Skin manifestations among GATA2-deficient patients A. Polat, M. Dinulescu, S. Fraitag, S. Nimubona, F. Toutain, S. Jouneau, E. Poullot, C. Droitcourt, A. Dupuy

To cite this version:

A. Polat, M. Dinulescu, S. Fraitag, S. Nimubona, F. Toutain, et al.. Skin manifestations among GATA2-deficient patients. British Journal of Dermatology, Wiley, 2018, 178 (3), pp.781-785. ￿10.1111/bjd.15548￿. ￿hal-01780493￿

HAL Id: hal-01780493 https://hal-univ-rennes1.archives-ouvertes.fr/hal-01780493 Submitted on 16 May 2018

HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Accepted and , of range wide a present syndromes These deficiency. cell NK and B monocyte, cell, dendritic myeloid acute syndrome, myelodysplastic familial syndrome, Emberger syndrome, monoMAC as such diseases, various in identified been have GATA2 ABSTRACT: Article affiliations: Author Droitcourt A. Polat manifestations patientsSkin among GATA2-deficient Mail id: Report : Article type Case 7. Rennes 1 University, Rennes, Rennes 1University, Institut France; Génétique développementet deRennes 7. Department, Pathology CHURennes, France. 6. Respiratory D 5. Department, Pediatric CHU Rennes,France. Rennes, 4. Haematology Department, CHU Rennes,France. Rennes, 3. APHP, Malades, Department, Necker-Enfants France. Pathology Hopital Paris, 2. Dermatology Department, CHU Rennes,France. Rennes, 1. UMR CNRS 6290, Rennes, France. UMR 6290,Rennes, France. CNRS University, Rennes, France. 1 , M. Dinulescu alain.dupuy@chu- 1 , A. Dupuy epartment, CHU Rennes, France; IRSET Rennes1 UMR 1085, 1,7 1 , S.Fraitag rennes.fr 2 , S.Nimubona

3 , F.Toutain 4 , S.Jouneau 5 ,

E. Poullot 6 , C. . Accepted preced features cutaneous where patients GATA2-mutated three on report We manifestations related to organ other systems. features. dermatologic pulmonary, infectious, predominantly hematological, with characteristics clinical of spectrum broad a identified and mutations Spinner myelodysplasia). (MDS/AML) leukemia myeloid deficiency cell (NK-) killer natural and B- monocyte, cell, dendritic in mutations GATA2 confirmed has research Further (monoMAC). Hsu by 2011 in described ArticleINTRODUCTION: encounter can Dermatologists lesions. patients recognizethisdisorder. GATA2-mutated andshould facial lupoid granulomatous and glossitis, and and macroglossitis dermatological hypertrophy, gingival described: previously been not have that manifestations common skin with with also but deficiency, GATA2 of presenting diagnosis the to leading patients features haematological 3 report and nodosum, We erythema or lymphedema. panniculitis warts, extra-genital or genital mainly features, dermatological have patients GATA2-mutated of 70% to Up syndrome. myelodysplastic haematologic and infections severe by dominated features, clinical eeoyos uain o GT2 a ic igr rncito fco, ee first were factor, transcription finger zinc a GATA2, of mutations Heterozygous et al et t al. et . 1 1 4 4 in patients with monocytopenia and mycobacterial infections mycobacterial and monocytopenia with patients in 3 eiwd h mdcl eod o 5 ptet wt GATA2 with patients 57 of records medical the reviewed n i Ebre snrm (rmr lmhdm with lymphedema (primary syndrome Emberger in and 2 i fmla meoypatc syndrome/acute myelodysplastic familial in , al nolsi, aclr n lymphatic and vascular neoplastic, , al iodr sc as such disorders ed the the . alveolitis. Accepted biopsy pulmonary Surgical proteinosis, alveolar pulmonary showed disease. lung interstitial and cough dry breath, of shortness Case 2 status. GATA2familial study to and deafness any investigate to underway are tests Further 5). exon on (p.R362X) (c.1084C>T GATA2 mutation confirmed testing Genetic syndrome. Emberger to pointed leucopenia and warts multiple lymphedema, congenital medium of association and syndrome, The normal. was karyotype marrow bone myelodysplastic The blasts. excess without density megakaryocyte without dysmyelopoiesis, showed biopsy marrow bone A monocytes. and lymphocytes neutrophils, of levels low but count, platelet revealed counts cell Article for cellulitis of right leg,treated the with antibiotics. hemorrh lymphedema, often was which hypertrophy bilateral evidenced examination Physical and aphta recurrent have to started epistaxis. At 11, he hedeveloped lymphedema right leg. ofthe when 9 was he until history medical no had He A twelve-year-old our to departmentfor whitepatientofthe wasreferred lymphedema leg,right lower age evolvingsince the ofeleven. Case 1: CASEREPORTS: A 28-year-old woman was admitted to the Respiratory department with increasing increasing with department Respiratory the to admitted was woman 28-year-old A a normal haemoglobin level alongside macrocytosis, normal normal macrocytosis, alongside level haemoglobin normal agic (Figures 1 A and B). The patient was hospitalized was patient The B). 1 Aand (Figures agic and broncho-alveolar lavage evidenced lymphocytic evidenced lavage broncho-alveolar and lna wrs n gingival and warts plantar (ENT) infections (otitis, (otitis, (ENT) infections rhinitis) and herpes. labial throat and nose ear, recurrent experienced she childhood In years. 5 lasting pancytopenia Case 3 stem-cell Hematopoietic deteriorated. parameters considered. transplantation (HSCT)being is respiratory her MDS but months, 9 stable mutation Over remained GATA2 identified. was and 5) syndrome, exon MonoMAC on (p.R3444GfsX43) have (c.1020_1029dup to thought was was anomaly She karyotype diagnosed. without (MDS) syndrome Myelodysplastic dysplasia. lineage three- with normo-cellular was biopsy marrow Bone pancytopenia. showed counts cell Blood . Accepted of complained she and areas, depapillated dysgueusia ( several with tongue enlarged an had She Article Long-term formycobacteria cultures negative were ( clusters in grouped observed, were cells inflammatory some periphery elasti fragmented with associated bundles collagen hyalinized the sparing and thickened totally horizontal, with sclerosis thick subcutis, showed They dermis. and epidermis the overlying in performed both were They lesions. similar roughly showed biopsies erythemanodosum.to concluded two limblesions The upper theof Biopsies legsand the panniculitis upperlimbson the 1C). (Figure on lesions sclerodermiform hands, the on warts multiple revealed also examination Physical (Figureearlier 1C).Lymphoscintigraphy lymphatichypoplasia. vessel suggested years five diagnosed legs, lower both affecting lymphedema idiopathic of history a had She 2-erod ht wmn a rfre t te eaooy eatet for department hematology the to referred was woman white 20-year-old A Figure 1 Figure

