Received: 20 April 2020 | Revised: 29 July 2020 | Accepted: 11 August 2020 DOI: 10.1002/ccr3.3304 CASE REPORT Many signs, one mutation: Early onset of de novo GATA2 deficiency syndrome. A case report Maria Laura Blanco1 | Montserrat Torrent2 | Elena Bussaglia1 | Isabel Badell2 | Josep F. Nomdedéu1 1 Department of Hematology, Hospital de la Santa Creu i Sant Pau, Universitat ABSTRACT Autònoma de Barcelona, IIB Sant Pau and We report a case with a broad spectrum of symptoms, related to GATA2 defi- Institut Josep Carreras, Barcelona, Spain ciency syndrome, which emerged as early as at 6 months of age. They ranged from 2 Department of and Pediatrics, Hospital lymphedema, deafness to myelodysplastic syndrome (MDS). de la Santa Creu i Sant Pau. Universitat Autònoma de Barcelona, IIB Sant Pau and KEYWORDS Institut Josep Carreras, Barcelona, Spain deafness, GATA2, lymphedema, myelodysplastic syndrome, warts Correspondence Josep F. Nomdedéu, Laboratori d´Hematologia, Hematology Department, Hospital de la Santa Creu i Sant Pau, IIB Sant Pau/Universitat Autònoma de Barcelona, Institut Josep Carreras, Sant Quintí, 89, 08041 Barcelona, Spain. Email: jnomdedeu@santpau.cat Funding information Instituto de Salud Carlos III Grant 16/0940. 1 | IN TRO D U C T ION or dendritic cell, monocyte, and B- and NK-lymphoid defi- ciency (DCML) syndromes.5 Myelodysplastic syndrome (MDS) is a rare disease of child- Emberger or deafness-lymphedema-leukemia syndrome hood, with a 0.8 to 1.8 per million children estimated fre- is a very rare, autosomal-dominant, genetic disorder with a quency1 and its diagnosis should include the investigation of prevalence of <1/1 000 000.6 It is characterized by primary a bone marrow failure syndrome (BMFS) or a familial form lymphedema, immunodeficiency, and MDS/AML. caused by GATA2 deficiency. GATA2 mutations were identified as a significant MDS/ AML genetic predisposition in 2011.2 Germline GATA2 mu- 2 | CASE REPORT tations account for 7% of primary childhood MDS3 being the most commonly known genetic cause. These mutations We report the case of an 18-year-old male patient who de- not only are linked to bone marrow failure (BMF), MDS, or veloped right leg lymphedema at the age of 6 months, which acute myeloid leukemia (familial MDS/AML),2 but these pa- improved with ambulation. He was diagnosed with bilateral tients can also show immune alterations with monocyte, B- sensorineural deafness at 3 years of age and started language and natural killer (NK)-cell deficiency, such as MonoMAC 4 acquisition after cochlear implant surgery. At the age of 7, This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd 3192 |  wileyonlinelibrary.com/journal/ccr3 Clin Case Rep. 2020;8:3192–3196. BLANCO et al.    | 3193 right hand finger warts appeared, followed by a lower lip At 14 years, mild anemia (hemoglobin 111 g/L) emerged, wart one year later. It was removed by cryosurgery. By that followed by thrombocytopenia (116 x 109/l). Three years same age, he was diagnosed with atopic dermatitis. At the later, dysmorphic red blood cells were noticed in the periph- age of 8, low neutrophil (0.92-1.8 × 109/L) and monocyte eral blood smear. Bone marrow biopsy showed a markedly (0.01-0.02 × 109/L) counts were noticed. IgG and IgM anti- hypocellular marrow with atypical megakaryocytes (large neutrophil antibodies were detected. B-cell lymphopenia forms with separated nuclear lobes). Bone marrow aspirate (4%) with a CD4/CD8 inversion was also found. assessment showed degranulated and hypolobated neutro- New lower lip warts developed at 15 and 16 years of age, phils (88%) and dysplastic erythropoiesis (40%), with no in- requiring further cryosurgery. At 13 years, right toe cellu- crease in the blast cell count (Figure 1A-D), fulfilling criteria litis developed following trauma, with apparent resolution for myelodysplastic syndrome with multilineage dysplasia. after oral antibiotics. However, two weeks later, hospitaliza- The cytogenetic assessment showed a normal karyotype. tion was needed due to right leg erythema, fever, and serum Next-generation sequencing with a molecular custom panel C-reactive protein levels above 320 mg/L. Intravenous amox- identified a previously reported pathogenic mutation at icillin-clavulanic was delivered, and surgical toenail removal GATA2 gene c.1084C > T; p.R362*. These findings were had to be performed. Ten more cellulitis episodes were re- confirmed by Sanger sequencing. Therefore, the patient was corded in the next 5 years, four of them requiring admission diagnosed with myeloid neoplasm with germline GATA2 to the hospital. All the cellulitis events were caused by meth- mutation, which is listed within the myeloid neoplasms with icillin-sensitive Staphylococcus aureus. Seven further toe- germline predisposition associated with other organ dys- nail removals had to be undertaken. Right limb lymphedema function in the WHO 2017 Classification.7 Family history (Figure 1E) relapsed after the first hospitalization. An indo- was unremarkable for infection susceptibility, solid, or he- cyanine green fluorescent lymphangiography at 15 years of matologic malignancies. His parents were born in Morocco, age confirmed the absence of right leg active lymphatic ves- and they showed no known consanguinity. The parents, as sels. Therefore, lymphatic venous anastomosis could not be well as his older sibling, tested negative for the GATA2 gene performed, and conservative care with compressive garment c.1084C > T; p.R362* mutation. and physiotherapy was implemented. After establishing the diagnosis mentioned above, a closer The