Molecular analysis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency in Hong Kong Chinese patients

Chan, Alex W.H.; But, WM; Ng, Ka Lun; Wong, Lap Ming; Lam, Y.Y.; Tiu, Sau Cheung; Lee, K.F.; Lee, C.Y.; Loung, P Y; Berry, Ian; Brown, Rebecca; Charlton, Ruth; Cheng, C.W.; Ho, Y.C.; Tse, W. Y.; Shek, Chi Chung

doi:10.1016/j.steroids.2011.04.010

Cited by 25 publications

(12 citation statements)

References 18 publications

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“…The former accounted for 27% and the latter 16% of all the mutations detected in 35 Chinese patients in a local study. 13 The missense mutation p.Ile172Asn is known to retain 1 to 2% of normal 21-hydroxylase activity and results in simple virilising CAH, compatible with the phenotype of our patient.…”

Section: Discussionsupporting

confidence: 83%

Late presentation of simple virilising 21-hydroxylase deficiency in a Chinese woman with Turner's syndrome

Lee¹,

Chan²,

Fok³

et al. 2013

Hong Kong Med J

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A 66-year-old Vietnam-born Chinese man was admitted to our department because of progressive abdominal swelling and bilateral ankle oedema for 1 year. On physical examination, he was noted to have a short stature with body height of 1.37 m. He had a normal complexion and no other dysmorphic features. His blood pressure was 99/55 mm Hg but with no postural drop. Abdominal examination revealed a distended abdomen without organomegaly or shifting dullness. Examination of his external genitalia revealed a micropenis with perineoscrotal hypospadias (Prader stage IV); no testes could be detected in/along both the scrotum and inguinal canals. However, he had male pattern of escutcheon, a beard, and no gynaecomastia. On further questioning, he reluctantly disclosed a history of urinary leakage since childhood and arrest of growth after puberty at the age of 10 years. Computed tomography of the abdomen revealed a 13.6 x 26.5 x 23.7 cm non-enhancing septated cystic mass arising from the retrovesical region.Initial investigations revealed normal serum electrolytes and acid-base status. His renal function was impaired (serum creatinine of 172; reference range [RR], 62-126 μmol/L), and he had hypoalbuminaemia (serum albumin of 24; RR, 32-46 g/L). Baseline serum sex hormone profiles were as follows: testosterone at 9.2 (RR for male, 9.0-34.7) nmol/L, oestradiol at 176 (RR for male, 26-156) pmol/L, progesterone at 22.8 (RR for male, 0.7-4.3) nmol/L, luteinising hormone at 1.9 (RR, 1.7-8.6) IU/L, follicle-stimulating hormone at 3.0 (RR, 1.5-12.4) IU/L, androstenedione at 31.5 (RR, 0.8-3.1) nmol/L, and dehydroepiandrosterone sulfate at 11.6 (RR, 2.2-15.2) nmol/L. Tumour markers including beta-human chorionic gonadotropin, alpha-fetoprotein, carcinoembryonic antigen, and CA-125 were normal. A mosaic Turner karyotype with 10% monosomy X, 4% trisomy X, and 86% normal female karyotype was detected. The short synacthen test with 250 μg tetracosactrin was performed to unravel the possibility of congenital adrenal hyperplasia (CAH) with the following results: baseline adrenocorticotropic hormone (ACTH) at 50.2 (RR, <10.1) pmol/L; baseline and 60-minute post-stimulation serum cortisol at 224 and at 260 nmol/L, respectively (reference level, >550 nmol/L post-stimulation); and baseline and 60-minute post-stimulation 17-hydroxyprogesterone (17-OHP) at 70 and 554 nmol/L, respectively (reference level of classical CAH, >300 nmol/L). Urinary steroid profiling (USP) by gas chromatography-mass spectrometry (GC-MS) showed grossly elevated metabolites of 17-OHP (Fig 1), including pregnanetriol, 17-hydroxypregnenolone and 11-oxo-pregnanetriol, compatible with 21-hydroxylase deficiency (21-OHD). Mutational analysis of the CYP21A2 gene by multiplex ligation-dependent probe amplification and by polymerase chain reaction (PCR) followed by direct DNA sequencing showed deletion/ conversion of the promoter to exon 4 in one allele and a hemizygous p.Ile172Asn mutation in the other allele. Using PCR no SRY gene could be amplified in the peripheral leukocyt...

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Section: Discussionsupporting

confidence: 83%

Late presentation of simple virilising 21-hydroxylase deficiency in a Chinese woman with Turner's syndrome

Lee¹,

Chan²,

Fok³

et al. 2013

Hong Kong Med J

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“…Among our 21-OHD CAH patients, the most prevalent CYP21A2 variants were c.293-13C > G (31.36%), Del (18.64%), p.I173N (16.95%), E3 Δ8 (5.08%), p.R483PfsX58 (4.24%) and p.R357W (3.39%). The rst three variants, c.293-13C > G, Del and p.I173N, were consistent with the most frequent variants in the Asian population [13][14][15][16][17]; however, our data showed higher E3 Δ8 and p.R483PfsX58 variant prevalence rates and a lower p.R357W variant prevalence. Ethnic differences were evident among different studies; the frequencies of p.P31L and p.V282L were 1.69% and 0.85% in our study, respectively, while the p.V282L…”

