The Prevalence of the Chimeric TNXA/TNXB Gene and Clinical Symptoms of Ehlers–Danlos Syndrome with 21-Hydroxylase Deficiency

2020 ◽  
Vol 105 (7) ◽  
pp. 2288-2299
Author(s):  
Yinjie Gao ◽  
Lin Lu ◽  
Bingqing Yu ◽  
Jiangfeng Mao ◽  
Xi Wang ◽  
...  
Keyword(s):  
Clinical Features ◽  
Clinical Symptoms ◽  
Gene Mutations ◽  
Hydroxylase Deficiency ◽  
Ehlers Danlos Syndrome ◽  
Chinese Cohort ◽  
21 Hydroxylase Deficiency ◽  
Danlos Syndrome ◽  
Dependent Probe ◽  
Generalized Hypermobility

Abstract Purpose Defects in both CYP21A2 and TNXB genes can cause congenital adrenal hyperplasia combined with hypermobility-type Ehlers–Danlos syndrome (EDS), which has recently been named CAH-X syndrome. The purpose of this study is to assess the prevalence of the chimeric TNXA/TNXB gene and clinical symptoms in a Chinese cohort with 21-hydroxylase deficiency (21-OHD). Methods A total of 424 patients with 21-OHD who were genetically diagnosed were recruited for this study. Multiplex ligation-dependent probe amplification and sequencing were used to identify the CAH-X genotype. Clinical features of joints, skin, and other systems were evaluated in 125 patients. Results Ninety-four of the 424 patients had a deletion on at least 1 allele of CYP21A2 and 59 of them harbored the heterozygotic TNXA/TNXB chimera. Frequencies of CAH-X CH-1, CH-2, and CH-3 were 8.2%, 3.1%, and 2.6%, respectively. The incidences of clinical features of EDS were 71.0% and 26.6% in patients with the chimeric TNXA/TNXB genes or without (P < .001). There were statistically significant differences in manifestations among articular (P < .001 in generalized hypermobility) and dermatologic features (P < .001 in hyperextensible skin, P = .015 in velvety skin and P = .033 in poor wound healing). The prevalence of generalized hypermobility was more common in CAH-X CH-2 or CH-3 than CH-1 patients (60% vs 20%, P = .028). Conclusions In summary, about 14% of patients with 21-OHD may have chimeric TNXA/TNXB gene mutations in our study and most of them showed EDS-related clinical symptoms. The correlation between CAH-X genotypes and clinical features in connective tissue, like joint or skin, needs to be further investigated.

scholarly journals Fibrillin-1 gene mutations in a Chinese cohort with congenital ectopia lentis: spectrum and genotype–phenotype analysis

2021 ◽  
pp. bjophthalmol-2021-319084
Author(s):  
Zexu Chen ◽  
Tianhui Chen ◽  
Min Zhang ◽  
Jiahui Chen ◽  
Michael Deng ◽  
...  
Keyword(s):  
Calcium Binding ◽  
Gene Mutations ◽  
Mutation Spectrum ◽  
Missense Mutations ◽  
Ectopia Lentis ◽  
Phenotype Analysis ◽  
Chinese Cohort ◽  
Fibrillin 1 ◽  
Epidermal Growth ◽  
Dependent Probe

AimsTo identify the mutation spectrum and genotype–phenotype correlations of fibrillin-1 (FBN1) mutations in a Chinese cohort with congenital ectopia lentis (EL).MethodsPatients clinically suspected of congenital zonulopathy were screened using panel-based next-generation sequencing followed by multiplex ligation-dependent probe amplification. All the probands were subjected to thorough ocular examinations. Molecular and clinical data were integrated in pursuit of genotype–phenotype correlation.ResultsA total of 131 probands of FBN1 mutations from unrelated families were recruited. Around 65% of the probands were children younger than 9 years old. Overall, 110 distinct FBN1 mutations were identified, including 39 novel ones. The most at-risk regions were exons 13, 2, 6, 15, 24 and 33 in descending order of mutation frequency. The most prevalent mutation was c.184C>T (seven, 5.34%) in the coding sequence and c.5788+5G>A (three, 2.29%) in introns. Missense mutations were the most frequent type (103, 78.63%); half of which were distributed in the N-terminal regions (53, 51.46%). The majority of missense mutations were detected in one of the calcium-binding epidermal growth factor-like domains (62, 60.19%), and 39 (62.90%) of them were substitutions of conserved cysteine residues. Microspherophakia (MSP) was found in 15 patients (11.45%). Mutations in the middle region (exons 22–42), especially exon 26, had higher risks of combined MSP (OR, 5.51 (95% CI 1.364 to 22.274), p=0.017).ConclusionsThis study extended the knowledge of the FBN1 mutation spectrum and provided novel insights into its clinical correlation regarding EL and MSP in the Chinese population.

