Congenital disorders of the bone marrow
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.; Rim Halaby, M.D. [2]; Serge Korjian M.D.
Synonyms and keywords: Congenital diseases of the bone marrow, hereditary disorders of the bone marrow, inherited disorders of the bone marrow, inherited bone marrow failure syndromes, IBMFS, congenital bone marrow failure syndromes, familial bone marrow failure syndromes, inherited bone marrow failure diseases
Overview
Congenital disorders of the bone marrow are classified into 1) inherited bone marrow failure syndromes which are the most commonly recognized entities as “inherited bone marrow disorders"; and 2) proliferative bone marrow failure syndromes that are very rare diseases with scarce data.
Inherited Bone Marrow Failure Syndromes
Inherited bone marrow failure syndromes (IBMFS) is a heterogenous group of diseases that are characterized by bone marrow failure (defective production of RBC, WBC, and/or platelets). While some may manifest during childhood, some IBMFS may not manifest until adulthood. Differentiation between diseases based on the pattern of inheritance (X-linked vs. autosomal recessive vs. autosomal dominant) is not possible since many diseases have more than one pattern of inheritance. All inherited bone marrow failure syndromes manifest with hematological abnormalities, such as pancytopenia and findings consistent with bone marrow failure (e.g. aplastic anemia or myelodysplastic syndrome). Almost all inherited bone marrow failure syndromes are considered pre-malignant conditions and predispose to both solid and hematologic malignancies. Although classically one gene is implicated in the disease pathogenesis, novel genes are being discovered in almost all inherited bone marrow failure syndromes, demonstrating the genetic heterogeneity of these disorders. Allogenic stem cell transplantation is not a universal cure for all congenital bone marrow failure syndromes.
Multiple Lineages Defect
| IBMDS involving multiple lineages | Other names of the disorder | Description |
| Fanconi anemia | FA, Fanconi’s anemia | Autosomal recessive (usually) but may be X-linked recessive disease caused by a mutation in DNA repair gene (FA/BRCA pathway). Additional manifestations include dermatologic, GI, GU and neurological abnormalities and sensitivity to DNA cross-linking agents (e.g. diepoxybutane or mitomycin C). |
| Dyskeratosis congenita | Zinsser-Engman-Cole syndrome | X-linked recessive, autosomal dominant/recessive disease characterized by failure to maintain normal telomeres. It is usually caused by mutation of the gene that encodes dyskerin (nucleolar protein), shelterin (telomere protector), or telomerase reverse transcriptases. It is characterized by triad of reticulate hyperpigmentation, mucosal leukoplakia, and nail dystrophy, Hoyeraal-Hreidarsson syndrome is a subset of dyskeratosis congenita with multisystem disorder. Allogenic stem cell transplantation has limited role in treatment. |
| Shwachman-Diamond syndrome | SDS, Shwachman Bodian Diamond syndrome | Autosomal recessive disorder caused by mutations of a gene that encodes proteins involved in synthesis of ribosomes. Additional manifestations include pancreatic insufficiency at infancy and metaphyseal dysostosis. |
Single Lineage Defect
| IBMDS involving multiple lineages | Other names of the disorder | Description |
| Defective RBC production | ||
| Diamond-Blackfan anemia | DBA, Dimond-Blackfan syndrome, congenital pure red cell aplasia, hereditary pure red cell aplasia, familial pure red cell aplasia | Congenital form classically characterized by pure red cell aplasia or selective failure of erythropoiesis (failure of RBC production only). DBA is differentiated from non-inherited causes of pure red cell aplasia by elevation of the enzyme red cell adenosine deaminase. Similar to Shwachman-Diamond syndrome, Diamond-Blackfan anemia is also caused by a mutation in the gene that encodes proteins involved in ribosome synthesis. Additional manifestations include radial and craniofacial abnormalities. |
| Congenital dyserythropoietic anemia | CDA, dyserythropoiesis | Abnormal erythropoiesis marked by dyserythropoiesis (unique dysplastic features of erythroblasts). |
| Defective platelet production | ||
| Congenital amegakaryocytic thrombocytopenia | CAMPT | Severe thrombocytopenia caused by mutation of the genes that encode the thrombopoietin receptor. |
| Thrombocytopenia absent radii | TAR | Autosomal recessive disorder characterized by hypomegakaryocytic thrombocytopenia with absence of radii bilaterally and presence of thumbs. |
| Defective neutrophil production | ||
| Severe congenital neutropenia | SCN, Kostmann syndrome | Neutropenia < 0.2 x 109/L often caused by mutation in genes that encode neutrophil elastase, growth factor, and granulocyte colony-stimulating factor (G-CSF) receptor. |
| Cyclic neutropenia | Cyclic hematopoiesis, CN | Autosomal dominant disorder characterized by cyclic changes of neutrophil caused by accelerated apoptosis. Neutrophil counts range from neutropenia to normal values approximately every 20 days. |
| Chronic benign neutropenia | Autosomal dominant disorder characterized by benign neutropenia among healthy individuals that is not explained by any other disease. | |
| Defective lymphocyte production | ||
| Congenital immunodeficiency syndromes | Primary immunodeficiency syndromes, hereditary immunodeficiency syndrome, congenital immunodeficiency disorders, primary immunodeficiency disorders, hereditary immunodeficiency disorders, congenital immunodeficiency diseases, primary immunodeficiency diseases, hereditary immunodeficiency diseases | Immunodeficiency syndromes may be caused by disorders of the bone marrow (site of immunocyte production). However, many primary immunodeficiency syndromes are caused by mutations that result in abnormalities in either the maturation of immunocytes or their function and are thus not considered bone marrow disorders per se. Accordingly, immunodeficiency syndromes are usually not listed under bone marrow failure syndromes and are often discussed separately. |