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1.
Zhonghua Yi Xue Za Zhi ; 99(48): 3765-3769, 2019 Dec 24.
Artigo em Chinês | MEDLINE | ID: mdl-31874511

RESUMO

Objective: To analyze the copy number variation of CYP21A2 gene in 21-hydroxylase deficiency (21-OHD) patients, and identify the three copy repetition, single copy deletion of CYP21A2 gene and the type and proportion of CYP21A1P/CYP21A2 fused gene in 21-OHD patients. Methods: A total of 424 patients (140 males and 284 females) with 21-OHD who visited Peking Union Medical College Hospital from January 2015 to January 2018 were enrolled and the average age was (17.1±12.4) years. All clinical and biochemical data were collected. DNAs were extracted from peripheral blood leukocytes, and CYP21A2 gene mutation and copy number variation were detected by Sanger sequencing and multiple ligation probe amplification (MLPA). Results: Of 424 21-OHD patients, 287 (67.7%) had two copies of CYP21A2 gene, 137 (32.3%) had copy number variation, of which 1 patients (0.2%) had 3 copies of CYP21A2 gene and 136 (32.1%) were carriers of large deletion/rearrangement mutation of CYP21A2 gene. Three pathogenic mutations including a truncated Q319X protein mutation were detected in the patient with 3 copies of CYP21A2 gene. Of 136 patients with large deletion/rearrangement mutation of CYP21A2 gene, 82 (60.3%) carried fused CYP21A1P/CYP21A2 gene, and the remaining 54 harbored the one allele deletion of CYP21A2. The most common types of fused CYP21A1P/CYP21A2 gene were CH-5, CH-1 and CH-2, with the frequency being 31.7% (26 cases), 26.8% (22 cases) and 19.5% (16 cases), respectively, and followed by CH-4 and CH-7, with the incidence being 8.5% (7 cases) and 4.9% (4 cases), respectively. In addition, two cases of CH-3, CH-6 and CH-8 and one case of CH-9 were detected. Conclusions: This is the first study to detect the occurrence of CYP21A2 gene copy number variation and fused CYP21A1P/CYP21A2 gene in a large cohort of 21-OHD patients. The number of CYP21A2 gene copies in 21-OHD patients includes 2 copies, 1 copy deletion and 3 copies duplication. One copy deletion of CYP21A2 includes one allele deletion of CYP21A2 gene and fused CYP21A1P/CYP21A2 gene. In patients with 3 copies of CYP21A2 gene, pathogenic mutations should be verified in all 3 copies of CYP21A2 gene to make the precise diagnosis. Therefore, the accurate molecular diagnosis of 21-OHD patients should take both genotype and copy number variation of CYP21A2 into account.


Assuntos
Hiperplasia Suprarrenal Congênita/genética , Variações do Número de Cópias de DNA , Pseudogenes/genética , Esteroide 21-Hidroxilase/genética , Adolescente , Feminino , Genótipo , Humanos , Masculino , Mutação , Adulto Jovem
2.
Clin Biochem ; 73: 50-56, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31344365

RESUMO

OBJECTIVE: Congenital adrenal hyperplasia (CAH) is an inborn error of metabolism and a common disorder of sex development where >90% of all cases are due to 21-hydroxylase deficiency. Novel and rare pathogenic variants account for 5% of all clinical cases. Here, we sought to investigate the functional and structural effects of four novel (p.Val358Ile, p.Arg369Gln, p.Asp377Tyr, and p.Leu461Pro) and three combinations of CYP21A2 variants (i.e. one allele containing two variants p.[Ile172Asn;Val358Ile], p.[Val281Leu;Arg369Gln], or p.[Asp377Tyr;Leu461Pro]) identified in patients with CAH. METHODS: All variants were reconstructed by in vitro site-directed mutagenesis, the proteins were transiently expressed in COS-1 cells and enzyme activities directed toward the two natural substrates (17-hydroxyprogesterone and progesterone) were determined. In parallel, in silico prediction of the pathogenicity of the variants based on the human CYP21 X-ray structure was performed. RESULTS: The novel variants, p.Val358Ile, p.Arg369Gln, p.Asp377Tyr, and p.Leu461Pro exhibited residual enzymatic activities within the range of non-classic (NC) CAH variants (40-82%). An additive effect on the reduction of enzymatic activity (1-17%) was observed when two variants were expressed together, as identified in several patients, resulting in either NC or more severe phenotypes. In silico predictions were in line with the in vitro data except for p.Leu461Pro. CONCLUSIONS: Altogether, the combination of clinical data, in silico prediction, and data from in vitro studies are important for establishing a correct genotype and phenotype correlation in patients with CAH.


