• Fanconi anaemia;
  • paediatrics;
  • myelodysplastic syndrome;
  • cytopenia

Refractory cytopenia of childhood (RCC) is the most common subtype of myelodysplastic syndrome (MDS) in children (Baumann et al, 2008, 2012). Because most patients with RCC have a hypocellular bone marrow (BM), differential diagnosis from aplastic anaemia and inherited bone marrow failure (IBMF) disorders, such as Fanconi anaemia (FA), is crucial (Kardos et al, 2003). The spectrum of phenotypic findings in patients with FA is extremely wide. Patients may be severely affected by multiple congenital anomalies or may have a mild phenotype without malformation (Alter, 2003). Moreover, dysplastic features in haematopoiesis are commonly observed in FA and RCC. Thus, it is not possible to reliably distinguish FA from RCC by morphological criteria only. The purpose of this study was to estimate the prevalence of FA in a cohort of patients with a morphological picture consistent with RCC.

Evaluating BM biopsies and smears based on previously published criteria (Baumann et al, 2008), reference pathologists of the European Working Group of MDS in Childhood (EWOG-MDS) provided a morphological report consistent with RCC in 137 children studied between January 1, 2007 and December 31, 2010 in Germany. Excluding patients with hypercellular BM and/or abnormal karyotype (n = 17), 120 children with hypo- or normocellular BM and normal or unavailable standard metaphases karyotypes were identified. Two of these were later diagnosed with dyskeratosis congenital (DC). Chromosome breakage assays (Auerbach et al, 1989) were performed in all but one patient with hypo- or normocellular BM. Thus, the remaining 117 patients with the morphological diagnosis of RCC were evaluated in detail.

Among these 117 patients, FA was diagnosed in 17 patients (14·5%) by chromosomal breakage assay. Seven patients (6%) had facial and/or skeletal anomalies typically noted in FA and 1 patient had a brother previously diagnosed with FA. In most of these patients, FA had been suspected by their local physicians. Nine patients (8%) without such typical anomalies or a family history of FA were subsequently diagnosed with FA by elevated chromosome breakage rate. This latter prevalence is strikingly similar to that recently reported by Pinto et al (2009), who confirmed the diagnosis of FA based on laboratory tests in 9 of 87 (8·0%) patients (55 children and 32 adults) with BM failure and absence of a full clinical picture of FA. Among our cohort of 117 patients, the diagnosis of RCC was finally made in the remaining 100 patients with normal chromosomal breakage rates.

The clinical and haematological features of the patients diagnosed with FA are summarized in Table 1. The red cell mean corpuscular volume (MCV) was above the 97th percentile for age in all patients with FA (Dallman & Siimes, 1979), but only in 65% of patients with RCC. Some non-haematological abnormalities were commonly observed in children with FA (Table 1). However, some of these patients had only mild phenotypes. For example, three patients had a single renal or urogenital anomaly (vesicoureteral reflux, horseshoe kidney or micropenis), which did not lead to the suspicion of FA by physicians. A few patients with RCC also had some non-haematological anomalies (Table 1), but an association of those with RCC is unknown. There is a possibility that other known or not yet described IBMF disorders remain uncovered in children with de novo RCC. Moreover, we recently observed that mutations of genes that have been reported to be responsible for DC were found in about 5% of patients with RCC without the typical clinical pictures of DC (Karow et al, 2011).

Table 1. Clinical characteristic of patients with Fanconi anaemia and refractory cytopenia of childhood
 FA (n = 17)RCC (n = 100)
  1. FA, Fanconi anaemia; RCC, refractory cytopenia of childhood; ANC, absolute neutrophil count; MCV, mean corpuscular volume.

  2. a

    Spastic hemiparesis with unknown origin.

Age at diagnosis (years): median (range)6 (2–16)11 (1–18)
ANC (×109/l): median (range)0·7 (0·3–2·8)0·6 (0·01–4·1)
MCV (age-adjusted value) < or ≥ 97th percentile0/1735/65
Non-haematological anomalies: number of patients (%)
Dysmorphic facial features4 (24)0
Hand or arm anomalies3 (18)2 (2)
Microcephaly9 (53)1 (1)
Small stature11 (65)4 (4)
Skin pigmentation or depigmentation9 (53)0
Hearing loss2 (12)1 (4)
Mental retardation2 (12)3 (3)
Renal and urogenital anomalies7 (41)0
Gastrointestinal malformations2 (12)0
Other01 (1)a

In summary, our results show that FA is found with a relatively high prevalence in patients with a morphological picture consistent with RCC. Some overlapping haematological features and congenital anomalies may be noted in FA and RCC. Most importantly, this situation indicates that the exclusion of FA by a chromosomal breakage assay or other methods is mandatory in all patients prior to the final diagnosis of RCC.

Author contributions

  1. Top of page
  2. Author contributions
  3. References

AY and CN designed the study, interpreted data and wrote the manuscript. IB and SS performed pathological evaluations and interpreted data. DS and WE performed diagnostic studies of FA and interpreted data. BS interpreted data. All authors critically revised the manuscript and contributed to the preparation in its final version.


  1. Top of page
  2. Author contributions
  3. References
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  • Auerbach, A.D., Rogatko, A. & Schroeder-Kurth, T.M. (1989) International Fanconi Anemia Registry: relation of clinical symptoms to diepoxybutane sensitivity. Blood, 73, 391396.
  • Baumann, I., Niemeyer, CM. & Benett, J. (2008) Childhood myelodysplastic syndrome. WHO Classification of Tumours of Haematopoietic and Lymphoid tissues (ed. by S. Swerdlow, E. Campo, N. Harris, E.S. Jaffe, S.A. Pileri, H. Stein, J. Thiele & J.W. Vardiman), pp. 104107. IARC Press, Lyon.
  • Baumann, I., Fuhrer, M., Behrendt, S., Campr, V., Csomor, J., Furlan, I., de Hass, V., Kerndrup, G., Leguit, R.J., De Paepe, P., Noellke, P., Niemeyer, C. & Schwarz, S. (2012) Morphological differentiation of severe aplastic anaemia from hypocellular refractory cytopenia of childhood: reproducibility of histopathological diagnostic criteria. Histopathology, 61, 1017.
  • Dallman, P.R. & Siimes, M.A. (1979) Percentile curves for hemoglobin and red cell volume in infancy and childhood. Journal of Pediatrics, 94, 2631.
  • Kardos, G., Baumann, I., Passmore, S.J., Locatelli, F., Hasle, H., Schultz, K.R., Stary, J., Schmitt-Graeff, A., Fischer, A., Harbott, J., Chessells, J.M., Hann, I., Fenu, S., Rajnoldi, A.C., Kerndrup, G., van Wering, E., Rogge, T., Nollke, P. & Niemeyer, C.M. (2003) Refractory anemia in childhood: a retrospective analysis of 67 patients with particular reference to monosomy 7. Blood, 102, 19972003.
  • Karow, A., Strahm, S., Flotho, C. & Wlodarski, M. (2011) Gene mutations of the telomerase complex in patients presenting with refractory cytopenia of childhood (RCC) – do we need to know? (Abstract) Haematologica, 96, 430.
  • Pinto, F.O., Leblanc, T., Chamousset, D., Le Roux, G., Brethon, B., Cassinat, B., Larghero, J., de Villartay, J.P., Stoppa-Lyonnet, D., Baruchel, A., Socie, G., Gluckman, E. & Soulier, J. (2009) Diagnosis of Fanconi anemia in patients with bone marrow failure. Haematologica, 94, 487495.