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Pediatric hematology Inherited marrow failure syndromes

I. Dokal ABSTRACT The inherited/constitutional (BM) failure syndromes are a diverse group of disorders Centre for Paediatrics, characterized by BM failure usually in association with one or more extra-hematopoietic abnormality. Blizard Institute, The BM failure, which can involve all or a single lineage, often presents in childhood but this may not Barts and The London School of be until adulthood in some cases. Furthermore, some patients initially labeled as “idiopathic aplastic Medicine and Dentistry, ” are cryptic presentations of these genetic syndromes. Significant advances in the genetics of Queen Mary University of London, these syndromes have been made with more than fifty disease identified to date. These Barts Health NHS Trust, advances have provided an insight into normal hematopoiesis and how this is disrupted in patients London with BM failure. They have also provided important information on fundamental biological pathways: DNA repair-Fanconi genes; maintenance-dyskeratosis congenita genes; ribosome biogene - Correspondence: sis-Shwachman Diamond syndrome and Diamond-Blackfan anemia genes. Additionally, as these dis - Inderjeet Dokal orders are usually associated with developmental abnormalities and an increased risk of , they E-mail: [email protected] are providing an insight into human development and the genesis of cancer. In the clinic, genetic tests Acknowledgments stemming from the recent advances are facilitating diagnosis and personalized management. I would like to thank my current col - Hematopoietic stem cell transplantation using fludarabine-based protocols has improved outcomes leagues (Laura Collopy, Upal significantly; management of some of the other complications remains a challenge. Hossain, Hemanth Tummala, Tom Learning goals Vulliamy and Amanda Walne) and past colleagues (Richard Beswick, At the conclusion of this activity, participants should know that: Michael Kirwan, Stuart Knight, Anna - the inherited BM failure syndromes are a very heterogeneous group of disorders characterized by Marrone, Philip Mason and David inability to make an adequate number of mature blood cells, usually in association with one or Stevens) whose contribution has more extra-hematopoietic abnormalities; been important to our research pro - - more than fifty disease genes have been identified and these have provided an important insight gram over the years. Hemanth into basic cell biology and hematopoiesis; Tummala provided useful comments - the genetic advances are facilitating accurate diagnosis and personalized management; on the manuscript. I am also grate - - hematopoietic stem cell transplantation using low-intensity fludarabine-based protocols is asso - ful to the patients and all our col - ciated with low toxicity and greater efficacy. leagues (doctors and nurses) for their support and to The Wellcome Trust and Medical Research Council for financial support over the years. Introduction atresia) and neurological abnormalities. Approximately 30% of FA patients have no Hematology Education: overt somatic abnormalities. The majority of the education program for the The inherited bone marrow (BM) failure syndromes are a diverse group of life-threaten - patients present towards the end of the first annual congress of the European 1 decade of life. However, increasingly some Hematology Association ing disorders. The features of the recognized inherited BM syndromes are summarized in patients are being diagnosed in adulthood and 2014;8:299-308 Tables 1 and 2. An outline of each syndrome is many patients diagnosed in childhood are sur - given below. viving into adulthood. FA cells display a high frequency of sponta - neous chromosomal breakage and hypersensi - tivity to DNA cross-linking agents such as diepoxybutane and mitomycin-C. This “FA Fanconi anemia (FA) was first described by cell hallmark” led to the development of a 2 Fanconi in 1927. It is usually inherited as an diagnostic test over two decades ago and has autosomal recessive (AR) trait, but in a small facilitated many advances, including clarifica - subset of patients it can be an X-linked reces - tion of the genetics, with 16 subtypes/comple - sive (XLR) disorder. FA patients are clinically mentation groups currently characterized. 4-19 3 heterogeneous. Characteristic features The encoded by the FA genes (Table include the progressive development of BM 2) participate in a complicated network impor - failure and an increased predisposition to tant in DNA repair. 20-22 Specifically, eight of malignancy (hematologic and non-hematolog - the FA proteins (FANCA, FANCB, FANCC, ic). Affected individuals may also have one or FANCE, FANCF, FANCG, FANCL and more developmental/somatic abnormality FANCM) interact with each other and form a including skin (e.g. cafe au lait spots), skeletal nuclear complex called the “FA core com - (e.g. radial hypoplasia), genitourinary (e.g. plex”. The FA core complex is required for the single kidney), gastrointestinal (e.g. duodenal activation of the FANCI-FANCD2 Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) | 299 | 19 th Congress of the European Hematology Association