Assuntos
Hiperplasia Suprarrenal Congênita , Alelos , Modelos Moleculares , Mutação de Sentido Incorreto , Esteroide 21-Hidroxilase , Adolescente , Hiperplasia Suprarrenal Congênita/enzimologia , Hiperplasia Suprarrenal Congênita/genética , Adulto , Substituição de Aminoácidos , Animais , Células COS , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Domínios Proteicos , Esteroide 21-Hidroxilase/química , Esteroide 21-Hidroxilase/genética
3.
Zhonghua Nei Ke Za Zhi ; 58(6): 428-434, 2019 Jun 01.
Artigo em Chinês | MEDLINE | ID: mdl-31159521

RESUMO

Objective: To analyze the clinical features and genotypes of adult patients with simple virilizing form of 21-hydroxylase deficiency (SV 21-OHD). Methods: This is a retrospective study including 33 patients with SV 21-OHD from January 2015 to March 2018 in the Ninth People's Hospital of Shanghai Jiao Tong University School of Medicine. Results: The diagnostic age of the patients was (26.3±6.5) years old. All patients presented with signs of masculinization, such as short stature (100%), clitoromegaly/microphallus (89.65%, 26/29), undeveloped breasts (82.76%, 24/29), deep voice (55.17%,16/29) and primary amenorrhea (89.65%, 26/29). The serum levels of 17-hydroxyprogesterone (17-OHP), androstenedione (AD) and testosterone were significantly elevated in 90.9%, 93.9% and 91.2% of the patients, respectively. Thirteen types of mutations were identified in CYP21A2 from these patients. Among them, I173N accounted for 40% and I2 G accounted for 18.33%. Four patients were found with multiple mutations in CYP21A2. Conclusions: Short stature, clitoromegaly/microphallus and primary amenorrhea are the most common clinical features in adult patients with SV 21-OHD. Serum levels of 17-OHP and AD are important indices for the diagnosis and monitoring of the patients. I173N and I2 G are the two most prevalent mutations in patients of the present study. Limitation of clinical recognition and delay in treatment contribute to the short stature of the SV 21-OHD patients.


Assuntos
Hiperplasia Suprarrenal Congênita/sangue , Hiperplasia Suprarrenal Congênita/diagnóstico , Esteroide 21-Hidroxilase/genética , 17-alfa-Hidroxiprogesterona/sangue , Adulto , Androstenodiona/sangue , China , Feminino , Humanos , Masculino , Estudos Retrospectivos , Testosterona/sangue
4.
J Pediatr Endocrinol Metab ; 32(5): 543-547, 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31026224

RESUMO

Background Steroid 21-hydroxylase deficiency is an autosomal recessive disorder, present in 90-95% of all cases with congenital adrenal hyperplasia (CAH). The classical simple virilizing (SV) form of the disease causes virilization of the external genitalia in newborn females and pseudo-precocious puberty in both sexes, due to reactive androgen overproduction. Case presentation We describe a 3.5-year-old girl presenting with pubarche, P2 according to Tanner, advanced bone age of 6 years and 10 months, and high serum levels of 17-hydroxyprogesterone (17-OHP). Molecular analysis of the nine most common pseudogene-derived CYP21A2 point mutations was performed in the patient and her family members using the polymerase chain reaction/amplification-created restriction site (PCR/ACRS) method. We detected the P30L/I172N genotype in the patient. She had inherited a mild P30L mutation from her mother and a severe I172N mutation from her father. Conclusions Although the CAH phenotype is determined by the allele that produces most of the enzyme activity and the mild non-classical (NC) phenotype should be expected, the mild P30L known to be more virilizing probably induced the classical SV phenotype in our patient. A continuous regimen of hydrocortisone at a recommended dose failed to decrease the 17-OHP sufficiently. Careful tapering of the dose did not help, and her pubic hair advanced to P3 according to Tanner. Individually tailored treatment is warranted in this patient.


