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.