|
1
|
Karlekar M, Sarathi V, Barnabas R, Lila A, Memon SS, Shah N, Bandgar T. 46, XX DSD with Atypical Genitalia: Clinical Insights and Diagnostic Approaches. Horm Metab Res 2025; 57:221-228. [PMID: 40043726 DOI: 10.1055/a-2538-3603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/12/2025]
Abstract
Congenital adrenal hyperplasia (CAH) is a rare disorder with autosomal recessive inheritance; it was historically known as adrenogenital syndrome. Patients with virilizing forms of CAH and a 46,XX karyotype present with varied degrees of hyperandrogenism due to different genetic defects in the adrenal steroidogenesis pathway. This comprehensive review describes a simplified diagnostic approach for patients with atypical genitalia and 46, XX DSD. It highlights the importance of a detailed history and clinical examination, with specific pointers toward the etiological diagnosis. There is a need for utilizing standardized liquid chromatography/tandem mass spectrometry (LC-MS/MS) assays to accurately diagnose these disorders of steroidogenesis. Choosing appropriate molecular testing methods has significant implications for establishing the diagnosis and providing genetic counseling.
Collapse
Affiliation(s)
- Manjiri Karlekar
- Endocrinology, Seth GS Medical College and KEM Hospital, Mumbai, India
| | - Vijaya Sarathi
- Endocrinology, Vydehi Institute of Medical Sciences and Research Centre, Bengaluru, India
| | - Rohit Barnabas
- Endocrinology, Seth GS Medical College and KEM Hospital, Mumbai, India
| | - Anurag Lila
- Endocrinology, Seth GS Medical College and KEM Hospital, Mumbai, India
| | - Saba Samad Memon
- Endocrinology, Seth GS Medical College and KEM Hospital, Mumbai, India
| | - Nalini Shah
- Endocrinology, Seth GS Medical College and KEM Hospital, Mumbai, India
| | - Tushar Bandgar
- Endocrinology, Seth GS Medical College and KEM Hospital, Mumbai, India
| |
Collapse
|
|
2
|
Wang X, Lu X, Zheng F, Lin K, Liao M, Dong Y, Chen T, He Y, Lu M, Chen J, Li Y, Zhou Y. Assessment of Long-Read Sequencing-Based Congenital Adrenal Hyperplasia Genotyping Assay for Newborns in Fujian, China. Int J Neonatal Screen 2025; 11:22. [PMID: 40136637 PMCID: PMC11942758 DOI: 10.3390/ijns11010022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Revised: 03/03/2025] [Accepted: 03/10/2025] [Indexed: 03/27/2025] Open
Abstract
Long-read sequencing (LRS) provides comprehensive genetic information, but research of LRS applied to congenital adrenal hyperplasia (CAH) newborn screening is limited. This study aimed to evaluate the clinical utility of LRS in genetic diagnosis and second-tier newborn screening. Neonates born between January 2017 and December 2022 in Fujian, China, were recruited for biochemical and LRS-based genetic screening assay. The LRS covers the entire gene regions and exon-intron boundary regions for CYP21A2, CYP11B1, CYP17A1, HSD3B2, and StAR. In this retrospective study, 1,774,555 newborns received 17α-OHP screening, yielding a screening positive rate of 0.20%. Of these high-risk neonates, 3411 were successfully recalled for re-evaluation. Finally, 66 neonates were diagnosed with CAH, with a positive predictive value of 28.82%. Based on this data, the overall prevalence of CAH in Fujian was estimated to be 1:26,883. LRS was performed on 57 neonates with 21-hydroxylase deficiency (21-OHD) and 109 variant alleles were identified. The c.293-13C>G variant (31.19%) was the most prevalent in Fujian. Additionally, 647 neonates with suspected positive results were genotyped, and 41 were identified as carriers, with carrier frequencies of 1:18 for CYP21A2, 1:162 for HSD3B2, and 1:324 for CYP17A1 in Xiamen. Therefore, LRS can provide comprehensive genotypes in approximately 1.5 days at a cost of less than $20 USD per sample, and effectively improve screening efficiency, reduce anxiety of parents during newborn screening (NBS), and shorten the time to referral of CAH patients (approximately 10 days). Such a combined screening strategy is worthy to be recommended for NBS programs in the future.
Collapse
Affiliation(s)
- Xudong Wang
- Xiamen Newborn Screening Center, Department of Pediatrics, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen 361102, China; (Y.H.); (Y.L.)
| | - Xingxiu Lu
- United Diagnostic and Research Center for Clinical Genetics, School of Public Health, Xiamen University, Xiamen 361100, China;
| | - Faming Zheng
- Center of Neonatal Disease Screening, Quanzhou Maternity and Children’s Hospital, Quanzhou 362000, China;
| | - Kun Lin
- Prenatal Diagnosis Center, The Affiliated Hospital of Putian University, Putian University, Putian 351100, China;
| | - Minjuan Liao
- Longyan Newborn Screening Center, The First Hospital of Longyan City, Longyan 364099, China;
| | - Yi Dong
- Screening Center of Neonatal Genetic Metabolic Disease, Ningde Maternity and Child Health Care Hospital, Ningde 352100, China
| | - Tiantian Chen
- Zhangzhou Newborn Screening Center, Zhangzhou Maternity and Child Care Hospital, Zhangzhou 363000, China;
| | - Ying He
- Xiamen Newborn Screening Center, Department of Pediatrics, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen 361102, China; (Y.H.); (Y.L.)
| | - Mei Lu
- Department of Pediatric Endocrinology, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen 361102, China;
- Department of Pediatrics, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen 361102, China;
| | - Jing Chen
- Department of Pediatrics, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen 361102, China;
- Department of Child Health, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Yanfang Li
- Xiamen Newborn Screening Center, Department of Pediatrics, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen 361102, China; (Y.H.); (Y.L.)
| | - Yulin Zhou
- Xiamen Newborn Screening Center, Department of Pediatrics, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen 361102, China; (Y.H.); (Y.L.)
| |
Collapse
|
|
3
|
Mercado Santis E, Campos A, Fernández P, Oriola J, Yeste D, Pérez V, Clemente M. Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency: clinical, biochemical and molecular characteristics and long-term outcomes. An Pediatr (Barc) 2025; 102:503747. [PMID: 39952853 DOI: 10.1016/j.anpede.2025.503747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 12/08/2024] [Indexed: 02/17/2025] Open
Abstract
INTRODUCTION 11β-hydroxylase (11β-OH) deficiency is the second most frequent cause of classic congenital adrenal hyperplasia (CAH) (5%-8% of cases). Clinically, it is characterized by virilization and arterial hypertension. The objective of this study was to describe the clinical, biochemical and genetic characteristics classic 11β-OH deficiency in patients managed in our hospital and its outcomes. PATIENTS AND METHODS Retrospective longitudinal, observational and descriptive study. INCLUSION CRITERIA Patients with clinical features of virilization, high levels of 11-deoxycortisol and study of CYP11B1 gene with detection of pathogenic and likely pathogenic variants. RESULTS We identified 6 patients (1 male, 5 female) from 4 families. In the 4 index cases, the median age at diagnosis was 2.3 years. The 46,XX patients exhibited a variable degree of virilization at diagnosis, with a predominance of Prader stage V, and one case of male sex assignment at birth. All patients had elevated serum concentrations of 17-hydroxyprogesterone and testosterone. Fifty percent of the patients had developed arterial hypertension during the follow-up, with onset at a median age of 9.3 years. Three 46,XX patients reached a median final height of 154 cm. Six different variants of theCYP11B1 gene were identified, 5 of which were novel variants (c.595 G > A, c.710 T > C, c.1156delG, c.395 + 2dupT, c.1159dupA). CONCLUSIONS There is considerable heterogeneity in the clinical presentation of patients with CAH due to 11β-OH deficiency. Early diagnosis and treatment are important to prevent complications and improve long-term outcomes. We report 6 different variants of the CYP11B1 gene, including 5 novel variants.
Collapse
Affiliation(s)
- Elida Mercado Santis
- Endocrinología Pediátrica, Hospital Universitario Vall d'Hebron Barcelona, Universidad Autónoma de Barcelona, Barcelona, Spain.
| | - Ariadna Campos
- Endocrinología Pediátrica, Hospital Universitario Vall d'Hebron, Universidad Autónoma de Barcelona, Barcelona, Spain
| | - Paula Fernández
- Área de Genética Clínica y Molecular, Hospital Universitario Vall d'Hebron, Barcelona, Spain
| | - Josep Oriola
- Centro de Diagnóstico Biomédico - Bioquímica y Genética Molecular, Hospital Clínic Barcelona, Barcelona, Spain
| | - Diego Yeste
- Endocrinología Pediátrica, Hospital Universitario Vall d'Hebron, CIBERER Barcelona, Univesidad Autónoma de Barcelona, Barcelona, Spain
| | - Víctor Pérez
- Nefrología Pediátrica, Hospital Universitario Vall d'Hebron, Barcelona, Spain
| | - María Clemente
- Endocrinología Pediátrica, Hospital Universitario Vall d'Hebron, CIBERER Barcelona, Univesidad Autónoma de Barcelona, Barcelona, Spain
| |
Collapse
|
|
4
|
He R, Xu L, Yang N, Zhu S, Fan H, Zou J, Chen R, Qian L, Liu Y. Novel compound heterozygous CYP17A1 mutations identified in a family with two siblings affected by 17α-hydroxylase/17,20-lyase deficiency. Steroids 2025; 214:109562. [PMID: 39874996 DOI: 10.1016/j.steroids.2025.109562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 01/16/2025] [Accepted: 01/24/2025] [Indexed: 01/30/2025]
Abstract
BACKGROUND 17α-Hydroxylase/17,20-lyase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia (CAH), caused by mutations in the CYP17A1 gene. It typically manifests clinically as variable degree of hypertension, hypokalemia, and disorders of sexual development (DSD), which can include abnormal sexual differentiation in males and sexual infantilism in females. Over 100 mutations in CYP17A1 have been identified, with most cases involving missense mutations or small deletions. METHOD This study examined the clinical features, biochemical profiles, and genetic background of two 46, XY siblings from the same family, both diagnosed with 17OHD-a scenario that is uncommonly seen in clinical practice. We performed a genetic analysis of the CYP17A1 gene in two generations of the family to confirm the diagnosis. RESULTS Both patients are phenotypically female, presenting with hypertension, hypokalemia, primary amenorrhea, and absent secondary sexual characteristics. Genetic analysis revealed two novel compound heterozygous mutations in the CYP17A1 gene: R45WfsTer5 (a frameshift mutation) and L361P (a missense mutation). Neither variant is reported in the ClinVar database, and the frameshift mutation (R45WfsTer5) is newly identified. CONCLUSIONS The discovery of these two novel CYP17A1 mutations expands the genetic spectrum of 17OHD and provides new insights into the genetic underpinnings of the disease. Personalized treatment plans are necessary, and the choice of glucocorticoids with stronger sodium retention effects may be required to manage hypertension and electrolyte imbalances in select patients.
Collapse
Affiliation(s)
- Rongbo He
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lin Xu
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Nan Yang
- Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shaoshi Zhu
- University of Illinois College of Medicine, Chicago, IL 60612, USA
| | - Hongqi Fan
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jing Zou
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Rourou Chen
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Li Qian
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yu Liu
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
| |
Collapse
|
|
5
|
Eitel KB, Fechner PY. Barriers to the Management of Classic Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency. J Clin Endocrinol Metab 2025; 110:S67-S73. [PMID: 39836619 PMCID: PMC11749880 DOI: 10.1210/clinem/dgae710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Indexed: 01/23/2025]
Abstract
Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is a rare genetic condition that requires lifelong management from birth. Individuals with CAH and their families often face structural barriers to obtaining comprehensive care and treatment, including limited access to appropriate newborn screening, comprehensive care centers, and medications. Social and cultural barriers to care may include stigmatization, discrimination, and adverse medical experiences. At the individual and family level, comprehensive care may be affected by education, finances, health-care coverage, geographic location, and lack of social supports. These barriers are often further magnified for individuals living in underresourced countries. Inadequate access to comprehensive care and medications increases the risk of life-threatening adrenal crisis and disease-related comorbidities. This review article examines the current structural, sociocultural, and individual barriers that individuals with CAH and their families may face when managing their condition throughout their lifetime.
Collapse
Affiliation(s)
- Kelsey B Eitel
- Department of Pediatrics, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA
| | - Patricia Y Fechner
- Department of Pediatrics, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA
| |
Collapse
|
|
6
|
Wang R, Luo X, Sun Y, Liang L, Mao A, Lu D, Zhang K, Yang Y, Sun Y, Sun M, Han L, Zhang H, Gu X, Qiu W, Yu Y. Long-Read Sequencing Solves Complex Structure of CYP21A2 in a Large 21-Hydroxylase Deficiency Cohort. J Clin Endocrinol Metab 2025; 110:406-416. [PMID: 39049755 DOI: 10.1210/clinem/dgae519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 07/10/2024] [Accepted: 07/23/2024] [Indexed: 07/27/2024]
Abstract
CONTEXT Genetic testing for 21-hydroxylase deficiency (21-OHD) is always challenging. The current approaches of short-read sequencing and multiplex ligation-dependent probe amplification (MLPA) are insufficient for the detection of chimeric genes or complicated variants from multiple copies. Recently developed long-read sequencing (LRS) can solve this problem. OBJECTIVE To investigate the clinical utility of LRS in precision diagnosis of 21-OHD. METHODS In the cohort of 832 patients with 21-OHD, the current approaches provided the precise molecular diagnosis for 81.7% (680/832) of cases. LRS was performed to solve the remaining 144 cases with complex chimeric variants and 8 cases with variants from multiple copies. Clinical manifestations in patients with continuous deletions of CYP21A2 extending to TNXB (namely CAH-X) were further evaluated. RESULTS Using LRS in combination with previous genetic test results, a total of 16.9% (281/1664) CYP21A1P/CYP21A2 or TNXA/TNXB chimeric alleles were identified in 832 patients, with CYP21A1P/CYP21A2 accounting for 10.4% and TNXA/TNXB for 6.5%. The top 3 common chimeras were CYP21 CH-1, TNX CH-1, and TNX CH-2, accounting for 77.2% (217/281) of all chimeric alleles. The 8 patients with variants on multiple copies of CYP21A2 were accurately identified with LRS. The prevalence of CAH-X in our cohort was 12.1%, and a high frequency of connective tissue-related symptoms was observed in CAH-X patients. CONCLUSION LRS can detect all types of CYP21A2 variants, including complex chimeras and pathogenic variants on multiple copies in patients with 21-OHD, which could be utilized as a first-tier routine test for the precision diagnosis and categorization of congenital adrenal hyperplasia.
