ABSTRACT
Germ line PTPN11 mutations cause 50% of cases of Noonan syndrome (NS). Somatic mutations in PTPN11 occur in 35% of patients with de novo, nonsyndromic juvenile myelomonocytic leukemia (JMML). Myeloproliferative disorders (MPDs), either transient or more fulminant forms, can also occur in infants with NS (NS/MPD). We identified PTPN11 mutations in blood or bone marrow specimens from 77 newly reported patients with JMML (n = 69) or NS/MPD (n = 8). Together with previous reports, we compared the spectrum of PTPN11 mutations in 3 groups: (1) patients with JMML (n = 107); (2) patients with NS/MPD (n = 19); and (3) patients with NS (n = 243). Glu76 was the most commonly affected residue in JMML (n = 45), with the Glu76Lys alteration (n = 29) being most frequent. Eight of 19 patients with NS/MPD carried the Thr73Ile substitution. These data suggest that there is a genotype/phenotype correlation in the spectrum of PTPN11 mutations found in patients with JMML, NS/MPD, and NS. This supports the need to characterize the spectrum of hematologic abnormalities in individuals with NS and to better define the impact of the PTPN11 lesion on the disease course in patients with NS/MPD and JMML.
Subject(s)
Intracellular Signaling Peptides and Proteins/genetics , Leukemia, Myelomonocytic, Chronic/genetics , Mutation , Myeloproliferative Disorders/genetics , Noonan Syndrome/genetics , Protein Tyrosine Phosphatases/genetics , Child , DNA Mutational Analysis , Humans , Mutation, Missense , Phenotype , Protein Tyrosine Phosphatase, Non-Receptor Type 11ABSTRACT
Primary myelodysplasia (MDS) without an increased number of blasts is a rare finding in childhood. We performed a retrospective analysis of 67 children with a diagnosis of primary MDS to determine the clinical and hematologic course of the disease. The median age at diagnosis was 8.3 years (range, 0.3-18.1 years). In contrast to refractory anemia in adults, 44% of patients had hemoglobin levels greater than 10 g/100 mL. The median white blood cell count and the absolute neutrophil count were 3.6 x 109/L and 0.9 x 109/L, respectively. Seventy-five percent of patients had thrombocytopenia. Bone marrow was hypocellular in 43% of the patients. Results of cytogenetic analysis showed monosomy 7 in 49%, trisomy 8 in 9%, and other abnormalities in 9% of the patients. The probability of survival 10 years after diagnosis was 0.48 (standard error [SE] = 0.10). Patients with monosomy 7 had significantly higher estimated probabilities of progression to advanced MDS than did patients with other chromosomal anomalies or normal karyotype. Of the 67 children, 41 underwent allogeneic stem cell transplantation (SCT). Patients whose disease did not progress to advanced MDS before SCT had significantly greater probability of survival than patients who experienced progression (0.76 [SE = 0.09] vs 0.36 [SE = 0.16]). SCT improved the outcomes for patients with monosomy 7 and should be offered early in the course of the disease. Recommendations for best treatment options for children with other chromosomal abnormalities or normal karyotype may have to await results of prospective clinical trials.
Subject(s)
Anemia, Refractory/genetics , Anemia, Refractory/mortality , Chromosomes, Human, Pair 7 , Monosomy , Adolescent , Anemia, Refractory/therapy , Child , Child, Preschool , Chromosomes, Human, Pair 6 , Chromosomes, Human, Pair 8 , Disease Progression , Female , Humans , Infant , Karyotyping , Male , Neutropenia/genetics , Neutropenia/mortality , Prognosis , Retrospective Studies , Stem Cell Transplantation , TrisomyABSTRACT
Se analizan las secuelas tardías del tratamiento de la leucemia y algunos tumores malignos de la infancia. Las más importantes fueron los trastornos neuropsicológicos. Debido al número cada vez mayor de pacientes curados es necesario conocer mejor la frecuencia, causa, prevención y rehabilitación de estos trastornos (AU)