Aarskog-scott syndrome: a review and case report.
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SUBMITTER: Closs LQ
PROVIDER: S-EPMC4155891 | biostudies-literature | 2012 Sep
REPOSITORIES: biostudies-literature
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Aarskog-scott syndrome: a review and case report.
Closs Luciane Q LQ Tovo Maximiano M Dias Caroline C Corradi Daniele P DP Vargas Ivana A IA
International journal of clinical pediatric dentistry 20120901 3
This paper reports the treatment and 12-year follow-up of a patient 7 years old who had been diagnosed with Aarskog-Scott syndrome. The patient had a history of premature multiple tooth loss, vertical dimension loss and severe dentoalveolar discrepancy. Orthopedic and orthodontic rehabilitation treatments were performed to improve the patient's esthetic, functional and psychological condition. How to cite this article: Closs LQ, Tovo M, Dias C, Corradi DP, Vargas IA. Aarskog-Scott Syndrome: A Re ...[more]
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Project description:Background Aarskog–Scott syndrome, a rare X-linked genetic disorder, is identified by combined clinical manifestations of short stature, facial, skeletal, and genital anomalies. Annually, two or three new cases are diagnosed with Aarskog–Scott syndrome, which is associated with FGD1 variants. However, there is no specific treatment for Aarskog–Scott syndrome due to its unclear mechanism. Methods Clinical data were collected when the patient first visited the hospital. Trio whole-exome sequencing and Sanger sequencing were performed for the genetic cause of disease. To evaluate the pathogenicity of the variants in vitro, stable cell lines were constructed using lentivirus infection in 143B cell. Furthermore, Western blot was used to verify the expression of signaling pathway-related proteins, and the transcription levels of osteogenic-related genes were verified by luciferase reporter gene assay. Results A 7-year-old boy was manifested with facial abnormalities, intellectual disability, and short stature (−3.98 SDS) while the growth hormone level of stimulation test was normal. Trio whole-exome sequencing and Sanger sequencing identified a variant (c.1270A>G, p.Asn424Asp) in FGD1 gene. The Asn424 residue was highly conserved and the hydrogen bond in the FGD1 variant protein has changed, which led to decrease in the interaction with CDC42 protein. In vitro study showed that the Asn424Asp variant significantly decreased the transcription levels of OCN, COL1A1, and ALP activity, and it activated the phosphorylation of JNK1. Conclusion Molecular biological mechanisms between abnormal expression of FGD1and Aarskog–Scott syndrome remain poorly understood. In our study, c.1270A>G variant of FGD1 resulted in Aarskog–Scott syndrome, and the analysis of pathogenicity supports the deleterious effect of the variant. Furthermore, we demonstrated the weakened affinity of the mutant FGD1 and CDC42. Decreased expression of osteogenic-related gene and abnormal activation of JNK1 were also shown in this work.
| S-EPMC9329920 | biostudies-literature
Project description:Aarskog-Scott syndrome (AAS) is most commonly inherited as an X-linked recessive genetic disease caused by FGD1 mutations. AAS patients are most frequently male, and the clinical manifestations of facial abnormalities, skeletal deformities, and abnormal genitalia comprise a characteristic triad of diagnostic features. The results on the clinical and molecular analysis of a family that reveals a novel FGD1 gene frameshift mutation in an 11-year-old boy displaying bilateral cryptorchidism associated with hypogonadism are reported here. This patient exhibited a characteristic triad of diagnostic features of ASS, including short stature, facial abnormalities, joint laxity, and typical scrotal fold. Whole-exome sequencing revealed the novel hemizygous mutation c.500delA in exon 3 of the patient's FGD1 gene, resulting after a frameshift in the Tyr167 residue, while his mother is heterozygous of the same variant. Further in silico studies were performed to identify the pathological consequence of this gene mutation. Thus, our study shows that frameshifts disrupting the RhoGEF gene domain of FGD1 represent the most prevalent causal mutations underlying AAS and expand the phenotypic and mutational spectra of this disease. Improved understanding of the phenotypic and pathological heterogeneity accompanying FGD1 mutation can greatly enhance the clinical prognostic capabilities in the future and aid genetic counseling for AAS patients.
