Inherited aplastic anemia in children and adolescents
- Timothy S Olson, MD, PhD
Timothy S Olson, MD, PhD
- Assistant Professor of Pediatrics
- Comprehensive Bone Marrow Failure Center and Blood and Marrow Transplant Section
- Divisions of Pediatric Oncology and Hematology
- The Children's Hospital of Philadelphia and University of Pennsylvania
Aplastic anemia (AA) is a rare disorder characterized by pancytopenia and a hypocellular bone marrow [1-3]. AA can result from either inherited or acquired causes (table 1). The incidence is triphasic, with one peak in childhood at two to five years (due to inherited causes), and two peaks in adulthood, 20 to 25 years and the majority of patients presenting beyond 55 to 60 years of age (typically due to acquired causes) . The associated neutropenia and thrombocytopenia can lead to potentially life-threatening infections and bleeding. Chronic red cell transfusion therapy for the associated anemia can lead iron overload, which, if not treated, can lead to significant morbidity and mortality.
The majority of children (75 percent) with inherited bone marrow failure have an identifiable etiology [4-6]. The four major inherited causes for AA in children are:
●Fanconi anemia (FA)
●Dyskeratosis congenita (DC)
●Shwachman-Diamond syndrome (SDS)
- Alter BP. Inherited Bone Marrow Failure Syndromes. In: Nathan and Oski's Hematology of Infancy and Childhood, Nathan DG, Orkin SH, Ginsburg D, Look AT (Eds), W.B. Saunders, Philadelphia 2003. p.280.
- Young NS. Acquired aplastic anemia. Ann Intern Med 2002; 136:534.
- Brodsky RA, Jones RJ. Aplastic anaemia. Lancet 2005; 365:1647.
- Teo JT, Klaassen R, Fernandez CV, et al. Clinical and genetic analysis of unclassifiable inherited bone marrow failure syndromes. Pediatrics 2008; 122:e139.
- Khincha PP, Savage SA. Genomic characterization of the inherited bone marrow failure syndromes. Semin Hematol 2013; 50:333.
- Chirnomas SD, Kupfer GM. The inherited bone marrow failure syndromes. Pediatr Clin North Am 2013; 60:1291.
- Shimamura A, Alter BP. Pathophysiology and management of inherited bone marrow failure syndromes. Blood Rev 2010; 24:101.
- Yamaguchi H, Calado RT, Ly H, et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N Engl J Med 2005; 352:1413.
- Savage SA, Stewart BJ, Weksler BB, et al. Mutations in the reverse transcriptase component of telomerase (TERT) in patients with bone marrow failure. Blood Cells Mol Dis 2006; 37:134.
- Vulliamy TJ, Walne A, Baskaradas A, et al. Mutations in the reverse transcriptase component of telomerase (TERT) in patients with bone marrow failure. Blood Cells Mol Dis 2005; 34:257.
- Armanios MY, Chen JJ, Cogan JD, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med 2007; 356:1317.
- Knight SW, Heiss NS, Vulliamy TJ, et al. Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia (Hoyeraal-Hreidarsson syndrome) due to mutations in the dyskeratosis congenita gene, DKC1. Br J Haematol 1999; 107:335.
- Dokal I. Dyskeratosis congenita in all its forms. Br J Haematol 2000; 110:768.
- Zhong F, Savage SA, Shkreli M, et al. Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita. Genes Dev 2011; 25:11.
- Nelson ND, Bertuch AA. Dyskeratosis congenita as a disorder of telomere maintenance. Mutat Res 2012; 730:43.
- Keller RB, Gagne KE, Usmani GN, et al. CTC1 Mutations in a patient with dyskeratosis congenita. Pediatr Blood Cancer 2012; 59:311.
- Ballew BJ, Yeager M, Jacobs K, et al. Germline mutations of regulator of telomere elongation helicase 1, RTEL1, in Dyskeratosis congenita. Hum Genet 2013; 132:473.
- Guo Y, Kartawinata M, Li J, et al. Inherited bone marrow failure associated with germline mutation of ACD, the gene encoding telomere protein TPP1. Blood 2014; 124:2767.
- Kocak H, Ballew BJ, Bisht K, et al. Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1. Genes Dev 2014; 28:2090.
- Tummala H, Walne A, Collopy L, et al. Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita. J Clin Invest 2015; 125:2151.
- Dokal I. Dyskeratosis congenita: recent advances and future directions. J Pediatr Hematol Oncol 1999; 21:344.
- Du HY, Pumbo E, Ivanovich J, et al. TERC and TERT gene mutations in patients with bone marrow failure and the significance of telomere length measurements. Blood 2009; 113:309.
