New insights into 5α-reductase type 2 deficiency based on a multi-centre study: regional distribution and genotype–phenotype profiling of SRD5A2 in 190 Chinese patients

2019 ◽  
Vol 56 (10) ◽  
pp. 685-692 ◽  
Author(s):  
Baoheng Gui ◽  
Yanning Song ◽  
Zhe Su ◽  
Fei-Hong Luo ◽  
Linqi Chen ◽  
...  
Keyword(s):  
Regional Distribution ◽  
Clinical Manifestations ◽  
Disorders Of Sex Development ◽  
Chinese Patients ◽  
Compound Heterozygous ◽  
Multi Centre Study ◽  
Proximal Hypospadias ◽  
Sex Development ◽  
Distal Hypospadias

BackgroundThe 5α-reductase type 2 (5α-RD2) deficiency caused by mutations in the steroid 5α-reductase 2 (SRD5A2) gene results in variable degrees of undervirilisation in patients with 46,XY disorders of sex development. This study aims to profile the regional distribution and phenotype–genotype characteristics of SRD5A2 in a large Chinese 5α-RD2 deficiency cohort through multi-centre analysis.Methods190 subjects diagnosed with 5α-RD2 deficiency were consecutively enrolled from eight medical centres in China. Their clinical manifestations and genetic variants were analysed.ResultsHypospadias (isolated or combined with microphallus and/or cryptorchidism) was fairly common in the enrolled subjects (66.32%). 42 variants, including 13 novel variants, were identified in SRD5A2. Homozygous and compound heterozygous mutations presented in 38.42% and 61.58% of subjects, respectively, and predominated in exons 1, 4 and 5. The most prevalent variant was c.680G > A (52.37%), followed by c.16C > T, (10.79%), c.607G > A, (9.21%) and c.737G > A, (8.95%). However, their distributions were different: c.680G > A was more common in South China than in North China (62.62% vs 39.16%, p < 0.001), whereas the regional prevalence of c.16C > T was reversed (6.07% vs 16.87%, p = 0.001). Furthermore, c.680G > A prevailed in cases with normal meatus (68.75%) or distal hypospadias (66.28%), compared with those with proximal hypospadias (35.54%, p < 0.001). However, cases with proximal hypospadias showed a higher frequency of c.16C > T (20.48%) than those with normal meatus (3.13%) or distal hypospadias (3.49%, p < 0.001).ConclusionsThis study profiled variable phenotypic presentation and wide mutational spectrum of SRD5A2, revealing its distinctive regional distribution in Chinese patients and further shaping the founder effect and genotype–phenotype correlation of SRD5A2.

Genome analyses and androgen quantification for an infant with 5α-reductase type 2 deficiency

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Kazuhisa Akiba ◽  
Keiko Aso ◽  
Yukihiro Hasegawa ◽  
Maki Fukami
Keyword(s):  
Disorders Of Sex Development ◽  
Reference Value ◽  
Ambiguous Genitalia ◽  
Chinese Patients ◽  
Sex Development ◽  
Liquid Chromatography Tandem Mass ◽  
Exon 1 ◽  
Genome Analyses ◽  
Immune Assays

Abstract Objectives 5α-reductase type 2 deficiency due to biallelic SRD5A2 variants is a common form of 46,XY disorders of sex development. Case presentation A Chinese neonate presented with ambiguous genitalia. He carried a homozygous likely_pathogenic SRD5A2 variant (c.650C>A, p.A217E). His apparently nonconsanguineous parents were heterozygotes for the variant. The variant has previously been identified in two Chinese patients. Our patient carried 14.2 Mb loss-of-heterogeneity regions distributed in the genome. The SRD5A2 variant in this family was invariably coupled with two polymorphisms in exon 1 and intron 1. In the patient, blood testosterone (T)/5α-dihydrotestosterone (5αDHT) ratios were elevated before and during mini puberty, and were higher when measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) than measured by conventional immune assays. Conclusions This study provides evidence for the founder effect of an SRD5A2 variant. Furthermore, our data indicate that there is a need to establish a new reference value for T/5αDHT ratios using LC-MS/MS.

scholarly journals Characterising SRD5A2 Gene Variants in 37 Indonesian Patients with 5-Alpha-Reductase Type 2 Deficiency

