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C H A P T E R 29

INHERITED BONE MARROW FAILURE SYNDROMES

Yigal Dror

INTRODUCTION Although the original report of FA in 1927 by Dr. Guido Fanconi
described pancytopenia combined with physical anomalies in three
Inherited bone marrow (BM) failure is defined herein as decreased brothers, a published summary in 2010 of more than 2000 FA cases
production of one or more of the major hematopoietic lineages caused has underscored the clinical variability of the condition. FA is a
by germline mutations that were derived from the parents or occurred genomic instability disorder characterized by chromosomal fragility
de novo (Table 29.1). Although outdated, the term “constitutional” has and breakage, a defect in DNA repair, progressive BM cell underpro-
been used interchangeably with “inherited” and similarly implies that a duction, peripheral blood cytopenias, developmental anomalies, and
genetic abnormality causes the BM dysfunction. The designation “con- a strong propensity for hematologic and solid tumor cancers.
genital” has a looser connotation and refers to conditions that manifest Patients with FA may present with either physical anomalies but
early in life, often at birth, but does not imply a particular causation. normal hematology, or normal physical features but abnormal hema-
Therefore “congenital BM failure” is not necessarily inherited and may tology, normal physical features and normal hematology, or physical
be caused by a de novo gene mutation during early embryogenesis or anomalies and abnormal hematology (Fig. 29.1). There can also be
by acquired factors such as viruses, drugs, or environmental toxins. sibling heterogeneity in presentation with discordance in clinical and
Hematopoiesis is an orderly but complex interplay of stem and hematologic findings, even in affected monozygotic twins. Using
progenitor cells, growth factors, BM stromal elements, and positive and published information, the median age at diagnosis of FA is about
negative cellular and humoral regulators. Thus BM failure can poten- 6.5 years with a reported range from birth to 49 years.
tially occur at several critical points in the hematopoietic lineage
pathways. With regard to inherited BM failure syndromes (IBMFSs),
germline mutations interfere with orderly hematopoiesis and cause the Epidemiology
BM failure. The discovery of specific, high-penetrance mutant alleles
associated with discrete IBMFSs provides evidence for this. Many of The overall prevalence of FA is 1 to 5 cases per million with a carrier
these alleles are of genes that directly affect physiologic cell survival and frequency of 1 in 200 to 300 in most populations. Data from the
function in pathways that are essential for normal hematopoiesis (e.g., CIMFR showed a prevalence of 11.4 cases per million live births
DNA repair, telomere maintenance, ribosome biogenesis, microtubule per year. It occurs in all racial and ethnic groups. Spanish Gypsies
stabilization, chemotaxis, signaling from hematopoietic growth factors, have the world’s highest prevalence of FA with a carrier frequency
signal transduction related to hematopoietic cell differentiation, and of 1 in 64 to 1 in 70 for a common founder mutation. A founder
granulocytic enzymes). Modifying genes, epigenetic processes, acquired effect has also been demonstrated in Afrikaners in South Africa
factors, and chance effects may also be operative and interact with the in whom one specific mutation is common (frequency, 1 in 83),
mutant genes to produce overt disease with varying clinical expression. as well as in Ashkenazi Jews (1 in 89), Moroccan Jews, Tunisians,
Hence the disorders listed in Table 29.1 are transmitted in a Mendelian sub-Saharan African blacks, Indians, Israeli Arabs, Brazilians, and
pattern determined primarily by mutant genes with inheritance pat- Japanese.
terns of autosomal dominant, autosomal recessive, or X-linked types.
Newly discovered IBMFSs may follow similar inheritance patterns or
be multifactorial in origin caused by an interaction of multiple genes Genetics
and a variety of exogenous or environmental determinants.
The incidence of the IBMFSs can be approximated from experi- Patients with FA show abnormal chromosome fragility that is readily
ence at large centers. Data from Children’s Hospital Boston show that seen in metaphase preparations of peripheral blood lymphocytes
the IBMFSs comprise about 30% of cases of pediatric BM failure cultured with phytohemagglutinin (PHA) and enhanced by adding
disorders, with Fanconi anemia (FA) cases leading the list. Data from a DNA interstrand cross-linking agent, either mitomycin C (MMC)
the Canadian Inherited Marrow Failure Registry (CIMFR) suggest an or diepoxybutane (DEB) (see Abnormal Chromosome Fragility
incidence of about 65 cases diagnosed per million live births per year. section later). This feature was used to discover the first FA genes by
Importantly, none of these syndromes is restricted to the pediatric age complementation. A breakthrough in the search for FA genes evolved
group. Patients with IBMFSs may be detected for the first time in from the important observation that fusion of normal cells with FA
adulthood. Reported cases include patients with FA, dyskeratosis cells (i.e., cell hybridization) resulted in correction of MMC hyper-
congenita (DC), Diamond-Blackfan anemia (DBA), and Kostmann/ sensitivity of the FA cells in a growth inhibition assay. Thus the cell
severe congenital neutropenia (K/SCN) among others, whose condi- hybridization corrected the abnormal FA chromosome fragility, a
tion first became evident when they reached adulthood. process known as complementation. It was further demonstrated that
cell hybridization in several unrelated patients with FA could also
INHERITED BONE MARROW FAILURE SYNDROME produce the corrective effect on chromosomal fragility by comple-
WITH PANCYTOPENIA mentation, which led directly to subtyping of patients into discrete
complementation groups. A second method for complementation
Fanconi Anemia testing, which is currently used more often for research and clinical
purposes, is retroviral transduction. The cDNA of each wild-type FA
gene can be transfected into T cells from a newly diagnosed patient
Background using retroviral vectors. If a specific wild-type FA gene corrects
(complements) the abnormal chromosome breakage in the patient’s
FA is inherited in an autosomal recessive manner in 98% of cases. In T cells in culture on exposure to DEB, the mutant gene is identified.
about 2% of cases, it is transmitted in an X-linked recessive mode So far, 18 genetic groups (termed types A, B, C, D1, D2, E, F, G, I,
caused by a mutant FA type B gene. J, L, M, N, O, P, Q, R, S) have been proposed, most of them on the

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