[GATA2 gene mutations: 3 cases]. / Mutations du gène GATA2 : à propos de 3 cas.

INTRODUCTION: Heterozygous germline mutations of GATA2 gene (guanine-adenine-thymine-adenine binding protein 2) are hereditary mutations that can be pathogenic, sometimes occurring sporadically, responsible for a florid clinical-biological picture, sometimes serious and quickly leading to the death. CASE REPORTS: We reported two women and one man with germline mutations in the GATA2 gene. The first patient, aged 19, initially presented with monocytopenia and chronic lymphedema of the four limbs, suggestive of Emberger syndrome. The second patient, 28-years-old, presented with a disseminated atypical mycobacterium (Mycobacterium kansasii) infection, raising suspicion of an immune deficiency such as MonoMAC syndrome (deficiency syndrome of dendritic cells, monocytes, B lymphocytes and NK cells). The last patient, 30-years-old, presented with pancytopenia, leading to the diagnosis of a family form of myelodysplastic syndromes and acute myeloid leukemia characterized by a mutation of the GATA2 gene. CONCLUSIONS: Each case illustrates a typical clinical presentation of GATA2 deficiency, although the evolution of these syndromes ultimately reveals a complex, heterogeneous and intricate picture of hematological, dermatological, infectious, pulmonary, ENT or oncological symptoms. Mutations in the GATA2 gene remain a diagnostic and therapeutic challenge for the internist, and require multidisciplinary management given the florid picture that can be of interest to all specialties. The clinical spectrum of these GATA2 mutations as well as the latest management recommendations from the recent litterature and the "GATA2 club" are described in this article.

Gynecologic manifestations in Emberger syndrome.

Immune system vulnerability seems to play a significant role in the development and malignant transformation of pre-malignant squamous cell lesions. Emberger syndrome is a condition that affects the immune system, which is caused by GATA2 gene mutations. Our objective was to present the gynecologic expressions of this rare syndrome in our case. Here, we discussed a relatively young patient with findings related to Emberger syndrome such as recurrent infections, myelodysplastic syndrome, lower extremity edema, and multifocal, multicentric premalignant/malignant genital lesions. Sequencing of the GATA2 gene was accomplished for suspected Emberger syndrome and a point mutation in intron5, c1143+8C >T was detected. Gynecologists may play an important role in the early detection of Emberger syndrome and guiding multidisciplinary treatment options as the initial signs related to this rare entity can appear on the genitalia.

Comparison of Outcomes of Myeloablative Allogeneic Stem Cell Transplantation for Pediatric Patients with Bone Marrow Failure, Myelodysplastic Syndrome and Acute Myeloid Leukemia with and without Germline GATA2 Mutations.

Germline mutations in GATA2 are associated with an inherited predisposition to bone marrow failure (BMF), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). Hematopoietic stem cell transplantation (HSCT) remains the only curative therapy. However, patients may be at an increased risk for transplant-related toxicity (TRT) and transplant-related mortality (TRM) due to their underlying disease biology. We performed a retrospective case-control study of pediatric patients with BMF/MDS/AML with germline GATA2 mutations, comparing HSCT outcomes to randomly selected patients without germline GATA2 mutations and BMF/MDS (control A) and acute leukemia (control B). The 5-year overall and disease-free survival rates in the GATA2 cohort (65%, 51%) were similar to control A (58%, 49%) and B (45%, 43%) cohorts. In contrast, the 5-year event-free survival rate was significantly lower in the GATA2 cohort (7% ± 6%, 28% ± 10%, and 33% ± 8% for GATA2, A, and B, respectively), due to an increased number of unique TRTs. Specifically, neurologic toxicities occurred significantly more frequently in GATA2 patients than in the control groups, and post-HSCT thrombotic events occurred only in the GATA2 cohort. There was no difference in TRM, infections, or graft-versus-host disease across groups. The higher incidence of thrombotic and neurologic events specific to GATA2 patients warrants further investigation and has potential treatment ramifications.

Myeloid malignancies with somatic GATA2 mutations can be associated with an immunodeficiency phenotype.

Germline mutations in GATA2 are associated with a complex immunodeficiency and cancer predisposition syndrome. Somatic GATA2mut in myeloid malignancies may impart a similar phenotype. We reviewed adult patients with a diagnosis of GATA2mut hematological malignancy who were referred to our HHMC for genetic testing, and identified to have somatic GATA2mut. Nine patients with a median age of 63 years were included. Six patients (66.7%) were males. Atypical CML and acute myeloid leukemia were the most common initial presentation. The median overall VAF was 47.14%. Monocytopenia was pronounced when the GATA2mut involved the C-terminal ZFD. GATA2 N-terminal ZFD mutations tend to be co-mutated with biCEBPAmut. Unlike germline GATA2 mutations, monocytopenia associated with somatic GATA2 mutations often resolved at remission. We concluded that similar to germline GATA2 mutations, a subset of somatic GATA2 mutations can impart a germline phenotype.

Emberger syndrome: A rare association with hearing loss.