complex to a monoubiquitinated form (FANCI-FANCD2- highly conserved nucleolar protein called . Ub). FANCI-FANCD2-Ub then interacts with DNA repair Dyskerin associates with the H/ACA class of small nucle - proteins (including BRCA2, BRCA1 and RAD51) leading olar RNAs in small nucleolar ribonucleoprotein particles to repair of the DNA damage. FA-D1 patients have biallel - (snoRNPs), which are important in guiding the conversion ic in BRCA2. These observations have linked of uracil to pseudouracil during the maturation of riboso - the FA proteins with BRCA1 and BRCA2 (FANCD1) in a mal RNA. Dyskerin also associates with the RNA compo - DNA damage response pathway: “the FA/BRCA path - nent of (TERC) where it is important in stabi - way”. The BRCA2 protein is important in the repair of lizing the telomerase complex, which is critical in the DNA damage by homologous recombination. Cells lack - maintenance of . 42-44 Heterozygous mutations in ing BRCA2 inaccurately repair damaged DNA and are TERC and TERT (telomerase ) have hypersensitive to DNA cross-linking agents. It has been been found in patients with AD-DC 29-31 and in some established that FANCJ is BRIP1 (partner of BRCA1), patients with aplastic anemia (AA), myelodysplasia FANCN is PALB2 (partner of BRCA2), and that SLX4 is (MDS), acute leukemia, pulmonary and liver fibrosis. 45-50 also a FA protein. These findings further strengthen the A subset of patients with the multi-system disorder connection between FA and DNA repair; specifically it Hoyeraal-Hreidarsson (HH) syndrome have been found to appears that the FA pathway orchestrates incisions at sites have DKC1 mutations. 51 It has also been established that of cross-linked DNA. 21 Recent studies suggest the FA pro - AR-DC is genetically heterogeneous with seven subtypes teins may be important in counteracting aldehyde-induced due to biallelic mutations in NHP2 , NOP10 , TERT, genotoxicity in hematopoietic stem cells. 23-24 In addition to TCAB1 , USB1 , CTC1 and RTEL1 . One AD-DC subtype their role in DNA repair, they also have other functions. was found to be due to mutations in TINF2 that encodes a For example, there is evidence of mitochondrial dysfunc - component of the shelterin complex that protects telom - tion and impaired ROS (reactive oxygen species) detoxi - eres and controls access of telomerase to the telomere. fying machinery in FA cells. 25 Collectively, these findings have demonstrated that classi - cal DC, HH, a subset of AA and MDS/AML are principal - ly due to a defect in telomere maintenance, and cells from Dyskeratosis congenita these patients have very short/and or abnormal telom - eres. 42,52 The multi-system abnormalities seen in these Classical dyskeratosis congenita (DC), first described in patients, including the increased incidence of malignancy, 1910, is an inherited BM failure syndrome characterized have highlighted the critical role of telomeres and led to by the muco-cutaneous triad of abnormal skin pigmenta - 26,27 the recognition of a new category of human diseases: “the tion, dystrophy and mucosal . A variety telomereopathies”. of other abnormalities have also been reported: dental (e.g. severe caries), gastrointestinal (e.g. esophageal stenosis), genitourinary (e.g. phimosis), neurological (e.g. cerebellar Shwachman-Diamond syndrome hypoplasia), ophthalmic (e.g. naso-lacrymal duct narrow - ing), pulmonary (e.g. fibrosis) and skeletal (e.g. osteo - Shwachman-Diamond syndrome (SDS), first described porosis). BM failure is the major cause of mortality with in 1964, is an AR disorder characterized by exocrine pan - an additional predisposition to malignancy (hematologic creatic insufficiency, BM failure and other somatic abnor - and non-hematologic) and fatal pulmonary complications. malities (particularly metaphyseal dysostosis). 53-54 XLR, autosomal dominant (AD) and AR subtypes of DC Features of pancreatic insufficiency are apparent early in are recognized. Ten DC genes ( DKC1 , TERC , TERT , infancy. The spectrum of hematologic abnormalities NOP10 , NHP 2, TINF2 , TCAB1 , USB1 , CTC1 and includes neutropenia, (approx. 20%), MDS RTEL1 )28-41 have been identified to date. and leukemia (approx. 25%). The majority (>90%) of SDS The mutated in X-linked DC ( DKC1 ) encodes a patients have biallelic mutations in the SBDS gene. 55 The

Table 1. Characteristics of the inherited bone marrow failure syndromes.

