosis of the malignancy. Survival significantly depends on the IPSS score (P<0.001). Confidence intervals of 95% are shaded gray. y: years.

Figure 5.

Schematic organization of the GATA2 locus and protein. The protein is composed of 480 amino acids (top) encoded by 1443 nucleotides (bottom). The 5 coding exons (E2 to E6) are separated by blue lines. Forty-one mutations are shown: whole locus deletion including the del3q21 are in orange, nonsense mutation in the top of the schematic protein is in red, missense mutations are in green, small deletion in the bottom of the scheme is in brown, intronic mutation and splice defects are in blue, at the bottom, and mutation of the enhancer is in dark blue. Recurrence of mutations is specified in brackets.