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Human Mutation Jul 2022Different pathogenic variants in the fibrillin-1 gene (FBN1) cause Marfan syndrome and acromelic dysplasias. Whereas the musculoskeletal features of Marfan syndrome... (Review)
Review
Different pathogenic variants in the fibrillin-1 gene (FBN1) cause Marfan syndrome and acromelic dysplasias. Whereas the musculoskeletal features of Marfan syndrome involve tall stature, arachnodactyly, joint hypermobility, and muscle hypoplasia, acromelic dysplasia patients present with short stature, brachydactyly, stiff joints, and hypermuscularity. Similarly, pathogenic variants in the fibrillin-2 gene (FBN2) cause either a Marfanoid congenital contractural arachnodactyly or a FBN2-related acromelic dysplasia that most prominently presents with brachydactyly. The phenotypic and molecular resemblances between both the FBN1 and FBN2-related disorders suggest that reciprocal pathomechanistic lessons can be learned. In this review, we provide an updated overview and comparison of the phenotypic and mutational spectra of both the "tall" and "short" fibrillinopathies. The future parallel functional study of both FBN1/2-related disorders will reveal new insights into how pathogenic fibrillin variants differently affect the fibrillin microfibril network and/or growth factor homeostasis in clinically opposite syndromes. This knowledge may eventually be translated into new therapeutic approaches by targeting or modulating the fibrillin microfibril network and/or the signaling pathways under its control.
Topics: Brachydactyly; Fibrillin-1; Fibrillin-2; Humans; Marfan Syndrome; Musculoskeletal Abnormalities; Phenotype
PubMed: 35419902
DOI: 10.1002/humu.24383 -
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 -
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 -
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 -
Brain and Behavior Aug 2021Intelligence quotient (IQ) testing is standard for evaluating cognitive abilities in genomic studies but requires professional expertise in administration and...
Intelligence quotient (IQ) testing is standard for evaluating cognitive abilities in genomic studies but requires professional expertise in administration and interpretation, and IQ scores do not translate into insights on implicated brain systems that can link genes to behavior. Individuals with 22q11.2 deletion syndrome (22q11.2DS) often undergo IQ testing to address special needs, but access to testing in resource-limited settings is challenging. The brief Penn Computerized Neurocognitive Battery (CNB) provides measures of cognitive abilities related to brain systems and can screen for cognitive dysfunction. To examine the relation between CNB measures and IQ, we evaluated participants with the 22q11.2DS from Philadelphia and Tel Aviv (N = 117; 52 females; mean age 18.8) who performed both an IQ test and the CNB with a maximum of 5 years between administrations and a subsample (n = 24) who had both IQ and CNB assessments at two time points. We estimated domain-level CNB scores using exploratory factor analysis (including bifactor for overall scores) and related those scores (intraclass correlations (ICCs)) to the IQ scores. We found that the overall CNB accuracy score showed similar correlations between time 1 and time 2 as IQ (0.775 for IQ and 0.721 for CNB accuracy), correlated well with the IQ scores (ICC = 0.565 and 0.593 for time 1 and time 2, respectively), and correlated similarly with adaptive functioning (0.165 and 0.172 for IQ and CNB, respectively). We provide a crosswalk (from linear equating) between standardized CNB and IQ scores. Results suggest that one can substitute the CNB for IQ testing in future genetic studies that aim to probe specific domains of brain-behavior relations beyond IQ.
Topics: Adolescent; Arachnodactyly; DiGeorge Syndrome; Female; Humans; Intelligence; Intelligence Tests; Marfan Syndrome
PubMed: 34213087
DOI: 10.1002/brb3.2221 -
Genetics in Medicine : Official Journal... Jan 2020Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder manifesting joint contractures, arachnodactyly, crumpled ears, and...
PURPOSE
Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder manifesting joint contractures, arachnodactyly, crumpled ears, and kyphoscoliosis as main features. Due to its rarity, rather aspecific clinical presentation, and overlap with other conditions including Marfan syndrome, the diagnosis is challenging, but important for prognosis and clinical management. CCA is caused by pathogenic variants in FBN2, encoding fibrillin-2, but locus heterogeneity has been suggested. We designed a clinical scoring system and diagnostic criteria to support the diagnostic process and guide molecular genetic testing.
