Congenital dyserythropoietic anemia type I (CDA I) is a rare autosomal recessive disorder with ineffective erythropoiesis, characteristic morphological abnormalities of erythroblasts, and iron overloading. CDA I is caused by mutations in the CDAN I gene, encoding a protein named codanin-1. Complex bone abnormalities, especially syndactyly, have not been systematically described with this disease. We present two cases of morphologically and genetically confirmed CDA I with striking bone abnormalities and response to treatment with alpha-interferon. Our cases clearly document the association of skeletal anomalism with CDA I and indicate that codanin-1 may play a role in the development of the skeleto

Benz, Rudolf

Fehr, Joerg

Goede, Jeroen

Heimpel, Hermann

Schwarz, Klaus

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Ann Hematol (2006) 85: 591–595DOI 10.1007/s00277-006-0143-zORIGINAL ARTICLEJeroen S. Goede . Rudolf Benz . Joerg Fehr .Klaus Schwarz . Hermann HeimpelCongenital dyserythropoietic anemia type I with boneabnormalities, mutations of the CDAN I gene, and significantresponsiveness to alpha-interferon therapyReceived: 27 April 2006 / Accepted: 3 May 2006 / Published online: 10 June 2006# Springer-Verlag 2006Abstract Congenital dyserythropoietic anemia type I(CDA I) is a rare autosomal recessive disorder withineffective erythropoiesis, characteristic morphologicalabnormalities of erythroblasts, and iron overloading.CDA I is caused by mutations in the CDAN I gene,encoding a protein named codanin-1. Complex boneabnormalities, especially syndactyly, have not beensystematically described with this disease. We presenttwo cases of morphologically and genetically confirmedCDA I with striking bone abnormalities and response totreatment with alpha-interferon. Our cases clearly docu-ment the association of skeletal anomalism with CDA I andindicate that codanin-1 may play a role in the developmentof the skeleton.Keywords CDA I . Dysostosis . Interferon . SkeletonIntroductionCongenital dyserythropoietic anemia type I (CDA I, MIM224120) is a rare autosomal recessive disorder withineffective erythropoiesis, characteristic morphologicalabnormalities of erythroblasts and peripheral red bloodcells and iron overloading independent of transfusions [1–4]. CDA I is caused by mutations in the CDAN I geneencoding codanin-1 [5, 6]. In the German CDA Registry,103 cases out of 88 families could be identified frompublished case reports and own unpublished observations.Furthermore, 70 cases in a large Bedouin tribe weredescribed by Tamary et al. from Israel [7, 8]. Complex boneabnormalities, especially acral dysostosis with syndactyly,have occasionally been described with CDA I [9–14]. TheCDAN I gene was sequenced in only a few families withdysostosis, and the relation of dysostosis with the defects inerythropoiesis is not understood. In this paper, we presenttwo cases of morphologically and genetically confirmedCDA I with striking bone abnormalities which share anidentical mutation in one but show a different mutation inthe other allele of the CDAN I gene. Both patients had asignificant response to treatment with alpha-interferon, asshown before in almost all cases reported to receive thistype of therapy [4].Case 1The first patient (UPN 178/01 of the German CDARegistry) is a 42-year-old Caucasian male from Switzerland.Two siblings died immediately after birth and one sister aswell as both parents are healthy without anemia and with-out bone malformations. The family was traced back forfour generations, all living within one area of Switzerland.The proband presented with congenital anemia first docu-mented at the age of 2 years and with acral dysostosis.Skeletal dysmorphology consisted of mutual syndactyly ofthe second and third toes with hypoplasia of the fourthmetatarsal and unilateral hypoplasia of the distal phalangeof the fourth left finger with an aplastic nail (Fig. 1). Themalformations of the feet prompted orthopedic correctionsshortly after adolescence, resulting in the missing fourthmetatarsals and scarred second and third toes (Fig. 1).Besides these skeletal malformations, moderate bilateralptosis is present since childhood. Our patient grew up withJ. S. Goede (*)Institute of Oncology and Haematology, City-Hospital Triemli,Birmensdorferstrasse 497, 8063 Zürich, Switzerlande-mail: