REVIEWPathophysiology and management of inherited bone marrow failure syndromes
Introduction
The inherited bone marrow failure syndromes (IBMFS) are undoubtedly underdiagnosed, in both pediatric and adult hematology/oncology practices. While the topic has been the subject of many earlier reviews, this report is current through 2009.[1], [2], [3] The differential diagnosis that must be considered when a patient presents with pancytopenia due to apparently acquired aplastic anemia is summarized in the diagram in Fig. 1. After examination of a bone marrow to confirm aplastic anemia and rule out acute leukemia or myelodysplastic syndrome (MDS), the pediatric approach usually begins with consideration of Fanconi anemia (FA) by physical examination and by testing for chromosome breakage, while the adult approach might be to rule out paroxysmal nocturnal hemoglobinuria (PNH) by flow cytometry for CD55 or CD59 negative clones. Although we estimate that about 30% of childhood aplasia is due to FA or the other syndromes to be discussed here, the proportion among adults is unknown. Appropriate classification of patients is imperative, since it impacts on medical and transplant management, choice of stem cell donors, estimated risks for complications including future neoplasms, and genetic and medical counseling and surveillance of the probands and their family members. Furthermore, patients with an IBMFS may not present with aplastic anemia, but may have characteristic physical anomalies, MDS, acute myeloid leukemia (AML), or a solid tumor, or even pulmonary fibrosis or liver disease as their first sign of an IBMFS. The major syndromes and their hematologic and neoplastic consequences are listed in Table 1.
In this article we will discuss the presentation, physical and laboratory findings, pathophysiology, and management of the major syndromes within the classification of IBMFS. The tables provide a comprehensive review from the literature of the distinctive physical features for the major syndromes and the frequency of these findings, the types and frequencies of cancers specific to each syndrome, and the known mutated genes and their frequencies. The figures demonstrate ages at diagnosis, cumulative survivals, cancer risks, physical features, and pathophysiologic pathways. While the literature may have publication bias, and does not provide good quantitative epidemiologic data, case reports do offer some initial insights into frequencies and complications. Using that metric, the most frequently reported syndrome was FA (2002 cases), followed by Diamond–Blackfan anemia (DBA, 970 cases), Shwachman–Diamond syndrome (SDS, 560 cases), and Dyskeratosis congenita (DC, 550 cases). Large series of cases (without individual-level data) have reported on FA, DBA, SDS and DC.[1], [2], [3], [4] One large series included 374 patients with severe congenital neutropenia (SCN),1 and smaller series discussed amegakaryocytic thrombocytopenia (Amega) and thrombocytopenia absent radii.[4], [5]
Section snippets
Fanconi anemia: Clinical features
Fanconi anemia (MIM 607139) was first described in 1927 by Dr Fanconi, a Swiss pediatrician who noted a family with 3 brothers who had “perniziosiforme anemia”, i.e. macrocytic red cells and pancytopenia, along with several physical anomalies. Since then, more than 2000 cases have been reported with case descriptions, as well as several different cohorts of patients in recent years.[6], [7], [8], [9] Initially, cases were recognized only when they had the combination of aplastic anemia and
Fanconi anemia: Molecular features
FA is a multigenic disorder with 13 genes currently identified (Table 4A). With the exception of the X-linked FANCB gene, the remaining 12 FA genes are autosomal recessive (Table 4). The encoded FA proteins function coordinately in the repair of DNA crosslinks (Fig. 7). Current evidence also points to additional functions of the FA proteins in stress signaling and apoptosis in response to oxidative damage and inflammatory cytokines.
While many FA proteins lack homology to know protein functional
Fanconi anemia: Management
Currently the only cure for the hematological complications of FA remains hematopoietic stem cell transplant. The optimal timing of transplant is challenging since outcomes are best prior to the development of complications such as infections from chronic severe neutropenia, high transfusion burden to treat anemia/thrombocytopenia, and the development of MDS or AML. The definition of MDS can be challenging in patients with inherited marrow failure syndromes since the diagnostic findings of MDS
Dyskeratosis congenita: Clinical features
In the evaluation of patients with aplastic anemia in which an inherited disease is suspected and FA has been ruled out, the next syndrome to consider is DC (MIM 305000, 127550, 224230). As with FA, the first descriptions involved physical findings. In fact, DC was considered a form of ectodermal dysplasia, and was called “Zinsser–Cole–Engman” syndrome after the physicians who provided the first descriptions from 1910 to 1930. Many case reports followed in the dermatologic literature, and only
Dyskeratosis congenita: Molecular features
DC is characterized by accelerated telomere shortening that results in cell loss or dysfunction.[39], [40] All six genes identified for DC to date function in telomere maintenance.[36], [41], [42] (see Table 4B). Mutations in DKC1 are associated with the X-linked form of DC. The autosomal dominant form of DC is caused by mutations in TINF2, TERC and TERT. NOP10/NOLA3 and, NHP2/NOLA2, have been identified in autosomal recessive forms of DC. Biallelic mutations in TERT have also been identified
Dyskeratosis congenita: Management
Treatment for the hematologic complications of DC is very similar to the plan for FA described above. While SCT may cure the bone marrow, it does not cure other tissues in the body. In addition, the intrinsic propensity for pulmonary fibrosis in DC may be exacerbated by the preparative regimen used for the transplant. In the past, when full myeloablation was used, survival was poor.37 Unexpected problems included hepatic and pulmonary fibrosis, and late onset veno-occlusive disease,
Diamond–Blackfan anemia: Clinical features
While patients with FA or DC were initially recognized because of a combination of physical findings and aplastic anemia (FA), or physical findings alone (DC), DBA (MIM 105650) was first identified only because of pure anemia, which was present at birth or soon thereafter, and required early treatment. Close to 1000 cases have now been reported in the literature, as well as several large case series including a total of another 1000 or so.[48], [49], [50] Approximately 25% of the patients in
Diamond–Blackfan anemia: Molecular features
DBA is caused by heterozygous mutations in genes encoding the protein components of either the small 40 S (RPS19, RPS17, and RPS24) or large 60 S (RPL35A, RPL5, and RPL11) ribosomal subunits.66 (see Table 4C, Fig. 12) Mutations in many of these genes have been shown to affect ribosomal RNA processing. Around 50% of DBA patients however lack identifiable genetic mutations so additional genes likely remain to be identified.