METHODS
In this retrospective study, we assessed 167 probands referred for FBN2 analysis and classified them into a FBN2-positive (n = 44) and FBN2-negative group (n = 123) following molecular analysis. We developed a 20-point weighted clinical scoring system based on the prevalence of ten main clinical characteristics of CCA in both groups.
RESULTS
The total score was significantly different between the groups (P < 0.001) and was indicative for classifying patients into unlikely CCA (total score <7) and likely CCA (total score ≥7) groups.
CONCLUSIONS
Our clinical score is helpful for clinical guidance for patients suspected to have CCA, and provides a quantitative tool for phenotyping in research settings.
Topics: Arachnodactyly; Child; Contracture; Diagnosis, Differential; Early Diagnosis; Female; Fibrillin-2; Genetic Testing; Humans; Male; Marfan Syndrome; Phenotype; Retrospective Studies; Sensitivity and Specificity; Sequence Analysis, DNA
PubMed: 31316167
DOI: 10.1038/s41436-019-0609-8 -
Diagnostics (Basel, Switzerland) Sep 2022A long list of syndromic entities can be diagnosed immediately through scrutinizing the clinical phenotype of the craniofacial features. The latter should be assisted...
A long list of syndromic entities can be diagnosed immediately through scrutinizing the clinical phenotype of the craniofacial features. The latter should be assisted via proper radiological interpretations. Different children aged from 1 month to 12 years were referred to our departments seeking orthopedic advice. Primarily, all received variable false diagnoses in other institutes. Two unrelated boys of one month and 12 months were falsely diagnosed as having positional plagiocephaly associated with contractures of idiopathic origin. Two unrelated boys of 14 months and 2 years were diagnosed with pseudo-hydrocephalus and non-specific syndrome, and were referred to explore their skeletal development. Two unrelated girls of 4 years old and 12 years old presented with multiple contractures were referred because of progressive scoliosis. A 4-year-old girl was referred with a false provisional diagnosis of facial diplegia. All children underwent detailed clinical, radiological and tomographic phenotypic characterizations and genetic testing, respectively. Idaho syndrome (craniosynostosis associated with multiple dislocations) was the final diagnosis in the two unrelated boys with plagiocephaly and multiple contractures. Two children falsely diagnosed with pseudo-hydrocephalus and non-specific syndrome, were diagnosed with Silver-Russell syndrome (RSS). Contractural arachnodactyly Beals (CAB) was confirmed as the definitive diagnosis in the two unrelated girls with progressive scoliosis and multiple contractures. Parry-Romberg syndrome (PRS) associated with congenital lumbar kyphosis was the final diagnosis of the girl with the diagnosis of facial diplegia. Hypomethylation of ICR1 was confirmed in the RSS patients. Whole exome sequencing (WES) revealed a heterozygous mutation in the PRS patients. WES and array-CGH showed that no relevant variants or copy number variations (CNV) were identified in the CAB patients. On the one hand, newborn children can manifest diverse forms of abnormal craniofacial features, which are usually associated with either major or minor dysmorphic stigmata. A cleft lip/ palate is a major craniofacial malformation, and frontal bossing or a disproportionate craniofacial contour can be falsely considered as a transient plagiocephaly, which is spontaneously resolved by time. On the other hand, many physicians fall into the problem of deeming a countless number of diseases, such as contractures, as an idiopathic or non-specific syndrome. The latter stems from limited clinical experience. Therefore, failing to establish between the onset of the deformity and other inexplicit abnormal features that the patient or their immediate families or relatives carry is the final outcome. In this study, we used, for the first time, a reconstruction CT scan to further delineate the congenital disruption of the craniofacial anatomy and the other skeletal malformation complex.
PubMed: 36292064
DOI: 10.3390/diagnostics12102375 -
Genetics in Medicine : Official Journal... Feb 2022Loeys-Dietz syndrome (LDS) is a connective tissue disorder affecting multiple organ systems, including bone.
