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1.
Chinese Journal of Pediatrics ; (12): 435-441, 2022.
Article in Chinese | WPRIM | ID: wpr-935716

ABSTRACT

Objective: To explore the heterogeneity and correlation of clinical phenotypes and genotypes in children with disorders of sex development (DSD). Methods: A retrospective study of 1 235 patients with clinically proposed DSD in 36 pediatric medical institutions across the country from January 2017 to May 2021. After capturing 277 DSD-related candidate genes, second-generation sequencing was performed to analyzed the heterogeneity and correlation combined with clinical phenotypes. Results: Among 1 235 children with clinically proposed DSD, 980 were males and 255 were females of social gender at the time of initial diagnosis with the age ranged from 1 day of age to 17.92 years. A total of 443 children with pathogenic variants were detected through molecular genetic studies, with a positive detection rate of 35.9%. The most common clinical phenotypes were micropenis (455 cases), hypospadias (321 cases), and cryptorchidism (172 cases) and common mutations detected were in SRD5A2 gene (80 cases), AR gene (53 cases) and CYP21A2 gene (44 cases). Among them, the SRD5A2 mutation is the most common in children with simple micropenis and simple hypospadias, while the AMH mutation is the most common in children with simple cryptorchidism. Conclusions: The SRD5A2 mutation is the most common genetic variant in Chinese children with DSD, and micropenis, cryptorchidism, and hypospadias are the most common clinical phenotypes. Molecular diagnosis can provide clues about the biological basis of DSD, and can also guide clinicians to perform specific clinical examinations. Target sequence capture probes and next-generation sequencing technology can provide effective and economical genetic diagnosis for children with DSD.


Subject(s)
3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics , Child , China/epidemiology , Cryptorchidism/genetics , Disorders of Sex Development/genetics , Female , Genital Diseases, Male , Genotype , Humans , Hypospadias/genetics , Male , Membrane Proteins/genetics , Penis/abnormalities , Phenotype , Retrospective Studies , Steroid 21-Hydroxylase/genetics
2.
Rev. chil. endocrinol. diabetes ; 14(2): 81-89, 2021. ilus, tab
Article in Spanish | LILACS | ID: biblio-1283557

ABSTRACT

La Hiperplasia Suprarrenal Congénita (HSRC) corresponde a un grupo de defectos genéticos en la síntesis de cortisol. El 95% de ellas son debidas al déficit de 21-hidroxilasa por lo que nos referiremos solo a esta deficiencia. La hiperplasia suprarrenal congénita clásica (HSRC-C) debuta en recién nacidos o lactantes con insuficiencia suprarrenal primaria, diferentes grados de hiperandrogenismo clínico en mujeres y puede coexistir con hipotensión, hiperkalemia e hiponatremia si hay un déficit clínico de aldosterona. El objetivo de este artículo es actualizar el conocimiento y enfoques sugeridos para el manejo de la HSRC-C desde el inicio de sus controles en la etapa adulta. El diagnóstico diferencial en retrospectiva de la HSRC-C y la no clásica (HSRC-NC) a veces resulta difícil ya que esta enfermedad es un espectro fenotípico continuo. La insuficiencia suprarrenal y la dependencia a terapia corticoidal son los eventos principales para diferenciar estas dos patologías que tienen enfoques terapéuticos diferentes. El tratamiento de la HSRC-C en adultos abarca 2 objetivos primarios: la adecuada sustitución de la falla suprarrenal y el control de hiperandrogenismo mediante el uso de corticoides en sus dosis mínimas efectivas. En la mujer existen terapias complementarias para el control del hiperandrogenismo como anticonceptivos y otras que se encuentran en diferentes fases de investigación. Esto permite disminuir las dosis de corticoides en algunos casos. Es importante a la vez abordar tres objetivos secundarios: controlar el riesgo cardiometabólico propio de la enfermedad, evitar el sobre tratamiento corticoidal y manejar la infertilidad. La correcta monitorización del tratamiento en adultos tomando en cuenta los objetivos descritos permite una mejor calidad de vida en estos pacientes. Finalmente el consejo genético debe realizarse en todos los pacientes con HSRC que deseen fertilidad y en sus parejas. El estudio requiere de secuenciación del gen CYP21A2 y debe realizarse en un laboratorio de experiencia.


