Congenital disorders of the bone marrow: Difference between revisions

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'''''For the main page of bone marrow disorders click [[bone marrow disorders|here]].'''''<br>
'''''For acquired bone marrow disorders click [[acquired bone marrow disorders|here]].'''''
{{CMG}}; {{AE}} {{YD}}; {{Rim}}; {{SSK}}
{{CMG}}; {{AE}} {{YD}}; {{Rim}}; {{SSK}}


{{SK}} 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
{{SK}} 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==
==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.
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 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 [[platelet]]s).  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.
Inherited bone marrow failure syndrome (IBMFS) is a heterogenous group of diseases characterized by bone marrow failure (defective production of [[RBC]], [[WBC]], and/or [[platelet]]s).  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===
===Multiple Lineages Defect===
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| style="padding: 0 5px; font-size: 100%; background: #4682B4; color: #FFFFFF; width: 20%" align=center |'''IBMDS involving multiple lineages''' || style="padding: 0 5px; font-size: 100%; background: #4682B4; color: #FFFFFF; width: 20%" align=center |'''Other names of the disorder''' || style="padding: 0 5px; font-size: 100%; background: #4682B4; color: #FFFFFF; width: 60%" align=center |'''Description'''
| style="padding: 0 5px; font-size: 100%; background: #4682B4; color: #FFFFFF; width: 20%" align=center |'''IBMFS involving multiple lineages''' || style="padding: 0 5px; font-size: 100%; background: #4682B4; color: #FFFFFF; width: 20%" align=center |'''Alternative names''' || style="padding: 0 5px; font-size: 100%; background: #4682B4; color: #FFFFFF; width: 60%" align=center |'''Description'''
|-
|-
| style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left |[[Fanconi anemia]] || style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left |[[FA]], [[Fanconi’s anemia]] || style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left |[[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]]).
| style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[Fanconi anemia]] || style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[FA]], [[Fanconi’s anemia]] || style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[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]]).
|-
|-
|style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left |[[Dyskeratosis congenita]] || style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left |[[Zinsser-Engman-Cole syndrome]]|| style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left |[[X-linked]] recessive, [[autosomal dominant]]/recessive disease characterized by failure to maintain normal [[telomere]]s. It is usually caused by mutation of the gene that encodes [[dyskerin]] ([[nucleolar]] protein), [[shelterin]] ([[telomere]] protector), or [[telomerase reverse transcriptase]]s. 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.
|style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[Dyskeratosis congenita]] || style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[Zinsser-Engman-Cole syndrome]]|| style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[X-linked]] recessive, [[autosomal dominant]]/recessive disease characterized by failure to maintain normal [[telomere]]s. It is usually caused by mutation in the gene that encodes [[dyskerin]] ([[nucleolar]] protein), [[shelterin]] ([[telomere]] protector), or [[telomerase reverse transcriptase]]s. 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.
|-
|-
|style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left |[[Shwachman-Diamond syndrome]] || style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left |[[SDS]], [[Shwachman Bodian Diamond syndrome]] || style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left |Autosomal recessive disorder caused by mutations of a gene that encodes proteins involved in synthesis of [[ribosome]]s.  Additional manifestations include [[pancreatic insufficiency]] at infancy and [[metaphyseal]] [[dysostosis]].
|style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[Shwachman-Diamond syndrome]] || style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[SDS]], [[Shwachman Bodian Diamond syndrome]] || style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |Autosomal recessive disorder caused by mutations in a gene that encodes proteins involved in synthesis of [[ribosome]]s.  Additional manifestations include [[pancreatic insufficiency]] at infancy and [[metaphyseal]] [[dysostosis]].
|}
|}