PURPOSE
Loeys-Dietz syndrome (LDS) is a connective tissue disorder affecting multiple organ systems, including bone.
METHODS
We defined the bone phenotype and clinical predictors of low bone density and fracture risk in 77 patients with LDS type 1 to type 5.
RESULTS
Patients with LDS had dual-energy x-ray absorptiometry (DXA) Z-scores significantly < 0, and 50% of children and 9% of adults had Z-scores < -2. Sixty percent of patients had ≥1 fracture, and 24% of patients with spinal x-rays scans showed spinal compression fractures. Lower body mass index, asthma, male sex and eosinophilic gastrointestinal disease were correlated with lower DXA Z-scores. The count of 5 LDS-associated skeletal features (scoliosis, pes planus, arachnodactyly, spondylolisthesis, and camptodactyly) in patients with LDS was correlated with DXA Z-score. Adults with ≥1 skeletal features had DXA Z-scores significantly < 0, and children with >2 features had DXA Z-score significantly < -2. Bone turnover markers suggest accelerated bone resorption. Data from 5 patients treated with bisphosphonates suggest a beneficial effect.
CONCLUSION
All LDS types are associated with reduced bone density and increased risk of fracture, which may be due to increased bone resorption. Clinical features can predict a subgroup of patients at highest risk of low bone density and fracture risk.
Topics: Absorptiometry, Photon; Bone Density; Bone Diseases, Metabolic; Fractures, Bone; Humans; Loeys-Dietz Syndrome; Male
PubMed: 34906513
DOI: 10.1016/j.gim.2021.10.002 -
Human Genetics Nov 2023CYP26B1 metabolizes retinoic acid in the developing embryo to regulate its levels. A limited number of individuals with pathogenic variants in CYP26B1 have been...
CYP26B1 metabolizes retinoic acid in the developing embryo to regulate its levels. A limited number of individuals with pathogenic variants in CYP26B1 have been documented with a varied phenotypic spectrum, spanning from a severe manifestation involving skull anomalies, craniosynostosis, encephalocele, radio-humeral fusion, oligodactyly, and a narrow thorax, to a milder presentation characterized by craniosynostosis, restricted radio-humeral joint mobility, hearing loss, and intellectual disability. Here, we report two families with CYP26B1-related phenotypes and describe the data obtained from functional studies of the variants. Exome and Sanger sequencing were used for variant identification in family 1 and family 2, respectively. Family 1 reflects a mild phenotype, which includes craniofacial dysmorphism with brachycephaly (without craniosynostosis), arachnodactyly, reduced radioulnar joint movement, conductive hearing loss, learning disability-and compound heterozygous CYP26B1 variants: (p.[(Pro118Leu)];[(Arg234Gln)]) were found. In family 2, a stillborn fetus presented a lethal phenotype with spina bifida occulta, hydrocephalus, poor skeletal mineralization, synostosis, limb defects, and a synonymous homozygous variant in CYP26B1: c.1083C > A. A minigene assay revealed that the synonymous variant created a new splice site, removing part of exon 5 (p.Val361_Asp382del). Enzymatic activity was assessed using a luciferase assay, demonstrating a notable reduction in exogenous retinoic acid metabolism for the variant p.Val361_Asp382del. (~ 3.5 × decrease compared to wild-type); comparatively, the variants p.(Pro118Leu) and p.(Arg234Gln) demonstrated a partial loss of metabolism (1.7× and 2.3× reduction, respectively). A proximity-dependent biotin identification assay reaffirmed previously reported ER-resident protein interactions. Additional work into these interactions is critical to determine if CYP26B1 is involved with other biological events on the ER. Immunofluorescence assay suggests that mutant CYP26B1 is still localized in the endoplasmic reticulum. These results indicate that novel pathogenic variants in CYP26B1 result in varying levels of enzymatic activity that impact retinoic acid metabolism and relate to the distinct phenotypes observed.
Topics: Humans; Retinoic Acid 4-Hydroxylase; Tretinoin; Homozygote; Exons; Craniosynostoses
PubMed: 37755482
DOI: 10.1007/s00439-023-02598-2