Congenital Adrenal Hyperplasia (CAH) are a group of genetic defects characterized by impaired cortisol synthesis. 95% of them are due to 21-hydroxylase deficiency. We will discuss only this enzyme's deficiency. Classic congenital adrenal hyperplasia (CAH-C) debuts in newborns or infants with primary adrenal insufficiency, some degree of clinical hyperandrogenism in newborn females, and can coexist with hypotension, hyperkalemia, and hyponatremia if there is a clinical aldosterone deficiency. The objective of this article is to update the knowledge and suggested approaches for the management of CAH-C from the beginning of its controls in the adult stage. The retrospective differential diagnosis of CAH-C and non-classical (CAH-NC) is sometimes difficult because this disease is a continuous phenotypic spectrum. Adrenal insufficiency and dependence on corticosteroid therapy are the main events to differentiate these two pathologies that have different therapeutic approaches. In adults, the treatment of CAH-C must include 2 primary objectives: adequate the replacement of adrenal failure and control of hyperandrogenism, through the use of corticosteroids in their minimum effective doses. In women there are complementary therapies for the control of hyperandrogenism, such as contraceptives and others that are in different phases of research. This makes it possible to reduce the doses of corticosteroids in some cases. It is important at the same time to address three secondary objectives: control the cardiometabolic risk of the disease secondary to corticosteroid treatment, avoid corticosteroid overtreatment and manage infertility. The correct monitoring of treatment in adults and taking in to account the objectives described, allows a better quality of life in these patients. Finally, genetic counseling must be carried out in all patients planning for children, with any type of CAH and in their partners. The study requires sequencing of the CYP21A2 gene and must be performed in a certified laboratory.


Subject(s)
Humans , Adrenal Hyperplasia, Congenital/therapy , Steroid 21-Hydroxylase , Adrenal Cortex Hormones/therapeutic use , Adrenal Insufficiency/etiology , Adrenal Insufficiency/therapy , Hyperandrogenism/etiology , Hyperandrogenism/therapy , Adrenal Hyperplasia, Congenital/complications , Adrenal Hyperplasia, Congenital/diagnosis , Metabolic Syndrome/prevention & control , Flutamide/therapeutic use , Genetic Counseling , Infertility/etiology , Infertility/therapy
3.
Medicina (B.Aires) ; 80(3): 197-202, jun. 2020. ilus, tab
Article in English | LILACS | ID: biblio-1125070

ABSTRACT

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder due to a deficiency of enzymes involved in cortisol biosynthesis. In more than 90% of cases, CAH is secondary to deleterious mutations in the CYP21A2 gene leading to 21-hydroxilase deficiency (21OHD). The CYP21A2 gene is located on the short arm of chromosome 6 (6p21·3) and encodes the cytochrome P450C21 enzyme. Neonatal screening programs detect the classic forms of CAH-21OHD quantifying 17OH-progesterone in dried blood spots (DBS). This test is very sensitive, but it has a low specificity, requiring a second sample to confirm the result. In these cases, a second-tier test in the same sample may be useful. Our aim was to evaluate a DNA extraction method from DBS and assess the performance of such DNA in the molecular analysis of the CYP21A2 gene mutations. Twelve individuals, who presumably had CAH based on the initial neonatal screening results, were analyzed using DNA extracted from freshly collected blood on EDTA and DBS. The CYP21A2 gene was analyzed by automated sequencing of all exons and intron boundaries and MLPA analysis in DBS. Molecular analysis results from both extraction methods were compared. In this study, we show that DNA extracted from neonatal screening DBS is a useful tool to define CYP21A2 gene mutations in 21-OHD diagnostic confirmation for the newborn screening program and that its results are comparable to traditional genotyping.


La hiperplasia suprarrenal congénita (HSC) es un desorden autosómico recesivo producido por la deficiencia de alguna de las enzimas involucradas en la biosíntesis de cortisol. Más del 90% se debe a mutaciones en el gen CYP21A2 que genera deficiencia de 21 hidroxilasa (21OHD). Este gen se encuentra en el brazo corto del cromosoma 6 (6p21·3) y codifica para la enzima citocromo P450C21. Los programas de pesquisa neonatal detectan la forma clásica de la HSC-21OHD cuantificando 17OH-progesterona en gota de sangre en papel de filtro (GSPF). Este test es muy sensible, pero tiene baja especificidad , por lo que se utiliza una segunda muestra para confirmar el resultado. En estos casos, una segunda determinación en la misma muestra podría ser de utilidad. Nuestro objetivo fue evaluar el método de extracción de ADN y posterior análisis molecular del gen CYP21A2 en muestras de GSPF. Analizamos doce individuos presumiblemente afectados por HSC en la pesquisa neonatal usando ADN extraído de sangre fresca recolectada sobre EDTA y de GSPF. Realizamos el análisis del gen CYP21A2 mediante secuenciación automática de todos los exones y regiones intrónicas flanqueantes y MLPA en GSPF, y comparamos los resultados con ambos métodos de extracción. En este estudio demostramos que el ADN extraído de GSPF es una herramienta muy útil para analizar las mutaciones del gen CYP21A2 en la confirmación diagnóstica de 21-OHD para los programas de pesquisa neonatal y que los resultados son comparables con la genotipificación tradicional.