Collapse
Affiliation(s)
- Ruifang Wang
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China
| | - Xiaomei Luo
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China
| | - Yu Sun
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China
| | - Lili Liang
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China
| | - Aiping Mao
- Department of Research and Development, Berry Genomics Corporation, Beijing 102200, China
| | - Deyun Lu
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China
| | - Kaichuang Zhang
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China
| | - Yi Yang
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China
| | - Yuning Sun
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China
| | - Manqing Sun
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China
| | - Lianshu Han
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China
| | - Huiwen Zhang
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China
| | - Xuefan Gu
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China
| | - Wenjuan Qiu
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China
| | - Yongguo Yu
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China
| |
Collapse
|
|
7
|
Lan T, Wang J, Chen K, Zhang J, Chen X, Yao H. Comparison of long-read sequencing and MLPA combined with long-PCR sequencing of CYP21A2 mutations in patients with 21-OHD. Front Genet 2024; 15:1472516. [PMID: 39553475 PMCID: PMC11563783 DOI: 10.3389/fgene.2024.1472516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 10/14/2024] [Indexed: 11/19/2024] Open
Abstract
Background 21-Hydroxylase deficiency (21-OHD) is caused by mutations in the CYP21A2 gene. Due to the complex structure and the high genetic heterogeneity of the CYP21A2 gene, genetic testing for 21-OHD is currently facing challenges. Moreover, there are no comparative studies on detecting CYP21A2 mutations by both second-generation sequencing and long-read sequencing (LRS, also known as third-generation sequencing). Objective To detect CYP21A2 variations in 21-OHD patients using targeted capture with LRS method based on the PacBio (Pacific Biosciences) Sequel II platform. Methods A total of 67 patients with 21-OHD were admitted in Wuhan Children's Hospital. The full sequence of CYP21A2 gene was analyzed by targeted capture combined with LRS based on the PacBio Sequel II platform. The results were compared with those of long-polymerase chain reaction (Long-PCR) combined with multiplex ligation probe amplification (MLPA) detection. Based on the in vitro study of 21-hydroxylase activity of common mutations, the patient genotypes were divided into groups of Null, A, B, and C, from severe to mild. The correlation between different genotype groups and clinical typing was observed. Results The study analyzed a total of 67 patients. Among them, 44 (65.67%) were males and 23 (34.33%) were females, with a male-to-female ratio of approximately 1.9:1. A total of 27 pathogenic variants were identified in the 67 patients, of which micro-conversion accounted for 61.9%, new variants of CYP21A2 accounted for 8.2%; deletion accounted for 22.4% (CYP21A2 single deletion and chimeric TNXA/TNXB accounted for 12.7%, chimeric CYP21A1P/CYP21A2 accounted for 9.7%); and duplication accounted for 3.0% (CYP21A2 Gene Duplication). I2G was the most common variant (26.9%). Targeted capture LRS and MLPA combined with Long-PCR detection of CYP21A2 mutations showed 30 detection results with differences. The overall genotype-phenotype correlation was 82.1%. The positive predictive rate of the Null group for salt wasting (SW) type was 84.6%, the A group for SW type was 88.9%, the group B for simple virilization (SV) type was 82.4%, and the group C for SV type was 62.5%. The correlation coefficient rs between the severity of the phenotype and the genotype group was 0.682 (P < 0.05). Conclusion Targeted capture combined with LRS is an integrated approach for detecting CYP21A2 mutations, allowing precise determination of connected sites for multiple deletions/insertions and cis/trans configurations without analyzing parental genomic samples. The overall genotype-phenotype correlation for 21-OHD is generally strong, with higher associations observed between genotype and phenotype for group Null, A, and B mutations, and larger genotype-phenotype variation in group C mutations. Targeted capture with LRS sequencing offers a new method for genetic diagnosis in 21-OHD patients.
Collapse
Affiliation(s)
- Tian Lan
- Department of Genetics, Metabolism and Endocrinology, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jin Wang
- Department of Genetics, Metabolism and Endocrinology, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kaibi Chen
- Department of Genetics, Metabolism and Endocrinology, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | | | - Xiaohong Chen
- Department of Genetics, Metabolism and Endocrinology, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hui Yao
- Department of Genetics, Metabolism and Endocrinology, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
8
|
Gurpinar Tosun B, Guran T. Rare forms of congenital adrenal hyperplasia. Clin Endocrinol (Oxf) 2024; 101:371-385. [PMID: 38126084 DOI: 10.1111/cen.15009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Revised: 11/10/2023] [Accepted: 12/07/2023] [Indexed: 12/23/2023]
Abstract
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders due to pathogenic variants in genes encoding enzymes and cofactors involved in adrenal steroidogenesis. Although 21-hydroxylase, 11β-hydroxylase, 3β-hydroxysteroid dehydrogenase type 2, 17α-hydroxylase/17,20-lyase, P450 oxidoreductase, steroidogenic acute regulatory protein, cholesterol side-chain cleavage enzyme deficiencies are considered within the definition of CAH, the term 'CAH' is often used to refer to '21-hydroxylase deficiency (21OHD)' since 21OHD accounts for approximately 95% of CAH in most populations. The prevalence of the rare forms of CAH varies according to ethnicity and geographical location. In most cases, the biochemical fingerprint of impaired steroidogenesis points to the specific subtypes of CAH, and genetic testing is usually required to confirm the diagnosis. Despite there are significant variations in clinical characteristics and management, most data about the rare CAH forms are extrapolated from 21OHD. This review article aims to collate the currently available data about the diagnosis and the management of rare forms of CAH.
Collapse
Affiliation(s)
- Busra Gurpinar Tosun
- Department of Paediatric Endocrinology and Diabetes, School of Medicine, Marmara University, Istanbul, Turkey
| | - Tulay Guran
- Department of Paediatric Endocrinology and Diabetes, School of Medicine, Marmara University, Istanbul, Turkey
| |
Collapse
|
|
9
|
Nowotny HF, Tschaidse L, Auer MK, Reisch N. Prenatal and Pregnancy Management of Congenital Adrenal Hyperplasia. Clin Endocrinol (Oxf) 2024; 101:359-370. [PMID: 39387451 DOI: 10.1111/cen.15131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 08/08/2024] [Accepted: 08/16/2024] [Indexed: 10/15/2024]
Abstract
Management of patients with congenital adrenal hyperplasia (CAH) poses challenges during pregnancy and prenatal stages, impacting fertility differently in men and women. Women with CAH experience menstrual irregularities due to androgen and glucocorticoid precursor interference with endometrial development and ovulation. Genital surgeries for virilization and urogenital anomalies further impact fertility and sexual function, leading to reduced heterosexual relationships among affected women. Fertility rates vary, with a lower prevalence of motherhood, primarily among those with classic CAH, necessitating optimized hormonal therapy for conception. Monitoring optimal disease control during pregnancy poses challenges due to hormonal fluctuations. Men with CAH often experience hypogonadotrophic hypogonadism and complications like testicular adrenal rest tissue, impacting fertility. Regular monitoring and intensified glucocorticoid therapy may restore spermatogenesis. Genetic counselling is vital to comprehend transmission risks and prenatal implications. Prenatal dexamethasone treatment in affected female fetuses prevents virilization but raises ethical and safety concerns, necessitating careful consideration and further research. The international "PREDICT" study aims to establish safer and more effective prenatal therapy in CAH, evaluating dosage, safety, and long-term effects.
Collapse
Affiliation(s)
| | - Lea Tschaidse
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Matthias K Auer
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Nicole Reisch
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| |
Collapse
|
|
10
|
Yuan D, Cai R, Mao A, Tan J, Zhong Q, Zeng D, Tang N, Wei X, Huang J, Zhang Y, Chen D, Yang J, Li Y, Zheng X, Li J, Li D, Yan T. Improved Genetic Characterization of Congenital Adrenal Hyperplasia by Long-Read Sequencing Compared with Multiplex Ligation-Dependent Probe Amplification Plus Sanger Sequencing. J Mol Diagn 2024; 26:770-780. [PMID: 38925455 DOI: 10.1016/j.jmoldx.2024.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 03/01/2024] [Accepted: 05/17/2024] [Indexed: 06/28/2024] Open
Abstract
Genetic analysis of congenital adrenal hyperplasia (CAH) has been challenging because of high homology between CYP21A2 and its pseudogene CYP21A1P. This study aimed to evaluate the clinical utility of long-read sequencing (LRS) in diagnosis of CAH attributable to 21-hydroxylase deficiency by comparing with multiplex ligation-dependent probe amplification plus Sanger sequencing. In this retrospective study, 69 samples, including 49 probands from 47 families with high-risk of CAH, were enrolled and blindly subjected to detection of CAH by LRS. The genotype results were compared with control methods, and discordant samples were validated by additional Sanger sequencing. LRS successfully identified biallelic variants of CYP21A2 in the 39 probands diagnosed as having CAH. The remaining 10 probands were not patients with CAH. Additionally, LRS directly identified two pathogenic single-nucleotide variations (SNVs; c.293-13C/A>G and c.955C>T) in the presence of interference caused by nearby insertions/deletions (indels). The cis-trans configuration of two or more SNVs and indels identified in 18 samples was directly determined by LRS without family analysis. Eight CYP21A1P/A2 or TNXA/B deletion chimeras, composed of five subtypes, were identified; and the junction sites were precisely determined. Moreover, LRS determined the exact genotype in two probands who had three heterozygous SNVs/indels and duplication, which could not be clarified by control methods. These findings highlight that LRS could assist in more accurate genotype imputation and more precise CAH diagnosis.
Collapse
Affiliation(s)
- Dejian Yuan
- Department of Medical Genetics, Liuzhou Municipal Maternity and Child Healthcare Hospital, Liuzhou, China; Department of Medical Genetics, Liuzhou Hospital of Guangzhou Women and Children's Medical Center, Liuzhou, China
| | - Ren Cai
- Department of Medical Genetics, Liuzhou Municipal Maternity and Child Healthcare Hospital, Liuzhou, China
| | - Aiping Mao
- Department of Research and Development, Berry Genomics Corp., Beijing, China
| | - Jianqiang Tan
- Department of Medical Genetics, Liuzhou Hospital of Guangzhou Women and Children's Medical Center, Liuzhou, China
| | - Qingyan Zhong
- Department of Medical Genetics, Liuzhou Municipal Maternity and Child Healthcare Hospital, Liuzhou, China
| | - Dingyuan Zeng
- Department of Gynecology, Liuzhou Municipal Maternity and Child Healthcare Hospital, Liuzhou 545001, Guangxi, China
| | - Ning Tang
- Department of Medical Genetics, Liuzhou Hospital of Guangzhou Women and Children's Medical Center, Liuzhou, China
| | - Xiaobao Wei
- Department of Medical Genetics, Liuzhou Hospital of Guangzhou Women and Children's Medical Center, Liuzhou, China
| | - Jun Huang
- Department of Medical Genetics, Liuzhou Municipal Maternity and Child Healthcare Hospital, Liuzhou, China
| | - Yu Zhang
- Department of Medical Genetics, Liuzhou Hospital of Guangzhou Women and Children's Medical Center, Liuzhou, China
| | - Dayu Chen
- Department of Medical Genetics, Liuzhou Municipal Maternity and Child Healthcare Hospital, Liuzhou, China
| | - Jinling Yang
- Department of Medical Genetics, Liuzhou Municipal Maternity and Child Healthcare Hospital, Liuzhou, China
| | - Yuanxiu Li
- Department of Medical Genetics, Liuzhou Hospital of Guangzhou Women and Children's Medical Center, Liuzhou, China
| | - Xiudan Zheng
- Department of Medical Genetics, Liuzhou Municipal Maternity and Child Healthcare Hospital, Liuzhou, China
| | - Jiaqi Li
- Department of Research and Development, Berry Genomics Corp., Beijing, China
| | - Danhua Li
- Department of Research and Development, Berry Genomics Corp., Beijing, China
| | - Tizhen Yan
- Department of Medical Genetics, Liuzhou Municipal Maternity and Child Healthcare Hospital, Liuzhou, China; Department of Prenatal Diagnosis Center, Dongguan Maternal and Child Health Hospital, Dongguan, China.
| |
Collapse
|
|
11
|
Adriaansen BPH, Utari A, Westra D, Juniarto AZ, Ariani MD, Ediati A, Schröder MAM, Span PN, Sweep FCGJ, Drop SLS, Faradz SMH, van Herwaarden AE, Claahsen – van der Grinten HL. 46,XX males with congenital adrenal hyperplasia: a clinical and biochemical description. Front Endocrinol (Lausanne) 2024; 15:1410122. [PMID: 39175568 PMCID: PMC11338787 DOI: 10.3389/fendo.2024.1410122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Accepted: 07/23/2024] [Indexed: 08/24/2024] Open
Abstract
Introduction Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) or 11-hydroxylase deficiency (11OHD) is characterized by underproduction of cortisol and overproduction of adrenal androgens. These androgens lead to a variable degree of virilization of the female external genitalia in 46,XX individuals. Especially in developing countries, diagnosis is often delayed and 46,XX patients might be assigned as males. This study aims to describe the clinical and biochemical characteristics of a unique cohort of untreated male-reared 46,XX classic CAH patients from Indonesia and discusses treatment challenges. Methods Nine untreated classic CAH patients with 46,XX genotype and 21OHD (n=6) or 11OHD (n=3), aged 3-46 years old, were included. Biometrical parameters, clinical characteristics, and biochemical measurements including glucocorticoids, renin, androgens, and the pituitary-gonadal axis were evaluated. Results All patients had low early morning serum cortisol concentrations (median 89 nmol/L) without significant increase after ACTH stimulation. Three patients with salt wasting 21OHD reported one or more periods with seizures and/or vomiting in their past until the age of 6, but not thereafter. The remaining patients reported no severe illness or hospitalization episodes, despite their decreased capacity to produce cortisol. In the 21OHD patients, plasma renin levels were elevated compared to the reference range, and in 11OHD patients renin levels were in the low-normal range. All adult patients had serum testosterone concentrations within the normal male reference range. In 21OHD patients, serum 11-oxygenated androgens comprised 41-60% of the total serum androgen concentrations. Glucocorticoid treatment was offered to all patients, but they refused after counseling as this would reduce their endogenous androgen production and they did not report complaints of their low cortisol levels. Discussion We describe a unique cohort of untreated classic 46,XX male CAH patients without overt clinical signs of cortisol deficiency despite their cortisol underproduction and incapacity to increase cortisol levels after ACTH stimulation. The described adolescent and adult patients produce androgen levels within or above the normal male reference range. Glucocorticoid treatment will lower these adrenal androgen concentrations. Therefore, in 46,XX CAH patients reared as males an individual treatment approach with careful counseling and clear instructions is needed.
Collapse
Affiliation(s)
- Bas P. H. Adriaansen
- Department of Pediatrics, Division of Pediatric Endocrinology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, Netherlands
- Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands
| | - Agustini Utari
- Center for Biomedical Research, Faculty of Medicine, Diponegoro University, Semarang, Indonesia
- Department of Pediatrics, Division of Pediatric Endocrinology, Faculty of Medicine, Diponegoro University, Semarang, Indonesia
| | - Dineke Westra
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
| | - Achmad Zulfa Juniarto
- Center for Biomedical Research, Faculty of Medicine, Diponegoro University, Semarang, Indonesia
| | - Mahayu Dewi Ariani
- Center for Biomedical Research, Faculty of Medicine, Diponegoro University, Semarang, Indonesia
| | | | - Mariska A. M. Schröder
- Department of Pediatrics, Division of Pediatric Endocrinology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, Netherlands
- Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands
| | - Paul N. Span
- Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Fred C. G. J. Sweep
- Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands
| | - Stenvert L. S. Drop
- Department of Pediatrics, Division of Endocrinology, Sophia Children’s Hospital, Erasmus Medical Center, Rotterdam, Netherlands
| | - Sultana M. H. Faradz
- Center for Biomedical Research, Faculty of Medicine, Diponegoro University, Semarang, Indonesia
| | | | - Hedi L. Claahsen – van der Grinten
- Department of Pediatrics, Division of Pediatric Endocrinology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, Netherlands
| |
Collapse
|
|
12
|
Olivera-Bernal GC, De Ita-Ley M, Ricárdez-Marcial EF, Garduño-Zarazúa LM, González-Cuevas ÁR, Sepúlveda-Robles OA, Huicochea-Montiel JC, Cárdenas-Conejo A, Santana-Díaz L, Rosas-Vargas H. Cytogenomic description of a Mexican cohort with differences in sex development. Mol Cytogenet 2024; 17:16. [PMID: 39010086 PMCID: PMC11251293 DOI: 10.1186/s13039-024-00685-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Accepted: 06/26/2024] [Indexed: 07/17/2024] Open
Abstract
BACKGROUND Differences in Sex Development (DSD) is a heterogeneous group of congenital alterations that affect inner and/or outer primary sex characters. Although these conditions do not represent a mortality risk, they can have a severe psycho-emotional impact if not appropriately managed. The genetic changes that can give rise to DSD are diverse, from chromosomal alterations to single base variants involved in the sexual development network. Epidemiological studies about DSD indicate a global frequency of 1:4500-5500, which can increase to 1:200-300, including isolated anatomical defects. To our knowledge, this study is the first to describe epidemiological and genetic features of DSD in a cohort of Mexican patients of a third-level care hospital. METHODS Descriptive and retrospective cross-sectional study that analyzed DSD patients from 2015 to 2021 attended a Paediatric Hospital from Mexico City. RESULTS One hundred one patients diagnosed with DSD were registered and grouped into different entities according to the Chicago consensus statement and the diagnosis defined by the multidisciplinary group. Of the total, 54% of them belong to the chromosomal DSD classification, 16% belongs to 46, XX and 30% of them belongs to the 46, XY classification. CONCLUSION The frequency for chromosomal DSDs was consistent with the literature; however, we found that DSD 46, XY is more frequent in our cohort, which may be due to the age of the patients captured, the characteristics of our study population, or other causes that depend on the sample size.