Assuntos
Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Anti-Inflamatórios/administração & dosagem , Hidrocortisona/administração & dosagem , Mutação , Esteroide 21-Hidroxilase/genética , Virilismo/tratamento farmacológico , Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/patologia , Adulto , Criança , Feminino , Genótipo , Humanos , Masculino , Linhagem , Fenótipo , Falha de Tratamento , Virilismo/complicações , Virilismo/patologia
5.
J Pediatr Endocrinol Metab ; 32(5): 499-504, 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31028712

RESUMO

Background Early diagnosis after newborn screening (NBS) for congenital adrenal hyperplasia (CAH) allows proper treatment, reducing mortality rates and preventing development of hyperandrogenic manifestations and incorrect sex assignment at birth. Despite the high NBS sensitivity to detect CAH classical forms, one of the main issues is identifying asymptomatic children who remained with increased 17-hydroxyprogesterone (17-OHP) levels. In this study, we aimed to contribute to understanding the diagnosis of these children. Methods Children with increased serum 17-OHP levels, and without disease-related clinical features during follow-up, underwent the entire CYP21A2 gene sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis (SALSA MLPA P050B CAH). Patients' genotypes were subsequently sorted as compatible with CAH disease, and children were evaluated to determine the clinical status. Results During the study period, 106,476 newborns underwent CAH NBS. During follow-up, 328 children (0.3%) were identified as having false-positive tests and 295 were discharged after presenting with 17-OHP levels within reference values. Thirty-three remained asymptomatic and with increased serum 17-OHP levels after a mean follow-up of 3.4 years, and were subjected to molecular analysis. Seventeen out of the 33 children carried mutations: seven in the heterozygous state, nine carried non-classical genotypes and the remaining child carried a classical genotype. Conclusions We found a high frequency of non-classical CAH (NCCAH) diagnosis among children with persistent elevation of 17-OHP levels. Our findings support molecular study as decisive for elucidating diagnosis in these asymptomatic children. Molecular analysis as a confirmatory test is relevant to guide their follow-up, allows genetic counseling and avoids over treating NCCAH form.


Assuntos
17-alfa-Hidroxiprogesterona/sangue , Hiperplasia Suprarrenal Congênita/sangue , Hiperplasia Suprarrenal Congênita/diagnóstico , Biomarcadores/sangue , Mutação , Triagem Neonatal/métodos , Esteroide 21-Hidroxilase/genética , Hiperplasia Suprarrenal Congênita/genética , Estudos Transversais , Diagnóstico Precoce , Feminino , Seguimentos , Genótipo , Humanos , Recém-Nascido , Masculino , Prognóstico
6.
Zhonghua Yi Xue Za Zhi ; 99(12): 912-917, 2019 Mar 26.
Artigo em Chinês | MEDLINE | ID: mdl-30917440

RESUMO

Objective: To explore the relationship between homozygous or heterozygous large deletion of CYP21A2 gene and clinical manifestation in 21-hydroxylase deficiency (21-OHD) patients. Methods: The records of 100 patients with 21-OHD were collected between June 2016 and December 2017 in Peking Union Medical College Hospital. Large deletion of CYP21A2 gene was detected by multiplex ligation probe amplification (MLPA). The biochemical results and clinical symptoms of patients with homozygous or heterozygous large deletion were analyzed in order to investigate the influence of complete or single allele deletion of CYP21A2 gene on 21-OHD patients. Results: Large deletion of CYP21A2 gene was detected in 33 patients by MLPA, including 13 males and 20 females, with an median age of 10 (6,16) years. Two of them had simultaneous deletions of two alleles. Among 31 patients with heterozygous deletion, 16 were combined with gene mutations that severely affected 21-hydroxylase enzyme activity (I2G and Q318X), 15 with mutations that retained part enzyme activity (I172N and P30L). Two patients with complete deletion of CYP21A2 gene had no significant difference in biochemical and clinical manifestations compared with those with single allele deletion combined with another gene mutation that severely affected enzyme activity. Both kinds of patients above were manifested as severe salt-wasting type. Patients with a single allele deletion and a mutation retaining part enzyme activity were manifested as mild simple-viralizing type. Conclusion: Large deletion of CYP21A2 gene could appear in 21-OHD patients and the phenotype is similar to that of salt-wasting patients with heterozygous large deletion.


Assuntos
Esteroide 21-Hidroxilase/genética , Adolescente , Hiperplasia Suprarrenal Congênita , Criança , Feminino , Deleção de Genes , Genótipo , Heterozigoto , Homozigoto , Humanos , Masculino , Mutação , Fenótipo
7.
Horm Res Paediatr ; 91(1): 33-45, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30889569