Subject(s)
Humans , Male , Female , Infant, Newborn , Steroid 21-Hydroxylase/genetics , Neonatal Screening/methods , Adrenal Hyperplasia, Congenital/diagnosis , Adrenal Hyperplasia, Congenital/genetics , Dried Blood Spot Testing/methods , Mutation , Reference Values , Spectrophotometry , Polymerase Chain Reaction , Reproducibility of Results , Gestational Age , 17-alpha-Hydroxyprogesterone/analysis , Alleles
4.
J. pediatr. (Rio J.) ; 95(3): 282-290, May-June 2019. tab, graf
Article in English | LILACS | ID: biblio-1012607

ABSTRACT

Abstract Objective: To describe the results obtained in a neonatal screening program after its implementation and to assess the clinical and molecular profiles of confirmed and suspicious congenital adrenal hyperplasia cases. Methods: A cross-sectional study was conducted. Newborns with suspected disease due to high 17-hydroxyprogesterone levels and adjusted for birth weight were selected. Classical congenital adrenal hyperplasia (salt-wasting and simple virilizing forms) was diagnosed by an increase in 17-hydroxyprogesterone levels as confirmed in the retest, clinical evaluation, and genotype determined by SNaPshot and multiplex ligation-dependent probe amplification. Results: After 24 months, 15 classic congenital adrenal hyperplasia cases were diagnosed in a total of 217,965 newborns, with an estimated incidence of 1:14,531. From 132 patients, seven non-classical and 14 heterozygous patients were screened for CYP21A2 mutations, and 96 patients presented false positives with wild type CYP21A2. On retest, increased 17-hydroxyprogesterone levels were found in classical congenital adrenal hyperplasia patients and showed significant correlation with genotype-related classical genital adrenal hyperplasia. The most frequent mutations were IVS2-13A/C>G followed by gene deletion or rearrangement events in the classical form. In non-classical and heterozygous diseases, p.Val282Leu was the most common mutation. Conclusions: The results underscore the effectiveness of congenital adrenal hyperplasia neonatal screening in the public health system and indicate that the adopted strategy was appropriate. The second sample collection along with genotyping of suspected cases helped to properly diagnose both severe and milder cases and delineate them from false positive patients.


Resumo Objetivo: Descrever os resultados obtidos em um programa de triagem neonatal após sua implementação e avaliar os perfis clínicos e moleculares de casos confirmados e suspeitos de hiperplasia adrenal congênita. Métodos: Foi feito um estudo transversal. Recém-nascidos com suspeita da doença devido aos altos níveis de 17-alfa-hidroxiprogesterona e ajustados pelo peso ao nascer foram selecionados. A hiperplasia adrenal congênita clássica (forma perdedora de sal e forma virilizante simples) foi diagnosticada por um aumento nos níveis de 17-alfa-hidroxiprogesterona confirmado no reteste, avaliação clínica e genótipo determinado com o uso do ensaio SNaPshot e amplificação multiplex de sondas dependente de ligação. Resultados: Após 24 meses, 15 casos clássicos de hiperplasia adrenal congênita foram diagnosticados em 217.965 recém-nascidos, com uma incidência estimada de 1:14.531. De 132 pacientes, sete não clássicos e 14 heterozigotos foram submetidos à triagem para mutações no gene CYP21A2 e 96 pacientes apresentaram resultados falso-positivos com CYP21A2 do tipo selvagem. No reteste, níveis aumentados de 17-alfa-hidroxiprogesterona foram encontrados em pacientes com hiperplasia adrenal congênita clássica e mostraram correlação significativa com HAC clássica relacionada ao genótipo. As mutações mais frequentes foram IVS2-13A/C>G, seguidas de deleção gênica ou eventos de rearranjo na forma clássica. Em casos de doenças não clássicas e heterozigose, a mutação p.Val282Leu foi a mais comum. Conclusões: Os resultados ressaltam a eficácia da triagem neonatal para a hiperplasia adrenal congênita no sistema público de saúde e indicam que a estratégia adotada foi adequada. A segunda coleta de amostras, juntamente com a genotipagem dos casos suspeitos, ajudou a diagnosticar adequadamente os casos graves e mais leves e diferenciá-los de pacientes com resultado falso-positivo.


Subject(s)
Humans , Male , Female , Infant, Newborn , Steroid 21-Hydroxylase/blood , Neonatal Screening/methods , Adrenal Hyperplasia, Congenital/diagnosis , 17-alpha-Hydroxyprogesterone/blood , Phenotype , Brazil/epidemiology , Biomarkers/blood , Incidence , Cross-Sectional Studies , Adrenal Hyperplasia, Congenital/genetics , Adrenal Hyperplasia, Congenital/epidemiology , Genotype , Mutation
5.
Article in Chinese | WPRIM | ID: wpr-775803