Collapse
Affiliation(s)
- Grecia C Olivera-Bernal
- Medical Research Unit in Human Genetics, Instituto Mexicano del Seguro Social (IMSS)/Hospital de Pediatría, Centro Médico Nacional SXXI, Ave. Cuauhtémoc 330, 06720, Mexico City, Mexico
| | - Marlon De Ita-Ley
- Medical Research Unit in Human Genetics, Instituto Mexicano del Seguro Social (IMSS)/Hospital de Pediatría, Centro Médico Nacional SXXI, Ave. Cuauhtémoc 330, 06720, Mexico City, Mexico
- Department of Genetics and Molecular Biology, Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Edgar F Ricárdez-Marcial
- Department of Genetics, Instituto Mexicano del Seguro Social (IMSS)/Hospital General Centro Médico Nacional "La Raza", Mexico City, Mexico
| | - Luz María Garduño-Zarazúa
- Medical Research Unit in Human Genetics, Instituto Mexicano del Seguro Social (IMSS)/Hospital de Pediatría, Centro Médico Nacional SXXI, Ave. Cuauhtémoc 330, 06720, Mexico City, Mexico
| | - Ángel Ricardo González-Cuevas
- Medical Research Unit in Human Genetics, Instituto Mexicano del Seguro Social (IMSS)/Hospital de Pediatría, Centro Médico Nacional SXXI, Ave. Cuauhtémoc 330, 06720, Mexico City, Mexico
| | - Omar A Sepúlveda-Robles
- Medical Research Unit in Human Genetics, Instituto Mexicano del Seguro Social (IMSS)/Hospital de Pediatría, Centro Médico Nacional SXXI, Ave. Cuauhtémoc 330, 06720, Mexico City, Mexico
| | - Juan Carlos Huicochea-Montiel
- Department of Paediatric Genetics, Instituto Mexicano del Seguro Social (IMSS)/Hospital de Pediatría, Centro Médico Nacional S XXI, Mexico City, Mexico
| | - Alan Cárdenas-Conejo
- Department of Paediatric Genetics, Instituto Mexicano del Seguro Social (IMSS)/Hospital de Pediatría, Centro Médico Nacional S XXI, Mexico City, Mexico
| | - Laura Santana-Díaz
- Department of Genetics, Instituto Mexicano del Seguro Social (IMSS)/Hospital General Centro Médico Nacional "La Raza", Mexico City, Mexico
| | - Haydeé Rosas-Vargas
- Medical Research Unit in Human Genetics, Instituto Mexicano del Seguro Social (IMSS)/Hospital de Pediatría, Centro Médico Nacional SXXI, Ave. Cuauhtémoc 330, 06720, Mexico City, Mexico.
| |
Collapse
|
|
13
|
Ravichandran L, Paul S, A R, Hs A, Mathai S, Simon A, Danda S, Thomas N, Chapla A. High carrier frequency of CYP21A2 gene mutations in Southern India - underscoring the need for genetic testing in Congenital Adrenal Hyperplasia. Endocrine 2024; 85:363-369. [PMID: 38441846 DOI: 10.1007/s12020-024-03747-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Accepted: 02/12/2024] [Indexed: 07/14/2024]
Abstract
PURPOSE Congenital Adrenal Hyperplasia (CAH) is one of the highly prevalent autosomal recessive endocrine disorders. The majority of CAH cases result from mutations in the CYP21A2 gene, leading to 21-hydroxylase deficiency. However, with the pseudogene-associated challenges in CYP21A2 gene analysis, routine genetic diagnostics and carrier screening in CAH are not a part of the first-tier investigations in a clinical setting. Furthermore, there is a lack of data on the carrier frequency for 21-OH deficiency. Therefore, this study is aimed at investigating the carrier frequency of common pseudogene derived CYP21A2 mutations in Southern India. METHODS Recently, a cost-effective Allele-specific PCR based genotyping for CYP21A2 hotspot mutations has been demonstrated to be a highly specific and sensitive assay at the authors' center. Leveraging this approach, a total of 1034 healthy individuals from South India underwent screening to identify the carrier frequency of nine hotspot mutations in the CYP21A2 gene. RESULTS In this study, it was observed that 9.76% of the subjects were carriers for one or more of the nine different CYP21A2 mutations. Among the carriers, the most common was the large 30 kb deletion, followed by II72N, E6 CLUS, and I2G mutations. CONCLUSION We have identified a high prevalence of CYP21A2 mutation carriers in Southern India. These findings emphasize the importance of implementing and expanding cost-effective genetic diagnostics and carrier screening throughout India. Such initiatives would play a crucial role in managing the disease burden, enabling early intervention, and establishing guidelines for CAH newborn genetic screening in the country. This study represents the first carrier screening data on CYP21A2 hotspot mutations from India and is the largest study conducted till date in this context.
Collapse
Affiliation(s)
- Lavanya Ravichandran
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, India
- Ph.D. Programme affiliated to, DBT-Regional Centre for Biotechnology (RCB), Faridabad, Haryana, India
| | - Shriti Paul
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, India
| | - Rekha A
- Department of Medical Genetics, Christian Medical College, Vellore, India
| | - Asha Hs
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, India
| | - Sarah Mathai
- Department of Pediatric Endocrinology, Christian Medical College, Vellore, India
| | - Anna Simon
- Department of Pediatric Endocrinology, Christian Medical College, Vellore, India
| | - Sumita Danda
- Department of Medical Genetics, Christian Medical College, Vellore, India
| | - Nihal Thomas
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, India
- DBT, Regional Centre for Biotechnology (RCB), Faridabad, Haryana, India
| | - Aaron Chapla
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, India.
- DBT, Regional Centre for Biotechnology (RCB), Faridabad, Haryana, India.
| |
Collapse
|
|
14
|
Culver SA, Suleman N, Kavuru V, Siragy HM. Renal Hypokalemia: An Endocrine Perspective. J Clin Endocrinol Metab 2024; 109:1694-1706. [PMID: 38546505 PMCID: PMC12102726 DOI: 10.1210/clinem/dgae201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Indexed: 06/18/2024]
Abstract
The majority of disorders that cause renal potassium wasting present with abnormalities in adrenal hormone secretion. While these findings frequently lead patients to seek endocrine evaluation, clinicians often struggle to accurately diagnose these conditions, delaying treatment and adversely impacting patient care. At the same time, growing insight into the genetic and molecular basis of these disorders continues to improve their diagnosis and management. In this review, we outline a practical integrated approach to the evaluation of renal hypokalemia syndromes that are seen in endocrine practice while highlighting recent advances in understanding of the genetics and pathophysiology behind them.
Collapse
Affiliation(s)
- Silas A Culver
- Division of Endocrinology, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Nawar Suleman
- Division of Endocrinology, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Varun Kavuru
- Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Helmy M Siragy
- Division of Endocrinology, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
| |
Collapse
|
|
15
|
Okpaise OO, Ahn H, Tonni G, Ruano R. Prenatal diagnosis and in utero treatment of congenital adrenal hyperplasia: An up-to-date comprehensive review. Prenat Diagn 2024; 44:635-643. [PMID: 38448010 DOI: 10.1002/pd.6542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 01/05/2024] [Accepted: 01/10/2024] [Indexed: 03/08/2024]
Abstract
Congenital adrenal hyperplasia (CAH) is a term that encompasses a wide range of conditions that affect the adrenals. Diagnosis and treatment before birth are important as irreparable birth defects can be avoided, decreasing the need for surgical intervention later in life, especially regarding genitalia anomalies. Although early implementation of dexamethasone in the prenatal treatment of CAH has been controversial, there is recent evidence that this treatment can reduce long-term complications.
Collapse
Affiliation(s)
| | - Hyunyoung Ahn
- Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology & Reproductive Sciences, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Gabriele Tonni
- Department of Obstetrics and Neonatology, Prenatal Diagnostic Centre, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), AUSL Reggio Emilia, Reggio Emilia, Italy
| | - Rodrigo Ruano
- Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology & Reproductive Sciences, University of Miami Miller School of Medicine, Miami, Florida, USA
- Women-Children Health Center of Excellence, Americas Group, United Health Care Brazil, São Paulo, Brazil
| |
Collapse
|
|
16
|
Ravichandran L, Asha HS, Mathai S, Thomas N, Chapla A. Congenital Adrenal Hyperplasia - A Comprehensive Review of Genetic Studies on 21-Hydroxylase Deficiency from India. Indian J Endocrinol Metab 2024; 28:117-128. [PMID: 38911104 PMCID: PMC11189293 DOI: 10.4103/ijem.ijem_303_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 09/23/2023] [Accepted: 02/06/2024] [Indexed: 06/25/2024] Open
Abstract
Congenital adrenal hyperplasia (CAH) comprises a heterogeneous group of autosomal recessive disorders impairing adrenal steroidogenesis. Most cases are caused by mutations in the CYP21A2 gene resulting in 21-hydroxylase (21-OH) deficiency (21-OHD). The genetics of 21-OH CAH is complexed by a highly homologous pseudogene CYP21A1P imposing several limitations in the molecular analysis. Therefore, genetic testing is still not a part of routine CAH diagnosis and is mainly dependent on 17-hydroxy progesterone (OHP) measurements. There are very few reports of CYP21A2 gene analysis from India and there is no comprehensive review available on genetic testing and the spectrum of CYP21A2 mutations from the country. This review focuses on the molecular aspects of 21-OHD and the genetic studies on CYP21A2 gene reported from India. The results of these studies insist the compelling need for large-scale CYP21A2 genetic testing and newborn screening (NBS) in India. With a high disease prevalence and consanguinity rates, robust and cost-effective genetic testing for 21-OH CAH would enable an accurate diagnosis in routine clinical practice. Whereas establishing affordable genotyping assays even in secondary care or resource-poor settings of the country can identify 90% of the mutations that are pseudogene derived, initiatives on reference laboratories for CAH across the nation with comprehensive genetic testing facilities will be beneficial in those requiring extended analysis of CYP21A2 gene. Further to this, incorporating genetic testing in NBS and carrier screening programmes will enable early diagnosis, better risk assessment and community-based management.
Collapse
Affiliation(s)
- Lavanya Ravichandran
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, Tamil Nadu, India
- DBT-Regional Centre for Biotechnology (RCB), Faridabad, Haryana, India
| | - Hesarghatta S. Asha
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, Tamil Nadu, India
| | - Sarah Mathai
- Department of Pediatric Endocrinology, Christian Medical College, Vellore, Tamil Nadu, India
| | - Nihal Thomas
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, Tamil Nadu, India
- DBT-Regional Centre for Biotechnology (RCB), Faridabad, Haryana, India
| | - Aaron Chapla
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, Tamil Nadu, India
- DBT-Regional Centre for Biotechnology (RCB), Faridabad, Haryana, India
| |
Collapse
|
|
17
|
Zhang R, Cui D, Song C, Ma X, Cai N, Zhang Y, Feng M, Cao Y, Chen L, Qiang R. Evaluating the efficacy of a long-read sequencing-based approach in the clinical diagnosis of neonatal congenital adrenocortical hyperplasia. Clin Chim Acta 2024; 555:117820. [PMID: 38307397 DOI: 10.1016/j.cca.2024.117820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/22/2024] [Accepted: 01/29/2024] [Indexed: 02/04/2024]
Abstract
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders predominantly characterized by impaired corticosteroid synthesis. Clinical phenotypes include hypoadrenocorticism, electrolyte disturbances, abnormal gonadal development, and short stature, of which severe hyponadrenocorticism and salt wasting can be life-threatening. Genetic analysis can help in the clinical diagnosis of CAH. However, the 21-OHD-causing gene CYP21A2 is arranged in tandem with the highly homologous CYP21A1P pseudogene, making it difficult to determine the exact genotypes using the traditional method of multiplex ligation-dependent probe amplification (MLPA) plus Sanger sequencing or next-generation sequencing (NGS). We applied a long-read sequencing-based approach termed comprehensive analysis of CAH (CACAH) to 48 newborns with CAH that were diagnosed by clinical features and the traditional MLPA plus Sanger sequencing method for retrospective analysis, to evaluate its efficacy in the clinical diagnosis of neonatal CAH. Compared with the MLPA plus Sanger sequencing method, CACAH showed 100 % consistency in detecting SNV/indel variants located in exons and exon-intron boundary regions of CAH-related genes. It can directly determine the cis-trans relationship without the need to analyze parental genotypes, which reduces the time to diagnosis. Moreover, CACAH was able to distinguish different CYP21A1P/CYP21A2 and TNXA/TNXB chimeras, and detect additional variants (CYP21A2 variants c.-121C > T, c.*13G > A, c.*52C > T, c.*440C > T, c.*443 T > C, and TNXB variants c.12463 + 2 T > C, c.12204 + 5G > A). We also identified the TNXB variant c.11435_11524 + 30del alone instead of as a part of the TNXA/TNXB-CH-1 chimera in two newborns, which might be introduced by gene conversion. All of these characteristics enabled clinicians to better explain the phenotype of subjects and manage them more effectively. CACAH has a great advantage over the traditional MLPA and Sanger sequencing methods, showing substantial potential in the genetic diagnosis and screening of neonatal CAH.
Collapse
Affiliation(s)
- Ruixue Zhang
- Center of Neonatal Disease Screening, Department of Clinical Genetics, Northwest Women's and Children's Hospital, China
| | - Di Cui
- Berry Genomics Corporation, Beijing 102200, China
| | - Chengrong Song
- Center of Neonatal Disease Screening, Department of Clinical Genetics, Northwest Women's and Children's Hospital, China
| | - Xiaoping Ma
- Center of Neonatal Disease Screening, Department of Clinical Genetics, Northwest Women's and Children's Hospital, China
| | - Na Cai
- Center of Neonatal Disease Screening, Department of Clinical Genetics, Northwest Women's and Children's Hospital, China
| | - Yan Zhang
- Center of Neonatal Disease Screening, Department of Clinical Genetics, Northwest Women's and Children's Hospital, China
| | - Mei Feng
- Center of Neonatal Disease Screening, Department of Clinical Genetics, Northwest Women's and Children's Hospital, China
| | - Yanlin Cao
- Berry Genomics Corporation, Beijing 102200, China
| | - Libao Chen
- Berry Genomics Corporation, Beijing 102200, China
| | - Rong Qiang
- Center of Neonatal Disease Screening, Department of Clinical Genetics, Northwest Women's and Children's Hospital, China.
| |
Collapse
|
|
18
|
Schröder MAM, Neacşu M, Adriaansen BPH, Sweep FCGJ, Ahmed SF, Ali SR, Bachega TASS, Baronio F, Birkebæk NH, de Bruin C, Bonfig W, Bryce J, Clemente M, Cools M, Elsedfy H, Globa E, Guran T, Güven A, Amr NH, Janus D, Taube NL, Markosyan R, Miranda M, Poyrazoğlu Ş, Rees A, Salerno M, Stancampiano MR, Vieites A, de Vries L, Yavas Abali Z, Span PN, Claahsen-van der Grinten HL. Hormonal control during infancy and testicular adrenal rest tumor development in males with congenital adrenal hyperplasia: a retrospective multicenter cohort study. Eur J Endocrinol 2023; 189:460-468. [PMID: 37837609 DOI: 10.1093/ejendo/lvad143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 08/28/2023] [Accepted: 09/19/2023] [Indexed: 10/16/2023]
Abstract
IMPORTANCE Testicular adrenal rest tumors (TARTs), often found in male patients with congenital adrenal hyperplasia (CAH), are benign lesions causing testicular damage and infertility. We hypothesize that chronically elevated adrenocorticotropic hormone exposure during early life may promote TART development. OBJECTIVE This study aimed to examine the association between commencing adequate glucocorticoid treatment early after birth and TART development. DESIGN AND PARTICIPANTS This retrospective multicenter (n = 22) open cohort study collected longitudinal clinical and biochemical data of the first 4 years of life using the I-CAH registry and included 188 male patients (median age 13 years; interquartile range: 10-17) with 21-hydroxylase deficiency (n = 181) or 11-hydroxylase deficiency (n = 7). All patients underwent at least 1 testicular ultrasound. RESULTS TART was detected in 72 (38%) of the patients. Prevalence varied between centers. When adjusted for CAH phenotype, a delayed CAH diagnosis of >1 year, compared with a diagnosis within 1 month of life, was associated with a 2.6 times higher risk of TART diagnosis. TART onset was not predicted by biochemical disease control or bone age advancement in the first 4 years of life, but increased height standard deviation scores at the end of the 4-year study period were associated with a 27% higher risk of TART diagnosis. CONCLUSIONS AND RELEVANCE A delayed CAH diagnosis of >1 year vs CAH diagnosis within 1 month after birth was associated with a higher risk of TART development, which may be attributed to poor disease control in early life.