FA DC SDS DBA CDA CAMT SCN Other Inheritance pattern AR, XLR XLR, AR AR AD AR AR AD AR, AD AD AD AR Somatic abnormalities Yes Yes Yes Yes Rare Rare Rare Rare Bone marrow failure AA (90%) AA (80%) AA (20%) RCA a Dysery Meg b Neut c AA Short telomeres Yes Yes d Yes No No No ?? Cancer Yes Yes Yes Yes No Yes Yes ?Yes Chromosome instability Yes Yes Yes ?? No ?? Genes identified 16 10 1 12 41 5 3 FA: Fanconi anemia; DC: dyskeratosis congenita; SDS: Shwachman-Diamond syndrome; DBA: Diamond-Blackfan anemia; CDA: congenital dyserythropoietic anemia; CAMT: congenital amegakaryocytic ; SCN: severe congenital neutropenia; AD: autosomal dominant; AR: autosomal recessive; XLR: X-linked recessive; RCA a: red cell aplasia although some patients can develop global BM failure; Dysery: usually dyserythro - poiesis; Meg b: low megakaryocytes which can progress to global BM failure; Neut C: usually low neutrophils; Yes d: usually very short.

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Table 2. Inherited BM failure genetic subtypes.

(i) FA Complementation group/gene Approximate % of FA patients Chromosome location Gene product Exons A ( FANCA ) 65 16q24.3 FANCA 43 B ( FANCB a) <1 Xp22.2 FANCB 10 C ( FANCC ) 12 9q22.3 FANCC 14 D1 ( FANCD1 b) <1 13q12.3 FANCD1 27 D2 ( FANCD2 ) <1 3p25.3 FANCD2 44 E ( FANCE )46p21.3 FANCE 10 F ( FANCF )411p15 FANCF 1 G ( FANCG ) 12 9p13 FANCG 14 I ( FANCI ) <1 15q26.1 FANCI 35 J ( FANCJ/BRIP1 c) <5 17q23.1 FANCJ 20 L ( FANCL ) <1 2p16.1 FANCL 14 M ( FANCM ) <1 14q21.3 FANCM 23 N ( FANCN/PALB2 d) <1 16p12.1 FANCN 13 O ( FANCO/RAD51C ) <1 17q25.1 FANCO 9 P ( FANCP/SLX4 )216p13.3 FANCP 15 Q ( FANCQ/ERCC4 ) <1 16p13.12 FANCQ 11 aFANCB is on the X-chromosome; bFANCD1 is BRCA2; cFANCJ is BRIP1 (partner of BRCA1); dFANCN is PALB2 (partner of BRCA2). (ii) DC DC subtype Approximate % of DC patients Chromosome location Gene product Exons X-linked recessive 25 Xq28 DKC1 (dyskerin) 15 Autosomal dominant 5 3q26 TERC 1 3 5p15 TERT 16 12 14q11 TIN2 6 Autosomal recessive <1 15q14 NOP10 2 <1 5p15 TERT 16 <1 5q35 NHP2 4 <1 17p13.1 TCAB1 13 <2 16q13 USB1 7 <1 17p13.1 CTC1 23 2 20q13.3 RTEL1 35 Uncharacterized >30 ??? Data based on the Dyskeratosis Congenita Registry in London. (iii) SDS SDS subtype Approximate % of SDS patients Chromosome location Gene product Exons Autosomal recessive >90 7q11 SBDS 5 Uncharacterized <10 ??? (iv) DBA DBA subtype Approximate % of DBA patients Chromosome location Gene product Exons Autosomal dominant 25 19q13.2 RPS19 6 2 10q22-23 RPS24 6 1 15q25.2 RPS17 5 7 1p22.1 RPL5 8 5 1p35-36.1 RPL11 6 3 3q29 RPL35A 6 1 2p RPS7 7 7 6q21.31 RPS10 6 3 12q13.2 RPS26 4 1 17p13.1 RPL26 4 <1 3p24.2 RPL15 4 X-linked recessive <1 Xp11.23 GATA1 6 Uncharacterized ~30 ???

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Table 2. Continued from previous page.

(v) CDA CDA subtype Approximate % of CDA patients Chromosome location Gene product Exons Type I (AR) Majority 15q15.2 CDAN1 15 Subset 15q14 C15ORF41 11 Type II (AR) Majority 20p11.23 SEC23B 8 Type III (AD) Majority 15q21 KIF23 23 Other variants 19p13.2 KLF1 3 (vi) CAMT CAMT subtype Approximate % of CAMT patients Chromosome location Gene product Exons Autosomal recessive Majority 1p34 MPL 12 Uncharacterized ???? (vii): SCN Subtype Approximate % of patients Chromosome location Gene product Exons Autosomal dominant 50-60 19p13.3 ELANE 6 < 2 1p22 GFI1 3 Autosomal recessive 15 1q21.3 HAX1 7 ?5 17q21.31 G6PC3 6 Rare 1q21.2 VPS45 4 Miscellaneous syndromes* *This is a heterogeneous group and includes patients with neutropenia as part of a broader syndrome such as Wiskot-Aldrich syndrome (WAS) and Shwachman-Diamond syndrome (SDS).