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Nanis S. Marzuki ◽  
Firman P. Idris ◽  
Hannie D. Kartapradja ◽  
Alida R. Harahap ◽  
Jose R. L. Batubara
Keyword(s):  
Autosomal Recessive ◽  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Compound Heterozygous ◽  
Phenotypic Characteristics ◽  
Sex Development ◽  
Srd5a2 Gene ◽  
Diagnostic Approaches ◽  
Autosomal Recessive Condition

The 5-alpha-reductase type 2 deficiency (5ARD2) is an autosomal recessive condition associated with impairment in the conversion of testosterone to dihydrotestosterone. This condition leads to undervirilisation in 46,XY individuals. To date, there have been more than 100 variations identified in the gene responsible for 5ARD2 development (steroid 5-alpha-reductase 2, SRD5A2). However, few studies have examined the molecular characterisation of Indonesian 5ARD2 cases. In the current study, we analysed 37 subjects diagnosed with 46,XY DSD (disorders of sex development) with confirmed variations in the SRD5A2 gene. We examined results from testosterone/dihydrotestosterone (T/DHT) and urinary etiocholanolone/androsterone (Et/An) ratios, as well as from molecular and clinical analyses. Twelve variants in the SRD5A2 gene were identified, and 6 of which were novel, namely, c.34–38delGinsCCAGC, p.Arg50His, p.Tyr136∗, p.Gly191Arg, p.Phe194Ile, and p.Ile253Val variants. Moreover, we determined that 20 individuals contained harmful mutations, while the remaining 17 variants were benign. Those containing harmful mutations exhibited more severe phenotypes with median external genitalia masculinisation scores (EMS) of 3 (1.5–9) and were more likely to be diagnosed at a later age, reared as female, and virilised at pubertal age. In addition, the respective sensitivities for detecting severe 5ARD2 cases using T/DHT (cutoff: 10) and urinary Et/An ratios (cutoff: 0.95) were 85% and 90%, whereas mild cases were only identified with 64.7% and 47.1% sensitivity, respectively. Although we were unable to identify clear correlations between genotypic and phenotypic characteristics in this study, we clearly showed that individuals who were homozygous or compound heterozygous for any of the harmful mutations were more likely to exhibit classic 5ARD2 phenotypes, lower EMS, female assignment at birth, and virilisation during puberty. These results serve to inform the development of improved clinical and molecular 5ARD2 diagnostic approaches, specifically in Indonesian patients.

scholarly journals A Survey of Compound Heterozygous Variants in Pediatric Cancers and Structural Birth Defects

2021 ◽  
Vol 12 ◽  
Author(s):  
Dustin B. Miller ◽  
Stephen R. Piccolo
Keyword(s):  
Heart Defects ◽  
Disorders Of Sex Development ◽  
Compound Heterozygous ◽  
Healthy Population ◽  
Alternative Mechanism ◽  
Disease Development ◽  
Data Resource ◽  
Sex Development ◽  
Gene Copies ◽  
Compound Heterozygous Variants

Compound heterozygous (CH) variants occur when two recessive alleles are inherited and the variants are located at different loci within the same gene in a given individual. CH variants are important contributors to many different types of recessively inherited diseases. However, many studies overlook CH variants because identification of this type of variant requires knowing the parent of origin for each nucleotide. Using computational methods, haplotypes can be inferred using a process called “phasing,” which estimates the chromosomal origin of most nucleotides. In this paper, we used germline, phased, whole-genome sequencing (WGS) data to identify CH variants across seven pediatric diseases (adolescent idiopathic scoliosis: n = 16, congenital heart defects: n = 709, disorders of sex development: n = 79, ewing sarcoma: n = 287, neuroblastoma: n = 259, orofacial cleft: n = 107, and syndromic cranial dysinnervation: n = 172), available as parent-child trios in the Gabriella Miller Kids First Data Resource Center. Relatively little is understood about the genetic underpinnings of these diseases. We classified CH variants as “potentially damaging” based on minor allele frequencies (MAF), Combined Annotation Dependent Depletion scores, variant impact on transcription or translation, and gene-level frequencies in the disease group compared to a healthy population. For comparison, we also identified homozygous alternate (HA) variants, which affect both gene copies at a single locus; HA variants represent an alternative mechanism of recessive disease development and do not require phasing. Across all diseases, 2.6% of the samples had a potentially damaging CH variant and 16.2% had a potentially damaging HA variant. Of these samples with potentially damaging variants, the average number of genes per sample was 1 with a CH variant and 1.25 with a HA variant. Across all samples, 5.1 genes per disease had a CH variant, while 35.6 genes per disease had a HA variant; on average, only 4.3% of these variants affected common genes. Therefore, when seeking to identify potentially damaging variants of a putatively recessive disease, CH variants should be considered as potential contributors to disease development. If CH variants are excluded from analysis, important candidate genes may be overlooked.

