Letters to the Editor 2247 interleukin-2 receptor expression and growth of leukemic Sezary cells. 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 therapy. Anticancer Drugs 2005; 16: of antigen expression with T-cell clonality studies. Leukemia 2011; 25: 1439–1443. 601–607.

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Highly variable clinical manifestations in a large family with a novel GATA2

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 in GATA2 have been described in and was classified as peripheral T-cell NHL, not otherwise specified. familial /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 ), 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 analysis was performed using Sanger sequencing bacterial sinopulmonary infections and mucocutaneous candidia- of peripheral 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 important for valve development, thus 3 explaining the mechanism of lymphedema. Semmelweis University, 1st Department of Pathology and The clinical heterogeneity of our pedigree illustrates that the Experimental Cancer Research, Budapest, Hungary E-mail: [email protected] interplay of additional molecular defects is likely to give rise to this 4 striking variation in phenotype. We report for the first time, two Present address: Department of Hematology, Erasmus University novel mutations occurring in all affected cases in this family and Medical Centre, ’s-Gravendijkwal 230 3015 CE Rotterdam also the first description of an aggressive T-cell NHL associated with GATA2 mutations. GATA2 mutations have only been described recently and pedigrees REFERENCES are rare. For now, clinical management and guidelines for risk 7 1 Hahn CN, Chong CE, Carmichael CL, Wilkins EJ, Brautigan PJ, Li XC et al. Heritable stratification and treatment are mostly based on expert opinion. GATA2 mutations associated with familial myelodysplastic syndrome and acute Since the discovery of the genetic defect, many new mutations in myeloid leukemia. Nat Genet 2011; 43: 1012–1017. GATA2 have been reported but little is known yet about the precise 2 Hsu AP, Sampaio EP, Khan J, Calvo KR, Lemieux JE, Patel SY et al. Mutations in functional effect of each different mutation. No clear relationship GATA2 are associated with the autosomal dominant and sporadic monocytopenia between genotype and phenotypical outcome has been described and mycobacterial infection (MonoMAC) syndrome. Blood 2011; 118: 2653–2655. making prediction of clinical course, as well as identifying those who 3 Dickinson RE, Griffin H, Bigley V, Reynard LN, Hussain R, Haniffa M et al. Exome might benefit from early intervention such as allogeneic bone sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B marrow transplantation, very challenging at the least. and NK lymphoid deficiency. Blood 2011; 118: 2656–2658. 4 Ostergaard P, Simpson MA, Connell FC, Steward CG, Brice G, Woollard WJ et al. The description of this pedigree, clearly illustrates that, even in Mutations in GATA2 cause primary lymphedema associated with a predisposition the case of seemingly sporadic AML, which is most often not a to acute myeloid leukemia (Emberger syndrome). Nat Genet 2011; 43: 929–931. familial disease entity, a thorough family history that goes beyond 5Bo¨ do¨ r C, Renneville A, Smith M, Charazac A, Iqbal S, Etancelin P et al. Germ-line first-degree relatives and the exclusion of hematological malig- GATA2 p.THR354MET mutation in familial myelodysplastic syndrome with acquired nancies, is clearly of importance in diagnosing a GATA2 mutation. monosomy 7 and ASXL1 mutation demonstrating rapid onset and poor survival. Furthermore, in patients with a combination of unexplained Haematologica 2012; 97: 890–894. immune deficiency, monocytopenia, lymphopenia, lymphedema 6 Kazenwadel J, Secker GA, Liu YJ, Rosenfeld JA, Wildin RS, Cuellar-Rodriguez J et al. and/or pulmonary defects, GATA2 mutation analysis should be Loss-of-function germline GATA2 mutations in patients with MDS/AML or Mono- considered. Although uncertainty in predicting clinical outcome of MAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature. Blood 2012; 119: 1283–1291. carriers could lead to reluctance in genetic testing, the identifica- 7 Churpek JE, Lorenz R, Nedumgottil S, Onel K, Olopade O, Sorrell A et al. Proposal for tion of a germline GATA2 mutation should prevent unnecessary the clinicaldetection and managment of patients and their family members with diagnostic procedures or intervention and could ensure familial myelodysplastic syndrome/acute leukemia predisposition syndromes. Leuk regular follow-up with an appropriate management plan should Lymphoma 2013; 54: 28–35. NPMc þ and FLT3_ITD mutations cooperate in inducing acute leukaemia in a novel mouse model

Leukemia (2013) 27, 2248–2251; doi:10.1038/leu.2013.114 leukaemia-related deaths. Karyotypic abnormalities have been widely used as a prognostic factor for risk stratification, leading to the identification of three risk-based groups: favourable, inter- Acute myelogenous leukaemia (AML) is the most common type of mediate and unfavourable.1 The intermediate group includes leukaemia in adults and is responsible for more than 40% of cytogenetically normal AMLs (CN-AML; about 50% of all cases) and

Accepted article preview online 15 April 2013; advance online publication, 14 May 2013

Leukemia (2013) 2242 – 2267 & 2013 Macmillan Publishers Limited