- Alter BP, Rosenberg PS, Giri N, et al. Telomere length is associated with disease severity and declines with age in dyskeratosis congenita. Haematologica 2012; 97:353.
- Lansdorp PM. Telomeres, stem cells, and hematology. Blood 2008; 111:1759.
- Mitchell JR, Wood E, Collins K. A telomerase component is defective in the human disease dyskeratosis congenita. Nature 1999; 402:551.
- Allsopp RC, Morin GB, DePinho R, et al. Telomerase is required to slow telomere shortening and extend replicative lifespan of HSCs during serial transplantation. Blood 2003; 102:517.
- Vulliamy T, Marrone A, Szydlo R, et al. Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC. Nat Genet 2004; 36:447.
- Goldman FD, Aubert G, Klingelhutz AJ, et al. Characterization of primitive hematopoietic cells from patients with dyskeratosis congenita. Blood 2008; 111:4523.
- Vulliamy TJ, Knight SW, Dokal I, Mason PJ. Skewed X-inactivation in carriers of X-linked dyskeratosis congenita. Blood 1997; 90:2213.
- Heiss NS, Knight SW, Vulliamy TJ, et al. X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat Genet 1998; 19:32.
- Vulliamy TJ, Marrone A, Knight SW, et al. Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation. Blood 2006; 107:2680.
- Ruggero D, Grisendi S, Piazza F, et al. Dyskeratosis congenita and cancer in mice deficient in ribosomal RNA modification. Science 2003; 299:259.
- Alder JK, Parry EM, Yegnasubramanian S, et al. Telomere phenotypes in females with heterozygous mutations in the dyskeratosis congenita 1 (DKC1) gene. Hum Mutat 2013; 34:1481.
- Vulliamy T, Marrone A, Goldman F, et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 2001; 413:432.
- Xin ZT, Beauchamp AD, Calado RT, et al. Functional characterization of natural telomerase mutations found in patients with hematologic disorders. Blood 2007; 109:524.
- Armanios M, Chen JL, Chang YP, et al. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc Natl Acad Sci U S A 2005; 102:15960.
- Walne AJ, Vulliamy T, Beswick R, et al. TINF2 mutations result in very short telomeres: analysis of a large cohort of patients with dyskeratosis congenita and related bone marrow failure syndromes. Blood 2008; 112:3594.
- Savage SA, Giri N, Baerlocher GM, et al. TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am J Hum Genet 2008; 82:501.
- Marrone A, Walne A, Tamary H, et al. Telomerase reverse-transcriptase homozygous mutations in autosomal recessive dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome. Blood 2007; 110:4198.
- Gramatges MM, Qi X, Sasa GS, et al. A homozygous telomerase T-motif variant resulting in markedly reduced repeat addition processivity in siblings with Hoyeraal Hreidarsson syndrome. Blood 2013; 121:3586.
- Walne AJ, Vulliamy T, Marrone A, et al. Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomerase-associated protein NOP10. Hum Mol Genet 2007; 16:1619.
- Vulliamy T, Beswick R, Kirwan M, et al. Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita. Proc Natl Acad Sci U S A 2008; 105:8073.
- Parry EM, Alder JK, Qi X, et al. Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase. Blood 2011; 117:5607.
- Alter BP, Baerlocher GM, Savage SA, et al. Very short telomere length by flow fluorescence in situ hybridization identifies patients with dyskeratosis congenita. Blood 2007; 110:1439.
- Knight S, Vulliamy T, Copplestone A, et al. Dyskeratosis Congenita (DC) Registry: identification of new features of DC. Br J Haematol 1998; 103:990.
- Alter BP, Giri N, Savage SA, Rosenberg PS. Cancer in dyskeratosis congenita. Blood 2009; 113:6549.
- Kirwan M, Dokal I. Dyskeratosis congenita: a genetic disorder of many faces. Clin Genet 2008; 73:103.
- Tsilou ET, Giri N, Weinstein S, et al. Ocular and orbital manifestations of the inherited bone marrow failure syndromes: Fanconi anemia and dyskeratosis congenita. Ophthalmology 2010; 117:615.
- Giri N, Lee R, Faro A, et al. Lung transplantation for pulmonary fibrosis in dyskeratosis congenita: Case Report and systematic literature review. BMC Blood Disord 2011; 11:3.
- Atkinson JC, Harvey KE, Domingo DL, et al. Oral and dental phenotype of dyskeratosis congenita. Oral Dis 2008; 14:419.
- Jyonouchi S, Forbes L, Ruchelli E, Sullivan KE. Dyskeratosis congenita: a combined immunodeficiency with broad clinical spectrum--a single-center pediatric experience. Pediatr Allergy Immunol 2011; 22:313.
