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The Pan African Medical Journal 2016Shprintzen-Goldberg Syndrome is an extremely infrequent disorder of connective tissue, characterized by craniosynostosis and marfanoid features, also known as Marfanoid... (Review)
Review
Shprintzen-Goldberg Syndrome is an extremely infrequent disorder of connective tissue, characterized by craniosynostosis and marfanoid features, also known as Marfanoid Craniosynostosis syndrome. The syndrome was first introduced by Sugarman and Vogel' (1981) however, Shprintzen and Goldberg established this as a separate clinical entity in the year 1982. Since then, approximately sixty such cases have been set down in writing in the medical literature. Herein, we present a short review of literature of this rare connective disorder, in order to create awareness about this condition, as the magnitude of this disorder is not measured properly due to the paucity of literature.
Topics: Arachnodactyly; Craniosynostoses; Humans; Marfan Syndrome
PubMed: 27761171
DOI: 10.11604/pamj.2016.23.227.7482 -
BMC Pediatrics Oct 2023Marfan syndrome is a genetic connective tissue disorder affecting skeletal, ocular, and cardiovascular organ systems. Previous research found that pathogenic variants...
BACKGROUND
Marfan syndrome is a genetic connective tissue disorder affecting skeletal, ocular, and cardiovascular organ systems. Previous research found that pathogenic variants clustered in exons 24-32 of fibrillin-1 (FBN1) gene result in more severe clinical phenotypes. Furthermore, genotype-phenotype correlation studies suggested that more severe cardiovascular phenotypes were related to variants held responsible for haploinsufficiency. Our objective was to analyze the differences in clinical manifestations and genotypes of individuals with early-onset Marfan syndrome and to assess their impact on management strategies.
METHODS
We analyzed clinical and genetic data of a new patient with early-onset Marfan syndrome together with 51 previously reported ones in the PubMed database between 1991 and 2022.
RESULTS
Analysis showed 94% (49/52) of pathogenic variants clustered in exons 24-32 of the FBN1. The most common skeletal features were arachnodactyly (98%), reduced elbow extension (48%), pectus deformity (40%), and scoliosis (39%). Haploinsufficiency variants were reported as having poor outcome in 87.5% of the cases. Among patients carrying variants that substitute a cysteine for another amino acid and those that do not change cysteine content, cardiac intervention was found to be associated with a better outcome (p = 0.035 vs. p = 0.002). Variants that create an extra cysteine residue were found to be associated with a higher risk of ectopia lentis. Additionally, children up to 36-months-old were more often reported as still alive at the time of publication compared to newborns (p < 0.01).
CONCLUSIONS
Our findings have implications for prognosis, because different genotype groups and their resulting phenotype may require personalized care and management.
Topics: Child; Humans; Infant, Newborn; Child, Preschool; Marfan Syndrome; Fibrillins; Cysteine; Mutation; Genotype; Phenotype; Prognosis
PubMed: 37891508
DOI: 10.1186/s12887-023-04357-8 -
Archives of Disease in Childhood Jan 2019
Topics: Arachnodactyly; DiGeorge Syndrome; Humans; Marfan Syndrome; Scoliosis; Spine
PubMed: 30032113
DOI: 10.1136/archdischild-2018-315395 -
Human Mutation Jun 2016Marfan syndrome (MFS) is a rare, autosomal-dominant, multisystem disorder, presenting with skeletal, ocular, skin, and cardiovascular symptoms. Significant clinical... (Review)
Review
Marfan syndrome (MFS) is a rare, autosomal-dominant, multisystem disorder, presenting with skeletal, ocular, skin, and cardiovascular symptoms. Significant clinical overlap with other systemic connective tissue diseases, including Loeys-Dietz syndrome (LDS), Shprintzen-Goldberg syndrome (SGS), and the MASS phenotype, has been documented. In MFS and LDS, the cardiovascular manifestations account for the major cause of patient morbidity and mortality, rendering them the main target for therapeutic intervention. Over the past decades, gene identification studies confidently linked the aforementioned syndromes, as well as nonsyndromic aneurysmal disease, to genetic defects in proteins related to the transforming growth factor (TGF)-β pathway, greatly expanding our knowledge on the disease mechanisms and providing us with novel therapeutic targets. As a result, the focus of the developing pharmacological treatment strategies is shifting from hemodynamic stress management to TGF-β antagonism. In this review, we discuss the insights that have been gained in the molecular biology of MFS and related disorders over the past 25 years.
Topics: Angiotensin Receptor Antagonists; Animals; Arachnodactyly; Craniosynostoses; Gene Expression Regulation; Gene Regulatory Networks; Genetic Predisposition to Disease; Humans; Loeys-Dietz Syndrome; Marfan Syndrome; Mitral Valve Prolapse; Myopia; Signal Transduction; Skin Diseases; Transforming Growth Factor beta
PubMed: 26919284
DOI: 10.1002/humu.22977 -
La Revue Du Praticien Nov 2020Marfan syndrome and related disorders. Marfan syndrome is an autosomal dominant disease, affecting about 1/5000 persons. It includes aortic wall fragility responsible...
