Pediatric hematology Inherited bone marrow failure syndromes I. Dokal ABSTRACT The inherited/constitutional bone marrow (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, anemia” 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 genes 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; telomere 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 cancer, 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 - Fanconi anemia 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 proteins 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 protein 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 dyskerin. 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 mutations 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 telomerase (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 telomeres. 42-44 Heterozygous mutations in ing BRCA2 inaccurately repair damaged DNA and are TERC and TERT (telomerase reverse transcriptase) 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, nail dystrophy and mucosal leukoplakia. 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, pancytopenia (approx. 20%), MDS RTEL1