The Inherited Bone Marrow Failure Syndromes

Inherited bone marrow failure syndromes (IBMFS) are a group of heterogeneous disorders that account for ∼30% of pediatric cases of bone marrow failure and are often associated with developmental abnormalities and cancer predisposition. This article reports the laboratory validation and clinical utility of a large-scale, custom-designed next-generation sequencing panel, Children's Hospital of Philadelphia (CHOP) IBMFS panel, for the diagnosis of IBMFS in a cohort of pediatric patients. This panel demonstrated excellent analytic accuracy, with 100% sensitivity, ≥99.99% specificity, and 100% reproducibility on validation samples. In 269 patients with suspected IBMFS, this next-generation sequencing panel was used for identifying single-nucleotide variants, small insertions/deletions, and copy number variations in mosaic or nonmosaic status. Sixty-one pathogenic/likely pathogenic variants (54 single-nucleotide variants/insertions/deletions and 7 copy number variations) and 24 hypomorphic variants were identified, resulting in the molecular diagnosis of IBMFS in 21 cases (7.8%) and exclusion of IBMFS with a diagnosis of a blood disorder in 10 cases (3.7%). Secondary findings, including evidence of early hematologic malignancies and other hereditary cancer-predisposition syndromes, were observed in 9 cases (3.3%). The CHOP IBMFS panel was highly sensitive and specific, with a significant increase in the diagnostic yield of IBMFS. These findings suggest that next-generation sequencing–based panel testing should be a part of routine diagnostics in patients with suspected IBMFS.

Aplastic anemia (AA) is the prototypic bone marrow failure syndrome and can be classified as either acquired or inherited. Inherited forms are due to the effects of germline mutations, while acquired AA is suspected to result from cytotoxic T-cell mediated immune attack on hematopoietic stem and progenitor cells. Once thought to be a purely “benign” condition, clonality in the form of chromosomal abnormalities and single nucleotide variants is now well recognized in AA. Mechanisms underpinning this clonality likely relate to selection of clones that allow immune evasion or increased cell survival the marrow environment under immune attack. Widespread use and availability of next generation and other genetic sequencing techniques has enabled us to better understand the genomic landscape of aplastic anemia. This review focuses on the current concepts associated with clonality, in particular somatic mutations and their impact on diagnosis and clinical outcomes in immune aplastic anemia.

Bone marrow failure syndromes, defined as peripheral cytopenias due to decreased hematopoiesis in the bone marrow, may be divided into acquired and inherited conditions and further divided into disorders that alter only one hematopoietic lineage (erythroids, myeloids, or platelets) and those that involve all three lineages. This chapter will discuss in detail the two major entities leading to acquired pancytopenia (aplastic anemia and paroxysmal nocturnal hemoglobinuria) as well as Fanconi anemia (FA) and dyskeratosis congenita (DKC), two of the most thoroughly characterized congenital bone marrow failure syndromes. Other acquired and congenital disorders associated with peripheral cytopenias caused by bone marrow failure will also be briefly discussed.

Although most children with acute lymphoblastic leukaemia (ALL) do not harbor germline mutations that strongly predispose them to development of this malignancy, large syndrome registries and detailed mapping of exomes or whole genomes of familial leukaemia kindreds have revealed that 3–5% of all childhood ALL cases are due to such germline mutations, but the figure may be higher. Most of these syndromes are primarily characterized by their non-malignant phenotype, whereas ALL may be the dominating or even only striking manifestation of the syndrome in some families. Identification of such ALL patients is important in order to adjust therapy and offer genetic counseling and cancer surveillance to mutation carriers in the family. In the coming years large genomic screening projects are expected to reveal further hitherto unrecognised familial ALL syndromes. The treatment of ALL cases harboring cancer predisposing mutations can be challenging for both the physician and the patient due to their preexisting symptoms, their reduced tolerance to radio- and/or chemotherapy with enhanced risk of life-threatening organ toxicities, and the paucity of data from ALL patients with the same or similar syndromes being treated by contemporary protocols. Recent studies clearly indicate that many of these patients stand a good chance of cure, and that they should be offered chemotherapy with the intention to cure. Some of these syndromes are characterized by reduced tolerance to radiotherapy and/or specific anticancer agents, while others are not. This review summarises our current knowledge on the risk of acute toxicities for these ALL patients and provides guidance for treatment adjustments.