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392 Part IV Disorders of Hematopoietic Cell Development

Patients with FA do not have skin hemangiomas like some patients is likely much better currently. Patients with TAR do not evolve into
with TAR, and patients with TAR rarely have prominent skin pig- having pancytopenia, but may develop acute leukemia in 1% to 2%
mentation defects like 40% of Fanconi patients. Confirmation of FA of cases.
is made by the clastogenic chromosome stress test showing increased
fragility and by mutational analysis. Patients with TAR do not have Platelet Transfusions
increased chromosomal breakage. As in other IBMFSs associated with thrombocytopenia, platelet
Some infants with trisomy 18 (+18) have absence or hypoplasia transfusions should be used judiciously. Bleeding and prophylaxis for
of radii and thrombocytopenia. However, in +18, thumbs are absent orthopedic surgical procedures are appropriate indications. Persistent
if radii are absent, and the disorder can also be distinguished from platelet counts below 10,000/µL may require preventive platelet
TAR syndrome cytogenetically. There are several syndromes with transfusions on a regular basis, especially in the first year of life when
radial abnormalities but with normal platelet counts that can be the expectation is that a spontaneous improvement in platelet number
diagnosed by mutational gene analysis. These include Roberts syn- will ensue with time in most infants. Single-donor platelets are pre-
drome (mutant ESC02); Holt-Oram syndrome (mutant TBX5); ferred to multiple random donor platelets to minimize the risk of
and the clinical spectrum of three disorders caused by mutant alloimmunization. HLA-partially matched or fully matched donors
RECQL4: Rothmund-Thomson syndrome, Baller-Gerold syn- for platelets may be required if patients become refractory to
drome, and RAPADILINO syndrome. transfusions.
Other Therapies
Therapy and Prognosis Supportive management is the mainstay, but in exceptional
situations, profound, persistent life-threatening thrombocytopenia
The risk of hemorrhage is greatest in the first year of life. Deaths are can be successfully treated by HSCT. Thrombopoietin receptor
usually caused by intracranial or gastrointestinal bleeding. If patients agonists, such as romiplostim and eltrombopag, have not been
survive the first year, platelet counts spontaneously increase inexpli- studied in TAR syndrome. Elevated serum thrombopoietin levels
cably to levels that are hemostatically safe and do not require platelet at baseline in patients with TAR may predict a poor response to
transfusional support. A minority of patients have sustained, pro- these products. IL-11, another thrombopoietic cytokine, has not
found thrombocytopenia that does not improve spontaneously. been studied in clinical trials either; however, endogenous IL-11
Published cases of TAR syndrome show an actuarial survival curve serum levels in patients with TAR are also elevated. Androgens,
plateau of 80% by age 1 to 2 years. Many reports of patients with corticosteroids, and splenectomy are ineffective therapies for TAR
TAR antedated the modern use of platelet transfusions, so the survival syndrome.

Inherited Bone Marrow Failure Syndromes (IBMFSs) and Malignant Leukemic Transformation
Historically, the IBMFSs were classified as “benign” hematology to con- the leukemogenic-initiating events in these conditions should become
trast sharply with hematologic cancer. Patients with IBMFSs often died evident.
early in life from complications of cytopenias. However, in the current Three of the syndromes illustrate the point. The best example is the
era of advanced supportive care and availability of recombinant cytokines multistep evolution of leukemic transformation over time in patients with
and other effective therapeutics, patients with these conditions usually K/SCN. The acquisition of activating RAS oncogene mutations, cyto-
survive the early years of life and beyond. With the extended lifespan of genetic abnormalities involving primarily +7, 7q− and +21, and G-CSF
patients, the natural history of these disorders has dramatically changed. receptor mutation occurs in the majority of patients who transform.
One of the most sobering observations is that the many IBMFSs confer In one patient with K/SCN who progressed to MDS/L, clonal evolution
an inordinately high predisposition to developing MDS and AML. These was assessed by exome sequencing of marrow cells. A pro-proliferative,
include conditions such as K/SCN, SDS, FA, DC, CAMT, DBA, and TAR differentiation-defective GCSFR mutation was found, that persisted and
syndrome, among others. Thus the distinction between “benign” and acquired secondary mutations. The frequency of RUNX1 mutations was
“malignant” hematology in the context of the IBMFSs has become blurred, high in a cohort of K/SCN patients, who developed MDS/L. Mutations in
and a new clinical and hematologic continuum is evident. Clearly, these RUNX1 and GCSFR cooperate to promote clonal expansion.
disorders are leukemia-predisposition syndromes and several of them Other than clonal cytogenetic changes, we know little about the timeline
(e.g., FA, DC, and DBA) are broader cancer-predisposition syndromes. or sequence of events that characterize the malignant phenotype of SDS.
Carcinogenesis occurs as a multistep sequence of events that is driven It is striking, though, that the syndrome from early age already shares
by genetic damage and by epigenetic factors. In the traditional view, the many of the findings of de novo adult MDS, including abnormal hema-
initiation of cancer starts in a normal cell through mutations from expo- topoietic colony growth, abnormally short leukocyte telomeres, elevated
sure to carcinogens. In the proliferative phase that follows, the genetically apoptotic index mediated by FAS/FAS ligand, an abnormal immune
altered, initiated cell undergoes selective clonal expansion that enhances system, an aberrant marrow microenvironment that shows impaired
the probability of additional genetic damage from endogenous mutations support of normal hematopoiesis, increased microvessel density, and
or DNA-damaging agents. Activation of proto-oncogenes, inactivation of impaired mitotic spindle stabilization. Many, if not all, of these findings
tumor-suppressor genes, or inactivation of genomic stability genes may may evolve in utero.
be central in this process. Finally, during malignant conversion and Finally, FA has a “short-cut” mechanism to leukemic conversion.
cancer progression, malignant cells show phenotypic changes, gene Biallelic mutant genes from conception result in genomic instability,
amplification, chromosomal alterations, and altered gene expression. compromised DNA repair, and chromosome breakage. In a study from
With respect to the leukemia-predisposition IBMFSs, there is reason France, the investigators used SNP arrays to analyze marrow cells of
to believe that leukemogenesis is also a multistep process. The first patients with FA with MDS/leukemia. They identified a relatively high
genetic “hit” or leukemia-initiating step may be the syndrome-specific frequency of somatic RUNX1 gene disruption compared with what is
inherited genetic abnormality itself, which initially manifests as the typically seen in patients with de novo MDS/leukemia. The opportunities
single- or multiple-lineage marrow failure state. The “predisposed” for blood cancers in this setting are infinite. Actuarial data from the IFAR
progenitor, already initiated, could conceptually develop decreased showed that the risk of acquiring clonal cytogenetic abnormalities was
responsiveness to the signals that regulate homeostatic growth, terminal 67% by 30 years of age in patients with BM failure. The actuarial risk of
cell differentiation, or programmed cell death. Leukemic promotion and MDS or AML was 52% by 40 years of age. This steady tempo of leukemic
progression with clonal expansion leading to MDS or AML could then evolution implies a stepwise acquisition over time of additional, critical
ensue readily. Because many of the mutant genes that produce the genetic “hits” before overt MDS/AML.
inherited BM failure syndromes have been discovered, the nature of