Collapse
Affiliation(s)
- Mariska A M Schröder
- Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Laboratory Medicine, Radboudumc Graduate School, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Mihaela Neacşu
- Department of Laboratory Medicine, Radboudumc Graduate School, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Bas P H Adriaansen
- Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Laboratory Medicine, Radboudumc Graduate School, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Fred C G J Sweep
- Department of Laboratory Medicine, Radboudumc Graduate School, Radboud University Medical Center, Nijmegen, The Netherlands
| | - S Faisal Ahmed
- Developmental Endocrinology Research Group, University of Glasgow, Glasgow, United Kingdom
- Office of Rare Conditions, University of Glasgow, Glasgow, United Kingdom
| | - Salma R Ali
- Developmental Endocrinology Research Group, University of Glasgow, Glasgow, United Kingdom
- Office of Rare Conditions, University of Glasgow, Glasgow, United Kingdom
| | - Tânia A S S Bachega
- Laboratory of Hormones and Molecular Genetics-LIM 42, Department of Endocrinology and Metabolism, University of Sao Paulo, Sao Paulo, Brazil
| | - Federico Baronio
- Department Hospital of Woman and Child, Pediatric Unit, IRCCS AOU di Bologna, Policlinico di S.Orsola, Bologna, Italy
| | - Niels Holtum Birkebæk
- Department of Pediatrics and Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
| | - Christiaan de Bruin
- Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
| | - Walter Bonfig
- Department of Pediatrics, Technical University Munich, Munich, Germany
- Department of Pediatrics, Klinikum Wels-Grieskirchen, Wels, Austria
| | - Jillian Bryce
- Office of Rare Conditions, University of Glasgow, Glasgow, United Kingdom
| | - Maria Clemente
- Pediatric Endocrinology Unit, Hospital Vall d'Hebron, Autonomous University of Barcelona, CIBERER, Barcelona, Spain
| | - Martine Cools
- Pediatric Endocrinology, Internal Medicine and Pediatric Research Unit, University Hospital Ghent, Ghent University, Ghent, Belgium
| | - Heba Elsedfy
- Pediatrics Department, Ain Shams University, Cairo, Egypt
| | - Evgenia Globa
- Ukrainian Research Center of Endocrine Surgery, Endocrine Organs and Tissue Transplantation, MOH of Ukraine, Kyiv, Ukraine
| | - Tulay Guran
- Pediatric Endocrinology and Diabetes, Marmara University, Istanbul, Turkey
| | - Ayla Güven
- Baskent University Medical Faculty, Istanbul Hospital, Pediatrics Department, Ain Shams University, Cairo, Egypt
| | | | - Dominika Janus
- Department of Pediatric and Adolescent Endocrinology, Institute of Pediatrics, Jagiellonian University Medical College, and Children's University Hospital, Krakow, Poland
| | - Nina Lenherr Taube
- Department of Pediatrics, Division of Endocrinology, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland
| | | | - Mirela Miranda
- Laboratory of Hormones and Molecular Genetics-LIM 42, Department of Endocrinology and Metabolism, University of Sao Paulo, Sao Paulo, Brazil
| | - Şükran Poyrazoğlu
- İstanbul Faculty of Medicine, Unit of Pediatric Endocrinology, İstanbul University, İstanbul, Turkey
| | - Aled Rees
- Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom
| | - Mariacarolina Salerno
- Pediatric Endocrine Unit, Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Marianna Rita Stancampiano
- Department of Pediatrics, Endocrine Unit, IRCCS San Raffaele Scientific Institute, Endo-ERN Center for Rare Endocrine Conditions, Milan, Italy
| | - Ana Vieites
- Centro de Investigaciones Endocrinológicas Buenos Aires, Buenos Aires, Argentina
| | - Liat de Vries
- The Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel and Felsenstein Medical Research Center at Petach Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Zehra Yavas Abali
- Pediatric Endocrinology and Diabetes, Marmara University, Istanbul, Turkey
| | - Paul N Span
- Radiotherapy & OncoImmunology Laboratory, Department of Radiation Oncology, Radboudumc Graduate School, Radboud University Medical Center, Nijmegen, The Netherlands
| | | |
Collapse
|
|
19
|
Tian Y, Hou L, Xiang S, Tian X, Xu J. Congenital adrenal hyperplasia disorder due to 17 α-hydroxylase deficiency: a case report. Gynecol Endocrinol 2023; 39:2250001. [PMID: 37683689 DOI: 10.1080/09513590.2023.2250001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 06/06/2023] [Accepted: 08/14/2023] [Indexed: 09/10/2023] Open
Abstract
Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder with a related enzyme deficiency involved in the adrenal corticosteroid synthesis pathway due to genetic mutations. 17α-hydroxylase deficiency(17α-OHD) is a rare form of CAH. Herein, we reported clinical data on diagnosis and treatment regimens for a 17α-hydroxylase-deficient patient. A 24-year-old female patient was admitted to the hospital with limb numbness for 7 days and sudden limb weakness. Full laboratory and radio-imaging investigations showed hypokalemia and abdominal occupation. Abnormal rhythm of cortisol(Cor) and adrenocorticotrophic hormone (ACTH)was observed. The diagnosis was confirmed by molecular mutation detection, which showed a homozygous mutation of c.987del in the 17-hydroxylase/17,20-lyase deficiency (17OHD) lease-related CYP17A1 from both biological parents. The patient was treated with prednisone acetate and estradiol valerate. After one year of treatment with predisoone acetate and estradiol valerate, the patient had normal menstruation, increased blood potassium, estradiol and 24h-UFC, and decreased ACTH level. There is no significant change in large adrenal hyperplasia lesions although sexual characteristics and menstrual cycles have recovered. Through this case and literature review, it can be concluded that CAH with 17α-OHD can be diagnosed according to the genetic detection.
Collapse
Affiliation(s)
- Yunling Tian
- Department of Endocrinology and Metabolic, The First Hospital of Lanzhou University, Lanzhou, Gansu, P.R.China
| | - Lijie Hou
- Department of Endocrinology and Metabolic, The First Hospital of Lanzhou University, Lanzhou, Gansu, P.R.China
| | - Shulan Xiang
- Department of General Family Medicine, The First Hospital of Lanzhou University, Lanzhou, Gansu, P.R.China
| | - Xuguang Tian
- Lintao Country People's Hospital, Lintao, Dingxi, Gansu, P.R.China
| | - Jinhui Xu
- Department of Respiratory medicine, The First Hospital of Lanzhou University, Lanzhou, Gansu, P.R.China
| |
Collapse
|
|
20
|
Albu AI, Iancu ME, Albu DN. Successful Treatment of Infertility in a Patient with Probable 17 Hydroxylase Deficiency and Particularities of Association with Adrenal Autoimmunity—A Case Report and Review of the Literature. Life (Basel) 2023; 13:life13040921. [PMID: 37109450 PMCID: PMC10143317 DOI: 10.3390/life13040921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 03/11/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023] Open
Abstract
Congenital adrenal hyperplasia (CAH) due to 17-hydroxylase deficiency (17OHD) is a rare disease accounting for less than 1% of cases of CAH. In female patients, fertility is severely affected mainly due to constantly increased progesterone affecting endometrium receptivity and implantation. The optimal treatment for infertility in these patients is not clearly established, with only a few recent case reports of successful pregnancies available in the literature. Hereby, we present the case of an infertile female patient with 17OHD who obtained pregnancy through an in vitro fertilization (IVF) freeze-all strategy and particularities of association with adrenal autoimmunity. A 32-year-old infertile female patient was referred for infertility evaluation and treatment. She had normal sex development and menstrual history with oligomenorrhea alternating with normal menstrual cycles. During the evaluation, a reduced ovarian reserve and obstruction of the left fallopian tube were identified, and IVF treatment was recommended. During a controlled ovarian stimulation for IVF, increased values of serum progesterone were observed; thus, all the embryos were frozen and additional tests were performed. Increased values of 17-hydroxyprogesteron, 11-deoxycorticosteron, and adrenocorticotropic hormones in association with low basal and stimulated serum cortisol, testosterone, androstenedione, and dehydroepiandrosterone sulfate were found, supporting the presence of 17OHD. She started treatment with oral hydrocortisone given at 20 mg/day but, because follicular phase serum progesterone remained high, hydrocortisone was replaced by an oral dexamethasone treatment of 0.5 mg/day, followed by the normalization of serum progesterone. A thawed blastocyst was transferred after preparation with oral estradiol at 6 mg/day and intravaginal progesterone at 600 mg/day under continuous suppression of endogenous progesterone production with a gonadotropin-releasing hormone agonist and oral dexamethasone. The patient became pregnant and delivered two healthy girls at term. One year after delivery, the presence of 21-hydroxylase antibodies was detected, which might explain the particularities of adrenal steroids in our patient. Our case report demonstrates that a patient with 17OHD can become pregnant through IVF and the transfer of thawed embryos in a subsequent cycle under continuous suppression of adrenal and ovarian progesterone production.
Collapse
Affiliation(s)
- Alice Ioana Albu
- Department of Endocrinology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Endocrinology Department, Elias Hospital, 011461 Bucharest, Romania
- Correspondence:
| | | | - Dragos Nicolae Albu
- Department of Obstetrics and Gynecology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania;
- Reproductive Medicine Department, Medlife Hospital, 010719 Bucharest, Romania
| |
Collapse
|
|
21
|
Tang P, Zhang J, Peng S, Wang Y, Li H, Wang Z, Zhang Y, Huang Y, Xu J, Zhang D, Liu Q, Wang L, Lan W, Jiang J. Genotype-phenotype correlation in patients with 21-hydroxylase deficiency. Front Endocrinol (Lausanne) 2023; 14:1095719. [PMID: 36992809 PMCID: PMC10042299 DOI: 10.3389/fendo.2023.1095719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 01/26/2023] [Indexed: 03/16/2023] Open
Abstract
INTRODUCTION 21-hydroxylase deficiency (21OHD) is the most common cause of congenital adrenal hyperplasia (CAH). However, patients with 21OHD manifest various phenotypes due to a wide-spectrum residual enzyme activity of different CYP21A2 mutations. METHODS A total of 15 individuals from three unrelated families were included in this study. Target Capture-Based Deep Sequencing and Restriction Fragment Length Polymorphism was conducted on peripheral blood DNA of the three probands to identify potential mutations/deletions in CYP21A2; Sanger sequencing was conducted with the DNA from the family members of the probands. RESULTS Dramatically different phenotypes were seen in the three probands of CAH with different compound heterozygous mutations in CYP21A2. Proband 1 manifested simple virilizing with mutations of 30-kb deletion/c.[188A>T;518T>A], the latter is a novel double mutants classified as SV associated mutation. Although both probands carry the same compound mutations [293-13C>G]:[518T>A], gonadal dysfunction and giant bilateral adrenal myelolipoma were diagnosed for proband 2 and proband 3, respectively. CONCLUSION Both gender and mutations contribute to the phenotypes, and patients with the same compound mutations and gender could present with different phenotypes. Genetic analysis could help the etiologic diagnosis, especially for atypical 21OHD patients.
Collapse
Affiliation(s)
- Peng Tang
- Department of Urology, Daping Hospital, Army Medical University, Chongqing, China
| | - Jun Zhang
- Department of Urology, Daping Hospital, Army Medical University, Chongqing, China
| | - Song Peng
- Department of Urology, Daping Hospital, Army Medical University, Chongqing, China
| | - Yapeng Wang
- Department of Urology, Daping Hospital, Army Medical University, Chongqing, China
| | - Haoyang Li
- Fifteen Squadron Five Brigade, School of Basic Medical Science, Army Medical University, Chongqing, China
| | - Ze Wang
- Department of Urology, Daping Hospital, Army Medical University, Chongqing, China
| | - Yao Zhang
- Department of Urology, Daping Hospital, Army Medical University, Chongqing, China
| | - Yiqiang Huang
- Department of Urology, Daping Hospital, Army Medical University, Chongqing, China
| | - Jing Xu
- Department of Urology, Daping Hospital, Army Medical University, Chongqing, China
| | - Dianzheng Zhang
- Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA, United States
| | - Qiuli Liu
- Department of Urology, Daping Hospital, Army Medical University, Chongqing, China
| | - Luofu Wang
- Department of Urology, Daping Hospital, Army Medical University, Chongqing, China
| | - Weihua Lan
- Department of Urology, Daping Hospital, Army Medical University, Chongqing, China
- *Correspondence: Jun Jiang, ; Weihua Lan,
| | - Jun Jiang
- Department of Urology, Daping Hospital, Army Medical University, Chongqing, China
- *Correspondence: Jun Jiang, ; Weihua Lan,
| |
Collapse
|
|
22
|
Tosun BG, Guran T. Congenital adrenal hyperplasia and hypertension. ENDOCRINE HYPERTENSION 2023:113-125. [DOI: 10.1016/b978-0-323-96120-2.00015-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
|
|
23
|
Paul B, Shewade LH, Buchholz DR. cyp21a2 Knockout Tadpoles Survive Metamorphosis Despite Low Corticosterone. Endocrinology 2022; 164:6775874. [PMID: 36301177 DOI: 10.1210/endocr/bqac182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Indexed: 01/16/2023]
Abstract
Corticosteroids are so vital for organ maturation that reduced corticosteroid signaling during postembryonic development causes death in terrestrial vertebrates. Indeed, death occurs at metamorphosis in frogs lacking proopiomelanocortin (pomc) or the glucocorticoid receptor (GR; nr3c1). Some residual corticosteroids exist in pomc mutants to activate the wild-type (WT) GR and mineralocorticoid receptor (MR), and the elevated corticosteroids in GR mutants may activate MR. Thus, we expected a more severe developmental phenotype in tadpoles with inactivation of 21-hydroxylase, which should eliminate all interrenal corticosteroid biosynthesis. Using CRISPR/Cas9 in Xenopus tropicalis, we produced an 11-base pair deletion in cyp21a2, the gene encoding 21-hydroxylase. Growth and development were delayed in cyp21a2 mutant tadpoles, but unlike the other frog models, they survived metamorphosis. Consistent with an absence of 21-hydroxylase, mutant tadpoles had a 95% reduction of aldosterone in tail tissue, but they retained some corticosterone (∼40% of WT siblings), an amount, however, too low for survival in pomc mutants. Decreased corticosteroid signaling was evidenced by reduced expression of corticosteroid-response gene, klf9, and by impaired negative feedback in the hypothalamus-pituitary-interrenal axis with higher messenger RNA expression levels of crh, pomc, star, and cyp11b2 and an approximately 30-fold increase in tail content of progesterone. In vitro tail-tip culture showed that progesterone can transactivate the frog GR. The inadequate activation of GR by corticosterone in cyp21a2 mutants was likely compensated for by sufficient corticosteroid signaling from other GR ligands to allow survival through the developmental transition from aquatic to terrestrial life.
