<strong>Diamond</strong>-<strong>Blackfan</strong> <strong>anemia</strong> in <strong>the</strong> Italian populationEpidemiology and inheritanceThe incidence <strong>of</strong> DBA is estimated to range <strong>from</strong> 5 to10 cases per million live births in Europe, with <strong>the</strong> lowestvalues in <strong>the</strong> UK and <strong>the</strong> highest in Nor<strong>the</strong>rnEurope; 7,8,10 <strong>the</strong> incidence in Italy is about 6.5 cases permillion live births. 11 The clustering <strong>of</strong> birth monthsobserved by Ball et al. in 1996, which suggested virusrelatedseasonality, 7 has not been confirmed by subsequentpopulation studies. 8,11 The sex ratio is about 1:1.The vast majority <strong>of</strong> cases are sporadic; 12,13 familiaritywith ei<strong>the</strong>r an autosomal dominant or, seldom, arecessive pattern <strong>of</strong> inheritance is reported in 10%-20% <strong>of</strong> patients. 12,13 In our series <strong>of</strong> 97 Italian patients,family inheritance is apparent in 16 families out <strong>of</strong> 91(17.5%), with an autosomal dominant pattern in tenand an autosomal recessive pattern, defined as <strong>the</strong>presence <strong>of</strong> DBA siblings <strong>from</strong> unaffected consanguineousparents, in six. The male: female ratio is1:1.04.Clinical presentationTable 1. Diagnostic criteria for DBA (accepted by <strong>the</strong>DBA working group <strong>of</strong> <strong>the</strong> European Society for PaediatricHaematology and Immunology, ESPHI).• normochromic, <strong>of</strong>ten macrocytic <strong>anemia</strong> developing in <strong>the</strong>first year <strong>of</strong> life• pr<strong>of</strong>ound reticulocytopenia• normocellular bone marrow with selective deficiency <strong>of</strong>erythroid precursors• normal or slightly reduced leukocyte count• normal or slightly increased platelet countHematologic featuresAll patients with DBA are, by definition, anemic. Anemiais already evident at birth in 25% <strong>of</strong> cases; inalmost all patients (95% in our series) presentation isin <strong>the</strong> first year <strong>of</strong> life. 12,13 Red blood cells are usuallymacrocytic; reticulocyte counts are decreased or zero.In our own series, hemoglobin (Hb) at diagnosis ranged<strong>from</strong> 2.3 to 10.8 g/dL (mean; 5.7±2.1 g/dL) and meancell volume (MCV) ranged <strong>from</strong> 67.3 to 111 fL (mean:93±9.9 fL).The o<strong>the</strong>r hematologic lineages are not involved as arule, though slightly abnormal low leukocyte and highplatelet counts have been reported at diagnosis. 14,15Bone marrow aspirates demonstrate isolated erythroblastopenia(erythroblasts
M.F. Campagnoli et al.<strong>of</strong> erythroid colonies, partially corrected by addition <strong>of</strong>SCF, make <strong>the</strong>se two parameters, not included in <strong>the</strong>major diagnostic criteria, useful in <strong>the</strong> diagnosis <strong>of</strong> DBA.TherapySteroid treatmentMore than 50% <strong>of</strong> patients respond to standardsteroid <strong>the</strong>rapy (prednisone 2 mg/kg/die orally), andsome achieve long periods <strong>of</strong> remission. 12,18 However,many responders become steroid-dependent and mayexperience steroid-related complications. High dosemethylprednisolone (30-100 mg/kg/die) has been proposedas a second-line treatment in non-responders;19,20,21 four <strong>of</strong> our ten patients treated with highdose steroids initially responded, but only one had a persistentlymodified status and subsequently achievedhematologic remission.Willig et al. reported that steroid resistance is not adefinitive feature, as some patients recover sensitivity tosteroids during <strong>the</strong> course <strong>of</strong> <strong>the</strong> disease; 8 <strong>the</strong>y <strong>the</strong>reforesuggest <strong>the</strong> repetition <strong>of</strong> standard doses before highdoses are considered.How glucocorticoids stimulate erythropoiesis isunknown. The steroid response seems not to be mediatedby <strong>the</strong> immunosuppressive activity <strong>of</strong> <strong>the</strong>se drugs,because most o<strong>the</strong>r immunosuppressants are ineffectivein DBA. Since steroids are transcription regulators,<strong>the</strong>y are thought to influence <strong>the</strong> expression <strong>of</strong>cytokines, growth factors and <strong>the</strong>ir receptors.O<strong>the</strong>r treatmentsTherapeutic options in steroid-resistant patients arechronic red cell transfusions or allogeneic stem celltransplantation (SCT). 