scholarly journals Clinical and molecular spectrum of 46, XY disorders of sex development that harbour MAMLD1 variations: Case series and review of literature

2020 ◽  
Author(s):  
Li Lele ◽  
Lijun Fan ◽  
Fenqi Gao ◽  
Di Wu ◽  
Chunxiu Gong
Keyword(s):  
Protein Function ◽  
Clinical Manifestations ◽  
Disorders Of Sex Development ◽  
Case Series ◽  
In Silico Analysis ◽  
Causative Role ◽  
Causative Gene ◽  
Sex Development ◽  
Clinical Series

Abstract Background Mastermind-like domain-containing 1 (MAMLD1) has previously been identified as a causative gene for "46, XY Disorders of Sex Development (DSD)". Recently, there has been some controversy regarding the causative role of MAMLD1 variations in DSDs. Here we describe a clinical series and review the reported cases to evaluate the role of MAMLD1 variants in children with 46, XY DSD. Cases of 46, XY DSD harbouring MAMLD1 variants from unrelated families were recruited from the Beijing Children’s Hospital in China (N = 10) or identified through a literature search (N = 26). The clinical manifestations and genetic variants of all the patients were evaluated.Results Hypospadias was the most prevalent phenotype among our 10 cases (8 out of 10 cases) and in all the previously reported ones. Central precocious puberty and isolated micropenis were observed for the first time. Among the 10 cases, nine variants were identified, including three nonsense (p.A356X, p.G152X, and p.G124X) and six missense (p.P334S, p.S662A, p.A421P,p.T992I, p.P542S, and p.A927L) variants. In silico analysis showed that the variants p.P334S, p.P542S, p.S662A, and p.A927Lmight lead to drastic changes in the interaction force of the amino acid chain and the flexibility of the spatial structure, and such changes may affect protein function.Conclusion Patients with 46, XY DSD harbouring MAMLD1variants manifest a broad spectrum of phenotypes and mostly present with hypospadias. The six novel variants reported here enrich the mutation database and contribute to our understanding of the pathogenesis of 46, XY DSD.

scholarly journals The Investigation of Quality of Life in 87 Chinese Patients with Disorders of Sex Development

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Chunqing Wang ◽  
Qinjie Tian
Keyword(s):  
Quality Of Life ◽  
Social Relationship ◽  
Disorders Of Sex Development ◽  
Androgen Insensitivity Syndrome ◽  
Chinese Patients ◽  
Sexual Life ◽  
Process Of Care ◽  
Sex Development ◽  
The Difference

Objective. In the process of care for disorders of sex development (DSD), clinical decisions should focus on the long-term quality of life (QOL). We sought to investigate the QOL of patients with DSD in China.Design. Case-control study was carried out.Patients.90 patients of DSD participated in the study. Finally, 87 patients were analyzed including Turner’s syndrome (23), Noonan syndrome (2), androgen insensitivity syndrome (22), testicular regression syndrome (2), congenital adrenal hyperplasia (16), and pure gonadal dysgenesis (22).Measurements. The WHOQOL-BREF questionnaire was chosen for the present investigation. Four domain scores were analyzed independently including physical, psychological, and social relationship and environmental domains.Results. The average age of the DSD group is 22.34 ± 4.97 years, and only 13.79% patients ever had sexual life. The scores of psychological and environmental domains were lower than that of the physical and social relationship domains, but the difference was not significant (P>0.05). Compared with the Chinese urban population, the QOL scores of DSD patients in China were not significantly lower.Conclusions. With proper treatment, including the follow-up and psychological support, the QOL of DSD patients cannot be significantly reduced. For DSD patients, more attention should be paid to the potential psychological and sexual problems.