Collapse
Affiliation(s)
- Bidisha Paul
- Department of Biological Sciences, University of Cincinnati, Cincinnati, OH 45221, USA
| | - Leena H Shewade
- Biotherapeutics Division, Codexis Inc., San Carlos, CA 94070, USA
| | - Daniel R Buchholz
- Department of Biological Sciences, University of Cincinnati, Cincinnati, OH 45221, USA
| |
Collapse
|
|
24
|
Cera G, Locantore P, Novizio R, Maggio E, Ramunno V, Corsello A, Policola C, Concolino P, Paragliola RM, Pontecorvi A. Pregnancy and Prenatal Management of Congenital Adrenal Hyperplasia. J Clin Med 2022; 11:jcm11206156. [PMID: 36294476 PMCID: PMC9605322 DOI: 10.3390/jcm11206156] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/26/2022] [Accepted: 10/15/2022] [Indexed: 11/21/2022] Open
Abstract
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive diseases that may cause cortisol insufficiency together with other hormonal alterations. The most common form is 21-hydroxylase deficiency, in which the lack of pituitary negative feedback causes an increase in ACTH and adrenal androgens. Classical forms of CAHs can lead to severe adrenal failure and female virilization. To date, the appropriate management of pregnant CAH patients is still debated regarding appropriate maternal therapy modifications during pregnancy and the risks and benefits of prenatal treatment of the fetus. We conducted a literature search of relevant papers to collect current evidence and experiences on the topic. The most recent and significant articles were selected, and current international guidelines were consulted to update current recommendations and guide clinical practice. Given the lack of randomized clinical trials and other high-quality scientific evidence, the issue is still debated, and great heterogeneity exists in current practice in terms of risk/benefit evaluation and pharmacological choices for pregnancy and prenatal treatment. Glucocorticoid therapy is advised not only in classical CAH patients but also in non-classical, milder forms. The choice of which glucocorticoid to use, and the safety and benefits of dexamethasone therapy aimed at preventing genital virilization are still debated issues. Several advances, however, have been made, especially in terms of fertility and reproduction. This review aims to present the most recent scientific and real-world updates on pregnancy and prenatal management of CAH, with the presentation of various clinical scenarios and specific case-by-case recommendations.
Collapse
Affiliation(s)
- Gianluca Cera
- Unit of Endocrinology, Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore—Fondazione Policlinico “A. Gemelli” IRCCS, Largo Gemelli 8, 00168 Rome, Italy
| | - Pietro Locantore
- Unit of Endocrinology, Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore—Fondazione Policlinico “A. Gemelli” IRCCS, Largo Gemelli 8, 00168 Rome, Italy
- Correspondence:
| | - Roberto Novizio
- Unit of Endocrinology, Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore—Fondazione Policlinico “A. Gemelli” IRCCS, Largo Gemelli 8, 00168 Rome, Italy
| | - Ettore Maggio
- Unit of Endocrinology, Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore—Fondazione Policlinico “A. Gemelli” IRCCS, Largo Gemelli 8, 00168 Rome, Italy
| | - Vittoria Ramunno
- Unit of Endocrinology, Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore—Fondazione Policlinico “A. Gemelli” IRCCS, Largo Gemelli 8, 00168 Rome, Italy
| | - Andrea Corsello
- Unit of Endocrinology, Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore—Fondazione Policlinico “A. Gemelli” IRCCS, Largo Gemelli 8, 00168 Rome, Italy
| | - Caterina Policola
- Unit of Endocrinology, Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore—Fondazione Policlinico “A. Gemelli” IRCCS, Largo Gemelli 8, 00168 Rome, Italy
| | - Paola Concolino
- Unit of Clinical Chemistry, Biochemistry and Molecular Biology, Department of Laboratory and Infectiology Sciences, Università Cattolica del Sacro Cuore—Fondazione Policlinico “A. Gemelli” IRCCS, Largo Gemelli 8, 00168 Rome, Italy
| | - Rosa Maria Paragliola
- Unit of Endocrinology, Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore—Fondazione Policlinico “A. Gemelli” IRCCS, Largo Gemelli 8, 00168 Rome, Italy
- Unicamillus, Saint Camillus International University of Medical Sciences, Via di S. Alessandro 10, 00131 Rome, Italy
| | - Alfredo Pontecorvi
- Unit of Endocrinology, Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore—Fondazione Policlinico “A. Gemelli” IRCCS, Largo Gemelli 8, 00168 Rome, Italy
| |
Collapse
|
|
25
|
Leventoğlu E, Döğer E, Büyükkaragöz B, Nalçacı S, Öner G, Alpman BN, Fidan K, Söylemezoğlu O, Bakkaloğlu SA. Late-onset hypertension in a child with growth retardation: Answers. Pediatr Nephrol 2022; 37:2341-2345. [PMID: 35288793 DOI: 10.1007/s00467-022-05510-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 01/28/2022] [Accepted: 01/31/2022] [Indexed: 12/25/2022]
Affiliation(s)
- Emre Leventoğlu
- Department of Pediatric Nephrology, Faculty of Medicine, Gazi University, Ankara, Turkey.
| | - Esra Döğer
- Department of Pediatric Endocrinology, Gazi University, Ankara, Turkey
| | - Bahar Büyükkaragöz
- Department of Pediatric Nephrology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Sinem Nalçacı
- Department of Pediatric Endocrinology, Gazi University, Ankara, Turkey
| | - Ganimet Öner
- Department of Pediatric Endocrinology, Gazi University, Ankara, Turkey
| | - Bedriye Nuray Alpman
- Department of Pediatric Nephrology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Kibriya Fidan
- Department of Pediatric Nephrology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Oğuz Söylemezoğlu
- Department of Pediatric Nephrology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Sevcan A Bakkaloğlu
- Department of Pediatric Nephrology, Faculty of Medicine, Gazi University, Ankara, Turkey
| |
Collapse
|
|
26
|
Gong Y, Qin F, Li WJ, Li LY, He P, Zhou XJ. Cytochrome P450 family 17 subfamily A member 1 mutation causes severe pseudohermaphroditism: A case report. World J Clin Cases 2022; 10:3553-3560. [PMID: 35611191 PMCID: PMC9048556 DOI: 10.12998/wjcc.v10.i11.3553] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 01/29/2022] [Accepted: 02/27/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND 17α-Hydroxylase deficiency (17-OHD) is a rare form of congenital adrenal hyperplasia, characterized by hypertension, hypokalemia, and gonadal dysplasia. However, due to the lack of a comprehensive understanding of this disease, it is prone to misdiagnosis and missed diagnosis, and there is no complete cure.
CASE SUMMARY We report a female patient with 17-OHD. The patient was admitted to the Department of Neurology of our hospital due to limb weakness. During treatment, it was found that the patient’s condition was difficult to correct except for hypokalemia, and her blood pressure was difficult to control with various antihypertensive drugs. She was then transferred to our department for further treatment. On physical examination, the patient's gonadal development was found to be abnormal, and chromosome analysis demonstrated karyotype 46,XY. Considering the possibility of 17-OHD, the cytochrome P450 family 17 subfamily A member 1 (CYP17A1) test was performed to confirm the diagnosis.
CONCLUSION The clinical manifestations of 17-OHD are complex. Hormone determination, imaging examination, chromosome determination and CYP17A1 gene test are helpful for early diagnosis.
Collapse
Affiliation(s)
- Yu Gong
- Department of Endocrine and Metabolism, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang 441000, Hubei Province, China
| | - Fang Qin
- Department of Endocrine and Metabolism, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang 441000, Hubei Province, China
| | - Wen-Jia Li
- Department of Endocrine and Metabolism, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang 441000, Hubei Province, China
| | - Le-Yu Li
- Department of Endocrine and Metabolism, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang 441000, Hubei Province, China
| | - Ping He
- Department of Endocrine and Metabolism, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang 441000, Hubei Province, China
| | - Xing-Jian Zhou
- Department of Endocrine and Metabolism, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang 441000, Hubei Province, China
| |
Collapse
|
|
27
|
Beştaş A, Bolu S, Unal E, Aktar Karakaya A, Eröz R, Tekin M, Haspolat YK. A rare cause of delayed puberty and primary amenorrhea: 17α-hydroxylase enzyme deficiency. Endocrine 2022; 75:927-933. [PMID: 34724156 DOI: 10.1007/s12020-021-02914-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 10/13/2021] [Indexed: 12/13/2022]
Abstract
AIM 17α-hydroxylase enzyme deficiency is a rare form of congenital adrenal hyperplasia (CAH) and is caused by mutations in the CYP17A1 gene. The main clinical findings are delayed puberty and primary amenorrhea in girls, and disorders of sex development in boys. It can also cause hypertension and hypokalemia in both genders. In this study, we aimed to present the clinical, laboratory and genetic results of 13 patients from eight different families who were diagnosed with complete 17α-hydroxylase enzyme deficiency. METHODS The age, symptoms, anthropometric measurements, blood pressure, Tanner stages, and hormonal and chromosome analysis results at the time of admission were recorded from the medical records of the patients. Whole gene next-generation sequencing of CYP17A1 gene was performed to detect mutations. Multiplex ligation dependent probe amplification (MLPA) method were used to detect deletions in the seven patients who had no point mutation were detected in the CYP17A1 gene. RESULTS The average age of the patients at the time of admission was 14.8 (range: 12.9-16.6) years. Also at this time, all patients were in adolescence and were raised as females. The karyotypes of eight patients were 46,XY, and of five patients were 46,XX. Ten patients presented with delayed puberty and primary amenorrhea, one patient with delayed puberty and hypertension, and two patients with hypertension and/or hypokalemia. Hypertension and hypokalemia were detected in nine and seven patients, respectively. CONCLUSIONS P450c17 enzyme deficiency should be considered in patients presenting with delayed puberty or primary amenorrhea in the adolescence period and diagnosed with hypergonadotropic hypogonadism, if hypertension and hypokalemia accompany. Early diagnosis prevents the occurrence of important health problems such as hypertension, psychological problems, and gender identity disorders, which affect the majority of these patients.
Collapse
Affiliation(s)
- Aslı Beştaş
- Faculty of Medicine, Department of Pediatric Endocrinology, Dicle University, Diyarbakır, Turkey.
| | - Semih Bolu
- Department of Pediatric Endocrinology, Adıyaman Training and Research Hospital, Adıyaman, Turkey
| | - Edip Unal
- Faculty of Medicine, Department of Pediatric Endocrinology, Dicle University, Diyarbakır, Turkey
| | - Amine Aktar Karakaya
- Faculty of Medicine, Department of Pediatric Endocrinology, Dicle University, Diyarbakır, Turkey
| | - Recep Eröz
- Medical Faculty, Department of Medical Genetics, Duzce University, Duzce, Turkey
| | - Mehmet Tekin
- Department of Pediatrics, Adıyaman Training and Research Hospital, Adıyaman, Turkey
| | - Yusuf Kenan Haspolat
- Faculty of Medicine, Department of Pediatric Endocrinology, Dicle University, Diyarbakır, Turkey
| |
Collapse
|
|
28
|
Zhao Z, Gao Y, Lu L, Tong A, Chen S, Zhang W, Zhang X, Sun B, Wu X, Mao J, Wang X, Nie M. The underlying cause of the simple virilizing phenotype in patients with 21-hydroxylase deficiency harboring P31L variant. Front Endocrinol (Lausanne) 2022; 13:1015773. [PMID: 36866166 PMCID: PMC9972294 DOI: 10.3389/fendo.2022.1015773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 11/11/2022] [Indexed: 02/16/2023] Open
Abstract
OBJECTIVE To analyze the relationship between genotype and phenotype in 21-Hydroxylase deficiency patients harboring P31L variant and the underlying mechanism. METHODS A total of 29 Chinese patients with 21-OHD harboring P31L variant were recruited, and the detailed clinical features of the patients were extracted and analyzed retrospectively. The TA clone combined with sequencing of the region containing the promotor and exon1 of CYP21A2 was performed to determine whether the variants in promotor and P31L aligned in cis. We further compared the clinical characteristics of 21-OHD patients between the promoter variant group and no promoter variant group. RESULTS Among the 29 patients diagnosed with 21-OHD harboring P31L variant, the incidence of classical simple virilizing form was 62.1%. Thirteen patients owned promoter variants (1 homozygote and 12 heterozygote) and all exhibited SV form. The promoter variants and the P31L variant were located in the same mutant allele as validated by TA cloning and sequencing. There were statistically significant differences in clinical phenotype and 17-OHP level between the patients with and without promoter region variations (P<0.05). CONCLUSION There exists high incidence (57.4%) of SV form among the 21-OHD patients harboring P31L variant, and the underlying mechanism is partially due to both the promoter variants and P31L aligning in cis on one allele. Further sequencing of promoter region will provide important hints for the explanation of phenotype in patients harboring P31L.
Collapse
Affiliation(s)
- Zhiyuan Zhao
- Department of Endocrinology, National Health Commission (NHC) Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Yinjie Gao
- Department of Endocrinology, National Health Commission (NHC) Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Lin Lu
- Department of Endocrinology, National Health Commission (NHC) Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Anli Tong
- Department of Endocrinology, National Health Commission (NHC) Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Shi Chen
- Department of Endocrinology, National Health Commission (NHC) Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Wei Zhang
- Department of Endocrinology, National Health Commission (NHC) Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaoxia Zhang
- Department of Endocrinology, National Health Commission (NHC) Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Bang Sun
- Department of Endocrinology, National Health Commission (NHC) Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xueyan Wu
- Department of Endocrinology, National Health Commission (NHC) Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Jiangfeng Mao
- Department of Endocrinology, National Health Commission (NHC) Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xi Wang
- Department of Endocrinology, National Health Commission (NHC) Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Min Nie
- Department of Endocrinology, National Health Commission (NHC) Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- State Key Laboratory of Complex, Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- *Correspondence: Min Nie,
| |
Collapse
|
|
29
|
Adriaansen BPH, Schröder MAM, Span PN, Sweep FCGJ, van Herwaarden AE, Claahsen-van der Grinten HL. Challenges in treatment of patients with non-classic congenital adrenal hyperplasia. Front Endocrinol (Lausanne) 2022; 13:1064024. [PMID: 36578966 PMCID: PMC9791115 DOI: 10.3389/fendo.2022.1064024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 11/25/2022] [Indexed: 12/14/2022] Open
Abstract
Congenital adrenal hyperplasia (CAH) due to 21α-hydroxylase deficiency (21OHD) or 11β-hydroxylase deficiency (11OHD) are congenital conditions with affected adrenal steroidogenesis. Patients with classic 21OHD and 11OHD have a (nearly) complete enzyme deficiency resulting in impaired cortisol synthesis. Elevated precursor steroids are shunted into the unaffected adrenal androgen synthesis pathway leading to elevated adrenal androgen concentrations in these patients. Classic patients are treated with glucocorticoid substitution to compensate for the low cortisol levels and to decrease elevated adrenal androgens levels via negative feedback on the pituitary gland. On the contrary, non-classic CAH (NCCAH) patients have more residual enzymatic activity and do generally not suffer from clinically relevant glucocorticoid deficiency. However, these patients may develop symptoms due to elevated adrenal androgen levels, which are most often less elevated compared to classic patients. Although glucocorticoid treatment can lower adrenal androgen production, the supraphysiological dosages also may have a negative impact on the cardiovascular system and bone health. Therefore, the benefit of glucocorticoid treatment is questionable. An individualized treatment plan is desirable as patients can present with various symptoms or may be asymptomatic. In this review, we discuss the advantages and disadvantages of different treatment options used in patients with NCCAH due to 21OHD and 11OHD.
