Congenital disorders of the bone marrow

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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, inherited bone marrow proliferation syndromes, familial bone marrow proliferation syndromes, congenital bone marrow proliferation syndromes, hereditary bone marrow proliferation syndromes

Overview

Congenital disorders of the bone marrow are classified into 1) inherited bone marrow failure syndromes which are the most commonly recognized entities of “inherited bone marrow disorders", and 2) proliferative bone marrow failure syndromes that are very rare diseases.

Inherited Bone Marrow Failure Syndromes

Inherited bone marrow failure syndrome (IBMFS) is a heterogenous group of diseases characterized by bone marrow failure (defective production of RBC, WBC, and/or platelets). While they typically manifest during childhood, some IBMFS may not manifest until adulthood. Differentiation between diseases based on the pattern of inheritance (e.g. 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

IBMFS involving multiple lineages	Alternative names	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 in 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 in a gene that encodes proteins involved in synthesis of ribosomes. Additional manifestations include pancreatic insufficiency at infancy and metaphyseal dysostosis.

Single Lineage Defect

IBMFS involving multiple lineages	Alternative names	Description
Defective RBC production
Diamond-Blackfan anemia	DBA, Diamond-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	CAMT	Severe thrombocytopenia caused by mutation in 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; and cycle repeats 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 syndromeprimary 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 outside the bone marrow 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. T-cells (cellular immunity) B-cells (humoral immunity) NK cells Mixed

Proliferative Bone Marrow Failure Syndromes

Congenital proliferative disorders	Alternative names	Description
Inherited essential thrombocythemia	Inherited essential thrombocytosis, congenital essential thrombocytosis, hereditary essential thrombocythemia, familial essential thrombocythemia	Increased number of platelets usually caused by mutations in the genes of the JAK/STAT pathway. While the majority of cases are sporadic, rarely ET may be inherited in an autosomal dominant pattern.
Primary familial and congenital polycythemia	PFCP, familial erythrocytosis, hereditary erythrocytosis, congenital erythrocytosis, inherited erythrocytosis	Increased number of RBC usually caused by mutations in the genes that encode erythropoietin receptor.
Hereditary neutrophilia	Congenital neutrophilia	An autosomal dominant disorder characterized by increased number of neutrophils.
Hereditary eosinophilia		Reported very rarely. Hereditary cause of eosinophilia has not been well-established.
Hereditary lymphoproliferative disease	X-linked lymphoproliferative disease	An X-linked disorder caused by mutations in genes that encode anti-apoptotic proteins.

Congenital Syndromes Associated with Pancytopenia

Other syndromes that are not considered IBMF syndromes but are associated with pancytopenia include:

• Barth syndrome
• Down syndrome
• Dubowitz syndrome
• Glycogen storage diseases
• Pearson syndrome
• Nijmege breakage syndrome
• Noonan syndrome
• Organic acid metabolism defect
• Seckel syndrome