| S-EPMC8192999 | biostudies-literature
Project description:Aarskog-Scott syndrome (AAS), also known as faciogenital dysplasia (FGD, OMIM # 305400), is an X-linked disorder of recessive inheritance, characterized by short stature and facial, skeletal, and urogenital abnormalities. AAS is caused by mutations in the FGD1 gene (Xp11.22), with over 56 different mutations identified to date. We present the clinical and molecular analysis of four unrelated families of Mexican origin with an AAS phenotype, in whom FGD1 sequencing was performed. This analysis identified two stop mutations not previously reported in the literature: p.Gln664* and p.Glu380*. Phenotypically, every male patient met the clinical criteria of the syndrome, whereas discrepancies were found between phenotypes in female patients. Our results identify two novel mutations in FGD1, broadening the spectrum of reported mutations; and provide further delineation of the phenotypic variability previously described in AAS.
| S-EPMC4444161 | biostudies-literature
Project description:Aarskog-Scott syndrome (ASS) is a rare, X-linked recessive inherited disorder. Affected individuals may develop short stature and exhibit distinctive skeletal and genital development. Mutations in the FYVE, rhogef and pleckstrin homology domain-containing protein 1 (FGD1) gene, located within the Xp11.21 region, are responsible for the occurrence of ASS. Since it is rare and complex, it can take a long time to obtain a definitive clinical diagnosis unless clinicians are familiar with the disease. In the present study, whole-exome sequencing (WES) was performed to screen for causal variants in a Chinese pediatric patient who exhibited a number of clinical symptoms of ASS, including short stature, facial abnormalities, stubby metacarpals and swollen testis. DNA sequencing revealed a novel c.1270 A>G mutation in exon 6 of the FGD1 gene, which led to an amino acid conversion of asparagine to aspartic acid on codon 424 and in silico analysis indicated that this novel missense mutation was pathogenic. The present study identified a novel variant of the FGD1 gene and to the best of our knowledge, is the first report of ASS in a Chinese individual. The results indicated that WES is an effective tool for the diagnosis of rare and complex syndromes such as ASS.
| S-EPMC5450764 | biostudies-literature
Project description:PurposeMedulloblastoma is known to be associated with multiple cancer-predisposition syndromes. In this article, we explore a possible association among a patient's Aarskog-Scott syndrome, development of medulloblastoma, and subsequent brainstem radiation necrosis.Case presentationA 5-year-old male with Aarskog-Scott syndrome initially presented to his pediatrician with morning emesis, gait instability, and truncal weakness. He was ultimately found to have a posterior fossa tumor with pathology consistent with group 3 medulloblastoma. After receiving a gross total resection and standard proton beam radiation therapy with concurrent vincristine, he was noted to develop brainstem radiation necrosis, for which he underwent therapy with high-dose dexamethasone, bevacizumab, and hyperbaric oxygen therapy with radiographic improvement and clinical stabilization.ConclusionBased on several possible pathologic correlates in the FDG1 pathway, there exists a potential association between this patient's Aarskog-Scott syndrome and medulloblastoma, which needs to be investigated further. In patients with underlying, rare genetic syndromes, further caution should be taken when evaluating chemotherapy and radiation dosimetry planning.
