Genetic and clinical characterization of 73 Pigmentary Mosaicism patients: revealing the genetic basis of clinical manifestations.

BACKGROUND: Pigmentary mosaicism constitutes a heterogeneous group of skin pigmentation alterations associated with multisystem involvement. The aim of this study was to establish a complete cytogenetic and molecular characterization of PM patients, emphasizing on searching for possible low chromosomal mosaicism and on establishing an accurate genotype-phenotype correlation. RESULTS: A total of 73 patients were included (3 months to 18 years of age), 52% male and 48% female. Observed in 69 (95%) patients, the most frequent pattern of pigmentation was fine and whorled BL, which was associated with disseminated skin extent in 41 (59%) patients. Central nervous system (84%) alterations were the most frequent observed in the group of patients, followed by the musculoskeletal (53%) and ophthalmologic (27%) alterations. Considering the pattern of pigmentation, no significant differences in association with skin extent or extracutaneous manifestations were detected. Following a strict cytogenetic analysis strategy, screening metaphases from three different tissues (peripheral blood, hyperpigmented and hypopigmented skin) we found that 23/73 patients had chromosomal abnormalities classified as follows: 1) Mosaic with 2 or more different cell lines with structural alterations n = 19; 2) Polyploidy (mosaic) n = 1 and 3) Alterations in all cells in three different tissues n = 3. SNP array, array CGH and FISH were useful for the complete characterization of the chromosomal aberrations, for the detection of microdeletions in patients with normal karyotype but with strong clinical suspicious of chromosomal alteration, and for a better establishment of genotype-phenotype correlation. In 2 patients we found genes associated with some of the extracutaneous manifestations (SHH, MNX1, PPP2R2C). CONCLUSIONS: This group of 73 patients finely described is the largest series of patients with pigmentary mosaicism reported worldwide. As we showed in this study, the followed analysis strategy allowed the detection of cytogenetic and molecular abnormalities, and made possible the establishment of genotype-phenotype associations in some patients. An important limitation of our study was the analysis of fibroblasts cultures instead of melanocytes and keratinocytes. In some cases the direct molecular DNA analysis of skin biopsy could be another choice.

[Clinical and cytogenetic variability in 12 Mexican families with Fanconi's anemia and its relationship with the complement gruoup to which they belong]. / Variabilidad clínica y citogenética en doce familias mexicanas con anemia de fanconi y su relación con el grupo de complementación al que pertenecen.

OBJECTIVE: To describe the clinical and cytogenetic features of Mexican patients with Fanconi anemia, while assessing whether the phenotypic variation is related to the complementation group. MATERIAL AND METHODS: The cytogenetic diagnosis was done using mitomycin C and diepoxybutane on peripheral blood lymphocytes. The severity of the anemia and each patient's clinical manifestations were classified using Alter's and Auerbach's clinical scores, respectively. Lymphoblastoid cell lines were established for eight patients and complementation group determined following cell fusion procedures in four propositi. RESULTS: Twenty-five Fanconi anemia patients from 12 families were studied. All patients had high, spontaneous and induced chromosomal breakages, no relationship was found between the clinical severity of the disease and the anemic state. Twelve patients were considered severely ill, while the remaining 13 were considered mild cases. Three individuals were anemia-free, while in 13 the anemia was mild, moderate in 7, and severe in 1. The mortality rate was 32% (8/25). No relationship was found between the clinical picture and degree of the anemia or mortality rate. Eleven patients were assigned to complementation group A with mild clinical findings and anemia. Their cytogenetic results showed variability. One patient assigned to group C was considered as a severe case with transfusion-dependent anemia and high sensitivity to mutagens. Thirteen patients were not classified. A lymphoblastoid cell line resistant to mitomycin C was obtained suggesting somatic mosaicism. CONCLUSIONS: The establishment of a complementation group does not necessarily explain variability. There are other important factors, such as somatic mosaicism, that modify the cellular phenotype.