- Jonassaint NL, Guo N, Califano JA, et al. The gastrointestinal manifestations of telomere-mediated disease. Aging Cell 2013; 12:319.
- Islam A, Rafiq S, Kirwan M, et al. Haematological recovery in dyskeratosis congenita patients treated with danazol. Br J Haematol 2013; 162:854.
- Khincha PP, Wentzensen IM, Giri N, et al. Response to androgen therapy in patients with dyskeratosis congenita. Br J Haematol 2014; 165:349.
- Dietz AC, Orchard PJ, Baker KS, et al. Disease-specific hematopoietic cell transplantation: nonmyeloablative conditioning regimen for dyskeratosis congenita. Bone Marrow Transplant 2011; 46:98.
- Nishio N, Takahashi Y, Ohashi H, et al. Reduced-intensity conditioning for alternative donor hematopoietic stem cell transplantation in patients with dyskeratosis congenita. Pediatr Transplant 2011; 15:161.
- Ayas M, Nassar A, Hamidieh AA, et al. Reduced intensity conditioning is effective for hematopoietic SCT in dyskeratosis congenita-related BM failure. Bone Marrow Transplant 2013; 48:1168.
- Guinan EC, Lee YS, Lopez KD, et al. Effects of interleukin-3 and granulocyte-macrophage colony-stimulating factor on thrombopoiesis in congenital amegakaryocytic thrombocytopenia. Blood 1993; 81:1691.
- Ballmaier M, Germeshausen M. Advances in the understanding of congenital amegakaryocytic thrombocytopenia. Br J Haematol 2009; 146:3.
- Ihara K, Ishii E, Eguchi M, et al. Identification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia. Proc Natl Acad Sci U S A 1999; 96:3132.
- van den Oudenrijn S, Bruin M, Folman CC, et al. Mutations in the thrombopoietin receptor, Mpl, in children with congenital amegakaryocytic thrombocytopenia. Br J Haematol 2000; 110:441.
- Ballmaier M, Germeshausen M, Schulze H, et al. c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia. Blood 2001; 97:139.
- Tijssen MR, di Summa F, van den Oudenrijn S, et al. Functional analysis of single amino-acid mutations in the thrombopoietin-receptor Mpl underlying congenital amegakaryocytic thrombocytopenia. Br J Haematol 2008; 141:808.
- Cremer M, Schulze H, Linthorst G, et al. Serum levels of thrombopoietin, IL-11, and IL-6 in pediatric thrombocytopenias. Ann Hematol 1999; 78:401.
- Berthet F, Caduff R, Schaad UB, et al. A syndrome of primary combined immunodeficiency with microcephaly, cerebellar hypoplasia, growth failure and progressive pancytopenia. Eur J Pediatr 1994; 153:333.
- King S, Germeshausen M, Strauss G, et al. Congenital amegakaryocytic thrombocytopenia: a retrospective clinical analysis of 20 patients. Br J Haematol 2005; 131:636.
- Young NS, Alter BP. Aplastic Anemia: Acquired and Inherited, WB Saunders, Philadelphia 1994. p.13.
- Maserati E, Panarello C, Morerio C, et al. Clonal chromosome anomalies and propensity to myeloid malignancies in congenital amegakaryocytic thrombocytopenia (OMIM 604498). Haematologica 2008; 93:1271.
- Walne AJ, Dokal A, Plagnol V, et al. Exome sequencing identifies MPL as a causative gene in familial aplastic anemia. Haematologica 2012; 97:524.
- Muraoka K, Ishii E, Tsuji K, et al. Defective response to thrombopoietin and impaired expression of c-mpl mRNA of bone marrow cells in congenital amegakaryocytic thrombocytopenia. Br J Haematol 1997; 96:287.
- MacMillan ML, Davies SM, Wagner JE, Ramsay NK. Engraftment of unrelated donor stem cells in children with familial amegakaryocytic thrombocytopenia. Bone Marrow Transplant 1998; 21:735.
- Lackner A, Basu O, Bierings M, et al. Haematopoietic stem cell transplantation for amegakaryocytic thrombocytopenia. Br J Haematol 2000; 109:773.
- Mehta P, Locatelli F, Stary J, Smith FO. Bone marrow transplantation for inherited bone marrow failure syndromes. Pediatr Clin North Am 2010; 57:147.
- Mahadeo KM, Tewari P, Parikh SH, et al. Durable engraftment and correction of hematological abnormalities in children with congenital amegakaryocytic thrombocytopenia following myeloablative umbilical cord blood transplantation. Pediatr Transplant 2015; 19:753.
- Woods G, Bajwa RP, Rose MJ. Reduced intensity transplantation for congenital amegakaryocytic thrombocytopenia: report of a case and review of the literature. Pediatr Transplant 2014; 18:E31.