SBDS gene product (SBDS) has an important role in the with heterozygous RPL11 mutations. Interestingly, a rare maturation of the 60S ribosomal subunit and, therefore, DBA subgroup has been recently found to be due to ribosome biogenesis. 56 SDS is thus principally a disorder GATA1 (encoding an erythroid transcriptional factor) of defective ribosome biogenesis. mutations, 67 highlighting the heterogeneity in the molecu - lar pathways that can give rise to a DBA . In Japanese populations, RPS19 mutations only account Diamond-Blackfan anemia for approximately 13% of DBA patients and there are also some differences in the clinical associated Diamond-Blackfan anemia (DBA), initially described in 57 with the different DBA genes compared to Western popu - 1934, usually presents in early infancy, with features of 68 58 lations. This suggests ethnic differences in phenotypic anemia. The hallmark of classical DBA is a selective expression, a feature that has been observed previously in decrease in erythroid precursors (reduced reticulocyte other genetic diseases, including FA. count) and normochromic macrocytic anemia associated with a variable number of somatic abnormalities such as craniofacial (e.g. high arched palate), thumb, cardiac and Congenital dyserythropietic urogenital malformations. MDS and AML have been reported in a few patients, suggesting an increased predis - The congenital dyserythropietic anemias (CDAs) com - position to hematologic cancer. There are also cases that prise a heterogeneous group of inherited disorders of ery - have evolved into AA. Thus, although DBA has been thropoiesis characterized by anemia, ineffective erythro - regarded classically as a pure red cell aplasia, a more glob - poiesis and morphological evidence of dyserythropoei - al hematopoietic defect can be observed in some patients. sis. 69,70 The first description of this group of disorders was The first DBA gene ( RPS19 ) was identified in 1999 59 in 1966 by Crookston and colleagues. In 1968, Wendt and and in Western populations accounts for approximately Heimpel classified the CDAs into three types: I, II and III. 25% of DBA patients. Subsequently heterozygous muta - Over the years, many additional subtypes (IV, V, VI and tions in other genes encoding proteins of the small VII) have been added to the list, often based on case report (RPS24, RPS17, RPS7, RPS10, RPS26) and large (RPL5, studies. With the emerging genetics it will be interesting to RPL11, RPL15, RPL26, RPL35A) ribosomal subunits see how this classification evolves. have also been reported; collectively the genetic basis of CDA type 1: the majority of patients present with approximately 60-70% of DBA patients can now be estab - splenomegaly and mild to moderate anemia (usually lished. 60-66 These observations have also demonstrated that macrocytic). In some cases, non-hematologic features DBA is principally a disorder of ribosome biogenesis. It is (e.g. skeletal abnormalities, abnormal skin pigmentation) noteworthy that patients with mutations in the RPL5 gene have been observed. Ineffective erythropoiesis is evi - tend to have multiple physical abnormalities, including denced by peripheral (anisocytosis) and marrow (mega - craniofacial, thumb and heart anomalies, whereas isolated loblastic erythroid precursors, internuclear chromatin thumb malformations are predominantly seen in patients bridging and binuclearity affecting 3-7% of erythroblasts)