F). in skin biopsies. the fbr (ren. n the In (Orcein). fibers c Figure 1 Figure D and E). and D . Accepted after month few a stemhematopoietic transplantation. cell occurred limbs lower both of Lymphedema remission. total showed marrow bone the and range normal the within were counts cell Blood healed. rapidly lesions cutaneous facial the and infection ENT further no had she transplantation after months Five pheno- curative underwent she afteridentical transplantation chemotherapy.allogenic stem-cell (AML), leukemia myeloid acute of risk the of Because patient's disorderwascaused by tested, were sister and parents Her with diagnosed MonoMAC syndrome. was she and identified was 5) exon on (p.T354P) (c.1060A>C mutation normal.AGATA2 was karyotype Her MDS. diagnosis the to leading dysplasia three-lineage showed examination marrow Bone counts). monocyte and lymphocyte neutrophil, cell, white blood platelet, low hemoglobin, low (including pancytopenia revealed counts cell Blood Article mycobacterianegative forbacteria, and fungi. were cultures Cutaneous negative. were tests staining fungal and mycobacterial Bacterial, and multinucleated cells neutrophils in the giant with associated epithelioid, them of some histiocytes, of This up made mostly follicles. was infiltrate hair between mainly located lesions, two the in dermis mid and upper the in infiltrate granulomatous a showing times, different 2 at performed were Twobiopsies skin effective. was zinc) and cyclins metronidazole, (topics, treatments different the of none and fifteen age ( temples and forehead cheeks, the of lesions lupoid and hands, both on warts multiple loss, weight fatigue, with presented She de-novo but no GATA2 mutation was detected, suggesting that the that GATA2suggesting no detected, but was mutation Figure 2 Figure

mutation. deeper ( part. A and B). These facial lesions first appeared at appeared first lesions facial These B). and A Figure 2

C).