ABSTRACT

OBJECTIVE@#Genetic screening and prenatal diagnosis was performed in eighteen families with high risk of 21-hydroxylase deficiency (21-OHD) to provide valuable information for genetic counseling in these affected families.@*METHODS@#First, multiplex ligation-dependent probe amplification (MLPA) combined with nested-PCR based Sanger sequencing was used to detect CYP21A2 gene mutations in probands and their parents of eighteen families, with seven probands had been dead. Second, paternity test was applied to exclude the possibility of maternal genomic DNA contamination, and fetal prenatal diagnosis is based on the mutations found in proband or parents of the family.@*RESULTS@#Ten mutations were identified in these eighteen families, including large fragment deletion, I2G, E3del8bp, I172N, V281L, E6 cluster, L307Ffs, Q318X, R356W and R484Pfs. All probands were caused by homozygous or compound heterozygous mutations of CYP21A2 gene and their parents were carriers. By comparing short tandem repeat sites contamination of maternal genomic DNA was not found in fetal DNA. Prenatal diagnosis showed that five fetus were 21-OHD patients, four fetus were carriers and the other nine fetus were normal.@*CONCLUSION@#CYP21A2 gene mutation is the etiology of 21-OHD. Genetic testing of CYP21A2 could assist physicians in 21-OHD diagnosis and provided genetic counseling and prenatal diagnosis for parents who are at risk for having a child with congenital adrenal hyperplasia.


Subject(s)
Adrenal Hyperplasia, Congenital , Diagnosis , Genetics , Female , Genetic Testing , Humans , Mutation , Pregnancy , Prenatal Diagnosis , Steroid 21-Hydroxylase
6.
Article in Chinese | WPRIM | ID: wpr-775799

ABSTRACT

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


Subject(s)
Adrenal Hyperplasia, Congenital , Genetics , Genotype , Humans , Mutation , Phenotype , Steroid 21-Hydroxylase , Genetics
7.
Article in English | WPRIM | ID: wpr-716846

ABSTRACT

We present a family with 2 members who received long-term steroid treatment for presumed classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, until molecular testing revealed nonclassic CAH, not necessarily requiring treatment. A 17-year-old male presented to our clinic on glucocorticoid and mineralocorticoid treatment for classic CAH. He was diagnosed at 4 years of age based on mild-moderate elevations of 17-hydroxyprogesterone (17-OHP) and adrenocorticotropic hormone (ACTH), but without evidence of precocious adrenarche/puberty. Due to his diagnosis, his clinically asymptomatic 3-year-old sister was tested and also found to have elevated ACTH and 17-OHP levels and was started on glucocorticoids for classic CAH. Family history revealed a healthy sibling who had no biochemical evidence of CAH and consanguineous healthy parents. We questioned the diagnosis of classic CAH and performed an ACTH1-24 stimulation test, which showed a level of 17-OHP in the borderline range between classic and nonclassic CAH. Molecular testing, using sequencing and multiplex ligation-dependent probe amplification analysis of CYP21A2, revealed that both affected siblings were compound heterozygotes for a whole-gene deletion and a, likely pathogenic (nonclassical), sequence variant, p.R124C. The asymptomatic father had the same genotype, while the mother showed one deleted copy and 2 active copies, making her an asymptomatic carrier. Our report demonstrates the importance of molecular testing in atypical cases of CAH, as well as the importance of both sequencing and deletion analysis. The results of molecular testing should be interpreted in clinical context, and treatment should be prescribed according to guidelines when available.


Subject(s)
17-alpha-Hydroxyprogesterone , Adolescent , Adrenal Hyperplasia, Congenital , Adrenocorticotropic Hormone , Child, Preschool , Diagnosis , Fathers , Gene Deletion , Genetic Testing , Genotype , Glucocorticoids , Heterozygote , Humans , Male , Mothers , Multiplex Polymerase Chain Reaction , Parents , Siblings , Steroid 21-Hydroxylase
8.
Article in Chinese | WPRIM | ID: wpr-775826

ABSTRACT

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


Subject(s)
Adrenal Hyperplasia, Congenital , Diagnosis , Genetics , Asian People , China , Female , Humans , Mutation , Pedigree , Pregnancy , Prenatal Diagnosis , Steroid 21-Hydroxylase , Genetics
9.
Arch. endocrinol. metab. (Online) ; 61(6): 633-636, Dec. 2017. graf
Article in English | LILACS | ID: biblio-887602