| 302 | Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) Milan, Italy, June 12-15, 2014 abnormalities as well as increased markers of hemolysis ated with a variable number of non-hematologic abnor - (elevated LDH and bilirubin). The defining ultrastructural malities. It is also important to note there are a number of feature is a spongy (‘Swiss cheese’) appearance of the het - other syndromes (reviewed by Hauck and Klein 77 ) that erochromatin in the majority of erythroblasts on electron have neutropenia as part of the broader syndrome. microscopy (EM). Recognized to be an AR disorder, the first gene ( CDAN1 ) responsible for CDA type 1 was iden - 71 Congenital amegakaryocytic thrombocytopenia tified in 2002. Recently, a second gene, C15ORF41 , was found to be responsible for some cases of CDA type 1. 72 CDA type II: this is the most common subtype of CDA Congenital amegakaryocytic thrombocytopenia and was initially described as hereditary erythroblastic (CAMT) usually presents in infancy and is characterized multinuclearity with a positive acidified serum lysis test by isolated thrombocytopenia, reduction/absence of (HEMPAS) in 1969. It is inherited as an AR trait. The ane - megakaryocytes in the BM with usually no somatic abnor - mia is variable (8-11 g/dL); approximately 10% of cases malities. Approximately 50% of patients will develop AA, require regular transfusions. The clinical presentations usually by the age of five years. They can also evolve into include a variable degree of jaundice, hepatomegaly and MDS or leukemia. CAMT patients have biallelic muta - tions in the gene ( MPL ) encoding the thrombopoietin splenomegaly, and cirrhosis. Mental retardation has been 83 reported in some cases. Peripheral blood morphology receptor. shows moderate to marked red cell anisocytosis. BM fea - tures include normoblastic erythroid hyperplasia with usu - Other subtypes of inherited bone marrow failure ally more than 10% binucleate erythroblasts. At the EM syndromes level, the erythroid cells have characteristic peripheral arrangement of the endoplasmic reticulum giving the There are cases of BM failure that are familial and/or appearance of ‘double membrane’. Red cells are hemol - have one or more extra-hematopoietic abnormality but ysed by some acidified sera but not by the patients own which do not fit into the recognized entities listed above. serum. In 2009, the gene encoding the secretory COPII The recent availability of next generation sequencing tech - component SEC23B was shown to be responsible for 73 nology is making it possible to clarify the genetic basis CDAII. and pathophysiology of these cases. Examples of such CDA type III: this subtype is rare. In one of the largest cases that have been recently characterized include the (Swedish) families investigated, the disease was character - familial aplastic anemia associated with constitutional ized by giant multinucleated erythroblasts in the marrow. thrombopoietin receptor (MPL), thrombopoietin ligand There appears to be an increased prevalence of lympho - and SRP72 mutations. 