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364 Part IV Disorders of Hematopoietic Cell Development

to thrive occur in approximately half of cases within the first 12 months, and BM testing every 1 to 3 years. The latter includes
months of life. Qualitative pancreatic function tests show depressed aspirates for smears and cytogenetics analyses. Concomitant BM
acinar function and reduced fluid and electrolyte secretion. Approxi- biopsies are recommended when the patient’s clinical status changes.
mately 50% of reported patients die early in life from sepsis, acidosis,
and liver failure; the others appear to improve spontaneously with G-CSF
reduced transfusion requirements. At autopsy, the pancreas shows G-CSF given for profound neutropenia has been very effective in
acinar cell atrophy and fibrosis; fatty infiltration as seen in SDS is not inducing a clinically beneficial neutrophil response. Data from the
a prominent feature. The need for long-term pancreatic enzyme Severe Chronic Neutropenia International Registry (SCNIR) dem-
replacement is unclear. These patients have a diagnostic deletion of onstrated that treatment with G-CSF results in a brisk neutrophil
mitochondrial deoxyribonucleic acid (mtDNA). mtDNA encodes response in about 90% of patients. The response was sustained in
enzymes in the mitochondrial respiratory chain that are relevant to some cases for more than 11 years (Beate Schwinzer, Hannover,
oxidative phosphorylation, including the reduced form of nicotin- Germany, personal communication).
amide adenine dinucleotide dehydrogenase (NADH), cytochrome
oxidase, adenosine triphosphatase (ATPase), mitochondrial transfer Androgens
ribonucleic acids (tRNAs), and mitochondrial ribosomal RNAs. The A smaller number of patients received androgens plus steroids for the
degree of heteroplasmy affects the disease expression. SDS shares some treatment of FA, and improved BM function was also noted. Anec-
manifestations with FA such as BM dysfunction and growth failure, dotal cases treated with androgens alone, cyclosporine, or erythropoi-
but patients with SDS can usually be distinguished because of malab- etin do not allow broad therapeutic conclusions. Few cases of patients
sorption syndrome, fatty changes within the pancreatic body that can who were treated with corticosteroids with some hematologic
be visualized by imaging, and characteristic skeletal abnormalities not improvement were reported in the 1980s.
seen in patients with FA. In difficult cases with incomplete disease
expression, the distinction relies on normal clastogenic stress-induced Blood Products and Other Supportive Care
chromosome fragility testing and genetic testing of SDS and FA genes. Anemia and thrombocytopenia are managed with transfusions of
Atypical SDS cases with only little evidence of pancreatic changes RBCs or platelets when symptoms appear or prophylactically for
can be difficult to distinguish from early-onset dyskeratosis con- profound cytopenias. Antifibrinolytic therapy with tranexamic acid
genita with no mucocutaneous manifestations. Establishing a diag- can also be given for mild mucosal bleeding. Broad-spectrum antibi-
nosis in such cases can be assisted by telomere length screening, which otics are indicated for febrile episodes and severe neutropenia.
might show telomere shortening in SDS, but typically not in the very
severe range seen in dyskeratosis congenita. Hematopoietic Stem Cell Transplantation
At present, the only curative option for severe BM failure in SDS
is allogeneic HSCT. The indications for HSCT include BM failure
Prognosis with severe or symptomatic cytopenia, MDS with excess blasts
(5–29%), or leukemia. Published data are limited and derived from
Because of the broad pleiotropy in SDS, the number of undiagnosed case reports or small case series with a mix of sibling and matched
patients with mild or asymptomatic disease is unknown. Hence the unrelated donors. Two registries in Europe have provided additional
overall prognosis may be better than previously thought. The major- information.
ity of SBDS mutations represent hypomorphic alleles with reduced The European Group for Blood and Bone Marrow Transplanta-
but variable protein expression. Also, there is phenotypic heterogene- tion (EBMT) Registry reported 26 transplanted patients with SDS.
ity in patients carrying identical SBDS mutations. Therefore, until The indications included aplastic anemia (n = 16), MDS/AML (n =
more information is forthcoming, the natural history and prognosis 9), or other (n = 1). Patients were transplanted with myeloablative
are not yet defined. conditioning regimens that included either busulfan or total-body
From a literature review, the projected median survival of patients irradiation. The majority of the donors were unrelated (n = 19).
with SDS was calculated as 35 years. During infancy, morbidity and Eighty-one percent were engrafted. The incidence of grade III to IV
mortality are mostly related to infections, thoracic dystrophy, and GVHD was 24%; chronic GVHD was 29%. The overall survival was
malabsorption. Later in life, the major problems are hematologic or 65% at 1.1 years. Deaths were primarily caused by infections,
complications related to their treatment. Cytopenias tend to fluctuate GVHD, or major organ toxicities. Factors associated with adverse
in severity but do not fully resolve spontaneously. The most common outcome included MDS/AML or usage of total-body irradiation.
cause of death in late childhood or adulthood is related to MDS/ The French Neutropenia Registry reported 10 transplanted
AML. patients with SDS. The indications included severe BM failure (n =
5) or MDS/leukemia (n = 5). Patients were conditioned with mye-
loablative regimens incorporating busulfan or total-body irradiation.
Therapy Six received grafts from unrelated donors and four from a sibling
donor. BM engraftment occurred in eight patients. The 5-year overall
Patient management is ideally shared by a multidisciplinary team survival was 60%. Causes of death included infections related to
consisting of a hematologist and a gastroenterologist as core members neutropenia, GVHD, relapse, and transplant-related toxicity. Factors
and other subspecialists such as a dentist, an orthopedic surgeon, and associated with adverse outcome included MDS/AML.
a psychologist as required. The malabsorption component of SDS A note of caution is sounded regarding HSCT for SDS. Left
responds to treatment with oral pancreatic enzyme replacement with ventricular fibrosis and necrosis without coronary arterial lesions has
meals and snacks using guidelines similar to those for cystic fibrosis. been reported in 50% of patients with SDS at autopsy, suggesting
Supplemental fat-soluble vitamins are also usually required. When that there may be an increased risk of cardiotoxicity as well as other
monitored over time, approximately 50% of patients convert from problems with the intensive preparatory chemotherapy used in
pancreatic insufficiency to sufficiency because of spontaneous HSCT. Indeed, published data emphasized that complications are
improvement in pancreatic enzyme secretion. This improvement is more common in patients with SDS who receive chemotherapy or
particularly evident after 4 years of age. A long-term plan should be undergo transplantation than in non-SDS patients with aplastic
initiated for early detection of severe cytopenias that require correc- anemia. Complications include cardiotoxicity, neurologic and renal
tive action or malignant myeloid transformation. There are currently complications, venoocclusive disease, pulmonary disease, posttrans-
no data about the cost effectiveness of a specific leukemia surveillance plant graft failure, and severe GVHD. The heightened risk for
program in SDS. However, it is generally accepted that it should patients with SDS after transplantation can be explained in three
include periodic blood counts with differentials and blood smears ways: (1) the presence of the SDS BM stromal defect that is not
every 3 to 4 months, a clinical evaluation by a hematologist every 6 corrected by the allograft and might be aggravated by the