Collapse
Affiliation(s)
- Bas P. H. Adriaansen
- Radboud Institute of Health Sciences, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands
- Department of Pediatric Endocrinology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, Netherlands
| | - Mariska A. M. Schröder
- Department of Pediatric Endocrinology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, Netherlands
| | - Paul N. Span
- Radiotherapy & OncoImmunology Laboratory, Radboud Institute of Molecular Life Sciences, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Fred C. G. J. Sweep
- Radboud Institute of Health Sciences, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands
| | - Antonius E. van Herwaarden
- Radboud Institute of Health Sciences, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands
| | - Hedi L. Claahsen-van der Grinten
- Department of Pediatric Endocrinology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, Netherlands
- *Correspondence: Hedi L. Claahsen-van der Grinten,
| |
Collapse
|
|
30
|
Apgar TL, Sanders CR. Compendium of causative genes and their encoded proteins for common monogenic disorders. Protein Sci 2022; 31:75-91. [PMID: 34515378 PMCID: PMC8740837 DOI: 10.1002/pro.4183] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 08/29/2021] [Accepted: 08/31/2021] [Indexed: 01/19/2023]
Abstract
A compendium is presented of inherited monogenic disorders that have a prevalence of >1:20,000 in the human population, along with their causative genes and encoded proteins. "Simple" monogenic diseases are those for which the clinical features are caused by mutations impacting a single gene, usually in a manner that alters the sequence of the encoded protein. Of course, for a given "monogenic disorder", there is sometimes more than one potential disease gene, mutations in any one of which is sufficient to cause phenotypes of that disorder. Disease-causing mutations for monogenic disorders are usually passed on from generation to generation in a Mendelian fashion, and originate from spontaneous (de novo) germline founder mutations. In the past monogenic disorders have often been written off as targets for drug discovery because they sometimes are assumed to be rare disorders, for which the meager projected financial payoff of drug discovery and development has discouraged investment. However, not all monogenic diseases are rare. Here, we report that that currently available data identifies 72 disorders with a prevalence of at least 1 in 20,000 humans. For each, we tabulate the gene(s) for which mutations cause the spectrum of phenotypes associated with that disorder. We also identify the gene and protein that most commonly causes each disease. 34 of these disorders are caused exclusively by mutations in only a single gene and encoded protein.
Collapse
Affiliation(s)
- Tucker L. Apgar
- Department of Biochemistry and Center for Structural BiologyVanderbilt University School of Medicine Basic SciencesNashvilleTennesseeUSA
| | - Charles R. Sanders
- Department of Biochemistry and Center for Structural BiologyVanderbilt University School of Medicine Basic SciencesNashvilleTennesseeUSA
| |
Collapse
|
|
31
|
|
|
32
|
Li J, Zhang Q, Chen J, Fu X, Yang J, Liu L. Case report: 17α- hydroxylase deficiency due to a hotspot variant and a novel compound heterozygous variant in the CYP17 A1 gene of five Chinese patients. Front Pediatr 2022; 10:935191. [PMID: 36210947 PMCID: PMC9532611 DOI: 10.3389/fped.2022.935191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 08/31/2022] [Indexed: 11/28/2022] Open
Abstract
17α-Hydroxylase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia caused by mutations in the CYP17A1 gene. It is characterized by impaired adrenal and gonad steroid biosynthesis. Affected patients present with hypertension, hypokalemia, and disorders of sexual development. Here, we describe the genotypes and phenotypes of five patients from three families with this rare disease. Most patients had the hotspot variant, c.985_987delTACinsAA, in CYP17A1, which may be caused by a founder effect. However, the patients in our study were younger than the typical age of onset of 17OHD, and there was a pair of twins with the karyotypes 46, XX and 46, XY, but they both had a female phenotype. Meanwhile, we identified a novel compound heterozygous variant, c.1243+6T>G (p.Y329fs/splicing) in the CYP17A1 gene.
Collapse
Affiliation(s)
- Jinying Li
- Department of Endocrinology, Genetics and Metabolism, Children's Hospital of Hebei Province, Shijiazhuang, China
| | - Qiang Zhang
- Department of Endocrinology, Genetics and Metabolism, Children's Hospital of Hebei Province, Shijiazhuang, China
| | - Jing Chen
- Department of Endocrinology, Genetics and Metabolism, Children's Hospital of Hebei Province, Shijiazhuang, China
| | - Xingjiao Fu
- Department of Endocrinology, Genetics and Metabolism, Children's Hospital of Hebei Province, Shijiazhuang, China
| | - Jingpin Yang
- Department of Endocrinology, Genetics and Metabolism, Children's Hospital of Hebei Province, Shijiazhuang, China
| | - Lijun Liu
- Department of Endocrinology, Genetics and Metabolism, Children's Hospital of Hebei Province, Shijiazhuang, China
| |
Collapse
|
|
33
|
Karaoğlan M, Nacarkahya G, Aytaç EH, Keskin M. Challenges of CYP21A2 genotyping in children with 21-hydroxylase deficiency: determination of genotype-phenotype correlation using next generation sequencing in Southeastern Anatolia. J Endocrinol Invest 2021; 44:2395-2405. [PMID: 33677812 DOI: 10.1007/s40618-021-01546-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 02/26/2021] [Indexed: 10/22/2022]
Abstract
BACKGROUND/PURPOSE Although it is known that there is generally a good correlation between genotypes and phenotypes, the number of studies reporting discrepancies has recently increased, exclusively between milder genotypes and their phenotypes due to the complex nature of the CYP21A2 gene and methodological pitfalls. This study aimed to assess CYP21A2 genotyping in children with 21-hydroxylase deficiency (21-OHD) and establish their predictive genotype-phenotype correlation features using a large cohort in Southeastern Anatolia's ethnically diverse population. METHODS The patients were classified into three groups: salt-wasting (SW), simple virilizing (SV) and non-classical (NC). The genotypes were categorized into six groups due to residual enzyme activity: null-A-B-C-D-E. CYP21A2 genotyping was performed by sequence-specific primer and sequenced with next generation sequencing (NGS), and the expected phenotypes were compared to the observed phenotypes. RESULTS A total of 118 unrelated children with 21-OHD were included in this study (61% SW, 24.5% SV and 14.5% NC). The pathogenic variants were found in 79.5% of 171 mutated alleles (60.2%, 22.2%, and 17.6% in SW, SV and NC, respectively). Patient distribution based on genotype groups was as follows: null-16.1%, A-41.4%, B-6.0%, C-14.4%, E-22%). In2G was the most common pathogenic variant (33.9% of all alleles) and the most common variant in the three phenotype groups (SW-38.8%, SV-22.2% and NC-23.3%). The total genotype-phenotype correlation was 81.5%. The correlations of the null and A groups were 100% and 76.1%, respectively, while it was lower in group B and poor in group C (71.4% and 23.5%, respectively). CONCLUSION This study revealed that the concordance rates of the severe genotypes with their phenotypes were good, while those of the milder genotypes were poor. The discrepancies could have resulted from the complex characteristics of 21-OHD genotyping and the limitations of using NGS alone without integrating with other comprehensive methods.
Collapse
Affiliation(s)
- M Karaoğlan
- Department of Pediatric Endocrinology, Gaziantep University Faculty of Medicine, Gaziantep, Turkey.
| | - G Nacarkahya
- Department of Molecular Biology, Gaziantep University Faculty of Medicine, Gaziantep, Turkey
| | - E H Aytaç
- Department of Pediatric Endocrinology, Gaziantep University Faculty of Medicine, Gaziantep, Turkey
| | - M Keskin
- Department of Pediatric Endocrinology, Gaziantep University Faculty of Medicine, Gaziantep, Turkey
| |
Collapse
|
|
34
|
Allis K. A Broken Pathway: Understanding Congenital Adrenal Hyperplasia in the Newborn. Neonatal Netw 2021; 40:286-294. [PMID: 34518380 DOI: 10.1891/11-t-694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/19/2020] [Indexed: 06/13/2023]
Abstract
Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder that leads to the partial or complete deficiency of cortisol and aldosterone production from the adrenal glands. The lack of these key hormones can precipitate acute adrenal crisis during the newborn period. This disorder can further lead to the development of virilized female genitalia from exposure to increased levels of androgens during fetal development. Nonclassical CAH is a common autosomal disorder, affecting 1/200 live births. The classical form of CAH affects 1/10,000-16,000 live births. Infants affected by classic CAH manifest with severe complications and an increased mortality risk. Early identification of CAH is critical to prevent significant sequela of adrenal crisis and to support families of affected females as they work through decisions of gender assignment. Newborn and pediatric nurses, as well as advanced practice providers, should maintain an active working knowledge of CAH to identify affected individuals early, implement needed interventions, and support families through education.
Collapse
|
|
35
|
Stephens Z, Milosevic D, Kipp B, Grebe S, Iyer RK, Kocher JPA. PB-Motif-A Method for Identifying Gene/Pseudogene Rearrangements With Long Reads: An Application to CYP21A2 Genotyping. Front Genet 2021; 12:716586. [PMID: 34394200 PMCID: PMC8355628 DOI: 10.3389/fgene.2021.716586] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 07/05/2021] [Indexed: 12/30/2022] Open
Abstract
Long read sequencing technologies have the potential to accurately detect and phase variation in genomic regions that are difficult to fully characterize with conventional short read methods. These difficult to sequence regions include several clinically relevant genes with highly homologous pseudogenes, many of which are prone to gene conversions or other types of complex structural rearrangements. We present PB-Motif, a new method for identifying rearrangements between two highly homologous genomic regions using PacBio long reads. PB-Motif leverages clustering and filtering techniques to efficiently report rearrangements in the presence of sequencing errors and other systematic artifacts. Supporting reads for each high-confidence rearrangement can then be used for copy number estimation and phased variant calling. First, we demonstrate PB-Motif's accuracy with simulated sequence rearrangements of PMS2 and its pseudogene PMS2CL using simulated reads sweeping over a range of sequencing error rates. We then apply PB-Motif to 26 clinical samples, characterizing CYP21A2 and its pseudogene CYP21A1P as part of a diagnostic assay for congenital adrenal hyperplasia. We successfully identify damaging variation and patient carrier status concordant with clinical diagnosis obtained from multiplex ligation-dependent amplification (MLPA) and Sanger sequencing. The source code is available at: github.com/zstephens/pb-motif.
Collapse
Affiliation(s)
- Zachary Stephens
- Department of Electrical and Computer Engineering, University of Illinois Urbana-Champaign, Urbana, IL, United States
| | | | | | | | - Ravishankar K Iyer
- Department of Electrical and Computer Engineering, University of Illinois Urbana-Champaign, Urbana, IL, United States
| | | |
Collapse
|
|
36
|
Yoon JY, Cheon CK. Genotype and clinical outcomes in children with congenital adrenal hyperplasia. Pediatr Int 2021; 63:658-663. [PMID: 32965796 DOI: 10.1111/ped.14478] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Revised: 09/03/2020] [Accepted: 09/10/2020] [Indexed: 01/01/2023]
Abstract
BACKGROUND The study aimed to delineate the genotypic features and endocrine / metabolic profiles in patients with 21-hydroxylase deficiency. METHODS Subjects were diagnosed with 21-hydroxylase deficiency by direct Sanger sequencing or multiple ligation-dependent probe amplification analysis and followed up in Pusan National University Children's Hospital from July 2008 to April 2019. The genotype, phenotype, and endocrine and metabolic profiles in children and young adults with congenital adrenal hyperplasia were investigated. RESULTS Of a total of 33 patients, 16 (48.5%) were males. Median age was 7.4 years (range, 0.1-23.8 years). Thirty (90.9%) had salt-wasting phenotypes. Eleven (33.3%) initially presented with abnormality in a neonatal screening test without other symptoms. Among the 17 girls, seven received genital surgery. Sixty-five alleles from the 33 patients were evaluated. The distribution of CYP21A2 gene mutations revealed an intron 2 splice site (c.293-13A>G or c.293-13C>G) mutation as the most common one (22, 33.8%), followed by c.518T>A (10, 15.4%) and a large deletion / conversion (7, 10.8%), in order. One novel mutation was detected, c.332del(p.G111fs). Among the 27 patients aged >2 years, fifteen (55.6%) were obese / overweight, and ten (37.0%) needed growth hormone therapy due to short stature. Among the seven subjects aged >2 years and having high-risk genotype, five had impaired fasting glucose, three had precocious puberty, and four used growth hormone. A greater proportion of the high current corticosteroid dose group had impaired fasting glucose than in the low-dose group (64.3 vs 23.1%, P = 0.031). CONCLUSIONS Early monitoring of endocrine and metabolic complications from childhood might benefit patients with congenital adrenal hyperplasia.
Collapse
Affiliation(s)
- Ju Young Yoon
- Division of Pediatric Endocrinology, Department of Pediatrics, Pusan National University Children's Hospital, Yangsan, Korea
| | - Chong Kun Cheon
- Division of Pediatric Endocrinology, Department of Pediatrics, Pusan National University Children's Hospital, Yangsan, Korea
| |
Collapse
|
|
37
|
Congenital Adrenal Hyperplasia (CAH) and Gitelman Syndrome (GS): Overlapping Symptoms in an Uncommon Association. Case Rep Pediatr 2021; 2021:6633541. [PMID: 33763274 PMCID: PMC7964118 DOI: 10.1155/2021/6633541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 02/22/2021] [Accepted: 03/02/2021] [Indexed: 11/18/2022] Open
Abstract
Background Classical salt-wasting (SW) congenital adrenal hyperplasia (CAH) and Gitelman syndrome (GS) are two genetic conditions in which dyselectrolytemia may occur. No association between the two conditions has been previously described. Case Presentation. We present the case of a boy with a neonatal diagnosis of SW-CAH who showed low potassium blood levels from the age of 15 years. This electrolytic alteration was, at first, attributed to an excessive action of mineralocorticoid drugs. Due to persistence of hypokalemia, SLC12A3 whole genome sequencing was performed, showing a heterozygous C to T base pair substitution at position 965 in gene SLC12A3. This mutation is related to Gitelman syndrome with autosomal recessive transmission. Conclusions SW-CAH and GS determine opposite values of potassium in the absence of specific therapy, with a natural tendency to compensate each other. The symptom overlap makes diagnosis difficult. Organic causes of hypokalemia in patients undergoing life-saving therapy should not be excluded.
Collapse
|
|
38
|
Molecular Analysis of 21-Hydroxylase Deficiency Reveals Two Novel Severe Genotypes in Affected Newborns. Mol Diagn Ther 2021; 25:327-337. [PMID: 33710594 DOI: 10.1007/s40291-021-00520-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/19/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND OBJECTIVE Congenital adrenal hyperplasia involves a series of autosomal recessive disorders where adrenal steroidogenesis is affected. We present a detailed molecular investigation of 13 newborns affected from the severe form of congenital adrenal hyperplasia related to 21-hydroxylase deficiency. METHODS All patients were diagnosed with classical congenital adrenal hyperplasia in the neonatal period due to adrenal crisis and/or ambiguous genitalia presentation. None of the infants was identified through a congenital adrenal hyperplasia newborn screening program. A molecular analysis of the CYP21A2 gene and a familiar segregation analysis were performed. RESULTS Adrenal crisis was the most severe manifestation in the male salt-wasting newborns while all female patients presented with atypical genitalia. Newborns were correctly genotyped and no genotype-phenotype divergences were found. Two novel severe genotypes, not previously reported, were identified. The novel CYP21A2 frameshift mutations (c.793delG and c.297dupG) were added to the other 45 variants recently reported in the literature, leading to a total count of 279 pathogenic variants affecting the gene. CONCLUSIONS We have successfully genotyped 13 infants diagnosed with classical congenital adrenal hyperplasia after birth. Our molecular approach led to the identification of two novel frameshift CYP21A2 pathogenic variants related to the salt-wasting form of congenital adrenal hyperplasia.
