Inherited bone marrow failure syndromes (IBMFSs) manifest as ineffective and stressed hematopoiesis owing to germline mutations that cause the failure of hematopoietic stem cell progenitor cells. Establishing an accurate etiology of bone marrow hypoplasia or BMF is challenging; however, it is absolutely critical for appropriate management, especially in differentiating between acquired and inherited forms of the disease. For example, the use of immuno- suppressive therapy in patients with IBMFS is not beneficial and could potentially be harmful.
With the evolution of diagnostic techniques, it is now known that different genes involved in diverse cellular functions underlie IBMFS. These disorders have a wide phenotypic spectrum and may present cryptically in adult patients with cytopenia of one or more lineages. The causes of BMF differ depending on the disease mechanisms, which include unresolved DNA cross-links in Fanconi anemia (FA), telomere shortening in dyskeratosis congenita (DC), and ribosomopathy in Shwachman-Diamond syndrome (SDS) and Diamond-Blackfan anemia (DBA). In some IBMFS, non- hematologic manifestations including congenital malformations, developmental delay, and other medical complications, may be present. Most IBMFSs are associated with a predisposition to aplastic anemia (AA), myelodysplastic syndrome (MDS), and malignancy.
Patients with IBMFS are usually diagnosed and followed up by pediatric hematologists, although some patients are diagnosed in adults. Clinical and family history can be useful for identifying the underlying cause, particularly prior documentation of long-standing cytopenia or macrocytosis can indicate a heritable cause. The suspicion of IBMFS is imperative in patients of all ages but is more important in pediatric and young adult assessments. A positive history and physical anomalies suggestive of IBMFS require a thorough workup for IBMFS. However, it is important to recognize that the usual symptoms and family history of IBMFS are absent in up to 40% of cases . Recent advances in genomic evaluations using next-generation sequencing can be used to identify suspected IBMFS with an atypical presentation that remains undiagnosed after the initial workup . Considering that the expected frequency of IBMFS among children and young adults aged ≤40 years with AA is 25% and 5–15%, respectively , a high index of suspicion is necessary for patients aged ≤40 years with BMF. However, the upper age cutoff for considering IBMFS remains challenging because IBMFS has been diagnosed in older patients. Careful attention to findings that suggest the presence of IBMFS is necessary. The clinical manifestation and laboratory finding in IBMFS are listed in Table 1.
The specific genetics and screening for each IBMFS are shown in Table 2.
FA is a chromosomal instability disorder caused by germline mutations in the DNA repair genes of the FA/BRCA pathway. Currently, pathogenic variants of at least 22 genes are known to cause FA in humans . Proteins encoded by FA genes play important roles in numerous cellular functions, including DNA repair, detoxification of reactive oxygen species and aldehydes, energy metabolism, and both proinflammatory and myelosuppressive cytokine homeostasis [5-7]. Patients with FA usually develop variable degrees of pancytopenia in childhood and often have short stature, hypopigmented or café au lait spots, thumb or radial ray abnormalities, micro- or hydrocephaly, structural renal anomalies, hypogonadism, and developmental delays. However, up to one-third of the patients with FA do not have congenital anomalies.
Approximately 40% of patients with FA develop severe BMF by the age of 20 years, and half of the patients with FA develop BMF by the age of 50 years. The risk of solid tumors and AML by the age of 50 years in FA is estimated to be 30% and 10%, respectively . The major cancers in FA include head and neck squamous cell cancer, AML, and cancers of the vulva, esophagus, and brain . The incidence of cancer among various IBMFS is highest in patients with FA. Given the impact of a diagnosis of FA has on treatment and surveillance strategies, a chromosomal breakage test is indicated in all patients with BMF . The increased risk of cancer in patients with FA is related to defective DNA repair, which makes somatic cells more susceptible to mutations that could initiate the carcinogenic process . BMF in FA has been proposed to be a consequence of cumulative DNA damage in hematopoietic stem cells, leading to cell death due to genomic instability .
Classic DC is characterized by a triad of abnormal skin pigmentation, oral leukoplakia, and nail dystrophy, but there is wide variability in clinical presentations. A growing number of older adults have been diagnosed with DC after the development of pulmonary fibrosis or hepatic disease, coupled with the expansion of genetic testing and appreciation of a broader clinical spectrum. DC is caused by germline mutations in telomere biology genes, which lead to dysfunctional telomere maintenance. Germline mutations in telomere components may result in short telomere length, which is associated with BMF, hepatic and pulmonary fibrosis, and cancer predisposition . The term “DC” is now used interchangeably with telomere biology disorders (TBD) and short telomere syndromes (STSs). DC and the spectrum of DC-related TBDs are diagnosed by leukocyte telomere lengths less than the first percentile for the age when measured by flow cytometry with fluorescence
Pathogenic variants of genes essential for ribosome assembly and function are associated with two IBMFS, DBA and SDS . Although these two IBMFS share a common underlying biology, there are distinct biological and clinical differences between DBA and SDS.
