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Highly Variable Clinical Manifestations in a Large Family with a Novel GATA2 Mutation

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Highly Variable Clinical Manifestations in a Large Family with a Novel GATA2 Mutation Letters to the Editor 2247 interleukin-2 receptor expression and growth of leukemic Sezary cells. Leukemia 8 Chiarle R, Simmons WJ, Cai H, Dhall G, Zamo A, Raz R et al. Stat3 is required for 2001; 15: 787–793. ALK-mediated lymphomagenesis and provides a possible therapeutic target. 7 Ohgami RS, Ohgami JK, Pereira IT, Gitana G, Zehnder JL, Arber DA. Refining the Nat Med 2005; 11: 623–629. diagnosis of T-cell large granular lymphocytic leukemia by combining distinct patterns 9 Jing N, Tweardy DJ. Targeting Stat3 in cancer therapy. Anticancer Drugs 2005; 16: of antigen expression with T-cell clonality studies. Leukemia 2011; 25: 1439–1443. 601–607. Supplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu) Highly variable clinical manifestations in a large family with a novel GATA2 mutation Leukemia (2013) 27, 2247–2248; doi:10.1038/leu.2013.105 non-Hodgkin lymphoma of the nasopharynx with rapidly progressive pancytopenia refractory to high-dose methylprednisolone and rituximab. The lymphoma was immunophenotypically CD3 and CD45 positive but CD4, CD8, CD20, CD30 and CD79a negative Recently, germline mutations in GATA2 have been described in and was classified as peripheral T-cell NHL, not otherwise specified. familial myelodysplastic syndrome/acute myeloid leukemia (MDS/ Bone marrow histology did not show marrow involvement of the AML) and in apparently related clinical conditions, designated lymphoma at the time of pancytopenia. DCML (dendritic cell-, mono- and lymphocytopenia), MonoMac The paternal grandmother of the index patient died at the age (monocytopenia and Mycobacterium avium complex infections) of 74 from AML. No prior medical history is available. She had and Emberger’s syndrome.1–4 These syndromes share autosomal conceived eight children. Her first daughter, patient II-1 had dominant inheritance with variable manifestations of immuno- recurrent bacterial infections from childhood and a stable deficiency, monocytopenia and early onset of MDS/AML. In leukocytopenia. In her mid-thirties she suffered a disseminated addition, Emberger’s syndrome is associated with primary infection with Mycobacterial avium complex and died at the age of lymphedema in combination with sensineural deafness. Clinical 42 due to histiocytosis X. Two younger sisters (paternal aunts of recognition of GATA2 mutation carriers can be difficult due to the the index patient) died at the ages of 58 and 7, respectively. No large variability of signs and symptoms. However, their medical documentation is available regarding their cause of identification is important as the onset of clinical manifestations death. A paternal uncle of the index patient (patient II-8) had been can occur at any age and prompt recognition will help direct given a diagnosis of Emberger’s syndrome presenting as primary clinical treatment strategies and follow-up. lymphedema of the legs with extensive verrucae palmaris. The We recently diagnosed a novel GATA2 mutation in a large oldest cousin of the index patient (patient III-2) died at the age of family, in which all known GATA2 mutation associated phenotypes 21 due to AML, without antecedent medical problems. The oldest are found, highlighting the clinical heterogeneity of mutation brother of the index patient (patient III-8) died at the age of 14 carriers. from AML. The index patient, a 30-year-old woman, had suffered recurrent GATA2 gene analysis was performed using Sanger sequencing bacterial sinopulmonary infections and mucocutaneous candidia- of peripheral blood DNA from the index patient and her father. sis since childhood. She developed refractory verrucae palmaris This revealed two novel mutations located within exon 2; both and plantaris during adolescence. Despite antibiotic treatment were present in father and daughter. One mutation was caused by and antimicrobial maintenance therapy, recurrent bacterial the deletion of a single base pair resulting in a frameshift at amino pulmonary infections ultimately led to bronchiectasis and acid 28 (G28fs), the second was a missense mutation (H26P), progressive fibrotic changes, leading to both restrictive- and which was predicted to be ‘probably damaging’ by PolyPhen2. obstructive pulmonary function test abnormalities, which greatly This large family is highly illustrative for the clinical variability impaired exercise tolerance. In early adulthood, she developed and difficulty in predicting outcome in GATA2 mutation carrier- nodular pulmonary lesions and pleural effusions. Open lung ship, due to the presence of all previously reported phenotypes biopsy showed sterile non-caseating granulomas. represented in one family with the unique finding