ABSTRACT

SUMMARY Isolated growth hormone deficiency (IGHD) is the most common pituitary hormone deficiency and, clinically, patients have delayed bone age. High sequence similarity between CYP21A2 gene and CYP21A1P pseudogene poses difficulties for exome sequencing interpretation. A 7.5 year-old boy born to second-degree cousins presented with severe short stature (height SDS −3.7) and bone age of 6 years. Clonidine and combined pituitary stimulation tests revealed GH deficiency. Pituitary MRI was normal. The patient was successfully treated with rGH. Surprisingly, at 10.8 years, his bone age had advanced to 13 years, but physical exam, LH and testosterone levels remained prepubertal. An ACTH stimulation test disclosed a non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency explaining the bone age advancement and, therefore, treatment with cortisone acetate was added. The genetic diagnosis of a homozygous mutation in GHRHR (p.Leu144His), a homozygous CYP21A2 mutation (p.Val282Leu) and CYP21A1P pseudogene duplication was established by Sanger sequencing, MLPA and whole-exome sequencing. We report the unusual clinical presentation of a patient born to consanguineous parents with two recessive endocrine diseases: non-classic congenital adrenal hyperplasia modifying the classical GH deficiency phenotype. We used a method of paired read mapping aided by neighbouring mis-matches to overcome the challenges of exome-sequencing in the presence of a pseudogene.


Subject(s)
Humans , Male , Infant , Child , Bone Diseases, Developmental/genetics , Steroid 21-Hydroxylase/genetics , Receptors, Neuropeptide/genetics , Adrenal Hyperplasia, Congenital/genetics , Dwarfism, Pituitary/genetics , Pedigree , Phenotype , Bone Diseases, Developmental/etiology , Receptors, Pituitary Hormone-Regulating Hormone/genetics , Adrenal Hyperplasia, Congenital/complications , Consanguinity , Dwarfism, Pituitary/complications , Mutation
10.
Rev. ecuat. pediatr ; 18(2): 24-25, diciembre 2017.
Article in Spanish | LILACS | ID: biblio-996597

ABSTRACT

La hiperplasia suprarrenal congénita (HSC) es una enfermedad endocrinológica frecuente, por defectos enzimáticos en la síntesis del cortisol, con elevación secundaria de ACTH e hiperplasia del córtex adrenal, la mayoría secundaria a déficit de 21-hidroxilasa. Hay formas severas, con déficit completo y manifestaciones en la época fetal o neonatal, y moderadas o no clásicas, con déficit parcial y manifestaciones en la infancia o adolescencia. Presentamos a un neonato masculino, macrosómico, con zonas hiperpigmentación genital y axilar, criptorquidia derecha, con HSC-no clásica, no perdedora de sal, con déficit de cortisol y elevación de 17 hidroxiprogesterona y testosterona, que requirió tratamiento con glucocorticoides. Determinando la importancia de un diagnóstico oportuno y la validez del tamizaje neonatal para pacientes asintomáticos, evitando morbilidad a largo plazo, y alteraciones en el neurodesarrollo.


Congenital adrenal hyperplasia (CAH) is a common endocrine disease, due to enzymatic defects in the synthesis of cortisol, with secondary elevation of ACTH and hyperplasia of the adrenal cortex, the majority secondary to a 21-hydroxylase deficit. Severe forms, with complete deficit and manifestations in the fetal or neonatal period, and moderate or non-classical, with partial deficit and manifestations in childhood or adolescence. We present a male neonatal, macrosomic, with areas of genital and axillary hyperpigmentation, right cryptorchidism, with non-classical HSC, no salt loser, with cortisol deficiency and elevation of 17 hydroxyprogesterone and testosterone, which require treatment with glucocorticoids. It is so important to make a timely diagnosis and the validity of neonatal screening for asymptomatic patients, avoiding long-term morbidity and alterations in neurodevelopment.


Subject(s)
Humans , Male , Infant, Newborn , Steroid 21-Hydroxylase , Hyperpigmentation , Adrenal Hyperplasia, Congenital , Congenital Abnormalities , Neonatal Screening , Early Diagnosis
11.
Article in English | WPRIM | ID: wpr-168716

ABSTRACT

Steroid 21-hydroxylase deficiency is the most prevalent form of congenital adrenal hyperplasia (CAH), accounting for approximately 95% of cases. With the advent of newborn screening and hormone replacement therapy, most children with CAH survive into adulthood. Adolescents and adults with CAH experience a number of complications, including short stature, obesity, infertility, tumor, osteoporosis, and reduced quality of life. Transition from pediatric to adult care and management of long-term complications are challenging for both patients and health-care providers. Psychosocial issues frequently affect adherence to glucocorticoid treatment. Therefore, the safe transition of adolescents to adult care requires regular follow-up of patients by a multidisciplinary team including pediatric and adult endocrinologists. The major goals for management of adults with 21-hydroxylase deficiency are to minimize the long-term complications of glucocorticoid therapy, reduce hyperandrogenism, prevent adrenal or testicular adrenal rest tumors, maintain fertility, and improve quality of life. Optimized medical or surgical treatment strategies should be developed through coordinated care, both during transition periods and throughout patients' lifetimes. This review will summarize current knowledge on the management of adults with CAH, and suggested appropriate approaches to the transition from pediatric to adult care.


