ALBERT

Description: Neonatal thrombocytopenia occurs in about 1% of all newborns. Inherited forms like 11q- or Jacobsen syndrome are rare. However, they may remain undetected with karyotyping because the deleted regions in 11q often involve small subtelomeric regions. Here we report on the detection of deletions in 11q in two newborns with normal routine karyotypes who were shown to carry subtelomeric deletions in 11q by means of fluorescence in situ hybridization (FISH) using a subtelomeric 11q probe (Abbott, Diagnostics, Wiesbaden, Germany). Both children showed thrombocytopenia (18.000/μl and 26.000/μl, respectively) and dysmegakaryopoiesis (absence of normal megakaryocytes and presence of micromegakaryocytes) associated with facial dysmorphism, cardiac defects and psychomotoric retardation. In the second case, the mother and the grandmother also showed mild thrombocytopenia. In both patients, FISH analyses on peripheral blood and bone marrow showed the loss of the telomere-associated region of 11q distal of the MLL gene. In the first patient, the deletion of 11q resulted from an unbalanced complex rearrangement with duplication of 11p. As the source of this chromosomal aberration, a paternal pericentric inversion of chromosome 11 was identified. The partial monosomy 11q and the partial trisomy 11p in the first patient were confirmed by comparative genomic hybridization (CGH) analysis. Array/matrix CGH assisted in determining the breakpoints at 11p15.1 and 11q24.1. No structural aberrations of 11q were found in the mother of the second patient, but further investigations are under way. These findings give further evidence that small subtelomeric deletions of 11q and probably mutations of genes located therein cause thrombocytopenia. Since it can be very difficult to detect these deletions by karyotyping, FISH using a subtelomeric 11q probe seems to be an extremely useful new diagnostic tool. This new method should be applied in children with congenital thrombocytopenia, in particular if they have additional complex dysmorphic features.

Description: Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood. In vivo response to initial therapy, as assessed by determination of minimal residual disease (MRD) at 5 and 12 weeks of treatment, has evolved as the strongest prognostic factor in pediatric ALL patients treated according to the BFM regime. In this study, ten patients with a poor treatment response (MRD load ≥ 10−3 at week 12, MRD-high risk, HR) and five treatment-sensitive (no measurable MRD at weeks 5 and 12, MRD-standard risk, SR) patients were investigated by means of high-resolution bacterial artificial chromosome (BAC) array-based comparative genomic hybridization (array-CGH). To ensure homogeneity with regard to prognostic factors, the following inclusion criteria were used: B cell precursor or common ALL, DNA index of 1.0, no BCR/ABL, no MLL/AF4, no TEL/AML1 rearrangements. A gain for all chromosome 21-related BAC clones was observed in all SR patients. None of the ten HR patients showed a gain of any region of chromosome 21. This result could be confirmed by means of fluorescence in situ hybridization using the LSI AML1/ETO DC probe set. Besides the basic level of chromosome 21 gain, higher levels of gain or amplification observed for individual regions were found in three SR patients. Recurrent genomic alterations in the group of HR patients were loss of chromosomal region 2p11.22 (9/10), a gain of 8q24.13 (7/10) and loss of 14q32 (8/10). To see whether these findings may help to further subdivide the intermediate risk group patients (any MRD positivity at week 5, MRD load 〈 10−3 at week 12) we additionally analyzed three patients of this group: two patients in long-term complete remission and one patient who relapsed 29 months after diagnosis. Again, a gain for all chromosome 21-related clones was detected in both patients in complete remission. In contrast, the leukemic sample of the relapsed patient demonstrated no gain of chromosome 21. We conclude that array CGH analysis in childhood ALL may lead to the identification of additional prognostic markers. The relevance of the observed gain of chromosome 21 has to be validated in a larger set of patients.