Fanconi anemia
— Autosomal recessive.
— Any of 13 gene mutations, FANCA through FANCN, account for about 95 percent 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 (e.g., dysplastic radii and thumbs); heart, kidney, and eye anomalies; microcephaly; and hypogonadism in different combinations often noted.
— Chromosome fragility, 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.
— Risk of acute myelogenous leukemia and other cancers.
Dyskeratosis congenita
— Autosomal dominant, autosomal recessive, and X-linked inheritance patterns may be present (see Williams Hematology 8th ed, Chap. 34, Table 34–9, p. 478).
— Gene mutations identified in 60 percent of cases.
— Mutations involving genes encoding proteins in the telomerase complex.
— Resulting abnormalities in telomere length.
— Mucocutaneous (e.g., skin hyperpigmentation or hypopigmentation, alopecia leukoplakia) and finger and toenail abnormalities (ridging and longitudinal splitting, atrophy) in childhood.
— Pulmonary (e.g., fibrosis), gastrointestinal (e.g., esophageal webs), urogenital (e.g., hypospadius), neurologic (e.g., learning impairment), skeletal (e.g., hypoplasia of mandible) findings.
— Aplastic anemia in early adulthood. Principal cause of death.
— Increased incidence of various mucosal cancers (e.g., squamous cell carcinoma of mouth, nasopharynx, esophagus, rectum, vagina, others).
Shwachman-Diamond syndrome
— Caused by mutation in SBDS gene (Shwachman-Bodian-Diamond syndrome) on chromosome 7.
— Exocrine pancreatic insufficiency and neutropenia. Pancreatic endocrine function (insulin secretion) generally remains intact (see Chap. 33).
— Neutropenia with functionally abnormal neutrophils (defective chemotaxis) present in virtually all patients.
— Anemia and thrombocytopenia less common.
— Elevated hemoglobin F in most patients.
— Pancytopenia in about 20 percent 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 percent of patients regain exocrine pancreatic function during later childhood.
— Skeletal anomalies are present in about 75 percent of patients. Short stature, osteochondrodysplasia (cartilage and bone anomalies), osteoporosis.
— Recurrent bacterial infections (e.g., upper respiratory tract infections, otitis media, sinusitis, pneumonia, paronychia, osteomyelitis, bacteremia) occur.
— Enzyme replacement therapy for exocrine pancreatic insufficiency.
— Progression to multicytopenia, hypoplastic marrow, myelodysplasia, or acute myelogenous leukemia can occur.
— Allogeneic hematopoietic stem cell transplantation can be curative.