Subject(s)
Adolescent , Adrenal Hyperplasia, Congenital , Adrenal Rest Tumor , Adult , Child , Fertility , Follow-Up Studies , Hormone Replacement Therapy , Humans , Hyperandrogenism , Infant, Newborn , Infertility , Mass Screening , Obesity , Osteoporosis , Quality of Life , Steroid 21-Hydroxylase , Transition to Adult Care
12.
Article in Chinese | WPRIM | ID: wpr-279882

ABSTRACT

<p><b>OBJECTIVE</b>To investigate gene mutations and the relationship between genotypes and clinical phenotypes in Uygur children with 21-hydroxylase deficiency (21-OHD) in Xinjiang, China.</p><p><b>METHODS</b>A total of 20 Uygur children with 21-OHD who visited the hospital between October 2013 and October 2014 were enrolled. Full-length direct sequencing and multiplex ligation-dependent probe amplification (MLPA) were used to detect the mutations of CYP21A2 gene, which encoded 21-hydroxylase. According to the type of mutation, the patients with 21-OHD were divided into different groups to analyze the consistency between predicted clinical phenotypes and actual clinical phenotypes.</p><p><b>RESULTS</b>A total of 9 mutation types were found in the 20 patients, and 8 of them were identified as pathogenic mutations, i.e., Del, conv, I2g, I172N, Cluster E6, 8-bp del, V281L, and R356W. The other mutation is the new mutation occurring in intron 5 (c.648+37A>G), which had not been reported, and its pathological significance remains unknown. Most clinical phenotypes predicted by mutation types had a higher coincidence rate with actual clinical phenotypes (above 67%), and the clinical phenotypes predicted by P30L and V281L had a lower coincidence rate with actual clinical phenotypes (below 33%).</p><p><b>CONCLUSIONS</b>The genotype of 21-OHD has a good correlation with phenotype, and the clinical phenotype can be predicted by detecting the patient′s genotype. The new mutation (c.648+37A>G) may be related to the pathogenesis of 21-OHD.</p>


Subject(s)
Adolescent , Adrenal Hyperplasia, Congenital , Ethnology , Genetics , Child , China , Ethnology , Female , Genotype , Humans , Male , Mutation , Phenotype , Steroid 21-Hydroxylase , Genetics
13.
Article in Chinese | WPRIM | ID: wpr-345362

ABSTRACT

<p><b>OBJECTIVE</b>To assess the frequencies of CYP21A2 gene mutations among patients from Fujian area with classical 21-hydroxylase deficiency.</p><p><b>METHODS</b>For 19 probands from different families affected with classical steroid 21-hydroxylase deficiency and 74 family members, mutations of the CYP21A2 gene were analyzed with combined nested polymerase chain reaction, Sanger sequencing and multiplex ligation-dependent probe amplification. Time resolved fluorescence immunoassay was performed to determine the level of 17-hydroxyprogesterone (17-OHP) in all family members. Clinical data and laboratory results of the probands and their family members were analyzed.</p><p><b>RESULTS</b>Eleven mutations were identified among the 38 alleles from the 19 probands. 92.1% (35/38) of the mutant CYP21A2 alleles were due to recombination between CYP21A2 and CYP21A1P. Gene conversion and deletions were identified in 84.2% (32/38) and 7.9% (3/38) of the alleles, respectively. IVS2-13A/C>G and chimeras were the most common mutations, which respectively accounted for 34.2% (13/38) and 18.4% (7/38) of all mutant alleles. Among these, IVS2+1G>A and Q318X+356W were first reported in China. 74.3% (55/74) of the family members were carriers of heterozygous mutations. However, no significant difference was found in the 17-OHP levels between carriers and non-carriers (P>0.05).</p><p><b>CONCLUSION</b>There seems to be a specific spectrum of CYP21A2 gene mutations in Fujian area, where IVS2-13A/C>G and chimeras are the most common mutations.</p>


Subject(s)
Adrenal Hyperplasia, Congenital , Genetics , Alleles , Female , Humans , Male , Mutation , Genetics , Steroid 21-Hydroxylase , Genetics
14.
Article in English | WPRIM | ID: wpr-180143

ABSTRACT

Congenital adrenal hyperplasia (CAH) during pregnancy is a rare condition. Only a few cases have been reported in the literature. CAH patients has lower pregnancy rate compared to normal women. A 27-year-old nulliparous woman, a diagnosed case of 21-hydroxylase deficient simple virilising form of classic CAH visited. She got pregnant spontaneously without any trial of assisted reproductive technology. At the age of 12, she underwent clitoral resection and vaginoplasty. She took dexamethasone or prednisolone after operation. She delivered healthy singleton female baby by cesarean section. Four years later, she delivered healthy singleton female baby by repeat cesarean section. Two female babies have shown normal external genitalia. Here, we report a case of successful pregnancy and delivery in a patient with CAH.