84-86 It is likely that more such cases proliferative disorders in CDA type III. CDA III exhibits of familial/constitutional BM failure will be characterized AD transmission and is caused by mutations in the KIF23 74 in the near future. They are also likely to provide new gene. KIF23 encodes mitotic kinesin-like protein 1, insights into hematopoiesis and how this might be disrupt - which plays a critical role in cytokinesis during cell divi - ed in BM failure. sion. The functional role of the proteins encoded by CDAN1 , C15ORF41 and SEC23B in CDA disease pheno - type remains unknown. 70 CDA variants due to mutations Epidemiology in erythroid factor genes ( GATA-1 and KLF1 )75 have also been recently identified. The true incidence and natural history of these disorders remains largely unknown. It is generally believed that SCN and DBA are amongst the most prevalent of these Severe congenital neutropenia (including disorders; the estimated annual birth incidence of DBA is Kostmann syndrome) 5 cases per 10 6. Tamary et al. reported on a retrospective population-based registry of inherited BM failure syn - Very severe peripheral neutropenia (frequently 87 9 dromes in Israel. One hundred and twenty-seven patients <0.2x10 /L) characterizes severe congenital neutropenia diagnosed between 1966 and 2007 were registered; 52% 76,77 (SCN). These patients usually present with recurrent had FA, 17% SCN, 14% DBA, 6% CAMT, 5% DC, 2% life-threatening infections in infancy. BM examination SDS, and 2% thrombocytopenia with absent radii. This typically shows a maturation arrest in the myeloid lineage. report represented the first comprehensive population- These patients can progress to MDS and leukemia, usually based study evaluating the incidence and complications of with acquisition of secondary mutations, including in the the different inherited BM failure syndromes. The most G-CSF receptor. In the majority of patients, heterozygous common disease was FA, which also carried the worst mutations in neutrophil elastase gene ( ELANE ) have been prognosis, with severe BM failure and cancer develop - 78 demonstrated. These mutations are thought to lead to ment. It is noteworthy that these data are probably only accumulation of the non-functional protein which in turn relevant to Israel. For example, based on the data from this triggers an unfolded protein response leading to matura - registry, the annual incidence of FA was calculated to be tional arrest. The original family described by Kostmann, approximately 2 per 100,000 live births. This is 7-fold had AR SCN, and has been shown to be associated with higher than expected from the world-wide carrier frequen - biallelic mutations in the HAX1 gene, 79 predicted to lead to cy of 1:300 and probably reflects the high rate of consan - defects in cell death. Mutations in other genes ( GFI1, guinity in Israel. G6PC3 and VPS45 )80-82 are also associated with SCN. In a recent report from the Canadian registry, 88 the most Whilst ELANE mutations tend to produce an isolated neu - common disease was DBA followed by FA; this gave an tropenia, mutations in some of the other genes are associ - approximate incidence for FA of 11.4 cases per 10 6 births.

