Cytogenomic characterization of small supernumerary marker chromosomes in patients with pigmentary mosaicism.

Introduction: The combination of gene content on the marker chromosome, chromosomal origin, level of mosaicism, origin mechanism (chromothripsis), and uniparental disomy can influence the final characterization of sSMCs. Several chromosomal aberrations, including sSMCs, have been observed in 30%-60% of patients with pigmentary mosaicism, and in more than 80%, chromosomal abnormalities are present in the mosaic state. In patients with pigmentary mosaicism the most representative chromosomes involved in sSMCs are 3, 5, 6, 9, 10, 13, 15, 18, 20, and X. In this study, we included the complete clinical, cytogenetic, and molecular characterization of seven patients with pigmentary mosaicism associated with the presence of SMCs of different chromosomal origins. Methods: The patients were diagnosed by the Genetics and Dermatology Department of three different hospitals. Cytogenetic and FISH analyses were performed on peripheral blood, light skin, and dark skin. FISH analysis was performed using different probes, depending on the marker chromosome description. Different array analysis was performed. Results: To date, of the seven cases studied, the chromosomal origins of six were successfully identified by FISH or array analysis. The chromosomes involved in SMCs were 6, 9, 15, and 18, X. The most frequently found was the centric minute structure. Discussion: To date, this group of seven patients constitutes the largest clinical and cytogenetically finely described study of cases with pigmentary mosaicism associated with sSMCs. Undoubtedly, analysis of the two skin types is a fundamental part of our study, as numerical differences may occur in the cell lines found in each skin type. The knowledge generated in this study will help delineate a very heterogeneous entity more accurately, and in the future, analyzing more patients with PM will likely establish a more definite association with the presence of this genetic alteration.

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.

Early detection of neurological manifestations in achondroplasia.

Achondroplasia (ACh) is the most frequent bone dysplasia. The mode of inheritance is autosomal dominant. The incident of neurological complications ranges between 20% and 47%; frequently the symptoms are subtle but are due to such serious conditions as cervicomedullary compressive syndromes, syringomyelia or hydrocephalus; thus, the early identification of this disorder is very important. We made a prospective study of 39 patients (20 female, 19 male) with ACh; their ages ranged from 3 months to 17 years (mean 4 years and 6 months). All patients had hypotonia and psychomotor delay; 3 had recurrent apnea, 1 developed radicular syndrome and 1 had leg paresthesias. The CT scan was normal in 5, 20 had cortical atrophy and 18 communicating hydrocephalus; we identified foramen magnum abnormalities in 28 patients, and reduced craniocervical junction with cervicomedullary compression in 6. Myelography and myelotomography demonstrated spinal compression in 12 patients. The MRI showed cervicomedullary infarct in 1, syringomyelia in 2 and diastematomyelia in 1. The somatosensory evoked responses (SSER) were very useful in the early identification of brain stem and spinal abnormalities. We concluded that the neurological manifestations of pediatric patients with ACh are frequent and very important, demanding comprehensive clinical evaluation even in asymptomatic patients, especially those with severe hypotonia or SSER alterations.