Subject(s)
Adrenal Hyperplasia, Congenital , Adult , Cesarean Section , Cesarean Section, Repeat , Dexamethasone , Female , Fertility , Genitalia , Humans , Prednisolone , Pregnancy Rate , Pregnancy , Reproductive Techniques, Assisted , Steroid 21-Hydroxylase
15.
Article in English | WPRIM | ID: wpr-34973

ABSTRACT

The term congenital adrenal hyperplasia (CAH) covers a group of autosomal recessive disorders caused by defects in one of the steroidogenic enzymes involved in the synthesis of cortisol or aldosterone from cholesterol in the adrenal glands. Approximately 95% of all CAH cases are caused by 21-hydroxylase deficiency encoded by the CYP21A2 gene. The disorder is categorized into classical forms, including the salt-wasting and the simple virilizing types, and nonclassical forms based on the severity of the disease. The severity of the clinical features varies according to the level of residual 21-hydroxylase activity. Newborn screening for CAH is performed in many countries to prevent salt-wasting crises in the neonatal period, to prevent male sex assignment in affected females, and to reduce long-term morbidities, such as short stature, gender confusion, and psychosexual disturbances. 17α-hydroxyprogesterone is a marker for 21-hydroxylase deficiency and is measured using a radioimmunoassay, an enzyme-linked immunosorbent assay, or a fluoroimmunoassay. Recently, liquid chromatography linked with tandem mass spectrometry was developed for rapid, highly specific, and sensitive analysis of multiple analytes. Urinary steroid analysis by gas chromatography mass spectrometry also provides qualitative and quantitative data on the excretion of steroid hormone metabolites. Molecular analysis of CYP21A2 is useful for genetic counseling, confirming diagnosis, and predicting prognoses. In conclusion, early detection using neonatal screening tests and treatment can prevent the worst outcomes of 21-hydroxylase deficiency.


Subject(s)
Adrenal Glands , Adrenal Hyperplasia, Congenital , Aldosterone , Cholesterol , Chromatography, Liquid , Diagnosis , Enzyme-Linked Immunosorbent Assay , Female , Fluoroimmunoassay , Gas Chromatography-Mass Spectrometry , Genetic Counseling , Humans , Hydrocortisone , Infant, Newborn , Male , Mass Screening , Neonatal Screening , Prognosis , Radioimmunoassay , Steroid 21-Hydroxylase , Tandem Mass Spectrometry
16.
Saudi Medical Journal. 2015; 36 (1): 113-116
in English | IMEMR | ID: emr-159969

ABSTRACT

The aim of this study is to determine congenital adrenal hyperplasia [CAH] with the pattern of CYP21A2 gene-mutations in Saudi children. Between January 2011 and March 2014 at King Fahad Military Complex, Dhahran, Saudi Arabia, we thoroughly examined 11 patients with CAH and 2 asymptomatic individuals with a history of affected siblings. Additionally, we sequenced the full coding regions of the CYP21A2 gene and screened the gene for deletion[s]/duplication[s] using the multiplex ligation-dependent probe amplification [MLPA] technique. Nine patients had classic CAH and presented with ambiguous genitalia and/or salt losing crisis. Two patients had the non-classic form of CAH and presented with precocious puberty. The remaining 2 subjects were asymptomatic. Screening the CYP21A2 gene, we detected p.Gln318X mutation in 4 patients, c.290 -13 C>G [IVS2-13C>G] in another 4, and a common deletion, involving exons 6 and 8 in 3 patients. Our strategy of Sanger sequencing followed by MLPA was very successful in detecting CYP21A2 mutations in all patients with CAH


Subject(s)
Humans , Molecular Biology , Steroid 21-Hydroxylase , Mutation
17.
Article in English | WPRIM | ID: wpr-115870

ABSTRACT

Congenital adrenal hyperplasia (CAH) is one of the most common inherited metabolic disorders. It comprises a group of autosomal recessive disorders caused by the mutations in the genes encoding for steroidogenic enzymes that involved cortisol synthesis. More than 90% of cases are caused by a defect in the enzyme 21-hydroxylase. Four other enzyme deficiencies (cholesterol side-chain cleavage, 17alpha-hydroxylase [P450c17], 11beta-hydroxylase [P450c11beta], 3beta-hydroxysteroid dehydrogenase) in the steroid biosynthesis pathway, along with one cholesterol transport protein defect (steroidogenic acute regulatory protein), and one electrontransfer protein (P450 oxidoreductase) account for the remaining cases. The clinical symptoms of the different forms of CAH result from the particular hormones that are deficient and those that are produced in excess. A characteristic feature of CAH is genital ambiguity or disordered sex development, and most variants are associated with glucocorticoid deficiency. However, in the rare forms of CAH other than 21-hydroxylase deficiency so-called "atypical CAH", the clinical and hormonal phenotypes can be more complicated, and are not well recognized. This review will focus on the atypical forms of CAH, including the genetic analyses, and phenotypic correlates.