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Notably, 53.5% of the cases fell into an uncharacterized and avoidance of sunlight is important. Subjects should category. also avoid occupations that expose them to hazardous chemicals or repeated physical trauma. When doing domestic chores such as washing up, use of protective General principles of diagnosis and management gloves is advisable (particularly in DC). Extremes of tem - perature, both hot and cold, should be avoided as the skin A diagnosis of an inherited BM failure should be con - is usually fragile compared to the normal population. sidered when there is one or more extra-hematopoietic Liver disease is more common in FA and DC patients features associated with the BM failure. In the context of than in the normal population. Alcohol consumption children presenting upfront with aplastic anemia (global should, therefore, be kept to a minimum, and all drug trilineage BM failure), a diagnosis of an inherited BM fail - administrations require close monitoring. ure also needs to be on the differential list. The specific Drugs also need to be used carefully, as patients with extra-hematopoietic abnormalities help in diagnosing a inherited BM failure syndromes tend to be small in stature recognized syndrome; however, this is not always possible and more sensitive to many drugs. This is particularly on clinical features alone. important in FA and DC patients undergoing allogeneic The chromosomal breakage analysis test on peripheral hematopoietic stem cell transplantation (SCT). blood lymphocytes following exposure to diepoxybutane or mitomycin-C remains a very useful way of diagnosing FA. All children presenting with AA should be tested for Management of the hematologic complications FA. Genetic testing for the FA genes is possible, but this is not straightforward and not always routinely available. Major advances in supportive treatments 90 have led to Telomere length, particularly using flow fluorescence in considerable improvement in the outcome of these situ hybridization (flow-FISH) can be a very useful initial patients. Blood product support has been a key component screening technique 89 in the diagnosis of DC. Patients with of this effort. Packed red cell transfusions should be given DC frequently (but not always) have very short telomeres to maintain the hemoglobin at a level that allows the compared to age-matched controls. Genetic testing for the patient to be asymptomatic (typically >8 g/dL), platelets DC genes ( DKC1 , TERC , TERT , NOP10 , NHP2 , TINF2 , should be maintained above 10x10 9/L. It is reasonable to USB1 , TCAB1 , CTC1 and RTEL1 ) can be helpful in sub - give prophylactic antimicrobials to patients with a neu - stantiating the diagnosis. However, as in FA, this is not trophil count consistently below 0.5x10 9/L. As a general straightforward (as many patients will have private muta - rule, all neutropenic patients need prompt therapy with tions and some of the genes are large), and in approxi - broad-spectrum intravenous antibiotics if they develop an mately one-third of patients the genetic basis will remain infection. Leuco-depleted and, where appropriate, CMV- unknown even after testing for all 10 DC genes. negative blood products should be chosen to prevent In patients with global BM failure, the other genetic development of HLA-antibodies and reduce the risk of tests to consider are those for the MPL and SBDS genes. CMV disease. For patients presenting with an isolated neutropenia, Inherited BM failure syndromes do respond to specific analysis for the ELANE , GFI1 and HAX1 may help sub - interventions. In patients with FA and DC who have sig - stantiate the underlying diagnosis. For those with an iso - nificant peripheral cytopenia (Hb < 8 g/dL, neutrophils lated anemia, testing for the DBA and CDA genes is indi - <0.5x10 9/L, platelets <20x10 9/L), the first-line medical cated. Once diagnosis of an inherited syndrome has been therapy is usually with oxymetholone that should be start - made (clinically and/or genetically) it is important to ed at a dose of 0.5-1.0 mg/kg/day and gradually increased, explain to the patient/family the chronic nature of these if necessary, to a maximal dose of 5 mg/kg/day. DC disorders. In general, patients need to be followed-up patients are usually more sensitive to oxymetholone than throughout life and will need to be monitored for compli - FA patients. There is also increasing experience in the use cations. The frequency of monitoring investigations (such of danazol in these patients. 