scholarly journals POR polymorphisms are associated with 21 hydroxylase deficiency

2021 ◽  
Author(s):  
F. Pecori Giraldi ◽  
S. Einaudi ◽  
A. Sesta ◽  
F. Verna ◽  
M. Messina ◽  
...  
Keyword(s):  
Clinical Features ◽  
Modifier Genes ◽  
Age At Diagnosis ◽  
Adrenal Hyperplasia ◽  
Phenotype Correlation ◽  
Hydroxylase Deficiency ◽  
Salt Wasting ◽  
Control Subjects ◽  
Younger Age ◽  
21 Hydroxylase Deficiency

Abstract Purpose Genotype–phenotype correlation in congenital 21 hydroxylase deficiency is strong but by no means absolute. Indeed, clinical and hormonal features may vary among patients carrying similar CYP21A2 mutations, suggesting that modifier genes may contribute to the phenotype. Aim of the present study was to evaluate whether polymorphisms in the p450  oxidoreductase (POR) gene may affect clinical features in patients with 21 hydroxylase deficiency Methods Sequencing of the POR gene was performed in 96 patients with 21 hydroxylase deficiency (49 classic, 47 non-classic) and 43 control subjects. Results Prevalence of POR polymorphisms in patients with 21 hydroxylase was comparable to controls and known databases. The rs2228104 polymorphism was more frequently associated with non-classic vs classic 21 hydroxylase deficiency (allelic risk 7.09; 95% C.I. 1.4–29.5, p < 0.05). Classic 21 hydroxylase-deficient carriers of the minor allele in the rs2286822/rs2286823 haplotype presented more frequently the salt-wasting form (allelic risk 1.375; 95% C.I. 1.138–1.137), more severe Prader stage at birth (allelic risk 3.85; 95% C.I. 3.78–3.92), higher ACTH levels, and younger age at diagnosis. Conclusions Polymorphisms in the POR gene are associated with clinical features of 21 hydroxylase deficiency both as regards predisposition to classic vs non-classic forms and severity of classic adrenal hyperplasia.

THE CLASSIC TYPE OF EHLERS–DANLOS SYNDROME: DIFFERENTIAL DIAGNOSIS AND PECULIARITIES OF PATIENT MANAGEMENT

2021 ◽  
Vol 100 (5) ◽  
pp. 62-69
Author(s):  
А.N. Semyachkina ◽  
◽  
E.А. Nikolaeva ◽  
А.R. Zabrodina ◽  
L.P. Melikyan ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Adult Population ◽  
Gene Mutations ◽  
Hereditary Disease ◽  
Ehlers Danlos Syndrome ◽  
Severe Pathology ◽  
Type V ◽  
Danlos Syndrome

The Classic Ehlers–Danlos syndrome (cEDS) is an autosomal dominant hereditary disease caused by type V collagen defect. The incidence of pathology is estimated at 1:20,000 of the population. The results of a long-term (15 years) follow-up of a group of patients (n=18) with cEDS, including 5 boys and 13 girls aged from 3 to 18 years, are presented. The diagnosis was made based on the presence of 2 large and 5 small international diagnostic criteria in all patients. The progreduated character of the disease is shown, which is most obvious in the dynamics of the state of the musculoskeletal system. Genetic verification of the diagnosis was performed in 6 patients; 5 probands had mutations in the COL5A1 gene, and one in the COL5A2 gene. Mutations already registered in the database were detected only in 2 children. Previously unknown substitutions were found in 4 patients. The article presents the issues of differential diagnosis of this severe pathology and touches upon the issue of continuity between medical pediatric specialists and doctors of various specialties working with the adult population.

scholarly journals Genetic Analysis of Three Korean Patients with Clinical Features of Ehlers-Danlos Syndrome Type IV

2007 ◽  
Vol 22 (4) ◽  
pp. 698 ◽  
Author(s):  
Jeong Hoon Yang ◽  
Seung-Tae Lee ◽  
Jee-Ah Kim ◽  
Sung Hae Kim ◽  
Shin-Yi Jang ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Clinical Features ◽  
Syndrome Type ◽  
Ehlers Danlos Syndrome ◽  
Korean Patients ◽  
Type Iv ◽  
Danlos Syndrome

scholarly journals Geno-phenotypic characteristics of Ehlers–Danlos syndrome: difficulties of disease type identification and approaches to pathogenetic treatment

