The clinical diagnosis of ASS (Aarskog-Scott syndrome or Faciogenital Dysplasia) was made in seven individuals belonging to a large Arabic family, which was supported by molecular studies revealing a 2189delA mutation in exon 15 of the FDG1 gene. The affected individuals in this family demonstrated clinical variability particularly in their cognitive skills, raising the question whether other genetic factors might be involved in the phenotypic evolution of ASS.
"Clinical findings are summarized in Table 4 (2). Typical facial features include a round face, facial edema in children younger than 4 years, downward slanting palpebral fissures, a short nose with anteverted nares, long filtrum, ocular hypertelorism with ptosis of different degrees, maxillary hypoplasia, a broad upper lip, widow’s peak, a crease below the lower lip, orthodontic problems and abnormal auricules (2,50,51,52). Brachydactyly, clinodactily of the fifth finger, joint laxity, mild interdigital webbing, short broad hands and feet, simian line, bulbous toes are the main skeletal features of ASS. Mild pectus excavatum can also occur (2,51). "
[Show abstract][Hide abstract] ABSTRACT: Short stature is one of the major components of many dysmorphic syndromes. Growth failure may be due to a wide variety of mechanisms, either related to the growth hormone (GH)/insulin-like growth factor axis or to underlying unknown pathologies. In this review, the relatively more frequently seen syndromes with short stature (Noonan syndrome, Prader-Willi syndrome, Silver-Russell syndrome and Aarskog-Scott syndrome) were discussed. These disorders are associated with a number of endocrinopathies, as well as with developmental, systemic and behavioral issues. At present, GH therapy is used in most syndromic disorders, although long-term studies evaluating this treatment are insufficient and some controversies exist with regard to GH dose, optimal age to begin therapy and adverse effects. Before starting GH treatment, patients with syndromic disorders should be evaluated extensively.
Journal of Clinical Research in Pediatric Endocrinology 03/2014; 6(1):1-8. DOI:10.4274/Jcrpe.1149
"FGD1 specifically activates Cdc42, which is a Rho GTPase central to signaling pathways that are important for cytoskeleton organization and embryogenesis (Gorski et al., 2000). Almost equal numbers of missense and nonsense mutations of FGD1 have been described (Orrico et al., 2000; Schwartz et al., 2000; Lebel et al., 2002; Orrico et al., 2004; Orrico et al., 2005; Kaname et al., 2006; Shalev et al., 2006; Bedoyan et al., 2009; Orrico et al., 2010), and marked allelic and phenotypic heterogeneity is evident in AAS patients with proven FGD1 mutations. "
[Show abstract][Hide abstract] ABSTRACT: In this report, we describe a kindred consisting of five affected males presenting with many of the well-recognized features of Aarskog-Scott syndrome. The diagnosis, which was confirmed by the identification of a novel nonsense mutation of FGD1, was associated with the presence of a symmetric distal arthropathy with electromyographic signs of myopathy. These features should be considered in the evaluation of future patients. Clin Dysmorphol 22:13-17 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. Clinical Dysmorphology 2013, 22:13-17
"These results imply a potential oncogenic function of the FDG1 and HMGB2 genes. The FDG1 gene is the susceptible gene for the Aarskog–Scott's faciogenital dysplasia syndrome (Shalev et al. 2006) and the HMGB2 gene is a DNA-binding protein with pleiotropic biological functions (Yamada & Maruyama 2007). A previous study in fact showed that expression of the FDG1 gene could cause cell transformation (Whitehead et al. 1998). "
[Show abstract][Hide abstract] ABSTRACT: The BRAF V600E mutation plays an important role in the tumorigenesis of papillary thyroid cancer (PTC). To explore an epigenetic mechanism involved in this process, we performed a genome-wide DNA methylation analysis using a methylated CpG island amplification (MCA)/CpG island microarray system to examine gene methylation alterations after shRNA knockdown of BRAF V600E in thyroid cancer cells. Our results revealed numerous methylation targets of BRAF V600E mutation with a large cohort of hyper- or hypo-methylated genes in thyroid cancer cells, which are known to have important metabolic and cellular functions. As hypomethylation of numerous genes by BRAF V600E was particularly a striking finding, we took a further step to examine the selected 59 genes that became hypermethylated in both cell lines upon BRAF V600E knockdown and found them to be mostly correspondingly under-expressed (i.e. they were normally maintained hypomethylated and over-expressed by BRAF V600E in thyroid cancer cells). We confirmed the methylation status of selected genes revealed on MCA/CpG microarray analysis by performing methylation-specific PCR. To provide proof of concept that some of the genes uncovered here may play a direct oncogenic role, we selected six of them to perform shRNA knockdown and examined its effect on cellular functions. Our results demonstrated that the HMGB2 gene played a role in PTC cell proliferation and the FDG1 gene in cell invasion. Thus, this study uncovered a prominent epigenetic mechanism through which BRAF V600E can promote PTC tumorigenesis by altering the methylation and hence the expression of numerous important genes.
Endocrine Related Cancer 09/2011; 18(6):687-97. DOI:10.1530/ERC-11-0212 · 4.81 Impact Factor
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