| S-EPMC8768897 | biostudies-literature
Project description:BackgroundThe X-linked condition "Aarskog-Scott syndrome (AAS)" causes a characteristic combination of short stature, facial, genital and skeletal anomalies. Studies elucidated a causative link between AAS and mutations in the FGD1 gene, which encodes a Rho/Rac guanine exchange factor. FGD1 is involved in regulating signaling pathways that control cytoskeleton organization and embryogenesis.Case presentationFGD1 was studied in an Emirati family with two cases of AAS using PCR amplification and direct sequencing of the entire coding region of the gene. Various in silico tools were also used to predict the functional consequences of FGD1 mutations. In the reported family, two brothers harbor a novel hemizygous mutation in FGD1 c.53del (p.Pro18Argfs*106) for which the mother is heterozygous. This frameshift deletion, being close to N-terminus of FGD1, is predicted to shift the reading frame in a way that it translates to 105 erroneous amino acids followed by a premature stop codon at position 106. Full molecular and clinical accounts about the variant are given so as to expand molecular and phenotypical knowledge about this disorder.ConclusionsA novel variant in FGD1 was found in an Emirati family with two brothers suffering from AAS. The variant is predicted to be a null mutation, and this is the first report of its kind from the United Arab Emirates.
| S-EPMC5248450 | biostudies-literature
Project description:Aarskog-Scott syndrome (AAS) is a developmental disorder, caused by disease-causing hemizygous variants in the FGD1 gene. AAS is characterized by dysmorphic features, genital malformation, skeletal anomalies, and in some cases, intellectual disability and behavioral difficulties. Myopathy has only been reported once in two affected siblings diagnosed with AAS. Only few adult cases have been reported. This article reports four adults with AAS (three male cases and one female carrier) from two unrelated Danish families, all males presented with variable features suggestive of myopathy. All four carried novel hemizygous pathogenic variants in the FGD1 gene; one family presented with the c.2266dup, p.Cys756Leufs*19 variant while the c.527dup; p.Leu177Thrfs*40 variant was detected in the second family. All males had some mild myopathic symptoms or histological abnormalities. Case 1 had the most severe myopathic phenotype with prominent proximal muscular fatigue and exercise intolerance. In addition, he had multiple deletions of mtDNA and low respiratory chain activity. His younger nephew, case 3, had difficulties doing sports in his youth and had a mildly abnormal muscle biopsy and relatively decreased mitochondrial enzyme activity. The singular case from family 2 (case 4), had a mildly myopathic muscle biopsy, but no overt myopathic symptoms. Our findings suggest that myopathic involvement should be considered in AAS.
| S-EPMC9321604 | biostudies-literature
Project description:Mutations in FGD1 cause Aarskog-Scott syndrome (AAS), an X-linked condition characterized by abnormal facial, skeletal, and genital development due to abnormal embryonic morphogenesis and skeletal formation. Here we report a novel FGD1 mutation in a family with atypical features of AAS, specifically bilateral upper and lower limb congenital joint contractures and cardiac abnormalities. The male proband and his affected maternal uncle are hemizygous for the novel FGD1 mutation p.Arg921X. This variant is the most carboxy-terminal FGD1 mutation identified in a family with AAS and is predicted to truncate the FGD1 protein at the second to last amino acid of the carboxy-terminal pleckstrin homology (PH) domain. Our study emphasizes the importance of the 3' peptide sequence in the structure and/or function of the FGD1 protein and further demonstrates the need to screen patients with X-linked congenital joint contractures for FGD1 mutations.
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Project description:Aarskog-Scott syndrome (AAS), also known as facio-genital dysplasia or faciodigitogenital syndrome, is a rare genetic disorder clinically characterised by facial, limb and genitalanomalies. Although also autosomal dominance and recessive patterns have been reported, up to now, only an X linked form associated to mutations of the FGD1 gene has been recognised as causative for this syndrome.In this case report, we describe a large Italian family in which three members across three generations show classical features of the syndrome. The youngest patient, the proband, and his mother were both molecularly studied and characterised for the not previously reported variant c.1828C>T (p. Arg610*) in the FGD1 gene but with the classic phenotype of AAS. Additionally, both the proband and his mother present a 2.5 Mb 16p13.11-p12.3 microduplication, a genetic variant still unclear for the phenotypic consequences: the co-occurrence of the two rare conditions is discussed for the possible clinical significance.
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| S-EPMC7902511 | biostudies-literature