of NK-cells or their dysfunction leads to these severe manifestations. Our 3 patients had had on warts numerous patients 3 Our manifestations. severe these to leads dysfunction their or NK-cells of generalized, warts and condylomata and warts generalized, infections HPV persistent have patients leukemia. and failure respiratory infections, life-threatening to asymptomatic from severity, of range . oncogenic with Acceptedinfected Patients instated. treatments the to resistant were but manifestations, limited had 3 estimated at onset91% 5yearsafter of and67%20 after symptoms years onset been has Survival manifestation. clinical no have to seem individuals some although years), of GATA2-mutated patients been have reported Article inheritance. ( spontaneously arise mutations allele mutated the of function of loss cause to appear They described. been GATA2100 Nearly development. have vascular mutations and lymphatic and differentiation, DISCUSSION: Tableresultsfor the3patients. 1summarizes clinical and blood test Dermatological features appear to be secondary to several conditions. Up to 70% of 70% to Up conditions. several to secondary be to appear features Dermatological GATA2-mutated( presentationsheterogeneous very have patients 78 to months 5 (range years 20 is manifestations clinical first the at age Median GATA2 mutations have been identified in more than 300 patients and 3 large cohorts cohorts large 3 and patients 300 than more in identified GATA2been have mutations haematopoietic early regulates that factor transcription finger zinc a is GATA2 7 n non-oncogenic and the limbs. Patient 2 had no recurrence of warts after HSCT. Patients 1 and 1 Patients HSCT.after warts of recurrence no had 2 Patient limbs. the e novo de 4 – 8 6 Ps ae en eotd Te aoiy f these of majority The reported. been have HPVs . Absence of cellular immunity caused by the paucity the by caused immunity cellular of Absence . bt r te tasitd i atsml dominant autosomal via transmitted then are but ) 6 Svr HV netos r rclirn, possibly recalcitrant, are infections HPV Severe . 4 – 6 .

Figure 3 Figure 4 1,4,5 – 6 ) and a wide a and ) . Germline . . underlying of setting the in reported are MDS/AML syndrome Sweet of described cases 3 been and also have carcinomas basal-cell and squamous-cell cell squamous or dysplasia intra-epithelial HPV-related Non important. therefore is dermatologists by patients of Monitoring carcinoma. squamous into evolve may condylomata as such mycobacteria non-tuberculous evidence may lesions nodular of samples Bacteriological lesions. granulomatous or nodosum erythema panniculitis, show biopsies Skin morphea. deep resembling subcutis, the in deep located changes sclerodermiform with presented 2) (Case patients the of one Here, syndrome). sclerosis-like multiple and damage liver cirrhosis-like phenomena auto-immune or infections bacterial infections, NTM causes: several have can conditions These extremities. lower the on usually lymphedema was first the symptom disease.of their 2 and 1 patients For report. our in 1 patient for as stockings, compression with managed be lesions skin been have limbs lower the of ulcers as such manifestations infections dermatological with described mycobacterial Non-tuberculous manifestations. cutaneous entail diagnosis. mutation GATA2 after recommended is vaccination HPV Early carcinoma. cell squamous malignancies HPV-related develop may They diagnosis. GATA2 before years warts develop patients

Accepted complex,avium abcessus.M szulgai, M M Article Other severeOther induced infections byimmunodeficiencyinGATA2 syndromesmay also Finally, dermatological manifestations can be neoplastic. Chronic, recurrent warts and warts recurrent Chronic, neoplastic. be can manifestations dermatological Finally, panniculitis, or nodosum erythema have patients GATA2-mutated of third one to Up 4 4 . . , including sq including , The most frequent complication is cellulitis. Lymphedema, with early care, can care, early with Lymphedema, cellulitis. is complication frequent most The uamous intra uamous - epithelial lesions, bowenoid papulosis and invasive invasive and papulosis bowenoid lesions, epithelial

