Pseudohermafroditismo masculino, con restos mullerianos: correlación clínica, genética e histológica

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina. Fecha de lectura: 24 de Abril de 197

Impact of Heterozygosity for Acid-Labile Subunit (IGFALS) Gene Mutations on Stature: Results from the International Acid-Labile Subunit Consortium

Context: To date, 16 IGFALS mutations in 21 patients with acid-labile subunit (ALS) deficiency have been reported. The impact of heterozygosity for IGFALS mutations on growth is unknown. Objective: The study evaluates the impact of heterozygous expression of IGFALS mutations on phenotype based on data collected by the International ALS Consortium. Subjects/Methods: Patient information was derived from the IGFALS Registry, which includes patients with IGFALS mutations and family members who were either heterozygous carriers or homozygous wild-type.Within each family, the effect ofIGFALSmutations on stature was analyzed as follows: 1) effect of two mutant alleles (2ALS) vs. wild-type (WT); 2) effect of two mutant alleles vs. one mutant allele (1ALS); and 3) effect of one mutant allele vs. wild-type. The differences in height SD score (HtSDS) were then pooled and evaluated. Results: Mean HtSDS in 2ALS was 2.31 0.87 (less than 2 SDS in 62%); in 1ALS, 0.83 1.34 (less than 2 SDS in 26%); and in WT, 1.02 1.04 (less than 2 SDS in 12.5%). When analyses were performed within individual families and pooled, the difference in mean HtSDS between 2ALS and WT was 1.93 0.79; between 1ALS and WT, 0.90 1.53; and between 2ALS and 1ALS, 1.48 0.83. Conclusions: Heterozygosity for IGFALS mutations results in approximately 1.0 SD height loss in comparison with wild type, whereas homozygosity or compound heterozygosity gives a further loss of 1.0 to 1.5 SD, suggestive of a gene-dose effect. Further studies involving a larger cohort are needed to evaluate the impact of heterozygous IGFALS mutations not only on auxology, but also on other aspects of the GH/IGF system.Fil: Fofanova Gambetti, Olga V.. Oregon Health & Science University; Estados UnidosFil: Hwa, Vivian. Oregon Health & Science University; Estados UnidosFil: Wit, Jan M.. Leiden University. Leiden University Medical Center.; Países BajosFil: Domene, Horacio Mario. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad Autonoma de Buenos Aires. Hospital General de Niños "ricardo Gutierrez". Departamento de Medicina.; ArgentinaFil: Argente, Jesús. Hospital Infantil Universitario Niño Jesús; España. Universidad Autónoma de Madrid; EspañaFil: Bang, Peter. Karolinska Institute and University Hospital; SueciaFil: Wolfgang, Hogler. Birmingham Children’s Hospital; Reino UnidoFil: Kirsh, Susan. University Of Toronto. Hospital For Sick Children; CanadáFil: Pihoker, Catherine. Children’s Hospital and Regional Medical Center; Estados UnidosFil: Chiu, Harvey K.. Children’s Hospital and Regional Medical Center; Estados UnidosFil: Cohen, Laurie. Children’s Hospital Boston; Estados UnidosFil: Jacobsen, Christina. Children’s Hospital Boston; Estados UnidosFil: Jasper, Hector Guillermo. Gobierno de la Ciudad Autonoma de Buenos Aires. Hospital General de Niños "ricardo Gutierrez". Departamento de Medicina.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Haeusler, Gabriele. Medical University of Vienna ; AustriaFil: Campos Barros, Angel. Hospital Universitario La Paz; España. Instituto de Salud Carlos III; EspañaFil: Gallego Gómez, Elena. Hospital Universitario 12 de Octubre; EspañaFil: Gracia Bouthelier, Ricardo. Hospital Universitario La Paz; EspañaFil: van Duyvenvoorde, Hermine A.. Leiden University. Leiden University Medical Center.; Países BajosFil: Pozo, Jesús. Hospital Infantil Universitario Niño Jesús; España. Universidad Autónoma de Madrid; EspañaFil: Rosenfeld, Ron G.. Oregon Health & Science University; Estados Unido

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