Hereditary hyperferritinemia-cataract syndrome in three Czech families: molecular genetic testing and clinical implications.

BACKGROUND: Hereditary hyperferritinemia-cataract syndrome (HHCS) is an autosomal dominant disorder manifesting with high serum ferritin levels and the formation of early-onset cataracts, with numerous small opacities, predominantly in the lens cortex. HHCS is caused by mutations in the iron-responsive element of the FTL gene. The aim of this study was to establish a molecular diagnosis in three Czech probands with suspected HHCS. METHODS: A complex ocular and systemic evaluation, including ferritin and iron measurements, was performed. The 5' untranslated region of FTL was directly sequenced in all available family members, followed by paternity testing in one family. RESULTS: Three different FLT pathogenic variants (c.-161C>T, c.-167C>T, and c.-168G>C) present in the heterozygous state were detected in each of the 3 probands. Two segregated with the disease phenotype within the families, but c.-167C>T occurred de novo (confirmed by paternity testing). Prior to establishing molecular diagnosis, two probands were misdiagnosed with hemochromatosis. One individual, aged 43 years, underwent phlebotomy; another, aged 8.5 years, was treated with the iron chelator deferasirox, leading to life-threatening acute hyperammonemia, without severe liver injury. CONCLUSIONS: Lack of family history does not exclude HHCS, because the pathogenic variant can arise de novo. Noncoding regions are often omitted from diagnostic gene panels, thus evading detection. Careful clinical evaluations and targeted genetic screening are important for avoiding potentially harmful treatments.

[The prospects for children with acute lymphoblastic leukemia of being cured has increased in the Czech Republic in the 21st century to 90% - outcome of the ALL-IC BFM 2002 trial]. / Sance na vylécení detí s akutní lymfoblastickou leukémií stoupla v Ceské republicev 21. století na 90 % - výsledky studie ALL IC-BFM 2002.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most frequent childhood malignancy. Treatment has been unified in the middle of 1980 in the Czech Republic. In 2002-2007 children and adolescents with acute lymphoblastic leukemia were treated in an international randomized trial ALL-IC BFM 2002 in the Czech Republic. 291 patients aged 1-18 years were enrolled; infants below 1 year entered a separate trial. METHODS AND RESULTS: Patients were stratified into three risk groups according to their age, initial leukocyte count, prednisone response, presence of fusion genes BCR/ABL or MLL/AF4, bone marrow D+15 and remission status D+33. The whole therapy took 24 months. Randomized late intensification compared standard BFM therapy with extended, usually more intensive experimental treatment. The median follow-up was 8.7 years. Complete remission was achieved in 97.9% patients, 1% died in remission. 11% of children relapsed, 1.7% with CNS involvement. Six children (2.1%) developed secondary malignancy. Event free survival (EFS) 8 years from diagnosis was 83.5%, overall survival (OS) 91.4%. EFS and OS of the risk groups were: standard risk: 89.4%; 98.1%; intermediate risk: 82.6%; 89.6%; high risk: 68.8%; 78.1%. Male sex and age above 10 years were adverse prognostic factors. CONCLUSIONS: In comparison with the previous trial ALL-BFM 95, significant improvement was achieved.

Prognosis of children with mixed phenotype acute leukemia treated on the basis of consistent immunophenotypic criteria.

BACKGROUND: Mixed phenotype acute leukemia (MPAL) represents a diagnostic and therapeutic dilemma. The European Group for the Immunological Classification of Leukemias (EGIL) scoring system unambiguously defines MPAL expressing aberrant lineage markers. Discussions surrounding it have focused on scoring details, and information is limited regarding its biological, clinical and prognostic significance. The recent World Health Organization classification is simpler and could replace the EGIL scoring system after transformation into unambiguous guidelines. DESIGN AND METHODS: Simple immunophenotypic criteria were used to classify all cases of childhood acute leukemia in order to provide therapy directed against acute lymphoblastic leukemia or acute myeloid leukemia. Prognosis, genotype and immunoglobulin/T-cell receptor gene rearrangement status were analyzed. RESULTS: The incidences of MPAL were 28/582 and 4/107 for children treated with acute lymphoblastic leukemia and acute myeloid leukemia regimens, respectively. In immunophenotypic principal component analysis, MPAL treated as T-cell acute lymphoblastic leukemia clustered between cases of non-mixed T-cell acute lymphoblastic leukemia and acute myeloid leukemia, while other MPAL cases were included in the respective non-mixed B-cell progenitor acute lymphoblastic leukemia or acute myeloid leukemia clusters. Analogously, immunoglobulin/T-cell receptor gene rearrangements followed the expected pattern in patients treated as having acute myeloid leukemia (non-rearranged, 4/4) or as having B-cell progenitor acute lymphoblastic leukemia (rearranged, 20/20), but were missing in 3/5 analyzed cases of MPAL treated as having T-cell acute lymphobastic leukemia. In patients who received acute lymphoblastic leukemia treatment, the 5-year event-free survival of the MPAL cases was worse than that of the non-mixed cases (53+/-10% and 76+/-2% at 5 years, respectively, P=0.0075), with a more pronounced difference among B lineage cases. The small numbers of MPAL cases treated as T-cell acute lymphoblastic leukemia or as acute myeloid leukemia hampered separate statistics. We compared prognosis of all subsets with the prognosis of previously published cohorts. CONCLUSIONS: Simple immunophenotypic criteria are useful for therapy decisions in MPAL. In B lineage leukemia, MPAL confers poorer prognosis. However, our data do not justify a preferential use of current acute myeloid leukemia-based therapy in MPAL.

Unrelated partially matched lymphocyte infusions in a patient with complete DiGeorge/CHARGE syndrome.

We present an infant with cDGS overlapping with CHARGE syndrome, who suffered from T-cell deficiency treated with screened healthy DLI from an unrelated donor (8/10 match). The first dose of DLI (1.1 x 10(6) CD3+/kg) was administered at the age of six months, the second one (0.9 x 10(6) CD3+/kg) 36 days later. No conditioning was employed, GvHD prophylaxis consisting of CsA was used only during the second infusion. Since day+10 after the first DLI, split chimerism showing T-cell engraftment has been documented. Proliferative response to PHA was detected on day+145. The treatment was complicated by severe acute GvHD (grade II-III) after the first DLI and prolonged chronic liver cholestatic GvHD developing after the second DLI. Vigorous EBV proliferation four wk after the second DLI was accompanied by peripheral expansion of CD8+ donor cells. The patient, 26-months old, is clinically well and has slowly started to gain his developmental milestones. We believe that infusions of small doses of DLI from an unrelated donor represent a potentially helpful therapeutic option in patients with cDGS/CHARGE phenotype.