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532 Part VI: The Erythrocyte Chapter 35: Aplastic Anemia: Acquired and Inherited 533

mutations should be used to confirm the clinical conclusion. Shortened aminotransaminase is seen in most young patients and appears to
telomere length in leukocytes also can be assessed by flow cytometric resolve with age. Delayed puberty is common. The neutropenia and
298
fluorescence in situ hybridization studies. 284 chemotactic abnormality may result in recurrent infections, including
sinusitis, otitis, pneumonia, osteomyelitis, and others. Pancreatic cell
Management lipase production improves with age, and as many as half the patients
Stem cell hematopoietic transplantation has had inconsistent results may have improvement in lipid absorption in the small bowel with time.
285
because of frequent and severe posttransplantation complications.
Nonmyeloablative transplantation might improve results. 286–288 Trans- Diagnosis
plantation might improve the cytopenias, but not the abnormalities of The diagnosis is based on the clinical findings of failure to thrive, steat-
other organs or the frequency of secondary nonhematopoietic cancer. orrhea, and neutropenia. Pancreatic insufficiency can be established
by low serum trypsinogen in patients younger than 3 years of age. The
Course and Prognosis marrow may be initially normal, but develops evidence of marrow fail-
The incidence of squamous cell carcinoma of mucosal sites is increased ure and sometimes cytogenetic abnormalities, particularly of chromo-
and the squamous cell carcinoma often originates in sites of leukopla- some 7, as the child ages. The age of expression of clonal hematopoiesis
kia in the skin, gastrointestinal, or genitourinary tracts. These carci- (e.g., myelodysplastic syndrome or AML) is variable. The SBDS gene
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nomas usually develop between the ages of 20 and 30 years. Mortality mutation is present in 90 percent of patients with Shwachman-Dia-
300
from neutropenic infection or thrombocytopenic hemorrhage occurs mond syndrome. The remaining 10 percent have the clinical features
in about two-thirds of patients with aplastic anemia. Median survival is of the syndrome, but the gene defects have not been defined.
approximately 30 years.
Management
Supportive care, particularly with supplemental pancreatic enzymes, to
SHWACHMAN-DIAMOND SYNDROME provide proper nutrition, and appropriate and prompt treatment of bac-
Definition terial infections with antibiotics is important. Many agents, including
G-CSF, glucocorticoids, pancreatic extract, vitamins, have been tried to
This disease is an uncommon inherited disorder that is estimated to improve the neutropenia with unpredictable results. Some agents have
occur once in every 75,000 births, manifesting exocrine pancreatic potential risks, such as G-CSF fostering clonal evolution and glucocor-
290
insufficiency with secondary steatorrhea, blood cell deficiencies, and ticoids fostering immunodeficiency. Severe hematopoietic dysfunction
skeletal abnormalities. It was first described in 1964. 291,292 and cytopenias can be corrected with allogeneic hematopoietic stem cell
transplantation. 301
Pathogenesis
Shwachman-Diamond syndrome results from mutations in the SBDS Course and Prognosis
gene on chromosome 7q11, which induces accelerated cellular apopto- Death from overwhelming sepsis is common. These patients, especially
sis via the FAS pathway. The resulting hyperproliferation may account males, have a significant risk of progression to a myelodysplastic syn-
293
for the abnormal telomere shortening that has been documented in the drome or AML. 292,302,303 Cytogenetic abnormalities are common, and
leukocytes in this condition. The pathogenetic mechanism that (1) telomeres are shortened, as in other marrow failure syndromes. Sur-
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304
prevents development of pancreatic acinar cells, (2) results in abnor- vival is a function of the severity of the cytopenias. If the cytopenias are
mal bone morphogenesis, and (3) causes marrow impairment of blood mild, survival is not uncommon into the fourth or fifth decade of life. It
cell production is not understood. SBDS knockdown in experimental is not clear whether Shwachman-Diamond syndrome is associated with
animals affects expression of genes involved in brain, bone, and mar- an increased incidence of solid tumors.
row development, and may be the result of the gene’s role in RNA
processing. 295,296 The SBDS gene promotes the release of eukaryotic ini-
tiation factor 6 from the pre-60s ribosome. 279a This action is necessary OTHER INHERITED APLASTIC ANEMIAS
for the formation of a mature 80s functional ribosome and production Several other rare syndromes are associated with aplastic pancytope-
of appropriate ribosome joining. The mutations in SBDS also result in nia, and these are described in Table 35–9. Congenital (hereditary)
abnormalities in neutrophil motility and chemotaxis, but pus formation amegakaryocytic thrombocytopenia (CAMT) results from mutations
in vivo seems adequate. in the TPO receptor gene, MPL. 305–307 The affected children can be
divided into two groups: CAMT I with mutations leading to complete
Clinical Findings loss of function of the TPO receptor, resulting in more severe thrombo-
Pancreatic insufficiency, steatorrhea, and neutropenia are present in cytopenia and a rapid progression to pancytopenia (aplastic anemia),
most patients at the time of diagnosis. 291,292,297 Pallor may reflect anemia and CAMT II, resulting from a variety of missense mutations, in which
and easy bruising; epistaxis or bleeding from other sites reflect throm- affected children have an increase in platelet count above 50 × 10 /L with
9
bocytopenia. Neutropenia occurs in approximately 95 percent, anemia time and much slower progression to and sometimes less-severe pancy-
in approximately 50 percent, and thrombocytopenia in approximately topenia. Reticular dysgenesis results from a pluripotential stem cell
306
35 percent of patients. Thus, a substantial plurality of patients has defect as both lymphoid and granulocytic progenitors are affected. 308,309
293
bicytopenia or tricytopenia with an hypoplastic marrow. Fetal hemo- It is a rare autosomal recessive disorder caused by mutations in the
globin levels are elevated in approximately 75 percent of the patients, adenylate kinase 2 gene (AK2) and characterized by bilateral sensori-
perhaps secondary to erythroid hypoplasia. Cytogenetic abnormalities neural deafness, severe combined immunodeficiency, and agranulocy-
involving chromosomes 7 and 20 have been described in marrow cells. tosis, which subjects infants to severe, often, life-threatening infections.
Nutritional inadequacies related to intestinal malabsorption result in a The Seckel syndrome results from mutations in the ATR gene, and
failure to thrive. Short stature is characteristic. Skeletal abnormalities marrow cells exhibit heightened sister chromatid exchange. 310–314 The
are present in most patients, notably osteopenia, but also syndactyly, ataxia-telangiectasia mutated and rad3-related (ATR) kinase mediates
supernumerary metatarsals, coax vera deformity, and dental enamel cellular responses to DNA damage and replication stress. Most of the
defects and caries. Hepatic dysfunction as evidenced by elevated serum eight syndromes delineated in Table 35–9 can be treated by marrow

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