scholarly journals Systematical analysis of nine Chinese patients with progressive pseudorheumatoid dysplasia and assessment of calcitriol treatment

2020 ◽  
Author(s):  
Lei Yin ◽  
Youying Mao ◽  
Yunfang Zhou ◽  
yongnian Shen ◽  
Huijin Chen ◽  
...  
Keyword(s):  
Early Stage ◽  
Clinical Manifestations ◽  
Blood Analysis ◽  
Chinese Patients ◽  
Compound Heterozygous ◽  
Normal Range ◽  
Treatment Benefit ◽  
Radiographic Findings ◽  
Progressive Pseudorheumatoid Dysplasia ◽  
Abnormal Gait

Abstract Background: Progressive pseudorheumatoid dysplasia (PPRD) (MIM 208230) is a rare genetic disease characterized by progressive noninflammatory arthropathy affecting primarily the articular cartilage. Most patients are initially misdiagnosed because of the rarity of the disease and lack of awareness by most clinicians. Therefore, the purpose of the present study was to provide further diagnostic options to help clinicians make early precise diagnosis, and to investigate a new potential treatment for patients with PPRD. Methods: Clinical manifestations, radiographic features, Sanger Sequencing to determine WISP3 gene mutation and follow-up records were collected in 9 Chinese patients with PPRD. The time until diagnosis, relationship between clinical phenotypes and genotypes, and treatment effects were analyzed. Results: The clinical history and characteristics, mutations in the WISP3 gene, radiological data, treatment and outcome of 9 PPRD children were collected and reviewed. There were 3 pairs of siblings in this group and one patient had parental consanguinity. Five patients were misdiagnosed with juvenile idiopathic arthritis (JIA). The onset of disease in most patients (8/9) was between 3 and 6 years of age. The interval between onset of symptoms and obtaining the diagnosis for 8 of the patients varied between 3.6 years to 20 years. The onset of symptoms included enlarged and stiff interphalangeal joints of the fingers, gait disturbance or joint pain. Blood analysis revealed normal range of inflammatory parameters (erythrocyte sedimentation rate, C-reactive protein). Serum levels of 25-hydroxyvitamin D3 were analyzed in six patients and ranged from 6.16 to 22.1ng/ml, all lower than the normal range. Radiographic findings included different degree of abnormal vertebral bodies, epiphyseal enlargement of the interphalangeal joints with juxta-articular osteopenia, or reduction in hip articular space and cyst-like structures femoral head. A total of 7 variants in the WISP3 gene were identified in the 9 cases, presenting with three homozygous variants (c.397_404delCAAGTGTT, c.667T>G, and c.589+2T>C) and three compound heterozygous variants (c.589+2T>C/c.667T>G, c.624dupA/c.756C>A, and c.646T>C/c.1000T>C). After the treatment of calcitriol in the 6 patients with low level of 25-hydroxyvitamin D3 for 1.25 years to 1.75 years, two cases showed stable clinical disease activity and the other four patients joints’ pain and abnormal gait had improved. Conclusions: Combining the patient’s family history, clinical features presenting with abnormal gait or enlarged and stiff interphalangeal joints of the fingers, normal inflammatory markers, and the characteristic radiographic findings, we can obtain the clinical diagnosis of PPRD for the patients at a very early stage of the disease. The patients with PPRD having c.624dupA mutation in WISP3 may have delayed onset. Calcitriol showed treatment benefit by improving symptoms and decelerating progression of PPRD disease.

scholarly journals Accuracy of Urinary Etiocholanolone/Androsterone Ratio as Alternative to Serum Testosterone/Dihydrotestosterone Ratio for Diagnosis of 5 Alpha-reductase Type 2 Deficiency Patients and Carriers in Indonesia

2021 ◽  
Vol In Press (In Press) ◽  
Author(s):  
Nanis Sacharina Marzuki ◽  
Firman Pratama Idris ◽  
Hannie Kartapradja ◽  
Shirley Renata ◽  
Alida Harahap ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Disorders Of Sex Development ◽  
Cost Benefit ◽  
Serum Testosterone ◽  
Diagnostic Value ◽  
Roc Curve Analysis ◽  
Sex Development ◽  
Srd5a2 Gene ◽  
Alternative Test