of two novel Complete blood counts taken since childhood had consistently germline mutations in each case screened. shown mild pancytopenia. Leukocyte differentiation had shown Germline GATA2 mutations were first described as an etiological complete absence of monocytes and immunophenotyping of defect in familial MDS and AML by Hahn et al.,1 where two peripheral blood showed almost complete absence of NK-and missense mutations localizing to the second zinc-finger domain B-cells, while neutrophil counts were normal. T-cells were present were identified amongst pedigrees with familial MDS/AML. In in normal numbers and subsets and showed normal interferon- these pedigrees the GATA2 mutation was associated with early gamma release after stimulation with recall antigens. Bone onset MDS/AML with poor prognosis without accessory marrow examination revealed dysplastic myelo-and erythropoiesis phenotype such as previous immunodeficiency, hematological without an excess of blasts or cytogenetic abnormalities. abnormalities or lymphedema. Our family demonstrates three These findings were consistent with MDS with multilineage generations affected by AML, either preceded by myelodysplasia dysplasia (MDS:RCMD). The patient received intermittent predni- or not. The range of disease latency varies from 14 to 74. solone for the pulmonary lesions with a good initial response but In previously reported cohorts, some patients developed AML has since shown a steady deterioration in pulmonary function with antecedent hematological abnormalities such as monocyto- over the past few years. penia or MDS while others developed de novo AML.1–4 This The father of the index patient (patient II-9) was diagnosed demonstrates that GATA2 heterozygosity alone is not sufficient to with MDS (RA) associated with monosomy-7. Six months before he predict the disease phenotype or its age of onset. The mechanism died he was diagnosed with an EBV-related peripheral T-cell behind this phenotypical variation is yet unknown although Accepted article preview online 8 April 2013; advance online publication, 3 May 2013 & 2013 Macmillan Publishers Limited Leukemia (2013) 2242 – 2267 Letters to the Editor 2248 acquisition of additional mutations are likely to be important symptoms or signs of disease develop. Also, given the possibility ‘drivers’ in initiating leukaemogenesis, one such mutation, ASXL1, of asymptomatic carriage of first-degree family members, screen- has significant prognostic implications.5 ing for GATA2 mutation should be considered when analyzing Immunodeficiency is an important feature in families with siblings as bone marrow donors. It will be a challenge elucidating GATA2 mutations, with its specific susceptibility for infections with the molecular effects of GATA2 mutation but a better under- intracellular organisms such as atypical mycobacteria and viruses, standing of phenotypical development is needed to identify those which is also prominently featured in our family. Adequate GATA2 who are at high risk for developing MDS/AML and with this those expression is crucial for myeloid differentiation of hematopoietic who would benefit from early intervention. Follow-up of our large stem cells and deficiency leads to profound monocytopenia, cohort might help delineate the phenotypical heterogeneity as all necessary for the eradication of intracellular organisms. In most phenotypes are represented in one family affected with two reported patients with DCML and MonoMac, the monocytopenia germline mutation. is accompanied by relative absence of NK- and B-cells while T-cell compartment is functionally and quantitatively unaffected. These findings were also reflected in our index patient where there was CONFLICT OF INTEREST NK- and B-cell lymphopenia, without hypogammaglobulinaemia, while T-cell numbers and subsets were present and functional on The authors declare no conflict of interest. stimulation with recall antigens. 1,4 1 2 Another disease entity, also featured in our family in patient II-8, PGNJ Mutsaers , AA van de Loosdrecht , K Tawana , CBo¨do¨r2,3, J Fitzgibbon2 and FH Menko1 is the occurrence of primary lymphedema, which has indepen- 1 dently been reported by two different groups.4,6 In a recent article, Department of Hematology, VU University Medical Center, 6 Cancer Center Amsterdam, Amsterdam, The Netherlands; Kazenwadel et al. demonstrated that wild-type homozygous 2 GATA2 is crucial for lymphoendothelial valve development and Centre for Haemato-Oncology Barts Cancer Institute - a Cancer that knockdown of GATA2 in lymphatic endothelial valves leads to Research UK Centre of Excellence Queen Mary, University of London, London, UK and absent expression of genes important for valve development, thus 3 explaining the mechanism of lymphedema. Semmelweis University, 1st Department of Pathology and The clinical heterogeneity of our pedigree
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