Severe aplastic anaemia in a child with brachydactyly type c
A 2-year-old boy, an only child of unrelated parents, came to us with purpura and gastrointestinal bleeding. Pregnancy, birth, delivery and developmental landmarks were normal. There was no exposure to bone marrow toxins, recent history of viral infections or a family history of blood abnormalities.
Physical examination showed petechiae, echymoses and an enlarged liver without splenomegaly. There were bilateral hand malformations with brachydactyly and camptodactyly.
Haemoglobin was 11·2 g/dl (after transfusion), reticulocytes 1 × 109/l, WBC 4 × 109/l, neutrophils 0·08 × 109/l and platelets 2 × 109/l. Bone marrow aspiration and biopsy showed severe hypocellularity, markedly decreased myelopoiesis with increased lymphocytes and plasma cells. The Ham's test, sucrose haemolysis test and Coombs' tests were negative.
A tentative diagnosis of Fanconi's anaemia was made. He received antibiotics, and packed red cell and platelet transfusions. However, subsequent diepoxybutane (DEB) testing (Arlene Auerbach, Rockefeller University) was negative and the diagnosis was rejected. Two months later he developed fever and neurological symptoms, and died. Autopsy was not performed.
Because of the hand abnormality and negative DEB test, we studied nine other family members in four generations: six had similar hand malformations in an autosomal dominant pattern of inheritance. Sequencing of aberrant amplimers of the growth differentiation factor-5 (CDF5) coding region showed a unique mutation consistent with brachydactyly type C [BDC; Online Mendelian Inheritance in Man (OMIM) # 113100; McKusick, 1994; Everman et al, 2002].
Several skeletal malformations are associated with haematological abnormalities, including Diamond–Blackfan anaemia, Instituto Venezolano de Investigaciones Cientificas (IVIC) syndrome and amegakaryiocytic thrombocytopenia (McKusick, 1994; Alter & Young, 1998; Ball et al, 1996); however, the most common one is Fanconi's anaemia which was initially suspected in our patient but was excluded based on inheritance and DEB testing. It is important to consider that hand abnormalities may be an incidental finding. For example, our patient had BDC and presumably unrelated aplastic anaemia. No association between BDC and aplastic anaemia has been reported and BDC-affected mice have normal bone marrow function. Physicians should be cautious to ascribe aplastic anaemia to Fanconi's anaemia and related disorders in subjects with hand abnormalities and bone marrow failure.