RESUMO

BACKGROUND: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is an autosomal recessive disorder characterized by 3 overlapping phenotypes: salt-wasting (SW), simple virilizing (SV), and non-classic (NC). We aimed at conducting a nationwide genotype description of the CAH pediatric patients and to establish their genotype-phenotype correlation. METHODS: CAH patients were recruited from Portuguese pediatric endocrinology centers and classified as SW, SV, or NC. Genetic analysis was performed by polymerase chain reaction (sequence specific primer, restriction fragment length polymorphism) or direct Sanger sequencing. Genotypes were categorized into 4 groups (0, A, B, and C), according to their predicted enzymatic activity. In each group, the expected phenotype was compared to the observed phenotype to assess the genotype-phenotype correlation. RESULTS: Our cohort comprises 212 unrelated pediatric CAH patients (29% SW, 11% SV, 60% NC). The most common pathogenic variant was p.(Val282Leu; 41.3% of the 424 alleles analyzed). The p.(Val282Leu) variant, together with c.293-13A/C>G, p.(Ile173Asn), p.(Leu308Thr), p.(Gln319*), and large deletions/conversions were responsible for 86.4% of the mutated alleles. Patients' stratification by disease subtype revealed that the most frequent pathogenic variants were c.293-13A/C>G in SW (31.1%), p.(Ile173Asn) in SV (46.9%), and p.(Val282Leu) in NC (69.5%). The most common genotype was homozygosity for p.(Val282Leu; 33.0%). Moreover, we found 2 novel variants: p.(Ile161Thr) and p.(Trp202Arg), in exons 4 and 5, respectively. The global genotype-phenotype correlation was 92.4%. Group B (associated with the SV form) showed the lowest genotype-phenotype correlation (80%). CONCLUSION: Our cohort has one of the largest NC CAH pediatric populations described. We emphasize the high frequency of the p.(Val282Leu) variant and the very high genotype-phenotype correlation observed.


Assuntos
Hiperplasia Suprarrenal Congênita/genética , Alelos , Bases de Dados Factuais , Genótipo , Mutação , Fenótipo , Esteroide 21-Hidroxilase/genética , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Portugal
8.
Mol Genet Genomic Med ; 7(5): e623, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30816000

RESUMO

BACKGROUND: Congenital adrenal hyperplasia (CAH) (OMIM #201910) is a complex disease most often caused by pathogenic variant of the CYP21A2 gene. We have designed an efficient multistep approach to diagnose and classify CAH cases due to CYP21A2 variant and to study the genotype-phenotype relationship. METHODS: A large cohort of 212 Vietnamese patients from 204 families was recruited. We utilized Multiplex Ligation-dependent Probe Amplification to identify large deletion or rearrangement followed by complete gene sequencing of CYP21A2 to map single-nucleotide changes and possible novel variants. RESULTS: Pathogenic variants were identified in 398 out of 408 alleles (97.5%). The variants indexed span across most of the CYP21A2 gene regions. The most common genotypes were: I2g/I2g (15.35%); Del/Del (14.4%); Del/I2g (10.89%); p.R356W/p.R356W (6.44%); and exon 1-3 del/exon 1-3 del (5.44%). In addition to the previously characterized and documented variants, we also discovered six novel variants which were not previously reported, in silico tools were used to support the pathogenicity of these variants. CONCLUSION: The result will contribute in further understanding the genotype-phenotype relationship of CAH patients and to guide better treatment and management of the affected.


Assuntos
Hiperplasia Suprarrenal Congênita/genética , Polimorfismo de Nucleotídeo Único , Esteroide 21-Hidroxilase/genética , Frequência do Gene , Genótipo , Humanos , Fenótipo , Vietnã
10.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(2): 120-123, 2019 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-30703227

RESUMO

OBJECTIVE: To explore the genotype-phenotype correlation among 18 patients with 21-hydroxylase deficiency (21-OHD). METHODS: PCR-Sanger sequencing was used to analyze the 10 exons and flanking regions of the CYP21A2 gene among the 18 patients and 20 healthy controls. RESULTS: Seventeen patients had variants of the CYP21A2 gene. Eight patients (44.4%, 8/18) carried homozygous variants including p.Ile 173Asn (62.5%, 5/8), p.Pro31Leu (25.0%, 2/8), and IVS2-13A/C>G (12.5%, 1/8), respectively. Six patients (33.3%, 6/18) carried compound heterozygous variant, among which IVS2-13 A>G+p.Ile 173Asn were most common (50.0%). 94.4% (34/36) of the variant were pathogenic, with the most common variants being p.Ile173Asn (41.7%), IVS2-13A/C>G (19.4%), and p.Ile173Asn (7.5%). No variant was identified among the 20 healthy controls. CONCLUSION: The majority of 21-OHD patients carried CYP21A2 gene variants in homozygous or compound heterozygous forms, among which the p.Ile173Asn was the most common one. There is a strong correlation between the genotypes and clinical phenotypes.