Collapse
|
|
39
|
Song F, Feng S, Shen X, Du M, Yin H, Liu R, Chen X. Next-Generation Sequencing Revealed Disease-Causing Variants in Two Genes in a Patient With Combined Features of Spherocytosis and Antley-Bixler Syndrome With Genital Anomalies and Disordered Steroidogenesis. Front Genet 2020; 11:976. [PMID: 32973886 PMCID: PMC7472872 DOI: 10.3389/fgene.2020.00976] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 07/31/2020] [Indexed: 12/30/2022] Open
Abstract
Conventionally, patients with combined rare diseases are often difficult to diagnose. This is because some clinicians tend to consider the multiple disease symptoms as the presentation of a complicated “syndrome.” This pattern of thinking also confines their way of filtering pathogenic mutations. Some real pathogenic mutations might be ignored due to not covering all disease presentations. Here we report the case of a girl who was suffering from spherocytosis and Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis. She remained undiagnosed even after targeted gene detection before. However, after performing next-generation sequencing and analyzing the sequencing data, we identified two mutations: c.2978T > A in ANK1 and c.1370G > A in POR. Our findings and experiences in diagnosing these mutations could contribute to the existing knowledge on the clinical and genetic diagnosis of patients with disease presentations in multiple systems.
Collapse
Affiliation(s)
- Fuying Song
- Department of Endocrinology, Capital Institute of Pediatrics, Beijing, China
| | - Shunqiao Feng
- Department of Hematology, Capital Institute of Pediatrics, Beijing, China
| | | | - Mu Du
- Department of Endocrinology, Capital Institute of Pediatrics, Beijing, China
| | - Hui Yin
- Department of Endocrinology, Capital Institute of Pediatrics, Beijing, China
| | - Rong Liu
- Department of Hematology, Capital Institute of Pediatrics, Beijing, China
| | - Xiaobo Chen
- Department of Endocrinology, Capital Institute of Pediatrics, Beijing, China
| |
Collapse
|
|
40
|
Liu Y, Zheng J, Liu N, Xu X, Zhang X, Zhang Y, Li G, Liu G, Cai C, Shu J. The spectrum of CYP21A2 gene mutations in patients with classic salt wasting form of 2l-hydroxylase deficiency in a Chinese cohort. Mol Genet Genomic Med 2020; 8:e1501. [PMID: 32959514 PMCID: PMC7667303 DOI: 10.1002/mgg3.1501] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 08/15/2020] [Accepted: 08/30/2020] [Indexed: 12/18/2022] Open
Abstract
Background 21‐Hydroxylase deficiency (21‐OHD) caused by the CYP21A2 gene mutations is the most common form of congenital adrenal hyperplasia. It is an autosomal recessive disorder that results in defective synthesis of cortisol and aldosterone. The incidences of various CYP21A2 gene mutations and the genotype–phenotype correlations vary among different populations. Materials and Methods The clinical and molecular data of 22 patients were analyzed in this study. All patients were recruited from the neonatal intensive care unit. Locus‐specific polymerase chain reaction and Sanger sequencing were applied to identify gene micro‐conversions, and multiplex ligation‐dependent probe amplification 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 All 22 patients were classified into classic salt wasting form of 21‐OHD. 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.R357 W (4.5%) and E6 Cluster (2.3%). Genotypes of 22 patients (100%) were consistent with the predictive phenotypes. Conclusion In this study, we identified the mutation spectrum of CYP21A2 gene in Chinese patients, especially the younger age cohort in pediatrics. Micro‐conversions were the most popular mutations. Moreover, the genotypes and phenotypes were well correlated in this cohort of salt wasting 21‐OHD recruited from neonatal intensive care unit. We identified the mutation spectrum of CYP21A2 gene in Chinese patients, especially the younger age cohort admitted in NICU. The genotypes and phenotypes in 21‐OHD were well correlated.
Collapse
Affiliation(s)
- Yang Liu
- Department of Neonatology, Tianjin Children's Hospital, the Pediatric Clinical College in Tianjin Medical University, Tianjin, China
| | - Jie Zheng
- Graduate College of Tianjin Medical University, Tianjin, China
| | - Nan Liu
- Graduate College of Tianjin Medical University, Tianjin, China.,Tianjin Children's Hospital (Children's Hospital of Tianjin University, Tianjin, China.,Tianjin Pediatric Research Institute, Tianjin, China.,Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin, China
| | - Xiaowei Xu
- Tianjin Children's Hospital (Children's Hospital of Tianjin University, Tianjin, China.,Tianjin Pediatric Research Institute, Tianjin, China.,Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin, China
| | - Xinjie Zhang
- Tianjin Children's Hospital (Children's Hospital of Tianjin University, Tianjin, China.,Tianjin Pediatric Research Institute, Tianjin, China.,Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin, China
| | - Ying Zhang
- Graduate College of Tianjin Medical University, Tianjin, China
| | - Guoxu Li
- Graduate College of Tianjin Medical University, Tianjin, China
| | - Geli Liu
- Department of Pediatrics, Tianjin Medical University General Hospital, Tianjin, China
| | - Chunquan Cai
- Tianjin Children's Hospital (Children's Hospital of Tianjin University, Tianjin, China.,Tianjin Pediatric Research Institute, Tianjin, China.,Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin, China.,Department of Neurosurgery, Tianjin Children's Hospital, Tianjin, China
| | - Jianbo Shu
- Tianjin Children's Hospital (Children's Hospital of Tianjin University, Tianjin, China.,Tianjin Pediatric Research Institute, Tianjin, China.,Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin, China
| |
Collapse
|
|
41
|
Lai F, Srinivasan S, Wiley V. Evaluation of a Two-Tier Screening Pathway for Congenital Adrenal Hyperplasia in the New South Wales Newborn Screening Programme. Int J Neonatal Screen 2020; 6:63. [PMID: 33117905 PMCID: PMC7569785 DOI: 10.3390/ijns6030063] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 08/07/2020] [Indexed: 12/12/2022] Open
Abstract
In Australia, all newborns born in New South Wales (NSW) and the Australia Capital Territory (ACT) have been offered screening for rare congenital conditions through the NSW Newborn Screening Programme since 1964. Following the development of the Australian Newborn Bloodspot Screening National Policy Framework, screening for congenital adrenal hyperplasia (CAH) was included in May 2018. As part of the assessment for addition of CAH, the national working group recommended a two-tier screening protocol determining 17α-hydroxyprogesterone (17OHP) concentration by immunoassay followed by steroid profile. A total of 202,960 newborns were screened from the 1 May 2018 to the 30 April 2020. A threshold level of 17OHP from first tier immunoassay over 22 nmol/L and/or top 2% of the daily assay was further tested using liquid chromatography tandem mass spectrometry (LC-MS/MS) steroid profiling for 17OHP (MS17OHP), androstenedione (A4) and cortisol. Samples with a ratio of (MS17OHP + A4)/cortisol > 2 and MS17OHP > 200 nmol/L were considered as presumptive positive. These newborns were referred for clinical review with a request for diagnostic testing and a confirmatory repeat dried blood spot (DBS). There were 10 newborns diagnosed with CAH, (9 newborns with salt wasting CAH). So far, no known false negatives have been notified, and the protocol has a sensitivity of 100%, specificity of 99.9% and a positive predictive value of 71.4%. All confirmed cases commenced treatment by day 11, with none reported as having an adrenal crisis by the start of treatment.
Collapse
Affiliation(s)
- Fei Lai
- Department of NSW Newborn Screening Programme, The Sydney Children Hospital Network, Westmead, NSW 2145, Australia;
- Faculty of Medicine and Health, The University of Sydney Children's Hospital Westmead Clinical School, Westmead, NSW 2145, Australia;
| | - Shubha Srinivasan
- Faculty of Medicine and Health, The University of Sydney Children's Hospital Westmead Clinical School, Westmead, NSW 2145, Australia;
- Department of Endocrinology, The Sydney Children's Hospital Network, Westmead, NSW 2145, Australia
| | - Veronica Wiley
- Department of NSW Newborn Screening Programme, The Sydney Children Hospital Network, Westmead, NSW 2145, Australia;
- Faculty of Medicine and Health, The University of Sydney Children's Hospital Westmead Clinical School, Westmead, NSW 2145, Australia;
| |
Collapse
|
|
42
|
Fernández CS, Taboas M, Bruque CD, Benavides-Mori B, Belli S, Stivel M, Oneto A, Pasqualini T, Delea M, Espeche LD, Kolomenski JE, Alba L, Buzzalino N, Dain L. Genetic characterization of a large cohort of Argentine 21-hydroxylase Deficiency. Clin Endocrinol (Oxf) 2020; 93:19-27. [PMID: 32289882 DOI: 10.1111/cen.14190] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 03/31/2020] [Accepted: 04/07/2020] [Indexed: 01/25/2023]
Abstract
CONTEXT 21-hydroxylase deficiency is the most common cause of Congenital Adrenal Hyperplasia. It presents as severe or classical forms-salt wasting and simple virilizing-and a mild or nonclassical (NC). Several studies have reported the frequency of pathogenic variants in different populations, although few of them included a large number of NC patients. OBJECTIVE To analyse the CYP21A2 gene defects in a large cohort of Argentine patients. DESIGN Molecular characterization of 628 patients (168 classical, 460 nonclassical, representing 1203 nonrelated alleles), 398 relatives, 126 partners. METHODS Genetic variants were assessed by allele-specific PCR, PCR-RFLP or direct sequencing. Deletions, duplications and large gene conversions (LGC) were studied by Southern blot/MLPA or long-range PCR. Biological implications of novel variants were analysed by structure-based in silico studies. RESULTS The most frequent pathogenic variants were p.V282L (58%) in NC alleles and c.293-13C>G (31.8%) and p.I173N (21.1%) in classical. Deletions and LGC were found at low frequency (6.2%), 57 alleles had rare pathogenic variants, and 3 had novel variants: p.(S166F); p.(P189R), p.(R436L). Genotype-phenotype correlation was observed in 98.6% of the cases, 11 asymptomatic first-degree relatives had pathogenic variants in both alleles, and 21/126 partners were carriers. CONCLUSIONS We conducted a comprehensive genetic characterization of the largest cohort of 21-hydroxylase patients from the region. In particular, we add to the molecular characterization of a large number of NC patients and to the estimation of the disease carrier's frequency in our population.
Collapse
Affiliation(s)
- Cecilia S Fernández
- Centro Nacional de Genética Médica, Administración Nacional de Laboratorios e Institutos de Salud (ANLIS) 'Dr. Carlos G. Malbrán', Buenos Aires, Argentina
- Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Melisa Taboas
- Centro Nacional de Genética Médica, Administración Nacional de Laboratorios e Institutos de Salud (ANLIS) 'Dr. Carlos G. Malbrán', Buenos Aires, Argentina
| | - Carlos D Bruque
- Centro Nacional de Genética Médica, Administración Nacional de Laboratorios e Institutos de Salud (ANLIS) 'Dr. Carlos G. Malbrán', Buenos Aires, Argentina
- Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Belén Benavides-Mori
- Centro Nacional de Genética Médica, Administración Nacional de Laboratorios e Institutos de Salud (ANLIS) 'Dr. Carlos G. Malbrán', Buenos Aires, Argentina
| | - Susana Belli
- División Endocrinología, Hospital Durand, Buenos Aires, Argentina
| | - Mirta Stivel
- División Endocrinología, Hospital Durand, Buenos Aires, Argentina
| | - Adriana Oneto
- División Endocrinología, Hospital Durand, Buenos Aires, Argentina
| | - Titania Pasqualini
- Sección Endocrinología, Crecimiento y Desarrollo, Departamento de Pediatría, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Marisol Delea
- Centro Nacional de Genética Médica, Administración Nacional de Laboratorios e Institutos de Salud (ANLIS) 'Dr. Carlos G. Malbrán', Buenos Aires, Argentina
| | - Lucía D Espeche
- Centro Nacional de Genética Médica, Administración Nacional de Laboratorios e Institutos de Salud (ANLIS) 'Dr. Carlos G. Malbrán', Buenos Aires, Argentina
| | - Jorge E Kolomenski
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IQUIBICEN-CONICET, Buenos Aires, Argentina
| | - Liliana Alba
- Centro Nacional de Genética Médica, Administración Nacional de Laboratorios e Institutos de Salud (ANLIS) 'Dr. Carlos G. Malbrán', Buenos Aires, Argentina
| | - Noemí Buzzalino
- Centro Nacional de Genética Médica, Administración Nacional de Laboratorios e Institutos de Salud (ANLIS) 'Dr. Carlos G. Malbrán', Buenos Aires, Argentina
| | - Liliana Dain
- Centro Nacional de Genética Médica, Administración Nacional de Laboratorios e Institutos de Salud (ANLIS) 'Dr. Carlos G. Malbrán', Buenos Aires, Argentina
- Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
- Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina
| |
Collapse
|
|
43
|
Arteaga E, Valenzuela F, Lagos CF, Lagos M, Martinez A, Baudrand R, Carvajal C, Fardella CE. Detection of a novel severe mutation affecting the CYP21A2 gene in a Chilean male with salt wasting congenital adrenal hyperplasia. Endocrine 2020; 67:258-263. [PMID: 31571129 DOI: 10.1007/s12020-019-02097-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 09/17/2019] [Indexed: 01/03/2023]
Abstract
PURPOSE 21-hydroxylase deficiency (21-OHD) is a congenital adrenal disease with more than 200 mutations published to date. The aim of this report is to describe a severe novel mutation of the CYP21A2 gene. METHOD We describe a case of a 39-year-old male diagnosed with a salt wasting congenital adrenal hyperplasia (SWCAH) due to 21-OHD. The genetic testing was done using a combination of three methods (PCR XL, SALSA-MLPA, and bidirectional sequencing) and finally an in silico analysis. RESULTS The genetic testing demonstrated three severe mutations of the CYP21A2 gene (p.Gln318*; c.290-13C>G; and p.Trp86*), being the last one a novel mutation not previously reported. The in silico modeling of the p.Trp86* (c.258G>A) showed a truncated CYP21A2 protein that loses all the main structural features required for activity, such as the HEM binding domain and the hormone binding site. CONCLUSION We present an adult man with an SWCAH due to 21-OHD who carried three severe mutations of the CYP21A2 gene, one of them, p.Trp86* (c.258G>A) has not been previously described.
