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Chapter 29 Inherited Bone Marrow Failure Syndromes 363

intravenous secretin or cholecystokinin confirm the presence of mark- to AML. Similarly, patients with SDS with del(20q) rarely evolve into
edly impaired enzyme secretion averaging 10% to 14% of normal advanced MDS/AML.
but with preserved ductal function. Because of its invasive nature, The pathophysiologic link between SBDS mutations and propen-
this test has largely been replaced by measuring the levels of pancreatic sity to MDS and AML is unknown. It is possible that patients with
enzymes in the serum. SDS cells develop more frequent mutations caused by genomic
During the first 3 years of life, serum trypsinogen is typically instability, possibly because of mitotic spindle dysregulation or telo-
reduced and can be used for diagnostic purposes. Serum isoamylase mere shortening. It is also possible that impaired ribosome biogenesis
levels are low in patients with SDS of all ages. However, normal and accelerated apoptosis cause a growth disadvantage for SDS BM
children younger than 3 years have low isoamylase levels, so its cells, allowing for a growth advantage and expansion of malignant
measurement is not diagnostically useful at this age. Fecal elastase is clones. Although molecular and cellular parameters do not distinguish
another pancreatic enzyme that is reduced in SDS. Approximately patients with SDS with transformation from those with SDS without
50% of patients exhibit a modest improvement in enzyme secretion transformation, it is remarkable that all SDS BM demonstrates many
with advancing age and normal fat absorption when assessed by characteristic features observed in MDS. These include impaired BM
72-hour fecal fat balance studies. These patients do not require stromal support of normal hematopoiesis, increased BM cell apoptosis
further pancreatic enzyme replacement therapy. mediated by the Fas pathway, telomere shortening of leukocytes,
increased BM neovascularization, high frequency of clonal cytoge-
Imaging Studies. Radiographs of the bone are useful as a screening netic abnormalities, and abnormal leukemia-related gene expression
diagnostic test for SDS. Osteopenia is seen in most patients but rarely in BM progenitor cells, such as overexpression of the oncogenes TAL1
results in clinical osteoporosis. Metaphyseal dysplasia has been and LARG.
reported in about 50% of patients, particularly of the femoral heads, The vast majority of the published cases of SDS-associated MDS/
knees, humeral heads, wrists, ankles, and vertebrae. Rib cage abnor- AML developed without previous G-CSF therapy. None of the six
malities can be found in 30% to 50% of patients. These include a patients with SDS-associated MDS/AML from our institution were
narrow rib cage, short ribs, flared anterior rib ends, and costochondral treated with G-CSF before transformation. However, it is still unclear
thickening. Digital abnormalities such as clinodactyly, syndactyly, whether G-CSF increases the risk of developing leukemia or promotes
and supernumerary thumbs have been reported but are rare. Spinal the expansion of existing malignant clones. Because G-CSF might
deformities, including kyphosis and scoliosis, have been reported. increase neutrophil counts and prevent infections in SDS, a fraction
Patients with SDS do not have macroscopic brain malformations of the reported patients with SDS-associated MDS/AML had been
by MRI testing. However, they may have a decreased global brain previously treated with G-CSF. For example, two of the 29 patients
volume (both gray matter and white matter) and a smaller posterior with SDS on the Severe Chronic Neutropenic International Registry
fossa, cerebellar vermis, corpus callosum, brainstem, and occipito- who received G-CSF therapy developed MDS/leukemia.
frontal head circumferences compared with control participants. The SBDS gene must play a critical role in preventing leukemic
These anomalies might be the basis for the neurocognitive and myeloid transformation because up to one-third of patients with SDS
neurobehavioral difficulties. develop MDS/AML. To address whether an acquired mutant SBDS
The French registry found cardiac anomalies in 11% of patients gene is associated with leukemic transformation in de novo AML, 77
with SDS. These include dilated and nondilated cardiomyopathy, AML BM samples at diagnosis or relapse were analyzed for SBDS
and structural malformations such as atrial septal defect, ventricular mutations, and none were identified. To see if a subset of patients
septal defect, coarctation of the aorta, and tetralogy of Fallot. with previously undiagnosed SDS presented for the first time with
Circumferential strain as measured by echocardiography was AML, 48 AML BM samples were studied at remission, but no SBDS
found to be decreased by the U.S. SDS registry, suggesting systolic mutations were found. Patients with SDS who also have MDS/AML
dysfunction. have common SBDS mutations, and a genotype–phenotype study of
21 patients with SDS with MDS/AML showed no relationship
Cancer Predisposition. SDS is characterized by a high propensity (Linda Ellis, RN, Toronto, personal communication). Thus the link
to develop MDS and leukemia, particularly AML. The published between mutant SBDS; hematologic cancer; and upregulated onco-
crude rate for MDS or AML (MDS/AML) in patients with SDS genes, including LARG, and TAL1, is undetermined.
ranges from 8% to 33%. Data from the CIMFR and the French Several cases of solid tumors have been described in SDS. These
Severe Chronic Neutropenia Registry, the cumulative risk of MDS/ include two cases of pancreatic ductal adenocarcinoma, one brain
AML by the age of 18 and 20 years, was 20% and 19%, respectively. frontal lobe B-cell lymphoma, one dermatofibrosarcoma protuberans
The risk of leukemia in the French registry was 36% by the age of and one breast cancer. However, more data are needed to determine
30 years. whether the risk of solid tumors is higher than in the general
There is an increased frequency of BM clonal cytogenetic abnor- population.
malities as the sole evidence for a clonal disease in an otherwise
hypocellular BM without excess blast counts or major prominent
multilineage dysplasia. The incidence is roughly estimated to be Differential Diagnosis
7% to 41% based on pooled published data. Isochromosome 7q
[i(7q)], an extremely uncommon finding rarely described in MDS or The introduction of genetic testing has improved the ability to
AML in patients without SDS, was seen in 44% of patients with diagnose the disorder and particularly has helped identify cases with
SDS. This high occurrence suggests that it is a fairly specific marker an atypical presentation (Y. Dror, unpublished data). The diagnostic
for SDS and might be related to the mutant gene on 7q(11). Other criteria include having at least two of the following: (1) chronic BM
chromosome 7 abnormalities are seen in 33% of patients with SDS failure, (2) exocrine pancreatic insufficiency, (3) positive genetic
and include monosomy 7, i(7q) combined with monosomy 7 and testing results or a first-degree relative with SDS. Several syndromes
deletions or translocations involving part of 7q. The prognostic sig- with overlapping features have to be excluded.
nificance of the cytogenetic changes requires prospective monitoring The syndrome of refractory sideroblastic anemia with vacuoliza-
for clarification. Of the patients with i(7q), progression to advanced tion of BM precursors, or Pearson syndrome, is clinically similar to
MDS with excess blasts or to AML has rarely been reported, but SDS but characterized by very different BM morphology. Severe
development of severe cytopenia and additional clones was described anemia requiring transfusions rather than neutropenia is often present
in three of four patients on long-term follow-up in the Canadian at birth and by 1 year of age in all cases. In contrast to SDS, the major
registry. Among a group of six patients with i(7q) from several hos- BM morphologic findings are ringed sideroblasts with decreased
pitals in the United Kingdom, none progressed to advanced MDS/ erythroblasts and prominent vacuolation of erythroid and myeloid
AML. In contrast, approximately 40% of patients with the other precursors. The disorder shares clinical similarities with SDS because
chromosomal 7 abnormalities progress to either advanced MDS or of exocrine pancreatic dysfunction. Malabsorption and severe failure