Background: The 5 Alpha-reductase type 2 deficiency (5ARD2) is an inherited condition, which clinically presents as variable degrees of under virilization in affected 46,XY individuals. In the diagnostic pathway of 5ARD2, the testosterone/dihydrotestosterone (T/DHT) ratio is broadly employed before molecular analysis of the SRD5A2 gene. However, due to cost-benefit considerations, the DHT test in our country is routinely lacking in clinical settings; therefore, we considered applying the urinary etiocholanolone/androsterone (Et/An) ratio as an alternative test. Objectives: We aimed to determine the diagnostic value of the urinary Et/An ratio versus the T/DHT ratio in diagnosing 5ARD2 patients and carriers. Methods: Sixty-six suspected 5ARD2 46,XY disorders of sex development (DSD) individuals and 95 family members were recruited in the study. Their physical manifestations, T/DHT and urinary Et/An ratios, and SRD5A2 genes were analyzed. Using molecular analysis of the SRD5A2 gene as the gold standard, we compared the accuracy of both ratios in diagnosing 5ARD2 patients and carriers with receiver operating characteristic (ROC) curve analysis. Results: Thirty-seven patients were confirmed molecularly to have 5ARD2, and the rest (n = 29) were assessed as normal controls, while in the carrier group, 53 were molecularly confirmed as carriers and 42 as controls. The AUCs (areas under the curve) of the T/DHT and urinary Et/An ratios were 57.7% (95% CI 43.0 - 72.4%, P > 0.05) and 79.7% (95% CI 69.0 - 90.4%, P < 0.001), respectively, in diagnosing 5ARD2 patients and 54.1% (95% CI 42.4 - 65.8%, P > 0.05) and 75.1% (95% CI 65.1 - 85.1%, P < 0.001), respectively, in diagnosing carriers. The cutoff value of the urinary Et/An ratio was set at ≥ 0.95 for detecting 5ARD2 patients and ≥ 0.99 for detecting carriers. Conclusions: The testosterone/DHT ratio was inaccurate in diagnosing 5ARD2 patients. When molecular analysis for the SRD5A2 gene is lacking, the urinary Et/An ratio may be a useful test to diagnose 5ARD2 patients and carriers.

scholarly journals Clinical and molecular spectrum of 46, XY disorders of sex development that harbour MAMLD1 variations: Case series and review of literature

2020 ◽  
Author(s):  
Li Lele ◽  
Lijun Fan ◽  
Fenqi Gao ◽  
Di Wu ◽  
Chunxiu Gong
Keyword(s):  
Clinical Manifestations ◽  
Disorders Of Sex Development ◽  
Case Series ◽  
In Silico Analysis ◽  
Central Precocious Puberty ◽  
Causative Role ◽  
Causative Gene ◽  
Sex Development ◽  
Clinical Series

Abstract Background Mastermind-like domain-containing 1 (MAMLD1) has previously been identified as a causative gene for "46, XY Disorders of Sex Development (DSD)". Recently, there has been some controversy regarding the causative role of MAMLD1 variations in DSDs. Here we describe a clinical series and review the reported cases to evaluate the role of MAMLD1 variants in children with 46, XY DSD. Cases of 46, XY DSD harbouring MAMLD1 variants from unrelated families were recruited from the Beijing Children’s Hospital in China (N = 10)or identified through a literature search (N = 26). The clinical manifestations and genetic variants of all the patients were evaluated.Results Hypospadias was the most prevalent phenotype among our 10 cases (8 out of 10 cases) and in all the previously reported ones. Central precocious puberty and isolated micropeniswere observedfor the first time. Among the 10 cases, nine variants were identified, including three nonsense (p.A356X, p.G152X, and p.G124X) and six missense (p.P334S, p.S662A, p.A421P,p.T992I, p.P542S, and p.A927L) variants. In silico analysis showed that the variants p.P334S, p.P542S, p.S662A, and p.A927Lmight lead to drastic changes in the interaction force of the amino acid chain and the flexibility of the spatial structure, and such changes may affect protein function.Conclusion Patients with 46, XY DSD harbouring MAMLD1variants manifest a broad spectrum of phenotypes and mostly present with hypospadias. The six novel variants reported here enrich the mutation database and contribute to our understanding of the pathogenesis of 46, XY DSD.

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