Emberger Syndrome (ES) is a rare genetic disorder characterized by lymphedema and myelodysplasia. It is also associated with hearing loss. The genetic mutations associated with ES are not part of the comprehensive 80 gene next generation sequencing (NGS) panel. As a result, the otolaryngologist should maintain an index of suspicion for ES in any child with SNHL who presents repeatedly with recurrent infections, lymphedema and/or cutaneous warts. This paper describes the clinical evolution and management of two children who were followed up for hearing loss and eventually were diagnosed with ES.

GATA2 deficiency and related myeloid neoplasms.

The GATA2 gene codes for a hematopoietic transcription factor that through its two zinc fingers (ZF) can occupy GATA-DNA motifs in a countless number of genes. It is crucial for the proliferation and maintenance of hematopoietic stem cells. During the past 5 years, germline heterozygous mutations in GATA2 were reported in several hundred patients with various phenotypes ranging from mild cytopenia to severe immunodeficiency involving B cells, natural killer cells, CD4+ cells, monocytes and dendritic cells (MonoMAC/DCML), and myeloid neoplasia. Some patients additionally show syndromic features such as congenital deafness and lymphedema (originally defining the Emberger syndrome) or pulmonary disease and vascular problems. The common clinical denominator in all reported cohorts is the propensity for myeloid neoplasia (myelodysplastic syndrome [MDS], myeloproliferative neoplasms [MPN], chronic myelomonocytic leukemia [CMML], acute myeloid leukemia [AML]) with an overall prevalence of approximately 75% and a median age of onset of roughly 20 years. Three major mutational types are encountered in GATA2-deficient patients: truncating mutations prior to ZF2, missense mutations within ZF2, and noncoding variants in the +9.5kb regulatory region of GATA2. Recurrent somatic lesions comprise monosomy 7 and trisomy 8 karyotypes and mutations in SETBP1 and ASXL1 genes. The high risk for progression to advanced myeloid neoplasia and life-threatening infectious complications guide decision-making towards timely stem cell transplantation.

GATA2 null mutation associated with incomplete penetrance in a family with Emberger syndrome.

INTRODUCTION: GATA2 mutations are associated with several conditions, including Emberger syndrome which is the association of primary lymphedema with hematological anomalies and an increased risk for myelodysplasia and leukemia. OBJECTIVE: To describe a family with Emberger syndrome with incomplete penetrance. METHODS: A DNA sequencing of GATA2 gene was performed in the parents and offspring (five individuals in total). RESULTS: The family consisted of 5 individuals with a GATA2 null mutation (c.130G>T, p.Glu44*); three of them were affected (two of which were deceased) while two remained unaffected at the age of 40 and 13 years old. The three affected siblings (two boys and one girl) presented with lymphedema of the lower limbs, recurrent warts, epistaxis and recurrent infections. Two died due to hematological abnormalities (AML and pancytopenia). In contrast, the two other family members who carry the same mutation (the mother and one brother) have not presented any symptoms and their blood tests remain normal. DISCUSSION: Incomplete penetrance may indicate that GATA2 haploinsufficiency is not enough to produce the phenotype of Emberger syndrome. It could be useful to perform whole exome or genome sequencing, in cases where incomplete penetrance or high variable expressivity is described, in order to probably identify specific gene interactions that drastically modify the phenotype. In addition, skewed gene expression by an epigenetic mechanism of gene regulation should also be considered.

Successful reduced-intensity stem cell transplantation for GATA2 deficiency before progression of advanced MDS.

A 13-yr-old boy bearing lymphedema and congenital deafness had distinct hematological abnormalities consisting of reduced monocytes, B cells, and dendritic cells in the peripheral blood as well as MDS with normal karyotype in the bone marrow. The patient was diagnosed with Emberger syndrome by sequencing of GATA2 DNA, and underwent RIST from an HLA-matched unrelated donor. Prompt engraftment and immunological reconstitution were observed without any severe RRT. As most patients with GATA2 anomaly died due to the development of AML or active infections, RIST could be a promising treatment option before progression of advanced MDS.

Genetic predisposition syndromes: when should they be considered in the work-up of MDS?

Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by cytopenias, ineffective hematopoiesis, myelodysplasia, and an increased risk of acute myeloid leukemia (AML). While sporadic MDS is primarily a disease of the elderly, MDS in children and young and middle-aged adults is frequently associated with underlying genetic predisposition syndromes. In addition to the classic hereditary bone marrow failure syndromes (BMFS) such as Fanconi Anemia and Dyskeratosis Congenita, in recent years there has been an increased awareness of non-syndromic familial MDS/AML predisposition syndromes such as those caused by mutations in GATA2, RUNX1, CEBPA, and SRP72 genes. Here, we will discuss the importance of recognizing an underlying genetic predisposition syndrome a patient with MDS, will review clinical scenarios when genetic predisposition should be considered, and will provide a practical overview of the common BMFS and familial MDS/AML syndromes which may be encountered in adult patients with MDS.