Marfan syndrome and related disorders. Marfan syndrome is an autosomal dominant disease, affecting about 1/5000 persons. It includes aortic wall fragility responsible for aortic root dilatation and risk of dissection, mitral valve prolapse, ophthalmological features (ectopia lentis, flat cornea, myopia), skeletal features (excessive height, arachnodactyly, thoracic deformity with pectus, scoliosis, and flat feet), cutaneous striae, particularly in the front of the shoulders, and dural ectasia. The gene affected is mainly FBN1 coding for fibrillin 1. Care includes beta-blockers, sport restriction, and prophylactic aortic surgery when the maximal aortic diameter (usually aortic root diameter) exceeds 50 mm. Many new related disorders have been discovered these last years.
Topics: Fibrillin-1; Humans; Marfan Syndrome; Mutation
PubMed: 33739763
DOI: No ID Found -
Transplant International : Official... 2022Cholangiocarcinoma (CCA) is currently a contraindication to liver transplantation (LT) in the United Kingdom (UK). Incidental CCA occurs rarely in some patients...
Cholangiocarcinoma (CCA) is currently a contraindication to liver transplantation (LT) in the United Kingdom (UK). Incidental CCA occurs rarely in some patients undergoing LT. We report on retrospective outcomes of patients with incidental CCA from six UK LT centres. Cases were identified from pathology records. Data regarding tumour characteristics and post-transplant survival were collected. CCA was classified by TNM staging and anatomical location. 95 patients who underwent LT between 1988-2020 were identified. Median follow-up after LT was 2.1 years (14 days-18.6 years). Most patients were male (68.4%), median age at LT was 53 (IQR 46-62), and the majority had underlying PSC (61%). Overall median survival after LT was 4.4 years. Survival differed by tumour site: 1-, 3-, and 5-year estimated survival was 82.1%, 68.7%, and 57.1%, respectively, in intrahepatic CCA ( = 40) and 58.5%, 42.6%, and 30.2% in perihilar CCA ( = 42; = 0.06). 1-, 3-, and 5-year estimated survival was 95.8%, 86.5%, and 80.6%, respectively, in pT1 tumours (28.2% of cohort), and 65.8%, 44.7%, and 31.1%, respectively, in pT2-4 ( = 0.018). Survival after LT for recipients with incidental CCA is inferior compared to usual outcomes for LT in the United Kingdom. LT for earlier stage CCA has similar survival to LT for hepatocellular cancer, and intrahepatic CCAs have better survival compared to perihilar CCAs. These observations may support LT for CCA in selected cases.
Topics: Humans; Male; Female; Liver Transplantation; Bile Duct Neoplasms; Retrospective Studies; Cholangiocarcinoma; Bile Ducts, Intrahepatic
PubMed: 36406780
DOI: 10.3389/ti.2022.10802 -
Journal of Experimental & Clinical... May 2022Cholangiocarcinoma (CCA) is still a deadly tumour. Histological and molecular aspects of thioacetamide (TAA)-induced intrahepatic CCA (iCCA) in rats mimic those of human...
New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming.
BACKGROUND
Cholangiocarcinoma (CCA) is still a deadly tumour. Histological and molecular aspects of thioacetamide (TAA)-induced intrahepatic CCA (iCCA) in rats mimic those of human iCCA. Carcinogenic changes and therapeutic vulnerabilities in CCA may be captured by molecular investigations in bile, where we performed bile proteomic and metabolomic analyses that help discovery yet unknown pathways relevant to human iCCA.
METHODS
Cholangiocarcinogenesis was induced in rats (TAA) and mice (Jnk + CCl + DEN model). We performed proteomic and metabolomic analyses in bile from control and CCA-bearing rats. Differential expression was validated in rat and human CCAs. Mechanisms were addressed in human CCA cells, including Huh28-KRAS cells. Cell signaling, growth, gene regulation and [U-C]-D-glucose-serine fluxomics analyses were performed. In vivo studies were performed in the clinically-relevant iCCA mouse model.
RESULTS
Pathways related to inflammation, oxidative stress and glucose metabolism were identified by proteomic analysis. Oxidative stress and high amounts of the oncogenesis-supporting amino acids serine and glycine were discovered by metabolomic studies. Most relevant hits were confirmed in rat and human CCAs (TCGA). Activation of interleukin-6 (IL6) and epidermal growth factor receptor (EGFR) pathways, and key genes in cancer-related glucose metabolic reprogramming, were validated in TAA-CCAs. In TAA-CCAs, G9a, an epigenetic pro-tumorigenic writer, was also increased. We show that EGFR signaling and mutant KRAS can both activate IL6 production in CCA cells. Furthermore, phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in serine-glycine pathway, was upregulated in human iCCA correlating with G9a expression. In a G9a activity-dependent manner, KRAS promoted PHGDH expression, glucose flow towards serine synthesis, and increased CCA cell viability. KRAS CAA cells were more sensitive to PHGDH and G9a inhibition than controls. In mouse iCCA, G9a pharmacological targeting reduced PHGDH expression.
