Introduction

A number of inherited (constitutional/genetic) disorders are characterized by aplastic anaemia (AA)/bone marrow (BM) failure, usually in association with one or more somatic abnormalities (Table 12.1). The features of some of these are summarized in Table 12.2. The precise incidence/prevalence of these remains unclear but, collectively, they represent approximately 10-20% of patients presenting with AA and constitute a significant clinical burden, as many are associated with premature

Table 12.1 The inherited bone marrow failure syndromes.

Pancytopenia Fanconi anaemia (FA) Dyskeratosis congenita (DC) Shwachman-Diamond syndrome (SDS) Reticular dysgenesis Pearson syndrome (PS)

Familial aplastic anaemia (autosomal and X-linked forms) Myelodysplasia

Non-haematological syndromes (Down, Dubowitz syndromes)

Single cytopenia (usually)

Anaemia (Diamond-Blackfan anaemia, DBA)

Neutropenia (severe congenital neutropenia, SCN, including

Kostmann syndrome) Thrombocytopenia (congenital amegakaryocytic thrombocytopenia, CAMT, amegakaryocytic thrombocytopenia with absent radii, TAR)

mortality. The BM failure may present at birth or at a variable time thereafter, including in adulthood in some cases. The BM failure may involve all or a single lineage; in some cases it may initially be associated with a single cytopenia and then progress to pancytopenia. Scientifically, they constitute an important group of diseases as recent advances in understanding the genetics of some of these are not only beginning to unravel their pathophysiology but are also providing important insights into normal haemopoiesis.

The two syndromes that are frequently associated with generalized BM failure/aplastic anaemia (AA) are Fanconi anaemia (FA) and dyskeratosis congenita (DC). These two syndromes are now also two of the best characterized and will be discussed in some detail in this chapter [followed by sections on Shwachman-Diamond syndrome (SDS), Diamond-Blackfan anaemia (DBA), congenital neutropenia, thrombocytopenia with absent radii (TAR) and congenital amegakaryocytic thrombocytopenia (CAMT)] to demonstrate their clinical and genetic heterogeneity, management and possible impact on our understanding of the pathophysiology of the more common 'idiopathic aplastic anaemia'. Indeed, both FA and DC patients can sometimes present with AA alone as their initial manifestation and can thus pose a diagnostic/management challenge.

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