jeroen.goede@triemli.stzh.chTel.: +41-44-4661898Fax: +41-44-4662747R. Benz . J. FehrClinic of Haematology, University-Hospital Zürich,Zürich, SwitzerlandK. SchwarzDepartment of Transfusion MedicineUniversity-Hospital Ulm,Ulm, GermanyH. HeimpelDepartment of Internal Medicine IIIUniversity-Hospital Ulm,Ulm, Germanychronic anemia disabling him from sportive activity.Anemia occasionally required transfusion therapy inchildhood. Because of increasing organomegaly, splenec-tomy was performed at the age of 9 years, without asignificant improvement of anemia. Mental developmentwas normal and the patient graduated as a chemist at theage of 26 years. The diagnosis of CDA I was establishedafter correspondence with H.H. at the end of the 1970s byC. Gasser who presented the two cases of this report at the6th meeting of the International Society of Hematology inAthens, 1981 [1]. After adolescence, the patient presentedstable anemia with hemoglobin concentrations of 8–9 g/dland a mean corpuscular volume (MCV) of 110–120 flwithout need for transfusions. He developed iron overloadthat has been treated with subcutaneous deferoxamine withfading compliance. Three years ago, the patient wasreferred to our institution with significant iron overload.According to the widely accepted diagnostic criteria [2],the diagnosis of CDA I was confirmed and we startedchelation with deferoxamine and deferiprone. Furtheranalysis showed a compound heterozygous mutation ofthe CDAN I gene with mutations in exon 24 [3259 insertion(ins) T], leading to a frameshift (fs) at the protein level and26 (C3503T, Pro1129Leu) [3]. Treatment with interfer-on-α-2b (3×3 Mio IE per week) resulted in a significantincrease of hemoglobin. Tolerance of interferon was goodand quality of life improved extensively. As main sideeffect, transitory asymptomatic neutropenia (minimal500/μl) developed. After 6 months of therapy, we switchedto Peginterferon-α-2b. Tolerance was comparable to thenon-pegylated form of interferon. We again observedasymptomatic neutropenia.Case 2The second patient (UPN 177/01 of the German CDARegistry) is a 48-year-old Caucasian female fromSwitzerland. One brother and both parents are not anemicand show no skeletal malformations. The family was tracedback for two generations. Besides inborn anemia, theproband has mutual malformations of her toes (Fig. 1) andmoderate bilateral ptosis like the first case. After birth andduring infancy, she received multiple transfusions. At theage of 9 years, splenectomy and, 6 years later, syndactylycorrection of the third and fourth toes on the right footwere performed. After splenectomy, the transfusion inter-val was reduced, and after adolescence there was no needfor further transfusions. Because of increasing ferritinlevels, a liver biopsy was carried out at the age of 38, whichshowed massive siderosis and beginning cirrhosis. An ironchelating therapy was started with deferiprone and wasproved to be successful in a second biopsy 3 years laterwith almost complete normalization of the former findings.Fig. 1 Pictures of dysostosis inCDA I. a X-ray photograph ofthe feet of case 1. b Feet of case1. c Hypoplasia of the distalphalange of the fourth finger atthe left with nail hypoplasia ofcase 1. d Right and left foot ofcase 2592Ferritin levels decreased to normal values and remained inthe normal range on continued therapy of very low dose ofdeferiprone (500–1,000 mg/d). Hemoglobin levels werestable during the last 10 years with concentrations of 9–10 g/dl and a MCV of 100–120 fl. The patient sufferedfrom unspecific fatigue most probably related to moderateanemia. A molecular analysis demonstrated a compoundheterozygous mutation of the CDAN I gene with affectionof exons 12 (A1910G, N598>S) and 24 [3259 ins T; fs] [3].The parents of the mother, who shares the mutation on exon24 with the proband, stem from the same region as theparents of the mother of case 1, who also shows themutation on exon 24. The father originated from England.We started a treatment with interferon-α-2b with theintention to increase the hemoglobin concentrations and, inthe long term, to maintain normal ferritin levels withoutchelation. Because of marked neutropenia after the initialfive doses (3×3 Mio units per week), we decreased thedose of interferon to 2 Mio units per week. Since startingthe treatment, the hemoglobin levels are