Luis Venancio Oceja Fernández

CDKN1C (p57Kip2) analysis in Beckwith–Wiedemann syndrome (BWS) patients: Genotype–phenotype correlations, novel mutations, and polymorphisms

Beckwith–Wiedemann syndrome (BWS) is an overgrowth syndrome characterized by macroglossia, macrosomia, and abdominal wall defects. It is a multigenic disorder caused in most patients by alterations in growth regulatory genes. A small number of individuals with BWS (5–10%) have mutations in CDKN1C, a cyclin‐dependent kinase inhibitor of G1 cyclin complexes that functions as a negative regulator of cellular growth and proliferation. Here, we report on eight patients with BWS and CDKN1C mutations and review previous reported cases. We analyzed 72 patients (50 BWS, 17 with isolated hemihyperplasia (IH), three with omphalocele, and two with macroglossia) for CDKN1C defects with the aim to search for new mutations and to define genotype–phenotype correlations. Our findings suggest that BWS patients with CDKN1C mutations have a different pattern of clinical malformations than those with other molecular defects. Polydactyly, genital abnormalities, extra nipple, and cleft palate are more frequently observed in BWS with mutations in CDKN1C. The clinical observation of these malformations may help to decide which genetic characterization should be undertaken (i.e., CDKN1C screening), thus optimizing the laboratory evaluation for BWS.

Beckwith–Wiedemann syndrome and uniparental disomy 11p: fine mapping of the recombination breakpoints and evaluation of several techniques

Beckwith–Wiedemann syndrome (BWS) is a phenotypically and genotypically heterogeneous overgrowth syndrome characterized by somatic overgrowth, macroglossia and abdominal wall defects. Other usual findings are hemihyperplasia, embryonal tumours, adrenocortical cytomegaly, ear anomalies, visceromegaly, renal abnormalities, neonatal hypoglycaemia, cleft palate, polydactyly and a positive family history. BWS is a complex, multigenic disorder associated, in up to 90% of patients, with alteration in the expression or function of one or more genes in the 11p15.5 imprinted gene cluster. There are several molecular anomalies associated with BWS and the large proportion of cases, about 85%, is sporadic and karyotypically normal. One of the major categories of BWS molecular alteration (10–20% of cases) is represented by mosaic paternal uniparental disomy (pUPD), namely patients with two paternally derived copies of chromosome 11p15 and no maternal contribution for that. In these patients, in addition to the effects of IGF2 overexpression, a decreased level of the maternally expressed gene CDKN1C may contribute to the BWS phenotype. In this paper, we reviewed a series of nine patients with BWS because of pUPD using several methods with the aim to evaluate the percentage of mosaicism, the methylation status at both loci, the extension of the pUPD at the short arm and the breakpoints of recombination. Fine mapping of mitotic recombination breakpoints by single-nucleotide polymorphism-array in individuals with UPD and fine estimation of epigenetic defects will provide a basis for understanding the aetiology of BWS, allowing more accurate prognostic predictions and facilitating management and surveillance of individuals with this disorder.

Constitutional mosaic genome-wide uniparental disomy due to diploidisation: an unusual cancer-predisposing mechanism

Molecular studies in a patient with Beckwith–Wiedemann syndrome phenotype who developed two different tumours revealed an unexpected observation of almost complete loss of heterozygosity of all chromosomes. It is shown, by means of numerous molecular methods, that the absence of maternal contribution in somatic cells is due to high-degree (∼85%) genome-wide paternal uniparental disomy (UPD). The observations indicate that the genome-wide UPD results from diploidisation, and have important implications for genetic counselling and tumour surveillance for the growing number of UPD associated imprinting disorders.

Efectos cotidianos de las normas perversas en la tolerancia a la corrupción

ResumenEl presente informe analiza empiricamente uno de los efectos mas importantes de las normas perversas (Fernandez-Dols, 1992): su capacidad para crear una mayor tolerancia a la corrupcion entre las personas que la sufren. Para ello se ha llevado a cabo un cuestionario en el que un grupo de 123 sujetos (66 conductores y 57 no conductores) evaluaban el comportamiento de una persona capaz de perdonar, de forma arbitraria, multas de trafico. En un caso las multas eran con respecto a la transgresion de una norma perversa en Espana (el limite de velocidad en las carreteras generales) mientras que en el otro caso se trataba de una norma cuya transgresion no es obvia y generalizada (el conducir tras haber ingerido alcohol). Los resultados muestran claramente una mayor tolerancia a la condonacion de la multa en el caso del exceso de velocidad, lo) que apoya la relacion entre corrupcion y norma perversa apuntada en nuestra hipotesis.

Unusual four-generation chromosome-22 rearrangement: When “normality” masks abnormality†

Juli an Nevado,* M. Luisa de Torres, Luis Fern andez, M. Angeles Mori, Amelia Villa, Marı́a Palomares, Fe Garcı́a-Santiago, Elena Mansilla, Sixto Garcı́a-Mi~naur, Alicia Delicado, and Pablo Lapunzina Instituto de Gen etica M edica y Molecular (INGEMM), Hospital Universitario La Paz, Universidad Aut onoma de Madrid, Madrid, Spain Centro de Investigaci on Biom edica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain Hospital Ruber Internacional, Madrid, Spain