Table 6.

Selected Inherited Bone Marrow Failure Syndromes^*

Fanconi anemia (FA)	Genetically and clinically heterogenous syndrome of progressive bone marrow failure accompanied by a wide variety of heterogenous developmental abnormalities, such as growth failure, missing or dysmorphic thumbs and radii, craniofacial abnormalities, VACTERL association, renal or urogenital dysplasia, and multiple café-au-lait macules. FA is caused by germline mutation of one of at least 18 FA genes that have been identified to date. FA is associated with a high risk of acute leukemias and solid tumors due to genomic instability. May have autosomal recessive or X-linked inheritance, depending on the affected gene.
	Laboratory screening tool: chromosome breakage test (positive result is diagnostic of FA).
Shwachman-Diamond syndrome	Progressive pancytopenia associated with failure to thrive, severe chronic diarrhea due to exocrine pancreatic insufficiency, skeletal abnormalities, and increased risk of myelodysplasia and leukemia. Autosomal recessive inheritance.
	Laboratory screening tool: age-adjusted pancreatic enzyme concentrations.
Dyskeratosis congenita (DC)	Genetically heterogenous disease that causes bone marrow failure and predisposition to cancer in addition to dystrophy of teeth and nails, oral leukoplakia, and reticulated hyperpigmentation of the skin. DC may cause pulmonary fibrosis, immunodeficiency, and liver disease. DC is caused by mutation of one of at least nine genes essential for the maintenance of telomeres (the DNA/protein complexes localized at the tips of chromosomes). Without telomerase, telomeres shorten with each cell division, eventually leading to decreased stem cell proliferation and genomic instability. Affected patients have a high risk of cancer and may require a stem cell transplant due to progressive bone marrow failure. Depending on the affected gene, DC may have autosomal recessive, autosomal dominant, or X-linked inheritance.
	Laboratory screening tool: telomere length measurement in lymphocytes.
Pearson syndrome	Genetic disorder caused by large deletions of mitochondrial DNA. Often diagnosed in the neonatal period due to growth failure, developmental delay, macrocytic anemia (frequently evolving into pancytopenia), metabolic acidosis, and exocrine pancreatic insufficiency. Bone marrow evaluation reveals multiple vacuoles in the hematopoietic cells. Most patients die in early childhood; survivors develop severe neuromuscular signs and symptoms due to mitochondrial dysfunction.
Cartilage-hair hypoplasia	Genetic syndrome with diverse features of short-limbed dwarfism, sparse and fine hair, immunodeficiency, autoimmunity, gastrointestinal dysfunction, pancytopenia, and predisposition to hematopoietic malignancies. This rare autosomal recessive disorder is caused by mutations in the RMRP (mitochondrial RNA-processing endonuclease) gene. Hematopoietic stem cell transplant may be used to cure immunodeficiency.
Congenital amegakaryocytic thrombocytopenia	Rare autosomal recessive disorder caused by mutations in the thrombopoietin receptor (MPL). Patients often present with severe thrombocytopenia at birth (which may lead to life-threatening hemorrhage) and reduced number of megakaryocytes in the bone marrow. Progressive bone marrow failure occurs in early childhood, indicating the importance of thrombopoietin for normal hematopoiesis. A hematopoietic stem cell transplant may be needed.

^*Specific genetic tests are available for all the genetic syndromes listed in the table. Useful laboratory tools are highlighted where available for specific bone marrow failure syndromes.