between 11 and12 g/dl and the patient feels markedly more vital.DiscussionThe diagnosis of CDA I is based on the general diagnosticcriteria of the CDAs and characteristic abnormalities oferythroblasts seen in light and electron microscopy [2, 3,13, 15]. Most patients have a life-long moderate macro-cytic anemia which is more severe in infancy andchildhood, requiring blood transfusions in this period butnot thereafter. Mutations of the CDAN I gene were morerecently detected in all members of the Bedouin tribes asobserved by scientists from Israel and in 22 out of 24unrelated European families [3, 6, 16]. Although electronmicroscopy was not done in the two patients described inthis report, they unequivocally fulfill the criteria of CDA I,including mutations in the two alleles of the CDAN I gene.The response to therapy with interferon-α is further supportof correct diagnosis.Morphologic body abnormalities are observed inapproximately 10% of CDA I cases [13] and may be thepresenting features for the referral of children [12] tospecialized institutions. Among them, dysostosis is partic-Fig. 2 Hemoglobin concentra-tion and neutrophil count afterthe beginning of interferontreatment in case 1 (above)and 2593ularly frequent, consisting of foot and hand dysmorphol-ogies as were seen in our patients (Fig. 1). The observationthat the two patients described show similar dysostosis ofboth feet and that the patients share an identical exon 24mutation of CDAN I allowed the hypothesis that either thisspecific allele of CDAN I or a variation in a gene linked tothis allele at chromosome 15q15 may act dominantly andbe causative for the dysmorphologies. This hypothesis wasdismissed on the fact that the ancestors of both probands,being heterozygotes for these mutations and coming fromthe same region in Switzerland (and may therefore berelated, although this was not proven by pedigree dataavailable), were unaffected. In addition, as shown inTable 1, similar patterns of dysostosis were observed inunrelated families showing other CDAN I mutations,excluding the specificity of the exon 24 mutation forskeletal dysmorphologies.In drosophila, the cytoplasmic codanin-1-like proteindiscs lost (dlt) is needed for cell survival and cell cycleprogression. In the absence of dlt, the S phase of the cellcycle cannot be completed and, thus, mitosis cannot beinitiated. A lack of dlt leads to a 30% reduction in thenumber of blood cells in third instar larvae and to a variableloss of imaginal discs [17]. These observations in dro-sophila hint at the possibility that codanin-1 may beinvolved in several developmental pathways, explainingthe human phenotype of dyserythropoietic anemia anddysostosis in some cases.The favorable response to interferon-α in the twopatients observed (Fig. 2) confirms similar data on patientswith CDA I, with the exception of three unrelated casesfrom India [18]. There is not only an improvement of thehemoglobin level but, in a long-term perspective, areduction of iron overload that can also be achieved [19].As side effects of interferon can reduce the compliance andmay result in neutropenia, dose adjustments are required.Our data, so far, confirm a decreased need for chelationtherapy among patients on an interferon regimen.References1. Delaunay J, Iolascon A (1999) The congenital dyserythropoie-tic anemias. Bailliere’s Best Pract Res Clin Haematol 12(4):691–7052. Heimpel H (2004) Congenital dyserythropoietic anemias:epidemiology, clinical significance and progress in under-standing their pathogenesis. Ann Hematol 83(9):613–6213. Heimpel H, Schwarz K, Ebnöther M, Goede JS, Heydrich D,Kamp T, Lothar P, Rath B, Roessler J, Schildknecht O, SchmidM, Wuillemin W, Einsiedler B, Leichtle R, Tamary H, Kohne E(2006) Congenital dyserythropoietic anemia type I (CDA I):molecular genetics, clinical appearance and prognosis based onlong-term observation. 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Congenital dyserythropoietic anemia type I with bone abnormalities, mutations of the CDAN I gene, and significant responsiveness to alpha-interferon therapy

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Congenital dyserythropoietic anemia type I with bone abnormalities, mutations of the CDAN I gene, and significant responsiveness to alpha-interferon therapy

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