Fanconi anemia (see Table 3–3)
— Inheritance is autosomal recessive.
— Any of 16 gene mutations, FANCA through FANCQ, account for about 95% of cases.
— Macrocytosis and poikilocytosis may precede cytopenias.
— Cytopenias, sometimes starting with thrombocytopenia, develop after age 5 to 10 years.
— Marrow hypocellularity explains cytopenias.
— Short stature; abnormal skin pigmentation (café-au-lait spots); skeletal abnormalities (eg, dysplastic radii and thumbs); heart, kidney, and eye anomalies; microcephaly; and hypogonadism in different combinations are often noted.
— Chromosome fragility may be present, especially after exposure to DNA cross-linking agents such as diepoxybutane (used as a diagnostic test).
— Androgens occasionally may improve hematopoiesis.
— Allogeneic hematopoietic stem cell transplantation can be curative.
— There is risk of acute myelogenous leukemia and other cancers.
Dyskeratosis congenita
— Inheritance patterns: autosomal dominant, autosomal recessive, and X-linked (see Williams Hematology, 9th ed, Chap. 35, Table 35–10)
— Gene mutations identified in majority of cases
— Mutations involving genes encoding proteins in the telomerase complex
— Resulting abnormalities in telomere length
— Mucocutaneous (eg, skin hyperpigmentation or hypopigmentation, alopecia leukoplakia) and finger and toenail abnormalities (ridging and longitudinal splitting, atrophy) in childhood
— Pulmonary (eg, fibrosis), gastrointestinal (eg, esophageal webs), urogenital (eg, hypospadias), neurologic (eg, learning impairment), skeletal (eg, hypoplasia of mandible) findings
— Aplastic anemia in early adulthood: principal cause of death
— Increased incidence of various mucosal cancers (eg, squamous cell carcinoma of mouth, nasopharynx, esophagus, rectum, vagina, others)
Shwachman-Diamond syndrome
— The cause is mutation in the SBDS (Shwachman-Bodian-Diamond syndrome) gene on chromosome 7.
— Exocrine pancreatic insufficiency and neutropenia occur. Pancreatic endocrine function (insulin secretion) generally remains intact.
— Neutropenia with functionally abnormal neutrophils (defective chemotaxis) is present in virtually all patients.
— Anemia and thrombocytopenia are less common.
— Elevated hemoglobin F occurs in most patients.
— Pancytopenia occurs in about 20% of patients.
— Patients usually present in early infancy with malabsorption; steatorrhea; failure to thrive; and deficiencies of fat-soluble vitamins A, D, E, and K.
— Approximately 50% of patients regain exocrine pancreatic function during later childhood.
— Skeletal anomalies (eg, short stature, osteochondrodysplasia [cartilage and bone anomalies], osteoporosis) are present in about 75% of patients.
— Recurrent bacterial infections (eg, upper respiratory tract infections, otitis media, sinusitis, pneumonia, paronychia, osteomyelitis, bacteremia) occur.
— Enzyme replacement therapy is given for exocrine pancreatic insufficiency.
— Progression to multicytopenia, hypoplastic marrow, myelodysplasia, or acute myelogenous leukemia can occur.
— Allogeneic hematopoietic stem cell transplantation can be curative.
Other rare causes of aplastic anemia are shown in Table 3–4