DBA is usually diagnosed based on the early childhood onset of severe, persistent, and often macrocytic anemia with reticulocytopenia . The BM of patients with DBA is usually normocellular or slightly hypocellular and shows characteristic erythroblastopenia with normal lymphoid, granulocytic, and megakaryocytic lineages. Inherited mutations in
SDS is characterized by congenital anomalies, BMF with neutropenia being the most prominent feature, and exocrine pancreatic insufficiency. Failure to thrive during infancy may be the first presenting feature of SDS due to pancreatic insufficiency . Biallelic mutations in the SBDS gene are the most common . Approximately 20–30% of patients develop AML/MDS, which is frequently accompanied by a complex karyotype .
Severe congenital neutropenia (SCN) is characterized by absolute neutrophil counts consistently less than 200/mL with recurrent severe infections, which often develop within the first few months of life . The most common cause is
Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare autosomal recessive disease characterized by an isolated and, severe hypomegakaryocytic thrombocytopenia that presents in infancy and progresses to pancytopenia and BMF in later childhood. CAMT occurs most commonly due to mutations in
Diseases such as
The development of persistent severe cytopenia, morphologic dysplasia, or clonal cytogenetic alterations raises suspicion of progression toward MDS/AML. Recently, somatic point mutation in myeloid driver genes have been identified in patients with IBMFS who do not have leukemia [32, 33], raising the possibility that the presence of clonal hematopoiesis may be predictive of transformation. The distinct mechanisms by which somatic mutations drive clonal advantage in each disease and their associations with leukemia risk are not well understood.
More than 70% of patients with AA have clonal hematopoiesis with somatic mutations detected by whole-exome sequencing or single-nucleotide polymorphism arrays early in the course of their disease. Clonal hematopoiesis is commonly observed in patients with IBMFS at a much younger age than that in the general population. Clonal hematopoiesis does not equate to malignancy and reflects an acquired genetic change in hematopoietic stem cells, allowing for competitive outgrowth of mutated hematopoietic stem cell progeny. The mutational spectrum in IBMFS is different from that in the general elderly population, as epigenetic regulators, such as
The majority of patients with IBMFS present with or develop cytopenia or hematologic malignancies, and thus the option of hematopoietic cell transplantation (HCT) is attractive. Although HCT may cure the BM problem, it may introduce new and unanticipated problems in other organs. Patients with IBMFS commonly experience post-HCT late effects, including acute or chronic graft-versus-host disease (GVHD), delayed immune reconstitution, iron overload, pulmonary complications, infertility, renal insufficiency, endocrinologic complications, and psychosocial impairment . The adverse effects of HCT in patients with IBMFS is often difficult to assess and distinguish from the complications of aging. The risk of solid tumors following HCT in FA and DC is significantly higher than that in non-transplanted patients ; however, causality to the preparative regimens or augmented inflammation associated with GVHD should be considered. Patients with DBA and SDS are less prone to cancer. Because of the systemic nature of IBMFS, transplant strategies are modified to decrease immediate and late toxicities, for example, radiation-free reduced-intensity conditioning regimen. With improvement in HCT-related strategies, HCT from HLA-matched related or unrelated donors offers promising outcomes for young patients with aplasia . The screening of family members is essential to exclude affected individuals as potential donors. For all IBMFSs, HCT does not correct the non-hematologic manifestations related to these diseases. The decision to proceed to HCT is complex, and all aspects of the transplant process should be considered.
Maintaining a high suspicion for rare IBMFSs is critical when evaluating patients of all ages with unusual cytopenia, especially in patients ≤40 years of age. Thorough physical examination and family history are important. An accurate diagnosis of IBMFS including laboratory workup, a surveillance schedule for malignancy, and potential therapeutic options according to disease severity, is critical for proper management. Additionally, cascade testing of at-risk relatives is required. Identifying markers of clonal evolution, thus enabling better monitoring and management of IBMFS is expected in future studies.
No potential conflicts of interest relevant to this article were reported.