2021 ◽  
Vol 66 (1) ◽  
pp. 22-30
Author(s):  
E. A. Nikolaeva ◽  
A. N. Semyachkina
Keyword(s):  
Connective Tissue ◽  
Clinical Symptoms ◽  
Molecular Genetic ◽  
Symptomatic Treatment ◽  
Pathological Process ◽  
Social Adaptation ◽  
Molecular Defect ◽  
Ehlers Danlos Syndrome ◽  
Pathogenetic Therapy ◽  
Danlos Syndrome

Veltischev Researchand Clinical Institutefor Pediatricsofthe Pirogov Russian National Research Medical University, Moscow, Russia The article presents modern data on the most common monogenic connective tissue disease – Ehlers–Danlos syndrome. The authors describe two previous classifications of the syndrome: Berlin (1988) classification, which distinguishes 11 types of the disease, and Beyton (1998) classification, which includes 6 types of the syndrome and takes into account the results of molecular genetic studies. Particular attention is paid to a new classification, proposed by the International Consortium in 2017. This classification is based on the clinical and molecular genetic data and unites 13 types of Ehlers–Danlos syndrome, divided in 7 groups (A–G), depending on the main molecular defect. This defect determines the violation of various collagen structures (primary, spatial, cross-linking) and others constituents of the connective tissue (myomatrix, glycosaminoglycans, complement component, etc.). The classification provides general clinical symptoms for all types of the disease and comprehensive information on the specific signs of each of the 13 types of the syndrome.The authors discuss approaches to the pathogenetic therapy of the syndrome, the possibilities of symptomatic treatment, including both medications of different spectrum of action, and physiotherapeutic measures, exercise therapy. The complex of the listed therapeutic measures is aimed at stabilizing the main pathological process, preventing complications, improving the patient’s quality of life and social adaptation. The authors emphasize that correct patient management, targeted medical supervision and medical genetic counseling requires molecular genetic verification of the diagnosis.

Screening of CYP21 gene mutations in 129 French patients affected by steroid 21-hydroxylase deficiency

1995 ◽  
Vol 5 (2) ◽  
pp. 126-130 ◽  
Author(s):  
Benoit Barbat ◽  
Any Bogyo ◽  
Marie-Charles Raux-Demay ◽  
Frédéarique Kuttenn ◽  
Joelle Boué ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Hydroxylase Deficiency ◽  
Cyp21 Gene ◽  
21 Hydroxylase Deficiency

scholarly journals Characterisation of three novel CYP11B1 mutations in classic and non-classic 11β-hydroxylase deficiency

2014 ◽  
Vol 170 (5) ◽  
pp. 697-706 ◽  
Author(s):  
Seher Polat ◽  
Alexandra Kulle ◽  
Züleyha Karaca ◽  
Ilker Akkurt ◽  
Selim Kurtoglu ◽  
...  
Keyword(s):  
Expression System ◽  
Three Dimensional ◽  
Gene Mutations ◽  
Dimensional Structure ◽  
Hydroxylase Deficiency ◽  
Mutant Proteins ◽  
Maximum Reaction ◽  
Functional Consequences ◽  
21 Hydroxylase Deficiency

BackgroundCongenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive inherited endocrine diseases. Steroid 11β-hydroxylase (P450c11) deficiency (11OHD) is the second most common form of CAH.AimThe aim of the study was to study the functional consequences of three novelCYP11B1gene mutations (p.His125Thrfs*8, p.Leu463_Leu464dup and p.Ser150Leu) detected in patients suffering from 11OHD and to correlate this data with the clinical phenotype.MethodsFunctional analyses were done by using a HEK293 cellin vitroexpression system comparing WT with mutant P450c11 activity. Mutant proteins were examinedin silicoto study their effect on the three-dimensional structure of the protein.ResultsTwo mutations (p.His125Thrfs*8 and p.Leu463_Leu464dup) detected in patients with classic 11OHD showed a complete loss of P450c11 activity. The mutation (p.Ser150Leu) detected in a patient with non-classic 11OHD showed partial functional impairment with 19% of WT activity.ConclusionFunctional mutation analysis enables the correlation of novelCYP11B1mutations to the classic and non-classic 11OHD phenotype respectively. Mutations causing a non-classic phenotype show typically partial impairment due to reduced maximum reaction velocity comparable with non-classic mutations in 21-hydroxylase deficiency. The increasing number of mutations associated with non-classic 11OHD illustrate that this disease should be considered as diagnosis in patients with otherwise unexplained hyperandrogenism.

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