10 lpslk snrms piay biliary primary syndromes, (-like 10,11 Additionally . 9 and nodular and skin HSCT are suggestive of this mechanism. Manifestations associated with GATA-2with associated Manifestations mechanism. this HSCTof suggestive are dysfu . Acknowledgement: authors thankThe Ms Angela Verdier for the editing manuscript. disease. HPV-related ornon-HPV-related skin . multiform this of diagnosis early Dermatologic in crucial are dermatologists symptoms, clinical other precede can they As spectrum. clinical mutation GATA2 recently-described The mechanisms.any clue to therelated immunodeficiencies. other in manifestation a unable as are we although newfinding, a constitute 2) (case changes sclerodermiform reported been not has it since p particular the non-specific, rather is hypertrophy gingival If manifestations. the of novelty the patients, our In immunodeficiency). infectious, (neoplastic, causes express are they numerous, are diverse from immunodeficiency causes with patients in occur cells. can inflammatory lesions chronically skin Granulomatous and acute mixed with biopsy lesions skin granulomatous The face. revealed her on exclusively located lesions lupoid involving presentation hypertrophy gingival of history a had Accepted non-infe facial of Articleresentation 12 Our patients had unusual cutaneous manifestations not described previously. 1 described Patient not manifestations cutaneous unusual had patients Our In conclusion, we highlight both well-known and new dermatologic new and well-known both highlight we conclusion, In . In our patient, the negative microbiological investigations and the resolution after resolution the and investigations microbiological negative the patient, our In al monitoring is important for patients identified in order to detect or prevent prevent or detect to order in identified patients for important is monitoring ctious granulomatous dermatosis (case 3) is worth mentioning, worth is 3) (case dermatosis granulomatous ctious ed n lre ra o ogn, n cn e eae t several to related be can and organs, of array large a in n rcret pt. ain 3 Patient aphta. recurrent and it is difficult to ascertain to difficult a a distinctive a had al features in the the in features to provide to provide nction . 12 11 10 9 8 7 6 5 4 3 2 1 REFERENCES: JL,Elghetany MT,CurryChu VH,Curry CV. idiopathic MonoMACversusCD4+ West ES,KingsberyMY, EM, Mintz Lübking A,VosbergS,Konstandin NP, M,Dickinson R, Collin V.HaematopoieticBigley andimmune associated with defects M, C,Bellanné-ChantelotPasquet Fieschi C, MA, LA,Spinner Sanchez Hsu AP, HS,Scott HahnCN, Carmichael CL, V,HaniffaBigley S, M,Doulatov Hsu AP,EP,Khan Sampaio J, with susceptibility fungi,to mycobacteria, papillomaviruses,myelodysplasia. and hematopoiesis, lymphatics, andimmunity. 2010; Familial (MDS) and LeukemiaAcute Myeloid (AML). deficiency. NKB and lymphoid Blood dominant and andmycobacterial sporadic monocytopenia infection(MonoMAC) syndrome. immunodeficiency disorders. immunodeficiency swelling, and deafness. 2010; 97 . Comment toHaematologica. 2011;96(8):1221-5. BrJDermatol deficiency. transplantation. GATA2dysplasia, ASXL1 mutation treatedand withallogeneic hematopoietic GATA2 mutation. Oncol HématologiePédiatrique pléomorphe.biologique Recommandation

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20 years 31 years 12 years Present Present Patient Case 3 Case 2 Case 1 Case age

.

Accepted ArticleGender M F F

Bilateral lymphedema of Bilateral of lymphedema granulomatous face (10):Lupoid ofthe lesions Warts (childhood)Recurrent labialherpes Warts effluviumTelogen (29) Glossitis(28) morphea Deep (23) Bilateral (right>left) lymphedema Gingival hypertrophy(9) Cellulitisof right lower leg (12) of Lymphedema lower right leg (11) Warts Recurrent (9) aphta Dermatologic clinical features clinical Dermatologic

(age atonset (age

-

like lesions aseptic

: years)

lesion

lower legs

(28)

s

Normal karyotype Low level MDS B Monocytopenia Thrombopenia Anemia Normal karyotype Hypergammaglobulinemia MDS Monocytopenia Thrombopenia Anemia Normal karyotype Myelodyspoiesis without MDS (IgG) Low level ofgammaglobulin Monocytopenia Neutropenia Macrocytosis - cell lymphopenia

Haematologic signsHaematologic

o f IgA

haematologic Age atfirstAge 11 years 28 years 11 years sign

al

Influenza (childhood) Recurrent ENTinfections Fatigue, loss of weight (11) aspergillosis colonisation (30) P me (30) P F proteinosis(28) Pulmonary alveolar Epistaxis (9) atigue, loss of weight (28) Other clinicalfeatures (age Other ulmonary pneumocystisand hyllodestumor ofleftbreast nometrorrhagia (29)

at onset: years)

Age at Age years year years visit first 11 23 11 s

diagnosis 19 years 28 years 12 years Age at Age

GATA2 mutationGATA2 c.1020_1029dup p.R3444GfsX43 c.1060A>C c.1084C>T p.R362X p.T354P Protein exon 5 exon 5 exon 5 exon

and pulmonary pulmonary and Allogenic HSCT Allogenic HSCT consideration (age: (age: graft under graft under Treatment Treatment None (19) years)

. Accepted Article . Accepted Article