Assuntos
Hiperplasia Suprarrenal Congênita/genética , Esteroide 21-Hidroxilase/genética , Genótipo , Humanos , Mutação , Fenótipo
11.
Fertil Steril ; 111(1): 13-20, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30611403

RESUMO

Nonclassical congenital adrenal hyperplasia (NC-CAH) is by far a subtler and milder enzymatic defect to the classical form of the disease. A nuanced understanding of NC-CAH will lead to increased detection of the disorder in those initially misdiagnosed as having polycystic ovary syndrome, will assist in the detection of pregnancies at risk for severe genetic steroid disorders, and will facilitate appropriate ovulation induction and reduction in the hyperandrogenic symptoms which are a cornerstone of the disease. We describe the history of the disease as well as elucidate the pathophysiology, diagnosis, and treatment of the disorder.


Assuntos
Hiperplasia Suprarrenal Congênita/enzimologia , Hiperplasia Suprarrenal Congênita/genética , Fertilidade/fisiologia , Hiperplasia Suprarrenal Congênita/terapia , Feminino , Humanos , Masculino , Esteroide 21-Hidroxilase/genética , Esteroide 21-Hidroxilase/metabolismo
12.
Fertil Steril ; 111(1): 24-29, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30611409

RESUMO

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is caused by mutations in the CYP21A2 gene, located on the short arm of chromosome 6. The two main underlying mechanisms of CYP21A2 defects are large gene deletion and conversion. Anticipation of the phenotypes associated with different combinations of CYP21A2 mutations remains the most important determinant in prenatal diagnosis and counseling of the expectant couple who are determined to be at risk for congenital adrenal hyperplasia.


Assuntos
Hiperplasia Suprarrenal Congênita/genética , Genótipo , Fenótipo , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/enzimologia , Feminino , Deleção de Genes , Humanos , Mutação/genética , Gravidez , Esteroide 21-Hidroxilase/genética , Esteroide 21-Hidroxilase/metabolismo
13.
Fertil Steril ; 111(1): 7-12, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30611420

RESUMO

Women with classic congenital adrenal hyperplasia (CAH) can suffer from impaired fertility rates as a result of increased androgen secretion or impaired sex steroid production. In virilizing CAH forms, such as 21-hydroxylase and 11ß-hydroxylase deficiency, the low reported pregnancy rate is mainly secondary to a diminished desire to conceive. Optimal glucocorticoid and/or mineralocorticoid replacement, sufficient to normalize androgen and P levels in the follicular phase, allows natural conception in most cases. The remaining CAH forms exemplified by StAR, P450scc, P450-oxidoreductase, and 17α-hydroxylase/17-20 lyase deficiencies are associated with impaired sex steroid production. Several factors are involved in the true low fertility rate in this group: folliculogenesis arrest, uterine hypoplasia, and inadequate endometrial thickness related to aberrant androgen, estrogen, and P secretion. There are several reports of successful term pregnancies achieved through controlled ovarian hyperstimulation, followed by estrogen replacement and IVF. Progress in female genitalia reconstructive surgery, individualized hormonal therapies, psychosexual evaluation, and assisted reproductive technology have improved fertility and pregnancy outcomes in women with classic CAH. Finally, successful gestational management in CAH patients requires the close coordination of care between endocrinologists and obstetricians.


Assuntos
Hiperplasia Suprarrenal Congênita/enzimologia , Hiperplasia Suprarrenal Congênita/genética , Fertilidade/fisiologia , Reprodução/fisiologia , Hiperplasia Suprarrenal Congênita/diagnóstico , Coeficiente de Natalidade/tendências , Feminino , Humanos , Masculino , Gravidez , Taxa de Gravidez/tendências , Esteroide 17-alfa-Hidroxilase/genética , Esteroide 17-alfa-Hidroxilase/metabolismo , Esteroide 21-Hidroxilase/genética , Esteroide 21-Hidroxilase/metabolismo
14.
Gene ; 687: 30-34, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30419250

