RESUMEN
Silver-Russell syndrome (SRS) is a rare genetic condition primarily characterized by growth restriction and facial dysmorphisms. While hypomethylation of H19/IGF2:IG-DMR (imprinting control region 1 [IC1]) located at 11p15.5 and maternal uniparental disomy of chromosome 7 (upd[7]mat) are the most common genetic mechanisms responsible for SRS, the expanding body of literature describing alternative causative variants suggests SRS is a highly heterogeneous condition, also involving variation in the HMGA2-PLAG1-IGF2 pathway. We report a familial PLAG1 deletion in association with a complex chromosomal rearrangement. We describe two siblings with differing unbalanced chromosomal rearrangements inherited from a mother with a 5-breakpoint balanced complex rearrangement involving chromosomes 2, 8, and 21. The overlapping but diverse phenotypes in the siblings were characterized by shared SRS-like features, underlined by a PLAG1 whole gene deletion. Genetic analysis and interpretation was further complicated by a meiotic recombination event occurring in one of the siblings. This family adds to the limited literature available on PLAG1-related SRS. We have reviewed all currently known cases aiming to define the associated phenotype and guide future genetic testing strategies. The heterogeneity of SRS is further expanded by the involvement of complex cytogenomic abnormalities, imposing requirements for a comprehensive approach to testing and genetic counseling.
Asunto(s)
Proteínas de Unión al ADN/genética , Pruebas Genéticas , Síndrome de Silver-Russell/genética , Niño , Preescolar , Metilación de ADN/genética , Femenino , Predisposición Genética a la Enfermedad , Impresión Genómica/genética , Proteína HMGA2/genética , Humanos , Factor II del Crecimiento Similar a la Insulina/genética , Masculino , Síndrome de Silver-Russell/diagnóstico , Síndrome de Silver-Russell/patologíaRESUMEN
A group of melanomas characterised by predominant growth as large nests within the epidermis has been described. These cases present a diagnostic challenge, as many traditional architectural criteria for the recognition of melanoma are absent. We report the clinical, histological, immunohistochemical, morphometric and cytogenetic features of a series of 12 cases of large nested melanoma. In this series, large nested melanoma accounted for 0.2% of cases of melanoma. The majority occurred on the trunk of middle aged patients with absent or minimal solar elastosis and 42% were associated with a component of benign intradermal melanocytic naevus, speaking to classification of these melanomas as falling within the spectrum of lesions developing in skin with low cumulative sun damage. In 67% of cases invasive melanoma was present. Criteria such as asymmetry, variation in nest size and intraepidermal nests with an underlying rim of junctional keratinocytes appear to be highly specific, and are strongly predictive of typical cytogenetic abnormalities of melanoma, which were identified in 92% of cases. Conversely, in addition to features which are definitionally absent or limited, features such as solar elastosis and cytological atypia do not appear to be particularly helpful in recognition of this variant.