Genetic Basis of Inherited Bone Marrow Failure Syndromes

Abstract

Inherited bone marrow failure syndromes (IBMFSs) are multi-system disorders with varying degrees of defective production of erythrocytes, granulocytes and platelets in the bone marrow, leading to single-lineage or multilineage cytopenia (Table 1).(Dror 2006) The term IBMFSs is reserved for disorders that are caused by mutations, which are either inherited from the parents or occurred de-novo.(Alter 2003; Dokal and Vulliamy 2008) Based on the transmission patterns of the diseases (e.g. dominant or recessive autosomal or X-linked) and the segregation of known IBMFSs genes within multiplex families, the IBMFSs are considered as monogenic (Mendelian) diseases.(Alter 2003; Shimamura 2006; Dokal and Vulliamy 2008) The incidence of establishing a diagnosis of IBMFSs is about two new cases per a general population of million people per year and 65 cases per 106 child births.(Tsangaris, Klaassen et al. 2011) In some IBMFSs (e.g. Fanconi anemia) pancytopenia (>2 lineages affected) usually evolves. In others, one lineage is predominantly affected (e.g. neutropenia in Kostmann/severe congenital neutropenia, anemia in Diamond Blackfan anemia or thrombocytopenia in thrombocytopenia absent radii). The bone marrow failure often causes substantial morbidity and mortality, and many patients require life-long blood transfusions, treatment for infections, growth factors and hematopoietic stem cell transplantation (HSCT). Due to hematological and nonhematological problems, high risk of cancer and major treatment-related toxicity, the life expectancy of the patients is substantially reduced.(Dror 2006; Alter 2007) IBMFSs have both unique and common features. The clinical manifestations could not always discriminate between the various IBMFSs or between IBMFSs from acquired bone marrow failure syndromes. The associations of bone marrow failure with either congenital malformations or presentation during the first year of life or an affected first-degree relative are important diagnostic features.(Teo, Klaassen et al. 2008) A wide range of physical anomalies (e.g. craniofacial, skeletal, cardiovascular, gastrointestinal, renal, neurological and dermatological) are associated with IBMFSs and may help to establish a diagnosis. However, substantial phenotypic overlap exists among the disorders, which frequently limits the ability to establish a diagnosis based solely on clinical manifestations. Further, some of the disorders are not associated with physical anomalies, or the malformations develop later in life; for example, nail dystrophy in dyskeratosis congenita and metaphyseal dysplasia in Shwachman-Diamond syndrome. Therefore, genetic testing is critical for establishing a diagnosis and provides family counseling and management.