51 research outputs found
Multiple endocrine neoplasias type 2B and RET proto-oncogene
Multiple Endocrine Neoplasia type 2B (MEN 2B) is an autosomal dominant complex oncologic neurocristopathy including medullary thyroid carcinoma, pheochromocytoma, gastrointestinal disorders, marphanoid face, and mucosal multiple ganglioneuromas. Medullary thyroid carcinoma is the major cause of mortality in MEN 2B syndrome, and it often appears during the first years of life. RET proto-oncogene germline activating mutations are causative for MEN 2B. The 95% of MEN 2B patients are associated with a point mutation in exon 16 (M918/T). A second point mutation at codon 883 has been found in 2%-3% of MEN 2B cases. RET proto-oncogene is also involved in different neoplastic and not neoplastic neurocristopathies. Other RET mutations cause MEN 2A syndrome, familial medullary thyroid carcinoma, or Hirschsprung's disease. RET gene expression is also involved in Neuroblastoma. The main diagnosis standards are the acetylcholinesterase study of rectal mucosa and the molecular analysis of RET. In our protocol the rectal biopsy is, therefore, the first approach. RET mutation detection offers the possibility to diagnose MEN 2B predisposition at a pre-clinical stage in familial cases, and to perform an early total prophylactic thyroidectomy. The surgical treatment of MEN 2B is total thyroidectomy with cervical limphadenectomy of the central compartment of the neck. When possible, this intervention should be performed with prophylactic aim before 1 year of age in patients with molecular genetic diagnosis. Recent advances into the mechanisms of RET proto-oncogene signaling and pathways of RET signal transduction in the development of MEN 2 and MTC will allow new treatment possibilities
Microarray based analysis of an inherited terminal 3p26.3 deletion, containing only the CHL1 gene, from a normal father to his two affected children
<p>Abstract</p> <p>Background</p> <p>terminal deletions of the distal portion of the short arm of chromosome 3 cause a rare contiguous gene disorder characterized by growth retardation, developmental delay, mental retardation, dysmorphisms, microcephaly and ptosis. The phenotype of individuals with deletions varies from normal to severe. It was suggested that a 1,5 Mb minimal terminal deletion including the two genes <it>CRBN </it>and <it>CNTN4 </it>is sufficient to cause the syndrome.</p> <p>In addition the <it>CHL1 </it>gene, mapping at 3p26.3 distally to <it>CRBN </it>and <it>CNTN4</it>, was proposed as candidate gene for a non specific mental retardation because of its high level of expression in the brain.</p> <p>Methods and Results</p> <p>we describe two affected siblings in which array-CGH analysis disclosed an identical discontinuous terminal 3p26.3 deletion spanning less than 1 Mb. The deletion was transmitted from their normal father and included only the <it>CHL1 </it>gene. The two brothers present microcephaly, light mental retardation, learning and language difficulties but not the typical phenotype manifestations described in 3p- syndrome.</p> <p>Conclusion</p> <p>a terminal 3p26.3 deletion including only the <it>CHL1 </it>gene is a very rare finding previously reported only in one family. The phenotype of the affected individuals in the two families is very similar and the deletion has been inherited from an apparently normal parent. As already described for others recurrent syndromes with variable phenotype, these findings are challenging in genetic counselling because of an evident variable penetrance.</p
P63 modulates the expression of the WDFY2 gene which is implicated in cancer regulation and limb development
TP63 is a member of the TP53 gene family, sharing a common gene structure that produces two groups of mRNAs\u2019 encoding proteins with different N-terminal regions ( 06N and TA isoforms); both transcripts are also subjected to alternative splicing mechanisms at C-terminus, generating a variety of isoforms. p63 is a master regulator of epidermal development and homoeostasis as well as an important player in tumorigenesis and cancer progression with both oncogenic and tumour suppressive roles. A number of studies have aimed at the identification of p63 target genes, allowing the dissection of the molecular pathways orchestrated by the different isoforms. In the present study we investigated in more detail the p63 responsiveness of the WDFY2 (WD repeat and FYVE domain containing 2) gene, encoding for an endosomal protein identified as a binding partner of the PI-3K/AKT signalling pathway. We showed that overexpression of different p63 isoforms was able to induce WDFY2 expression in TP53-null cells. The p63-dependent transcriptional activation was associated with specific response elements (REs) that have been identified by a bioinformatics tool and validated by yeast- and mammal-based assays. Interestingly, to confirm that WDFY2 belongs to the p63 network of cancer regulation, we analysed the impact of WDFY2 alterations, by showing its frequent deletion in different types of tumours and suggesting its expression level as a prognostic biomarker. Lastly, we identified a chromosomal translocation involving the WDFY2 locus in a patient affected by a rare congenital limb anomaly, indicating WDFY2 as a possible susceptibility gene placed downstream p63 in the network of limb development
Assessment of copy number variations in 120 patients with Poland syndrome
Poland Syndrome (PS) is a rare congenital disorder presenting with agenesis/hypoplasia of the pectoralis major muscle variably associated with thoracic and/or upper limb anomalies. Most cases are sporadic, but familial recurrence, with different inheritance patterns, has been observed. The genetic etiology of PS remains unknown. Karyotyping and array-comparative genomic hybridization (CGH) analyses can identify genomic imbalances that can clarify the genetic etiology of congenital and neurodevelopmental disorders. We previously reported a chromosome 11 deletion in twin girls with pectoralis muscle hypoplasia and skeletal anomalies, and a chromosome six deletion in a patient presenting a complex phenotype that included pectoralis muscle hypoplasia. However, the contribution of genomic imbalances to PS remains largely unknown
Consensus based recommendations for diagnosis and medical management of Poland syndrome (sequence)
Background Poland syndrome (OMIM: 173800) is a disorder in which affected individuals are born with missing or underdeveloped muscles on one side of the body, resulting in abnormalities that can affect the chest, breast, shoulder, arm, and hand. The extent and severity of the abnormalities vary among affected individuals. Main body The aim of this work is to provide recommendations for the diagnosis and management of people affected by Poland syndrome based on evidence from literature and experience of health professionals from different medical backgrounds who have followed for several years affected subjects. The literature search was performed in the second half of 2019. Original papers, meta-analyses, reviews, books and guidelines were reviewed and final recommendations were reached by consensus. Conclusion Being Poland syndrome a rare syndrome most recommendations here presented are good clinical practice based on the consensus of the participant experts
HLXB9 (MNX1), Sacral Agenesis, and the Currarino Syndrome in : Epstein's Inborn Errors of Development: The Molecular Basis of Clinical Disorders of Morphogenesis (3 ed.)
none4siChapters provides overview of pathways of development and reviews of dysmorphic syndromes for which the causative gene has been identified. For each disorder, an analysis of the role of the gene in the relevant developmental pathway is provided, along with the mechanism by which mutations in the gene cause the developmental pathology. Emphasis is placed the developmental roles of genes in the causation of hereditary conditions affecting appearance and function.Chapter:HLXB9 (MNX1), Sacral Agenesis, and the Currarino Syndrome
Authors : Stephen Scherer, Giuseppe Martucciello, Margherita Lerone, and Elena BelloninoneStephen Scherer, Giuseppe Martucciello, Margherita Lerone, and Elena BelloniScherer, Stephen; Martucciello, Giuseppe; Lerone, Margherita; Elena Belloni, An
Functional analysis of a novel 5âUTR variant of the LMX1B gene associated with a familial case of Nail-Patella Syndrome
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