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{| style="cellpadding=0; cellspacing= 0; width: 1000px;"
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| style="padding: 0 5px; font-size: 100%; background: #4682B4; color: #FFFFFF; width: 20%" align=center |'''IBMDS involving multiple lineages''' || style="padding: 0 5px; font-size: 100%; background: #4682B4; color: #FFFFFF; width: 20%" align=center |'''Other names of the disorder''' || style="padding: 0 5px; font-size: 100%; background: #4682B4; color: #FFFFFF; width: 60%" align=center |'''Description'''
| style="padding: 0 5px; font-size: 100%; background: #4682B4; color: #FFFFFF; width: 20%" align=center |'''IBMFS involving multiple lineages''' || style="padding: 0 5px; font-size: 100%; background: #4682B4; color: #FFFFFF; width: 20%" align=center |'''Alternative names''' || style="padding: 0 5px; font-size: 100%; background: #4682B4; color: #FFFFFF; width: 60%" align=center |'''Description'''
|-
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| style="padding: 0 5px; font-size: 100%; background: #F5F5F5;" align=center colspan=3 | '''''Defective RBC production'''''
| style="padding: 0 5px; font-size: 100%; background: #F5F5F5;" align=center colspan=3 | '''''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.
|style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[Diamond-Blackfan anemia]] || style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[DBA]], [[Diamond-Blackfan syndrome]], [[congenital pure red cell aplasia]], [[hereditary pure red cell aplasia]], [[familial pure red cell aplasia]] || style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |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 [[erythroblast]]s).
|style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[Congenital dyserythropoietic anemia]] || style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[CDA]], [[dyserythropoiesis]] ||style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left | Abnormal [[erythropoiesis]] marked by [[dyserythropoiesis]] (unique dysplastic features of [[erythroblast]]s).
|-
|-
|style="padding: 0 5px; font-size: 100%; background: #F5F5F5;" align=center colspan=3 | '''''Defective platelet production'''''
|style="padding: 0 5px; font-size: 100%; background: #F5F5F5;" align=center colspan=3 | '''''Defective platelet production'''''
|-
|-
|[[Congenital amegakaryocytic thrombocytopenia]]  || [[CAMT]] ||Severe [[thrombocytopenia]] caused by mutation of the genes that encode the [[thrombopoietin]] receptor.
|style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[Congenital amegakaryocytic thrombocytopenia]]  || style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[CAMT]] ||style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |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 [[thumb]]s.
|style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[Thrombocytopenia absent radii]] || style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[TAR]] || style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |Autosomal recessive disorder characterized by hypomegakaryocytic [[thrombocytopenia]] with absence of radii bilaterally and presence of [[thumb]]s.
|-
|-
|style="padding: 0 5px; font-size: 100%; background: #F5F5F5;" align=center colspan=3 | '''''Defective neutrophil production'''''
|style="padding: 0 5px; font-size: 100%; background: #F5F5F5;" align=center colspan=3 | '''''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.
|style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[Severe congenital neutropenia]] || style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[SCN]], [[Kostmann syndrome]] ||style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left | [[Neutropenia]] < 0.2 x 10<sup>9</sup>/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.
|style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[Cyclic neutropenia]] || style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[Cyclic hematopoiesis]], [[CN]] || style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |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.
|style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[Chronic benign neutropenia]] ||style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left | || style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |Autosomal dominant disorder characterized by benign [[neutropenia]] among healthy individuals that is not explained by any other disease.
|-
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|style="padding: 0 5px; font-size: 100%; background: #F5F5F5;" align=center colspan=3 | '''''Defective lymphocyte production'''''
|style="padding: 0 5px; font-size: 100%; background: #F5F5F5;" align=center colspan=3 | '''''Defective lymphocyte production'''''
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|[[Congenital immunodeficiency syndrome]]s || [[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.
|style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[Congenital immunodeficiency syndrome]]s || style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[Primary immunodeficiency syndromes]], [[hereditary immunodeficiency syndrome]][[primary immunodeficiency disorders]], [[hereditary immunodeficiency disorders]], [[congenital immunodeficiency diseases]], [[primary immunodeficiency diseases]], [[hereditary immunodeficiency diseases]]|| style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[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.
* Cellular involvement ([[T-cell]]s)
* [[T-cell]]s (cellular immunity)
* Humoral involvement ([[B-cell]]s)
* [[B-cell]]s (humoral immunity)
* Both cellular and humoral involvement
* [[NK cells]]
* Mixed
|}
 
==Proliferative Bone Marrow Failure Syndromes==
{| style="cellpadding=0; cellspacing= 0; width: 1000px;"
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| style="padding: 0 5px; font-size: 100%; background: #4682B4; color: #FFFFFF; width: 20%" align=center |'''Congenital proliferative disorders''' || style="padding: 0 5px; font-size: 100%; background: #4682B4; color: #FFFFFF; width: 20%" align=center |'''Alternative names''' || style="padding: 0 5px; font-size: 100%; background: #4682B4; color: #FFFFFF; width: 60%" align=center |'''Description'''
|-
| style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[ Inherited essential thrombocythemia]] || style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left | [[Inherited essential thrombocytosis]], [[congenital essential thrombocytosis]], [[hereditary essential thrombocythemia]], [[familial essential thrombocythemia]] || style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |Increased number of [[platelet]]s 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.
|-
|style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left | [[Primary familial and congenital polycythemia]] || style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[PFCP]], [[familial erythrocytosis]], [[hereditary erythrocytosis]], [[congenital erythrocytosis]], [[inherited erythrocytosis]]|| style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |Increased number of [[RBC]] usually caused by mutations in the genes that encode [[erythropoietin]] receptor.
|-
|style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[Hereditary neutrophilia]] || style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[Congenital neutrophilia]] || style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |An autosomal dominant disorder characterized by increased number of [[neutrophil]]s.
|-
|style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[Hereditary eosinophilia]] || style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |  || style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left | Reported very rarely. Hereditary cause of eosinophilia has not been well-established.
|-
|style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[Hereditary lymphoproliferative disease]] || style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |[[X-linked lymphoproliferative disease]] || style="font-size: 100; padding: 0 5px; background: #DCDCDC" align=left |An X-linked disorder caused by mutations in genes that encode anti-apoptotic proteins.
|}
|}


==Prolferative Bone Marrow Failure Syndromes==
==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 disease]]s
* [[Pearson syndrome]]
* Nijmege breakage syndrome
* [[Noonan syndrome]]
* Organic acid metabolism defect
* [[Seckel syndrome]]


==References==
{{Reflist|2}}


[[Category:Hematology]]
[[Category:Hematology]]
[[Category:Immunology]]

Latest revision as of 20:41, 16 February 2015

For the main page of bone marrow disorders click here.
For acquired bone marrow disorders click here.

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.

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:

References