91,92 Approximately 70% of as blood tests, BM examinations, pulmonary function patients with DC and FA will have a hematologic response tests) is difficult to define precisely in view of the consid - to anabolic steroids; this can be durable for years in some erable clinical heterogeneity. However, regular (possibly patients. Patients with severe BM failure and with HLA- on an annual basis) follow up is advisable, with more fre - compatible donors can be cured of their hematologic com - quent monitoring (and appropriate investigations) being plications. Over the years, it has been recognized that implemented if there is a specific problem. patients with inherited BM failure syndromes have greater In view of the significant risk of cancer in many of these efficacy and lower toxicity using low-intensity fludara - syndromes, patients should be advised (according to age) bine-based protocols. There is now considerable experi - to avoid active and passive smoking. They should also ence using such protocols in both FA and DC patients, 93-97 avoid sunbathing and keep alcohol intake to a minimum as representing a major advance in outcome following SCT they go through adolescence and adulthood. Treatment for in FA and DC patients. cancer depends on the specific cancer but consideration In patients with DBA, the first-line therapy remains cor - has to be given to the underlying genetic defect (i.e. more ticosteroids (usually prednisolone). Up to 80% of patients supportive care, reduce drug doses). With regards to pul - respond to steroids as a single agent. The dose and fre - monary disease in FA and DC, patients should be encour - quency of prednisolone is titrated to the lowest amount aged to avoid smoking. Medical treatment is usually diffi - required to maintain a hemoglobin response to minimize cult in severe lung disease; lung transplant may be an side-effects. In the minority of patients who are refractory option in some cases. to steroids, or when patients lose steroid responsiveness, Advice on skin care (e.g. use of moisturising creams) supportive treatment with regular red blood transfusions is

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Figure 1. Interconnections of molecules mutated in different bone marrow failure syndromes. Images (A-F) are derived using the STRING database: http://string-db.org/newstring_cgi/show_input_page.pl STRING is a database of known and predicted protein interactions. The key protein (red at the center node) and its asso - ciated interactions (blue lines) are achieved through confidence view, which include direct (physical) and indirect (func - tional) associations. Variability in confidence of protein-protein interactions are determined by increasing thickness of blue line annotated. These interactions are derived from four sources such as genomic context, high-throughput experiments, conserved co-expression studies and previous knowledge (databases). (A) In this image FANCA (mutated in FA-A) is used as the reference and shows all its associations with other proteins both FA (FANCB, FANCC, FANCE, FANCF, FANCG, FANCL and FANCM) and non-FA (e.g. BLM). (B) Image is based around DKC1 (mutated in X-linked DC); it associates with several other DC proteins (e.g. NOP10, NHP2, TERT) but also others that are linked with other BM failure syndromes (e.g. EIF6 which has a strong connection with SBDS, shown in E). (C) This image is based around FANCD2. It shows its associations with several FA proteins (FANCA FANCB, FANCC, FANCE, FANCI, and BRCA2) and BRCA1. (D) Associations are based around TINF2 that is mutated in AD-DC. TINF2 interacts with several proteins important in telomere maintenance (POT1, TERF1, and TERF2) but also with BRCA1 (important in DNA repair and in the FA pathway, denoted with **). (E) Associations are focused on SBDS (mutated in SDS). It shows its interesting connection with EIF6 that also interacts with DKC1 (mutated in DC, denoted with *). (F) Image based around RPS19; it shows its associations with several other ribosomal proteins mutated in DBA. Gene names for those mutated as well as for several key interconnecting bone marrow failure proteins are as follows: RP: ribosomal protein; FANC: Fanconi anemia complementation group; DKC1: dyskeratosis congenita 1; NOP10: nucleolar protein 10 homolog; NHP2; non-histone ribonucleoprotein 2 homolog; GAR1: and rich ribonucleoprotein 1 homolog; TERF1: telomeric repeat binding factor 1; TERF2: telomeric repeat binding factor 2; TINF2: TERF1-interacting nuclear factor 2; TERF2IP: TERF2 interacting protein (RAP1); POT1: protection of telomeres 1 homolog; TPP1: TIN2 interacting protein 1 (=ACD, adrenocortical dysplasia homolog); PINX1: PIN2 (=TERF1) interacting protein; ATM: ataxia telangiectasia mutated; MRE1: meiotic recombination 11 homolog; BRCA1: breast cancer 1; BRIP1: BRCA1 interacting protein C-terminal helicase 1; PALB2: partner and localizer of BRCA2; BLM: protein.

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