RESUMO

The CYP21A2 gene encoding 21­hydroxylase is on chromosome 6p21.3 within the human leukocyte antigen (HLA) class III major histocompatibility complex and an association between congenital adrenal hyperplasia (CAH) due to 21­hydroxylase deficiency and HLA class I and II alleles has been shown in genetically isolated populations. One-third of CAH causing alleles are 30-kb deletions due to homologous recombination events between active and pseudogenes resulting in chimeric genes. The aim of this study was to re-visit the association between the CYP21A2 variants and HLA polymorphisms in a large ethnically diverse cohort of patients with CAH who underwent comprehensive CYP21A2 genotyping, including specification of chimeric gene subtypes (CAH CH-1 through CH-9 of CYP21A1P/CYP21A2 chimeras; CAH-X CH-1 through CH-3 of TNXA/TNXB chimeras) in alleles with 30-kb deletions. The study population included 201 patients (86 males, 115 females, age 3-75 years) with CAH due to 21­hydroxylase deficiency (159 classic, 42 nonclassic) and 194 parents. Based on the availability of parental genotype, we determined the haplotypes of CYP21A2 mutations and HLA types in 95 probands (190 alleles). Five prevalent haplotype associations were found: p.V281L and B*14-C*08 (P < 0.0001); p.I172N and DQB1*03 (P = 0.035); and of the chimeric genes caused by 30-kb deletions: CH-1 and A*03 (P = 0.033); CH-5 and C*06-DRB1*07 (P < 0.0001); and CAH-X CH-1 and DQB1*03 (P = 0.004). Our findings show that a number of associations between HLA alleles and haplotypes and CYP21A2 mutations, including large 30-kb deletions, exist commonly across ethnicities. These HLA associations may have clinical implications for patients with CAH and may provide insight into the genetics of this highly complex region of the human genome.


Assuntos
Hiperplasia Suprarrenal Congênita/genética , Biomarcadores/metabolismo , Antígenos HLA/genética , Haplótipos , Mutação , Esteroide 21-Hidroxilase/genética , Adolescente , Hiperplasia Suprarrenal Congênita/patologia , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
15.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 35(6): 832-835, 2018 Dec 10.
Artigo em Chinês | MEDLINE | ID: mdl-30512157

RESUMO

OBJECTIVE: To identify pathogenic mutations in 25 Chinese pedigrees affected with congenital adrenal hyperplasia (CAH). METHODS: Mutations of the CYP21A2 gene were detected with locus-specific PCR/restriction endonuclease analysis, multiplex ligation-dependent probe amplification assay, and direct sequencing of the entire CYP21A2 gene. Prenatal diagnosis was offered to fetuses at risk for CAH. RESULTS: All 50 alleles of the CYP21A2 gene carried by the 25 pedigrees were successfully delineated. Large deletions and conversions have accounted for 16 (32%) of the alleles, which included 9 entire CYP21A2 gene deletions, 6 chimeric CYP21A1P/CYP21A2 genes, and 1 partial conversion of the CYP21A2 gene. For the remaining 34 alleles, there were 9 micro-conversions and 4 de novo mutations [including a previously unreported c.62G>A (p.Trp21X) mutation]. Prenatal diagnosis was provided for 28 fetuses with a high risk for CAH, among whom 8 were found to be affected. CONCLUSION: The detection of CYP21A2 gene mutations can facilitate appropriate genetic counseling and prenatal diagnosis for the affected pedigrees.


Assuntos
Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/genética , Diagnóstico Pré-Natal , Esteroide 21-Hidroxilase/genética , Grupo com Ancestrais do Continente Asiático , China , Feminino , Humanos , Mutação , Linhagem , Gravidez
16.
Hum Genet ; 137(11-12): 955-960, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30465166

RESUMO

CYP21A2 defects result in congenital adrenal hyperplasia (CAH), an autosomal recessive disorder characterized by impaired adrenal steroidogenesis. CYP21A2 lies within the major histocompatibility complex in an area of the genome highly susceptible to genetic variation. Alterations in the neighboring complement component 4 isotypes C4A and C4B have been associated with psychiatric and autoimmune disease. The purpose of this study was to evaluate C4A and C4B in patients with CAH in relation to CYP21A2 genotype and psychiatric and autoimmune comorbidity. We determined the copy numbers of C4A and C4B in 145 patients with CAH (median age: 15.5 years, IQR: 16.8) and 108 carrier relatives (median age: 41.5 years, IQR: 12.0) and evaluated serum C4 concentrations. Comorbidity was determined by medical record review. Only 30% of subjects had the expected two copies each of the two C4 genes. C4B copy number determined total C4 copy number and serum C4 concentration, negatively correlated with carriership of a 30-kb deletion (P < 10- 5), and positively correlated with carriership of p.V281L (P < 10- 5). High C4A copy number (≥ 3) was associated with increased risk of having an externalizing psychiatric condition (relative risk: 2.67, 95% CI: 1.03-6.89, P = 0.04). No association was found between C4 copy number and autoimmune disease. Mutation-specific C4 structural variations commonly occur in patients with CAH and may have important clinical consequences, including increased risk of psychiatric morbidity. Trial registration NCT00250159 (November 7, 2005).