CONCLUSIONS
In CCA, we identified new pro-tumorigenic mechanisms: Activation of EGFR signaling or KRAS mutation drives IL6 expression in tumour cells; Glucose metabolism reprogramming in iCCA includes activation of the serine-glycine pathway; Mutant KRAS drives PHGDH expression in a G9a-dependent manner; PHGDH and G9a emerge as therapeutic targets in iCCA.
Topics: Animals; Arachnodactyly; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carcinogenesis; Cholangiocarcinoma; Contracture; Epigenesis, Genetic; ErbB Receptors; Glucose; Glycine; Humans; Interleukin-6; Mice; Phosphoglycerate Dehydrogenase; Proteomics; Proto-Oncogene Proteins p21(ras); Rats; Serine
PubMed: 35619118
DOI: 10.1186/s13046-022-02386-2 -
Frontiers in Genetics 2021Birt-Hogg-Dubé (BHD) syndrome and congenital contractural arachnodactyly (CCA) or Beals-Hecht syndrome are clinically rare autosomal dominant genetic diseases. In this...
Birt-Hogg-Dubé (BHD) syndrome and congenital contractural arachnodactyly (CCA) or Beals-Hecht syndrome are clinically rare autosomal dominant genetic diseases. In this study, we describe an extremely rare family with BHD syndrome and CCA. To investigate the clinical and genetic characteristics of a family with BHD syndrome and CCA. We describe the clinical characteristics, family history, and clinical manifestations of the patient's family members. The patient underwent a blood test, computed tomography (CT) of the chest, color Doppler ultrasound of the abdomen and heart, and digital radiography of the hands. Whole exome sequencing was performed on his family members. Two years ago, the male proband developed chest tightness and shortness of breath that was accompanied by an irritating cough as well as repeated (four times) spontaneous pneumothorax. The chest CT indicated spontaneous pneumothorax on the right side and cyst and bullae in both lungs. He had no kidney tumors or skin lesions. His son had a history of pulmonary bullae and experienced spontaneous pneumothorax twice. The proband, his mother, and his son were all born with a hand deformity. The sequencing results demonstrated that both the proband and his son had heterozygous variations of the folliculin (FLCN) gene c.1015C > T (p. Gln339Ter) and fibrillin-2 (FBN2) gene c.3485G > A (p. Cys1162Tyr), which are associated with BHD syndrome and CCA, respectively. For patients with chest tightness, shortness of breath, recurrent spontaneous pneumothorax, and congenital hand deformity without inducement, genetic testing should be carried out as soon as possible to make a clear diagnosis, which can then guide treatment and genetic counseling.
PubMed: 35126451
DOI: 10.3389/fgene.2021.768342 -
Journal of Psychiatric Research Jun 2021The presentation of neurogenetic disorders such as 22q11.2 Deletion Syndrome (22q11.2DS) includes broad neuropsychiatric phenotypes that impact functioning and require...
BACKGROUND
The presentation of neurogenetic disorders such as 22q11.2 Deletion Syndrome (22q11.2DS) includes broad neuropsychiatric phenotypes that impact functioning and require assessment and treatment. Like in non-syndromal neuropsychiatric disorders, there is heterogeneity in symptom severity and illness course. The study of risk and resilience in the general population has benefited from measurement tools that parse heterogeneity and guide treatment. Suitability of such tools in neurogenetic disorders has not been examined and is essential to establish as prerequisite for examining whether similar processes modulate psychopathology in these populations.
METHOD
We applied the Risk & Resilience Battery assessing intrapersonal, interpersonal, and environmental domains, to 80 patients with 22q11.2DS, 30 from Philadelphia, USA and 50 from Tel-Aviv, Israel. We also evaluated global functioning and obtained self-reports of anxiety and depression. We examined the Risk & Resilience Battery reliability for each factor and used partial correlations to examine relations between the Risk & Resilience Battery factors and clinical measures.
RESULTS
Across samples, items within each risk and resilience factor showed good to excellent internal consistency. Higher scores on peer victimization, emotion dysregulation, and hostile close relationships were related to reports of anxiety and depression. Higher levels of self-reliance related to lower anxiety while greater security in close relationships related to lower depression.
CONCLUSION
The Risk & Resilience Battery can be applied to 22q11.2DS samples and advance Gene X Environment research and interventions.
Topics: Arachnodactyly; DiGeorge Syndrome; Humans; Israel; Marfan Syndrome; Reproducibility of Results
PubMed: 33894539
DOI: 10.1016/j.jpsychires.2021.03.058 -
Circulation. Cardiovascular Genetics Oct 2017
Topics: Arachnodactyly; DiGeorge Syndrome; Genome-Wide Association Study; Humans; Marfan Syndrome; Receptors, G-Protein-Coupled; Tetralogy of Fallot
PubMed: 29025762
DOI: 10.1161/CIRCGENETICS.117.001891