Collapse
Affiliation(s)
- Eugenio Arteaga
- Departamento de Endocrinología and Centro Traslacional en Endocrinología (CETREN), Facultad de Medicina, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, Piso 4, Santiago Centro, 8330077, Santiago, Chile.
| | - Felipe Valenzuela
- Departamento de Endocrinología and Centro Traslacional en Endocrinología (CETREN), Facultad de Medicina, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, Piso 4, Santiago Centro, 8330077, Santiago, Chile
| | - Carlos F Lagos
- Facultad de Medicina y Ciencia, Universidad San Sebastián, Campus Los Leones, Lota 2465, Providencia, 7510157, Santiago, Chile
| | - Marcela Lagos
- Departamento de Laboratorios Clínicos, Facultad de Medicina, Pontificia Universidad Católica de Chile, Av. Vicuña Mackenna 4686, Piso 3, Macul, 7820436, Santiago, Chile
| | - Alejandra Martinez
- Departamento de Endocrinología and Centro Traslacional en Endocrinología (CETREN), Facultad de Medicina, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, Piso 4, Santiago Centro, 8330077, Santiago, Chile
| | - Rene Baudrand
- Departamento de Endocrinología and Centro Traslacional en Endocrinología (CETREN), Facultad de Medicina, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, Piso 4, Santiago Centro, 8330077, Santiago, Chile
- Instituto Milenio en Inmunología e Inmunoterapia IMII, Portugal 49, Santiago Centro, 8330075, Santiago, Chile
| | - Cristian Carvajal
- Departamento de Endocrinología and Centro Traslacional en Endocrinología (CETREN), Facultad de Medicina, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, Piso 4, Santiago Centro, 8330077, Santiago, Chile
| | - Carlos E Fardella
- Departamento de Endocrinología and Centro Traslacional en Endocrinología (CETREN), Facultad de Medicina, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, Piso 4, Santiago Centro, 8330077, Santiago, Chile
- Instituto Milenio en Inmunología e Inmunoterapia IMII, Portugal 49, Santiago Centro, 8330075, Santiago, Chile
| |
Collapse
|
|
44
|
Espinosa-Herrera F, Espín E, Tito-Álvarez AM, Beltrán LJ, Gómez-Correa D, Burgos G, Llamos A, Zurita C, Rojas S, Dueñas-Espín I, Cueva-Ludeña K, Salazar-Vega J, Pinto-Basto J. A report of congenital adrenal hyperplasia due to 17α-hydroxylase deficiency in two 46,XX sisters. Gynecol Endocrinol 2020; 36:24-29. [PMID: 31464148 DOI: 10.1080/09513590.2019.1650342] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Congenital adrenal hyperplasia (CAH) is a group of rare orphan disorders caused by mutations in seven different enzymes that impair cortisol biosynthesis. The 17α-hydroxylase deficiency (17OHD) is one of the less common forms of CAH, corresponding to approximately 1% of the cases, with an estimated annual incidence of 1 in 50,000 newborns. Cases description - two phenotypically female Ecuadorian sisters, both with primary amenorrhea, absence of secondary sexual characteristics, and osteoporosis. High blood pressure was present in the older sister. Hypergonadotropic hypogonadism profile was observed: decreased cortisol and dehydroepiandrosterone sulfate (DHEAS), increased adrenocorticotropic hormone (ACTH) and normal levels of 17-hydroxyprogesterone, extremely high deoxycorticosterone (DOC) levels, and a tomography showed bilateral adrenal hyperplasia in both sisters. Consanguinity was evident in their ancestors. Furthermore, in the exon 7, the variant c.1216T > C, p.Trp406Arg was detected in homozygosis in the CYP17A1 gene of both sisters. We report a homozygous missense mutation in the CYP17A1 gene causing 17OHD in two sisters from Loja, Ecuador. According to the authors, this is the first time such deficiency and mutation are described in two members of the same family in Ecuador.
Collapse
Affiliation(s)
- Fernando Espinosa-Herrera
- Escuela de Medicina, Facultad de Ciencias de la Salud, Universidad de las Américas (UDLA), Quito, Ecuador
- Sociedad Ecuatoriana de Medicina Familiar (SEMF), Hospital Vozandes Quito, Quito, Ecuador
| | - Estefanía Espín
- Escuela de Medicina, Facultad de Ciencias de la Salud, Universidad de las Américas (UDLA), Quito, Ecuador
| | - Ana M Tito-Álvarez
- Escuela de Enfermería, Facultad de Ciencias de la Salud, Universidad de las Américas (UDLA), Quito, Ecuador
| | - Leonardo-J Beltrán
- Escuela de Medicina, Facultad de Ciencias de la Salud, Universidad de las Américas (UDLA), Quito, Ecuador
| | - Diego Gómez-Correa
- Escuela de Medicina, Facultad de Ciencias de la Salud, Universidad de las Américas (UDLA), Quito, Ecuador
| | - German Burgos
- Escuela de Medicina, Facultad de Ciencias de la Salud, Universidad de las Américas (UDLA), Quito, Ecuador
| | - Arianne Llamos
- Facultad de Ciencias Médicas, de la Salud y de La Vida, Escuela de Odontología, Universidad Internacional del Ecuador (UIDE), Quito, Ecuador
| | - Camilo Zurita
- Unidad de Investigaciones en Biomedicina, Zurita & Zurita Laboratorios, Cátedra de Inmunología, Facultad de Medicina, Universidad Central del Ecuador (UCE), Quito, Ecuador
| | - Samantha Rojas
- Hospital Isidro Ayora de Loja, Ministerio de Salud Pública del Ecuador, Quito, Ecuador
| | - Iván Dueñas-Espín
- Instituto de Salud Pública, Facultad de Medicina, Pontificia Universidad Católica del Ecuador, Quito, Ecuador
| | - Kenny Cueva-Ludeña
- Hospital General Docente de Calderón, Ministerio de Salud Pública del Ecuador, Quito, Ecuador
| | - Jorge Salazar-Vega
- Escuela de Medicina, Facultad de Ciencias de la Salud, Universidad de las Américas (UDLA), Quito, Ecuador
- Hospital Eugenio Espejo, Ministerio de Salud Pública del Ecuador, Quito, Ecuador
| | - Jorge Pinto-Basto
- Molecular Diagnostics and Clinical Genomics Laboratories, CGC Genetics, Porto, Portugal
| |
Collapse
|
|
45
|
Lin B, Zhang H, Zheng Q. How do mutations affect the structural characteristics and substrate binding of CYP21A2? An investigation by molecular dynamics simulations. Phys Chem Chem Phys 2020; 22:8870-8877. [DOI: 10.1039/d0cp00763c] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
CYP21A2 mutations affect the activity of the protein leading to CAH disease.
Collapse
Affiliation(s)
- Baihui Lin
- Laboratory of Theoretical and Computational Chemistry
- Institute of Theoretical Chemistry
- International Joint Research Laboratory of Nano-Micro Architecture Chemistry
- Jilin University
- Changchun 130023
| | - Hongxing Zhang
- Laboratory of Theoretical and Computational Chemistry
- Institute of Theoretical Chemistry
- International Joint Research Laboratory of Nano-Micro Architecture Chemistry
- Jilin University
- Changchun 130023
| | - Qingchuan Zheng
- Laboratory of Theoretical and Computational Chemistry
- Institute of Theoretical Chemistry
- International Joint Research Laboratory of Nano-Micro Architecture Chemistry
- Jilin University
- Changchun 130023
| |
Collapse
|
|
46
|
Abstract
Fertility rates in classic congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are substantially decreased for various reasons, including hormonal, anatomic, psychosocial, and psychosexual causes. However, fecundity is comparable with the general population. Under optimal hormone replacement, the course and outcome of pregnancies is also good. This article summarizes successful gestational management, including preconceptional considerations, adjustment of hormone replacement during pregnancy, delivery and lactation, as well as the prevention of adrenal crises. In nonclassic 21-hydroxylase deficiency, preconceptional low-dose hydrocortisone replacement normalizes the otherwise increased miscarriage rate. Pregnancy reports in rarer forms of congenital adrenal hyperplasia are summarized as well.
Collapse
Affiliation(s)
- Nicole Reisch
- Medizinische Klinik IV, Department of Endocrinology, Klinikum der Universität München, Ziemssenstraße 1, München 80336, Germany.
| |
Collapse
|
|
47
|
Güran T, Tezel B, Gürbüz F, Selver Eklioğlu B, Hatipoğlu N, Kara C, Şimşek E, Çizmecioğlu FM, Ozon A, Baş F, Aydın M, Darendeliler F. Neonatal Screening for Congenital Adrenal Hyperplasia in Turkey: A Pilot Study with 38,935 Infants. J Clin Res Pediatr Endocrinol 2019; 11:13-23. [PMID: 30111524 PMCID: PMC6398187 DOI: 10.4274/jcrpe.galenos.2018.2018.0117] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 08/10/2018] [Indexed: 12/01/2022] Open
Abstract
Objective Congenital adrenal hyperplasia (CAH) is the most common form of primary adrenal insufficiency in children. Neonatal screening for CAH is effective in detecting the salt-wasting (SW) form and in reducing mortality. In this study, our aim was to estimate the incidence of CAH in Turkey and to assess the characteristics and efficacy of the adopted newborn CAH screening strategy. Methods A pilot newborn CAH screening study was carried out under the authority of the Turkish Directorate of Public Health. Newborn babies of ≥32 gestational weeks and ≥1500 gr birth weight from four cities, born between March 27-September 15, 2017 were included in the study. Screening protocol included one sample two-tier testing. In the first step, 17α-hydroxyprogesterone (17-OHP) was measured by fluoroimmunoassay in dried blood spots (DBS) obtained at 3-5 days of life. The cases with positive initial screening were tested by steroid profiling in DBS using a liquid chromatography-tandem mass spectrometry method to measure 17-OHP, 21-deoxycortisol (21-S), cortisol (F), 11-deoxycortisol and androstenedione as a second-tier test. The babies with a steroid ratio (21-S+17-OHP)/F of ≥0.5 were referred to pediatric endocrinology clinics for diagnostic assessment. Results 38,935 infants were tested, 2265 (5.82%) required second-tier testing and 212 (0.54%) were referred for clinical assessment, six of whom were diagnosed with CAH (four males, two females). Four cases were identified as SW 21-hydroxylase deficiency (21-OHD) (two males, two females). One male baby had simple virilizing 21-OHD and one male baby had 11-OHD CAH. The incidence of classical 21-OHD in the screened population was 1:7,787. Conclusion The incidence of CAH due to classical 21-OHD is higher in Turkey compared to previous reports. We, therefore, suggest that CAH be added to the newborn screening panel in Turkey. The use of steroid profiling as a second-tier test was found to improve the efficacy of the screening and reduce the number of false-positives.
Collapse
Affiliation(s)
- Tülay Güran
- Marmara University Faculty of Medicine, Department of Paediatric Endocrinology and Diabetes, İstanbul, Turkey
| | - Başak Tezel
- Turkish Directorate of Public Health, Ankara, Turkey
| | - Fatih Gürbüz
- Çukurova University Faculty of Medicine, Department of Paediatric Endocrinology and Diabetes, Adana, Turkey
| | - Beray Selver Eklioğlu
- Necmettin Erbakan University Meram Faculty of Medicine, Department of Paediatric Endocrinology and Diabetes, Konya, Turkey
| | - Nihal Hatipoğlu
- Erciyes University Faculty of Medicine, Department of Paediatric Endocrinology and Diabetes, Kayseri, Turkey
| | - Cengiz Kara
- Ondokuz Mayıs University Faculty of Medicine, Department of Paediatric Endocrinology and Diabetes, Samsun, Turkey
| | - Enver Şimşek
- Osmangazi University Faculty of Medicine, Department of Paediatric Endocrinology and Diabetes, Eskişehir, Turkey
| | - Filiz Mine Çizmecioğlu
- Kocaeli University Faculty of Medicine, Department of Paediatric Endocrinology and Diabetes, Kocaeli, Turkey
| | - Alev Ozon
- Hacettepe University Faculty of Medicine, Department of Paediatric Endocrinology and Diabetes, Ankara, Turkey
| | - Firdevs Baş
- İstanbul University İstanbul Faculty of Medicine, Department of Paediatric Endocrinology and Diabetes, İstanbul, Turkey
| | - Murat Aydın
- Ondokuz Mayıs University Faculty of Medicine, Department of Paediatric Endocrinology and Diabetes, Samsun, Turkey
| | - Feyza Darendeliler
- İstanbul University İstanbul Faculty of Medicine, Department of Paediatric Endocrinology and Diabetes, İstanbul, Turkey
| |
Collapse
|
|
48
|
Abstract
Congenital adrenal hyperplasia (CAH) is a group of seven autosomal recessively inherited disorders of various enzymes participating in adrenal steroid hormone synthesis. Patients present with various symptoms depending on the nature and severity of the enzymatic block. More than 95% of all CAH patients suffer from 21-hydroxylase deficiency. The genetic background is well characterized for all CAH subtypes. Characterization of their genetic background has provided important pathophysiologic understanding of steroid biosynthesis disorders. Genotyping is important for confirming diagnosis, determining prognostic factors, and for genetic counseling for family planning and may reveal new therapeutic approaches.
Collapse
Affiliation(s)
- Dóra Török
- 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
| |
Collapse
|
|
49
|
Dahl SR, Nermoen I, Brønstad I, Husebye ES, Løvås K, Thorsby PM. Assay of steroids by liquid chromatography-tandem mass spectrometry in monitoring 21-hydroxylase deficiency. Endocr Connect 2018; 7:1542-1550. [PMID: 30530876 PMCID: PMC6311459 DOI: 10.1530/ec-18-0453] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 12/07/2018] [Indexed: 12/26/2022]
Abstract
Immunoassays of steroid hormones are still used in the diagnosis and monitoring of patients with congenital adrenal hyperplasia. However, cross-reactivity between steroids can give rise to falsely elevated steroid levels. Here, we compare the use of immunoassays and liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the monitoring of patients with classic 21-hydroxylase deficiency (21OHD). Steroid profiles in different mutation groups (genotypes) were also compared. Fifty-five patients with classic 21OHD (38 women) were studied. Blood samples were collected in the morning after an overnight medication fast. LC-MS/MS and immunoassays were employed to assay 17-hydroxyprogesterone (17OHP), testosterone and androstenedione. In addition, 21-deoxycortisol (21DF), 11-deoxycortisol (11DF), corticosterone, deoxycorticosterone, cortisone and cortisol were analyzed by LC-MS/MS. Testosterone, androstenedione and 17OHP levels were consistently lower (by about 30-50%) when measured by LC-MS/MS compared with immunoassays, with exception of testosterone in men. There was a significant correlation between 21DF and 17OHP (r = 0.87, P < 0.001), but three patients had undetectable 21DF. Subjects with no enzyme activity had significantly lower mean 11DF concentrations than subjects with residual activity. The use of LC-MS/MS gives a more specific view of adrenal steroid levels in 21OHD compared with immunoassays, which seem to considerably overestimate the levels of 17OHP and androstenedione. Falsely elevated levels of 17OHP and androstenedione could lead to overtreatment with glucocorticoids.
Collapse
Affiliation(s)
- Sandra R Dahl
- Hormone Laboratory, Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | - Ingrid Nermoen
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Division of Medicine, Akershus University Hospital, Lørenskog, Norway
- Correspondence should be addressed to I Nermoen:
| | - Ingeborg Brønstad
- National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Eystein S Husebye
- Department of Clinical Science, University of Bergen, Bergen, Norway
- K.G. Jebsen-Center for Autoimmune Diseases, University of Bergen, Bergen, Norway
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - Kristian Løvås
- Department of Clinical Science, University of Bergen, Bergen, Norway
- K.G. Jebsen-Center for Autoimmune Diseases, University of Bergen, Bergen, Norway
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - Per M Thorsby
- Hormone Laboratory, Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| |
Collapse
|
|
50
|
Abstract
Primary adrenal insufficiency (PAI) is a life-threatening disorder of adrenal cortex which is characterized by deficient biosynthesis of glucocorticoids, with or without deficiency in mineralocorticoids and adrenal androgens. Typical manifestations of primary adrenal insufficiency include hyperpigmentation, hypotension, hypoglycaemia, hyponatremia with or without hyperkalemia that are generally preceded by nonspecific symptoms at the onset. Recessively inherited monogenic disorders constitute the largest group of primary adrenal insufficiency in children. The diagnostic process of primary adrenal insufficiency includes demonstration of low cortisol concentrations along with high plasma ACTH and identifying the cause of the disorder. Specific molecular diagnosis is achieved in more than 80% of children with PAI by detailed clinical and biochemical characterization integrated with advanced molecular tools. Hormone replacement therapy determined on the type and the severity of deficient adrenocortical hormones is the mainstay of treatment. Optimized methods of steroid hormone delivery, improved monitoring of hormone replacement along with intensive education of patients and families on the rules during intercurrent illness and stress will significantly reduce the morbidity and mortality associated with primary adrenal insufficiency.
Collapse
Affiliation(s)
- Tarik Kirkgoz
- Marmara University School of Medicine, Department of Paediatric Endocrinology and Diabetes, Istanbul, Turkey.
| | - Tulay Guran
- Marmara University School of Medicine, Department of Paediatric Endocrinology and Diabetes, Istanbul, Turkey.
| |
Collapse
|