Assuntos
Hiperplasia Suprarrenal Congênita/genética , Complemento C4/genética , Esteroide 21-Hidroxilase/genética , Adolescente , Hiperplasia Suprarrenal Congênita/patologia , Adulto , Variações do Número de Cópias de DNA/genética , Feminino , Genótipo , Haplótipos , Humanos , Masculino , Mutação , Psicopatologia , Adulto Jovem
17.
Medicine (Baltimore) ; 97(33): e11888, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30113485

RESUMO

RATIONALE: Adrenal incidentaloma is sometimes complicated with 21-hydroxylase deficiency (21-OHD). Latent nonclassical 21-OHD in incidentaloma is difficult to diagnose. Although adrenalectomy in 21-OHD has been conducted when malignancy could not be excluded, adrenal insufficiency sometimes occurs, and it might not be observed immediately after operation. Here, we report a case of a 71-year-old man who experienced adrenal insufficiency over 2 decades postadrenalectomy, leading to a diagnosis of latent nonclassical 21-OHD. PATIENT CONCERNS: A 71-year-old man was admitted to the hospital due to difficulty in movements and a sodium level of 119 mEq/L. His medical history revealed precocious puberty and left adrenalectomy because of an incidentaloma at 49 years of age, diagnosed pathologically as an adenoma. He did not attend follow-up visits because he did not have any symptoms. In 2017, 3 months before hospitalization, he experienced general fatigue. A few days before admittance, he complained of difficulty in moving and visual hallucination of small animals. DIAGNOSES: Laboratory evaluations revealed a high level of adrenocorticotropic hormone (ACTH) and low cortisol level. ACTH-stimulating test revealed a low basal level and low response for cortisol, and a high basal level and low response for 17-hydroxyprogesterone. We analyzed large gene deletion or conversion and the 9 most common micro mutations in the CYP21A2 gene by polymerase chain reaction; micro mutation of I172N and heterozygous large gene deletion or conversion were detected leading to the diagnosis of nonclassical 21-OHD. INTERVENTIONS: Immediately, 100 mg hydrocortisone was administered, followed by daily hydrocortisone and saline. The symptoms and hyponatremia improved in a few days. He was discharged from the hospital on day 34 with a daily dose of 15 mg hydrocortisone. LESSONS: Clinicians should be aware of late onset of adrenal insufficiency after adrenalectomy. In such cases, clinicians should not overlook the latent nonclassical 21-OHD.


Assuntos
Insuficiência Adrenal/etiologia , Adrenalectomia/efeitos adversos , Transtornos de Início Tardio/etiologia , Complicações Pós-Operatórias/etiologia , Esteroide 21-Hidroxilase , 17-alfa-Hidroxiprogesterona/sangue , Hormônio Adrenocorticotrópico/sangue , Idoso , Humanos , Hidrocortisona/administração & dosagem , Hidrocortisona/sangue , Masculino , Esteroide 21-Hidroxilase/genética
18.
Clin Chim Acta ; 486: 142-150, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30048636

RESUMO

Classical 21-hydroxylase deficiency (21-OHD) due to mutations in the cytochrome P450 family 21 subfamily A member 2 (CYP21A2) gene is the most common type of congenital adrenal hyperplasia (CAH). In this study, we analyzed clinical and molecular data of 166 patients with classical CAH in South China. Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) method were used to detect mutations in these 99 salt wasting (SW) patients and 67 simple virilizing (SV) patients. Micro-conversion mutation IVS2-13A/C > G (I2G) was the most frequent mutation in both SW form (42.9%) and SV form (41.8%) in our large cohort, and large gene deletion or large gene conversion also commonly resulted in classical CAH. Rare mutations only account for 8.4% of all alleles, among them four novel variants p.S126X, p.C429X, c.1209_1210insT and c.840delG were responsible for the clinical presentations. CYP21A2 gene duplications linked to the mutation Q319X were found in our cohort, though these cases were rather rare. In this study, we provided detailed clinical data and mutation spectrum to confirm the common mutations in Chinese populations, especially in South China,which will contribute to further genetic consultation and prenatal diagnosis. Sanger sequencing combined with MLPA method could detect most mutation types in the CYP21A2 gene effectively.