22-24 Androgens, 13 growth factors(interleukin-3 and erythropoietin) 25,26 and cyclosporineA (CSA) 27,28 have occasionally been used, but eventuallydiscontinued on account <strong>of</strong> adverse effects or lowefficacy. The recent report that metoclopramide maymodulate erythropoiesis in DBA by increasing prolactinlevels has yet to be validated by larger studies. 29 Thrombopoietin(TPO) stimulates <strong>the</strong> growth <strong>of</strong> BFU-E <strong>from</strong>DBA patients in vitro, but its pharmacological effect hasnot been evaluated. 30Three <strong>of</strong> our patients underwent treatment with CSA,seven with interleukin-3, one with androgens and twowith metoclopramide. Only two subjects treated withinterleukin-3 achieved an initial response, but had tointerrupt <strong>the</strong> treatment due to side effects. Metoclopramidewas ineffective.Stem cell transplantation (SCT) has been explored asan alternative to chronic transfusions since 1976. 31 Morethan 70 DBA patients have undergone SCT so far 8,32,33with an overall survival <strong>of</strong> about 85% at three years<strong>from</strong> sibling donors in more recent reports. 8,33 The candidatesibling donor for a DBA patient with mutation inRPS19 should undergo molecular analysis to rule out<strong>the</strong> presence <strong>of</strong> <strong>the</strong> mutation, which could be due to agerminal mosaicism in an unaffected parent. Alternativedonor transplantation (MUD, matched unrelated donor)has been reported to be burdened by high mortality, withan actuarial survival <strong>of</strong> about 15% at 62 months, 33 butthis poor outcome was not confirmed in our recentexperience, probably due to <strong>the</strong> improvement <strong>of</strong> both <strong>the</strong>conditioning regimen and HLA matching <strong>of</strong> <strong>the</strong> donors.Five successful cord blood transplants (CBT) have beenreported in DBA patients, although <strong>the</strong> indications forsuch transplants for bone marrow failure syndromes arestill controversial. 34-38SCT was performed in twelve <strong>of</strong> our patients (5 <strong>from</strong>a sibling donor, 4 MUD and 3 CBT). No significant differencein <strong>the</strong> outcome was observed between transplants<strong>from</strong> a sibling and MUD (F. Locatelli, personalcommunication).Gene <strong>the</strong>rapyIdentification <strong>of</strong> RPS19 as <strong>the</strong> first causal gene forDBA opened <strong>the</strong> road to gene transfer experiments.Hamaguchi et al. have demonstrated that forced expression<strong>of</strong> RPS19 in CD34 + cells <strong>from</strong> four RPS19-deficientDBA patients using oncoretroviral vectors significantlyenhanced erythroid colony formation in vitro, <strong>the</strong>rebyimplying that early erythroid development can beimproved by gene transfer. 39 However, since erythroidcolony formation varies <strong>from</strong> one patient to ano<strong>the</strong>r, <strong>the</strong>effects <strong>of</strong> RPS19 gene transfer may well be different.Gene <strong>the</strong>rapy for RPS19-deficient DBA seems thus feasibleand promising, but fur<strong>the</strong>r studies are necessary.Follow-upResponse to treatment and outcomeAter and Young have summarized long-term survivalfor more than 500 DBA patients reported in <strong>the</strong> literature.13 The median survival age for <strong>the</strong> patients reportedin <strong>the</strong> past ten years is 54 years, with a significantimprovement <strong>of</strong> survival in steroid-responsive versustransfusion-dependent patients. Of 76 patients followedover a 60-year period in Boston, one-third (n=24)were in remission <strong>of</strong>f treatment and <strong>the</strong> remaining twothirdswere dependent on ei<strong>the</strong>r transfusions (n=36) orsteroids (n=13); three had been lost to follow-up. 40In our series, 85 patients were available for long-termevaluation (mean follow-up: 150±95 months). Their statusat <strong>the</strong> time <strong>of</strong> <strong>the</strong> study is reported in Figure 1:61,2% were undergoing treatment (two-thirds weretransfusion-dependent and one-third steroid-dependent)and 30,6% were free <strong>from</strong> treatment, one-third482haematologica 2004; 89(4):April 2004
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