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Chapter 29 Inherited Bone Marrow Failure Syndromes 361

promotes eIF6 removal from the 60S subunit by a mechanism that failure in patients with SDS. A group from Boston used iPSCs from
requires guanosine triphosphate (GTP) binding and hydrolysis by patients with SDS and demonstrated an alternative mechanism for
EFL1. SBDS interacts with multiple proteins with diverse molecular cell death. During differentiation of iPSCs to promyelocytes protease
functions; many of them are involved in ribosome biogenesis, such levels are increased and apoptosis is enhanced. Supplementing the
as RPL4, and DNA metabolism, such as RPA70. culture media with protease inhibitors provides a rescue.
SBDS is critical for cell survival. When SBDS is lost in SDS BM Two other abnormalities have been identified in SDS. When the
cells or in SBDS-knockdown K562 and HeLa cells, the cells undergo averages of telomere lengths adjusted for age are compared with those
accelerated apoptosis. The accelerated apoptosis in BM cells and of control participants, a tendency toward shortening of telomeres is
SBDS-knockdown cells seems to be through the Fas pathway and not found in patient leukocytes, reflecting premature cellular aging. This
through the Bax/Bcl-2/Bcl-XL pathway. SBDS deficiency in primary may represent either an inherent defect in telomere maintenance or
SDS cells and in SBDS-knockdown cells results in abnormal accu- compensatory stem cell hyperproliferation. In addition to an inherent
mulation of functional Fas (transcript 1) at the plasma membrane hematopoietic defect, it has also been shown that the BM stroma is
level. markedly defective in terms of its ability to support and maintain
+
Interestingly, knocking down SBDS in CD34 hematopoietic normal hematopoiesis.
stem cells/early progenitors and in cell lines increased the levels of
ROS, and antioxidants reduced Fas-mediated cell death and improved
hematopoiesis from primary SDS cells. This suggests that SBDS Clinical Features
balances the levels of ROS and thereby protects hematopoietic cells
from cell death. The many clinical manifestations that occur in varying combinations
Patients with SDS have a defect in leukocyte chemotaxis. Consis- are shown in Table 29.4. Most patients present in infancy with evi-
tent with this observation, the SBDS homologue in amoeba was dence of growth failure, feeding difficulties, diarrhea, and infections.
found to localize to the pseudopods during chemotaxis. These Steatorrhea and abdominal discomfort are frequent. Approximately
observations suggest that the SBDS protein deficiency in SDS causes 50% of patients exhibit a modest improvement in pancreatic function
a chemotaxis defect in patients. and do not require further pancreatic enzyme replacement therapy.
SBDS has been shown to colocalize to the mitotic spindle and Hepatomegaly is a common physical finding in young children but
bind microtubules and stabilize them. Its deficiency results in centro- typically resolves with age and does not have clinical significance.
somal amplification and multipolar spindles. Patients with SDS are particularly susceptible to bacterial and
The pathophysiologic link between SBDS mutations and BM fungal infections, including otitis media, bronchopneumonia, osteo-
failure is still unclear. Initial studies in the 1970s and early 1980s myelitis, septicemia, and recurrent furuncles. Overwhelming sepsis is
showed reduced CFU-GM and BFU-E colony formation in most a well-recognized fatal complication of this disorder, particularly early
patients compatible with a defective stem cell origin of the BM in life.
failure. Recent investigations have characterized a much more exten- Short stature is a fairly consistent feature of the syndrome. When
sive hematopoietic phenotype (Table 29.3). SDS BM has decreased treated with pancreatic enzyme replacement, most patients show a
+
+
numbers of CD34 cells as well as an impaired ability for CD34 cells normal growth velocity yet remain consistently below the third per-
to form multilineage hematopoietic colonies in vitro, confirming that centile for height and weight, indicating an intrinsic growth defect.
they are intrinsically defective. Patients’ BM cells overexpress Fas, the The occasional adult achieves the 25th percentile for height. Although
membrane receptor for Fas ligand, and show increased patterns of metaphyseal dysplasia is a common radiologic abnormality (44–77%
apoptosis after preincubation with activating anti-Fas antibody, of patients), particularly in the femoral head and the proximal tibia,
pinpointing this as a central pathogenetic mechanism for the BM in most patients it fails to produce any symptoms. Occasional patients
failure. Induction of differentiation (at least toward erythroid lineage) have clinical joint deformities, resulting in pain, functional impair-
results in markedly accelerated apoptosis in SBDS-deficient cells, ment, or cosmetic problems, necessitating surgery. Some patients
with only a minimal effect on proliferation. Importantly, oxidative present at birth with respiratory distress caused by thoracic dystrophy.
stress is increased during differentiation of SBDS-deficient erythroid Others may have asymptomatic short and flared ribs.
cells, and antioxidants enhance the expansion capability of both
differentiating SBDS-knockdown K562 cells and colony production
of SDS patient HSCs and progenitors. Erythroid differentiation also TABLE Clinical and Hematologic Features of Shwachman–
results in reduction of all ribosomal subunits and global translation. 29.4 Diamond Syndrome
These studies indicate that when SBDS protein is deficient, several
biologic pathways may be dysfunctional during hematopoietic cell Major Features Patients (%)
development; this may be the cause of the high predilection for BM Pancreatic insufficiency (decreased digestive enzymes) 86–100
Hematologic cytopenias
Neutropenia 88–100
TABLE Hematopoietic Phenotype in Shwachman-Diamond Thrombocytopenia 24–70
29.3 Syndrome
Anemia 42–66
+
Decreased BM CD34 cells
+
Decreased colonies from CD34 cells Pancytopenia 10–44
Abnormal telomere shortening of leukocytes MDS/AML ≈30
Increased apoptosis of BM cells Other Features
Apoptosis is mediated by Fas pathway Short stature 50
Impaired BM stromal cell function Delayed bone maturation 100
Abnormal lymphoid immune function
Increased BM microvessel density Metaphyseal dysplasia 44–77
BM cell upregulation of specific oncogenes Rib cage anomalies 32–52
Increased levels of reactive oxygen species Hepatomegaly or elevated enzymes <50
Accentuation of the ribosome biogenesis defects with reduced ribosome
subunits, ribosomes, and polysomes Poor oral health (caries, ulcers, tooth loss) >50
Accentuation of the protein translation defect Learning and behavioral problems >50
BM, Bone marrow. AML, Acute myeloid leukemia; MDS, myelodysplastic syndrome.