Assuntos
Hiperplasia Suprarrenal Congênita/genética , Hiperplasia Suprarrenal Congênita/fisiopatologia , Análise Mutacional de DNA , Mutação , Esteroide 21-Hidroxilase/genética , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/metabolismo , China , Estudos de Coortes , Feminino , Humanos , Masculino , Reação em Cadeia da Polimerase Multiplex , Estudos Retrospectivos , Esteroide 21-Hidroxilase/metabolismo
19.
Pediatr Res ; 84(4): 533-536, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29976972

RESUMO

BACKGROUND: Basal levels of androgens, in particular 17-hydroxyprogesterone (17OHP), are widely debated as predictors of non-classical congenital adrenal hyperplasia (NCCAH) among patients with precocious pubarche (PP). Many authors have recommended the use of adrenocorticotropic hormone (ACTH) stimulation test in children with PP. The aim of our study was to identify clinical and biochemical predictors of NCCAH in children with PP. METHODS: We conducted a prospective study of 92 patients with PP undergoing an ACTH stimulation test. We tested the association of basal clinical and biochemical parameters with NCCAH diagnosis. Patients were suspected to have NCCAH if their stimulated 17OHP plasma levels were >10 ng/mL. In these patients, the diagnosis was confirmed by genetic test. RESULTS: Seven (7.6%) patients resulted having NCCAH. The best basal biochemical predictor for NCCAH was 17OHP level >2 ng/mL. In fact, a basal 17OHP level >2 ng/mL had 100% (95% confidence interval (CI), 59.04-100) sensitivity and 93% (95% CI, 85.3-97.37) specificity. The area under the receiver-operating characteristic curve for 17OHP was 0.99 (95% CI, 0.98-1.007). CONCLUSIONS: Basal 17OHP cut-off of 2 ng/mL was very effective in predicting NCCAH among our patients with PP. Assay-specific cut-off would probably be the best strategy to avoid unnecessary ACTH test.


Assuntos
17-alfa-Hidroxiprogesterona/sangue , Hiperplasia Suprarrenal Congênita/diagnóstico , Puberdade Precoce/diagnóstico , Hiperplasia Suprarrenal Congênita/sangue , Hormônio Adrenocorticotrópico/sangue , Criança , Pré-Escolar , Feminino , Testes Genéticos , Cabelo/crescimento & desenvolvimento , Humanos , Hidrocortisona/sangue , Masculino , Valor Preditivo dos Testes , Estudos Prospectivos , Puberdade Precoce/sangue , Curva ROC , Valores de Referência , Sensibilidade e Especificidade , Esteroide 21-Hidroxilase/genética
20.
BMC Med Genet ; 19(1): 115, 2018 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-29996815

RESUMO

BACKGROUND: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is an autosomal recessive disorder caused by mutations in the CYP21A2. Congenital nephrogenic diabetes insipidus (NDI) is a rare X-linked recessive or autosomal recessive disorder caused by mutations in either AVPR2 or AQP2. Genotype-phenotype discordance caused by genetic mosaicism in CAH patients has not been reported, nor the concomitant CAH and NDI. CASE PRESENTATION: We investigated a patient with concomitant CAH and NDI from a consanguineous family. She (S-1) presented with clitoromegaly at 3 month of age, and polydipsia and polyuria at 13 month of age. Her parents and two elder sisters (S-2 and S-3) were clinically normal, but elevated levels of serum 17-hydroxyprogesterone (17-OHP) were observed in the mother and S-2. The coding region of CYP21A2 and AQP2 were analyzed by PCR-sequencing analysis to identify genetic defects. Two homozygous CYP21A2 mutations (p.R357W and p.P454S) were identified in the proband and her mother and S-2. The apparent genotype-phenotype discordance was due to presence of small amount of wild-type CYP21A2 alleles in S-1, S-2, and their mother's genome, thus protecting them from development of classic form of 21OHD (C21OHD). A homozygous AQP2 mutation (p.A147T) was also found in the patient. The patient was treated with hydrocortisone and hydrochlorothiazide. Her symptoms were improved with normal laboratory findings. The clitoromegaly is persisted. CONCLUSIONS: Genetic mosaicism is a novel mechanism contributing to the genotype-phenotype discordance in 21OHD and small percentage of wild-type CYP21A2 alleles may be sufficient to prevent phenotype development. This is a first report of concurrent 21OHD and NDI caused by simultaneous homozygous CYP21A2 and AQP2 mutations.


Assuntos
Hiperplasia Suprarrenal Congênita/genética , Diabetes Insípido Nefrogênico/genética , Adolescente , Adulto , Alelos , Aquaporina 2/genética , Criança , Feminino , Estudos de Associação Genética/métodos , Genótipo , Humanos , Masculino , Mosaicismo , Mutação/genética , Linhagem , Fenótipo , Irmãos , Esteroide 21-Hidroxilase/genética
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