The original Rps19−/− mouse model had an embryonic lethal phenotype and
Diamond–Blackfan anemia: Management
As for the disorders discussed above, SCT is the only current modality for cure of the hematopoietic defect. The choice for SCT for a syndrome that affects only red cell production and not other lineages is difficult, and depends on the trade-offs of steroids, transfusions, and possible treatment-free remissions (see below). The post-SCT survival probability for the approximately 100 patients reported leveled off at 70% by 5 years. While era of publication did not matter, there was a significant
Shwachman–Diamond syndrome: Clinical features
The first description of Shwachman–Diamond syndrome (SDS, MIM 260400) was motivated by the observation that several children with malabsorption due to pancreatic insufficiency also had neutropenia.82 As in FA and DC, the initial clue to a syndrome was non-hematologic. Although the inheritance is autosomal recessive, there is a statistically significant excess of male case reports (male:female 1:48:1, p < 0.001). Characteristic physical abnormalities have also been noted in more than half of the
Shwachman–Diamond syndrome: Molecular features
The majority of SDS patients (> 90%) harbor biallelic mutations in the SBDS gene (Table 4D).86 SBDS is highly conserved across eukaryotes and archaea and widely expressed across different tissues.86 Abrogation of SBDS gene expression in mouse models results in early embryonic lethality indicating that it is an essential gene.87 Consistent with these findings, no patients have been identified with homozygous null mutations in SBDS. SBDS encodes a protein whose crystal structure lacks any apparent
Shwachman–Diamond syndrome: Management
The leading causes of mortality in SDS are the hematological complications of marrow failure and malignancy. Patients with severe neutropenia are at increased risk for infections. Neutrophil functional abnormalities and immunologic abnormalities may compound the risk of infection in some patents. In contrast to disorders of neutrophil chemotaxis, SDS patients maintain the ability to localize neutrophils to sites of infection and form abscesses.106 Neutropenic patients with recurrent or severe
Severe congenital neutropenia: Clinical features
Patients with severe congenital neutropenia (SCN, MIM 202700) do not have any significant birth defects that would provide a clue to their diagnosis. They present early in infancy with severe infections, such as abscesses or pneumonia. The neutrophil count is well below the normal value of 1.5 × 109/L, often less than 0.5 × 109/L, on multiple occasions, while the hemoglobin and platelet count are usually normal. Bone marrow examination reveals an arrest at the promyelocyte/myelocyte stage, with
Severe congenital neutropenia: Molecular features
Congenital neutropenia is emerging as a heterogenous disorder arising from a variety of genetic mutations affecting multiple diverse molecular pathophysiologic pathways (Table 4E) (reviewed in114). All of the molecular pathways share in common an increased propensity to activate apoptosis. In some cases, characteristic phenotypic findings have been associated with specific genes or mutations.
Heterozygous mutations in the ELA2/ELANE gene are found in approximately 50% of patients with severe
Severe congenital neutropenia: Management
Prior to the availability of G-CSF, prognosis was poor with early mortality from bacterial infections. A randomized phase III trial of G-CSF therapy for SCN patients with neutrophil counts < 0.5 × 109/L (500/µL) demonstrated that 90% of patients receiving G-CSF increased their neutrophil counts to > 1.5 × 109/L.134 The incidence and duration of infections were significantly reduced. Cases of MDS and AML were reported in SCN patients prior to the advent of G-CSF treatment, suggesting an inherent
Amegakaryocytic thrombocytopenia
Patients with amegakaryocytic thrombocytopenia (Amega or CAMT, MIM 604498) do not have characteristic birth defects. They usually present in infancy with petechiae or more serious hemorrhages, although they may sometimes evolve to aplastic anemia or even MDS or AML without the preceding thrombocytopenia being recognized. Although more than 100 cases have been reported, this is an underestimate of the frequency of this condition. It may be under-recognized, and is certainly under-reported. Since
Conclusions
In summary, the classical phenotypes originally described for the inherited marrow failure syndromes are now recognized as the more severe end of the highly variable clinical spectrum of these disorders. Early recognition of these disorders allows appropriate medical management and surveillance. An understanding of the indications and limitations of the growing number of available laboratory tests for these disorders is essential. These syndromes offer unique insights into global molecular
Conflict of interest statement
None to declare.
Acknowledgements
This work was supported in part by the Intramural Program of the National Institutes of Health and the National Cancer Institute (B.P.A.) and a grant from the National Heart Lung and Blood Institute of the National Institutes of Health (A.S.).
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