patient developed acne at 12 years, and he received follow-up with biannual blood tests and physical examination various treatments over the years. At 20, it evolved into a pap- were established. A matched related donor (MRD) search ule pustulous form, and the patient is now on isotretinoin PO was unsuccessful, and a matched unrelated donor (MUD) and topic tacrolimus. search is being carried out. (A) (C) (E) (B) (D) F I G U R E 1 A, Degranulated neutrophil. B and D, Atypical megakaryocytes. C, Bone marrow section showing hypocellularity. E) Right lower extremity lymphedema 3194 |    BLANCO et al. The patient is in good clinical condition at present, and his A known pathogenic nonsense mutation c.1084C > T in blood cell counts have remained stable for the last six years the ZNF2 domain (exon 5) was detected on NGS analysis and (hemoglobin 101-125 g/L, platelets 75-134 × 109/L, neutro- confirmed by Sanger sequencing. The patient also harbored a phils 0.75 × 109/L, monocytes 0-0. × 109/L, and lymphocytes nonpathogenic variant allele at GATA2 (c.490G > A), shared 0.44-1.54 × 109/L). The last hospitalization for cellulitis took by his parents and sister, which were all healthy and tested place two years ago, and the last skin infection event, one negative for the pathogenic GATA2 mutation both by NSG year ago. He is a computer science student and carries out an and Sanger sequencing (Figure 2). These findings imply that independent life. the GATA2 mutation was de novo. More than 100 GATA2 mutations have been reported to date.11 Approximately one-third of germline mutations are 3 | D IS C U S S ION inherited while the rest occur, as in our case, de novo.3,12 Pathogenic germline variants comprise three main types: GATA2 deficiency caused by inactivating mutations may 45% missense or indel mutations within ZF2; 40% truncating give rise to a disorder with multiple clinical manifestations. (nonsense, indels, and splice site changes) mutations preced- Hematologic malignancy is a relevant and common feature ing or within ZF2; and 10% belong to noncoding variants in (>80%) 3,8-10 and may develop without any other symp- intron 4 which alter the + 9.5 kb regulatory site. Much less toms. In the largest series reported,3,8-10 infections were the common (around 5%) are complete gene deletions or frame- second in frequency—mostly viral 8—followed by pulmo- shift and nonsense mutations scattered along the gene, and nary alveolar proteinosis (PAP), HPV-related dysplasia, missense mutations C-terminal of ZF2.12,13 Pathogenic vari- chronic lymphedema, venous thrombosis, sensorineural ants seem to induce haploinsufficiency by different mech- hearing loss, miscarriage, hypothyroidism, and autoim- anisms. These include hemizygosity due to loss or reduced mune phenomena. transcription of one allele or truncation of GATA2 protein In this report, we describe a GATA2 deficiency case show- and the resulting reduced or abolished function.12 This, in ing Emberger syndrome features that emerged as early as the turn, could cause decreased DNA-binding capability and age of 6 months old as lymphedema and deafness at three years transactivation alterations.14 Moreover, protein changes can old. Hematologic manifestations appeared later. Neutropenia, cause loss of GATA2 autoregulation 15 along with monocytopenia and low B-lymphocyte count, was A study of a pedigree with the recurrent p.T354M gave first noticed at eight years of age and followed by anemia and some insight into epigenetic control and allelic balance be- thrombocytopenia nine years later. tween the WT and mutated allele.16 F I G U R E 2 GATA2 Sanger sequencing for the patient and his family (top). NGS findings are also shown (bottom) BLANCO et al.    | 3195 High levels of GATA2 protein have been found in lym- ETHICAL APPROVAL STATEMENT phatic vessels of embryonic and adult mice, especially in Photographies were obtained with written informed leaflets from vascular valves.17 Oscillating shear stress can permission. induce GATA2, and it binds to a –11 kb PROX1 enhancer, resulting in its transactivation.18 Investigation of the three ACKNOWLEDGMENTS most prevalent GATA2 missense mutations 14 showed a gen- Published with written consent of the patient. otype-phenotype correlation where GATA2 mutants with re- sidual activity in terms of DNA-binding capability did not CONFLICT OF INTEREST develop lymphedema. Therefore, GATA2 haploinsufficiency None declared. resulting from a null mutation may combine with either in- flammation or infections to trigger lymphedema onset,18 as AUTHOR CONTRIBUTION in our case. MLB: has made substantial contributions to conception, de- Given the various mutational spectrum of GATA2, a sign, and analysis and interpretation of data, and wrote the negative NGS panel in the context of clinical suspicion manuscript; MT and IB cared for the patient and made contri- cannot rule out a GATA2 deficiency syndrome. In some butions to the paper; EB: performed molecular analysis; JFN: cases, whole gene deletions or intronic mutations may be was involved in the design and interpretation of data, wrote missed when testing only for coding exons. In patients with and review the manuscript. immunodeficiency, recurrent infections and somatic fea- tures, or an MDS diagnosis at a young age, it is mandatory ORCID to screen for germline mutations. This approach should in- Josep F. Nomdedéu https://orcid. clude analysis of intron 4 of GATA2 and MLPA or DNA org/0000-0003-3399-346X arrays to search for large chromosomal deletions encom- passing GATA2. 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