Section: Discussionsupporting

confidence: 84%

Genetic Aetiology of Primary Adrenal Insufficiency in Chinese Children

Chang

Lü

Zhao

et al. 2020

Preprint

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Background: Primary adrenal insufficiency (PAI) is a life-threatening condition, and a definitive aetiological diagnosis is essential for management and prognostication. We conducted this study to investigate the genetic aetiologies of PAI in South China and explore their clinical features.Methods: Seventy children were enrolled. Clinical information was collected, and combined genetic tests were performed according to the children’s manifestations. Statistical analysis was performed among the different groups. In silico or in vitro experiments were applied to determine the pathogenicity of novel variants.Results: Among the 70 children, 84.29% (59/70) were diagnosed with congenital adrenal hyperplasia (CAH), and a diagnosis of 21-hydroxylase deficiency (21-OHD) was subsequently genetically confirmed in 91.53% of the cases. Salt wasting (SW), simple virilization (SV), and non-classic (NC) CAH accounted for 66.10% (39/59), 30.51% (18/59), and 3.39% (2/59) of the cases, respectively. Interestingly, 17-hydroxyprogesterone (17-OHP) and testosterone levels in females were significantly higher than those in males among both SW and SV CAH patients. Additionally, 15.71% (11/70) of the patients were diagnosed with PAI, 72.73% (8/11) of whom had positive genetic findings. Among all the cases, two novel variants in CYP21A2, c.833dupT (p.279GfsX17) and c.651+2T>G, were harboured by CAH patients. A microdeletion (Xp21.2-21.3) and five novel variants, including 2 in the NR0B1 gene (p.108S>X, p.L411Vfs*6, c.1231_1234delCTCA, p.L411Vfs*6), 2 in the AAAS gene (c.399+1G>A, p.V103Afs*8, c.250delT, p.W84Gfs*10) and 1 in the NNT gene (p.I758Mfs*10), were detected. The novel variant c.399+1G>A in the AAAS gene was further confirmed to lead to exon 4 deletion in mRNA transcription and produce a truncated ALADIN protein.Conclusions: We found ethnic differences in the CYP21A2 gene variant spectrum among different study populations. Female 21-OHD patients tended to have higher 17-OHP and testosterone levels, which warrants caution in relation to the virilization effect both physically and psychologically. Novel gene variants detected in the CYP21A2, NR0B1, AAAS and NNT genes expanded the genetic spectrum of paediatric PAI; however, further improvement of genetic testing tools beyond our protocol is still needed to uncover the complete aetiology of PAI in children.

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“…In present study, large gene deletions and conversions accounted for 10 alleles (22.7%), while the most common was I2G mutation (70.5%), followed by p.R357W (4.5%) and E6 Cluster (2.3%). Micro-conversions comprised a major portion in current study and I2G is the most popular point mutation, which is the same as other regions in China and other Asian populations [15,17,[20][21][22][23][24]. Two common mutations (I2G and p.R357W) in our research were also predominant in other populations.…”

Section: Discussionsupporting

confidence: 66%

The spectrum of CYP21A2 gene mutations in patients with 2l-hydroxylase deficiency -induced congenital adrenal hyperplasia in a Chinese cohort

Y¹,

Zheng²,

Xu³

et al. 2020

Preprint

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Background 21-hydroxylase deficiency (21-OHD) caused by the CYP21A2 gene mutations is the most popular form of congenital adrenal hyperplasia. It is an autosomal recessive disorder results in the defective synthesis of cortisol and aldosterone. The incidences of various CYP21A2 gene mutations and the genotype-phenotype correlations vary among different populations. Therefore, the aim of current study was to identify the spectrum of CYP21A2 gene mutations of patients from northern China and analyze the genotype-phenotype correlation.Methods The clinical and molecular data of 22 patients were analyzed in this study. Locus-specific polymerasechain reaction and Sanger sequencing were applied to identify gene micro-conversions, and multiplex ligation-dependent probe amplification as an alternative to Southern blotting was used to detect large fragment deletions/conversions. Then the genotypes were categorized in to Null, A, B, C and D groups to analyze the relationships between genotypes and phenotypes.Results Molecular defects were detected in 44 alleles (100%). Micro-conversion mutation IVS2-13A/C> G (70.5%) is most common in our cohort, followed by large gene deletions and conversions (22.7%).The other mutations present were p.R357W (4.5%) and E6 Cluster (2.3%). Genotypes of 22 patients (100%) were consistent with the predictive phenotypes.Conclusions In this study, we collected 22 21-OHD patients' clinical and mutations data in Chinese population, especially in northern China. Micro-conversions were the most popular mutations and the frequencies were consistent with other cohorts. Moreover, thegenotypes and phenotypes in 21-OHDwere well correlated. This studyidentifiedthe mutation spectrum of CYP21A2gene and conduced to genetic counseling and prenatal diagnosis.

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Molecular analysis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency in Hong Kong Chinese patients

Cited by 25 publications

References 18 publications

Late presentation of simple virilising 21-hydroxylase deficiency in a Chinese woman with Turner's syndrome

Late presentation of simple virilising 21-hydroxylase deficiency in a Chinese woman with Turner's syndrome

Genetic Aetiology of Primary Adrenal Insufficiency in Chinese Children

The spectrum of CYP21A2 gene mutations in patients with 2l-hydroxylase deficiency -induced congenital adrenal hyperplasia in a Chinese cohort

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