• familial leukaemia;
  • infantile;
  • monosomy-7;
  • puerperal

A 26-year-old mother (G1P1) presented with generalized lymphadenopathy 2 months after spontaneous vaginal delivery of a normal 3·5 kg daughter. A peripheral blood examination (haemoglobin 133 g/l, white cell count 4·2 × 109 /l, platelet count 183 × 109 /l) showed occasional blasts, and a marrow biopsy showed sheets of blasts (Fig 1A) that were negative for myeloperoxidase and non-specific esterase, but showed weak granular periodic acid-Schiff positivity. Flow cytometric immunophenotyping of the blasts showed expression of CD4, CD7, CD56 and HLA-DR, but negativity for Tdt, MPO, CD13, CD34 and other B and T cell markers (CD19, CD20, CD22 and CD2, CD3, CD5, CD8). Cytogenetics (Fig 1B) showed 44, XX, t(1;6)(q21;q23),−9,−13[5]/44,idem,t(9;17)(p22;p13)[3]/46XX[10]. She was treated as undifferentiated acute leukaemia with a lymphoid leukaemia protocol (Au et al, 1998) followed by allogeneic haemopoietic stem cell transplantation (HSCT) from an unrelated donor (two younger brothers were not a human leucocyte antigen (HLA) match) in first remission (conditioning: cyclophosphamide, total body irradiation). At 18 months of age, her infant daughter presented with recurrent fever and anaemia (haemoglobin 56 g/l, white cell count 5·5 × 109 /l, platelet count 393 × x109 /l). The peripheral film was unremarkable, but a marrow biopsy showed 14% granulated blasts and dysplastic megakaryocytes (Fig 1C), compatible with refractory anaemia with excess blasts, stage 2 (RAEB-2). Cytogenetic study showed 45, XX, −7[2]/46, XX[2]. Using a directly labelled chromosome 7 centromeric probe (D7Z1; Vysis, Downers Grove, IL, USA), monosomy 7 was shown in 58% of marrow nucleated cells (Fig 1D). Chromosome fragility screening using diepoxybutane-induced chromosome breakage was negative, but sequencing for RUNX1 mutation was not performed. The peripheral count was static for 6 weeks and the child underwent direct HSCT from another unrelated donor (conditioning: bulsuphan, cyclophasmide, melphalan, anti-thymocyte globulin). Both patients remained well at 2 and 1-year follow-up respectively. They denied any herbal or toxin exposure, nor any family history of leukaemia or malignancies; and neither patient had any dysmorphic features.


Figure 1.  (A) Sample from the mother showing hypercellular marrow with diffuse infiltration of blasts that were medium in size with high nuclear to cytoplasmic ratio and a rim of pale blue granular cytoplasm, but no Auer rods. They were negative for myeloperoxidase (MPO) and non-specific esterase, with weak granular positivity for periodic acid-Schiff. (B) Complete karyotype of the mother showing 44,XX,t(1;6)(q21;q23),−9,−13 (arrows: G-banding with trypsin-Giemsa). (C) Marrow aspirate from the daughter, showing left-shifted granulopoiesis with increase in blasts that were focally prominent. The blasts were MPO positive and CD117 staining showed many immature cells. Megakaryocytes are increased and dysplastic, mostly showing small, hypolobulated or separate nuclei. (D) Sample from the daughter. Fluorescent in situ hybridization showing monosomy 7 (arrows) with a chromosome 7 centromeric probe.

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Infantile myelodysplasia is uncommon and familial association is rare. A retrospective series of monosomy 7-related paediatric leukaemia reported a 10% incidence of familial leukaemia, but almost exclusively in siblings (Hasle et al, 1999). Registry data showed an even lower incidence of familial leukaemia in paediatric leukaemia patients, with or without monosomy 7 (Hasle & Olsen, 1997). The genetic mechanism of monosomy 7-related familial leukemogenesis is not fully understood, and putatively involved a gene dosage effect (Savage et al, 1994) as well as linkages with other chromosomal loci (Shannon et al, 1989). This is the first familial report of puerperal leukaemia and infantile myelodysplasia in quick succession (16 months apart). To explain this, additional environmental factors, such as an undefined common leukemogenic exposure during late pregnancy (Zhang et al, 2005), as well as puerperal and infantile immune deficiencies, may be implicated. Clinically, although the two leukaemias appeared to be of discordant lineages, both belonged to poor risk groups in terms of prognosis (complex chromosomal abnormalities, monosomies, morphological dysplasia and lineage ambiguity). Coupled with the familial leukaemia setting, early, unrelated donor HSCT appeared to be a prudent treatment choice for both patients (Hasle et al, 2007).


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  2. References
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