Subject(s)
Adrenal Hyperplasia, Congenital , Cholesterol , Disorders of Sex Development , Genotype , Hydrocortisone , Phenotype , Rare Diseases , Sexual Development , Steroid 21-Hydroxylase
18.
Article in Chinese | WPRIM | ID: wpr-291748

ABSTRACT

<p><b>OBJECTIVE</b>To establish an allele-specific PCR method for detect screening of CYP21A2 gene mutation.</p><p><b>METHODS</b>Allele-specific PCR primers and analogy primers were designed based on the sequence alignment of CYP21A2 and CYP21AP genes. Genomic DNA was extracted from blood specimens of 4 patients with 21-hydroxylase deficiency and 5 healthy controls and respectively amplified with allele-specific PCR primers and analogy primers and sequenced.</p><p><b>RESULTS</b>Mutations of CYP21A2 including IVS2-13A/C>G, Arg356Trp and Arg149Pro were found with the established method in all of the 4 patients but not in the healthy controls. When detected with the analogy primers set, IVS2-13A/C>G and Arg356Trp were observed in both patients and healthy controls.</p><p><b>CONCLUSION</b>The allele-specific PCR-based method is a simple, effective and reliable method for the detection of CYP21A2 gene mutation.</p>


Subject(s)
Adrenal Hyperplasia, Congenital , Genetics , Alleles , Base Sequence , DNA Mutational Analysis , Methods , DNA Primers , Genetics , Humans , Molecular Sequence Data , Mutation , Polymerase Chain Reaction , Methods , Steroid 21-Hydroxylase , Genetics
19.
Article in Chinese | WPRIM | ID: wpr-254464

ABSTRACT

<p><b>OBJECTIVE</b>To analyze CYP21A2 gene mutation in two families with 21-hydroxylase deficiency (21-OHD) and to explore the correlation between genotype and clinical phenotype.</p><p><b>METHODS</b>Two patients with 21-OHD and their families were investigated. CYP21A2 gene mutation was analyzed by PCR and direct sequencing.</p><p><b>RESULTS</b>The probands from family 1 and 2 have been respectively diagnosed with simple virilizing and non-classical 21-OHD. Both showed increased baseline serum 17hydroxyprogesterone, testosterone and adrenocorticotropic hormone (ACTH), but had no evidence of salt loss. Computer tomography revealed bilateral adrenal hyperplasia in both patients. After 1 year treatment, both had conceived successfully. DNA sequencing revealed that the proband of family 1 had compound heterozygous mutations for IVS2 13 A>G and Ile172Asn. Her father was heterozygous for Ile172Asn, whilst her mother and brother were heterozygous for IVS213A/C>G. In family 2, the proband was heterozygous for Arg341Trp and Gln318X. Her father, sister and nephew were heterozygous for Arg341Trp, whilst her mother was heterozygous for Gln318X. her brother and niece were non-affected. Carriers of single heterozygous mutations in both families had no clinical sign.</p><p><b>CONCLUSION</b>In both families, the disease has been caused by compound heterozygous mutations, for which there has been a good genotype-phenotype agreement. Screening of CYP21A2 gene can facilitate both diagnosis and genetic counseling.</p>


Subject(s)
Adrenal Hyperplasia, Congenital , Blood , Genetics , Adrenocorticotropic Hormone , Blood , Adult , Base Sequence , Child , Female , Genotype , Humans , Male , Molecular Sequence Data , Mutation, Missense , Pedigree , Phenotype , Steroid 21-Hydroxylase , Genetics , Metabolism , Testosterone , Blood , Young Adult
20.
Article in English | WPRIM | ID: wpr-178355

ABSTRACT

PURPOSE: The purpose of the study was to evaluate endocrine patterns of patients with congenital adrenal hyperplasia and each gene mutation and to analyze the correlation between each phenotype and genotype. METHODS: This was a retrospective study of the patients with congenital adrenal hyperplasia in the pediatric outpatient clinic at the Samsung Medical Center from November 1994 to December 2012. We analyzed the medical records of 27 patients (male, 19; female, 8) with congenital adrenal hyperplasia who had been diagnosed by genetic testing to have 21-hydroxylase deficiency. RESULTS: In genetic analysis of 54 alleles from 27 patients, 13 types of mutations were identified. The distribution of 21-hydroxylase deficiency gene mutations revealed that intron 2 splice site (c.293-13A/C>G) mutations and large deletions were the most common, at 31.5% and 22.2% respectively, followed by p.I173N, p.R356W, and p.I172N mutations at 11.1%, 9.3%, and 9.3%, respectively. Other mutations were observed at 1.9-3.7%. No novel mutations were detected. CONCLUSION: The analysis of 54 alleles revealed 13 types of mutation. The salt wasting form showed a good correlation between genotype and phenotype, but the simple virilizing and nonclassic forms showed inconsistencies between genotype and phenotype. The distribution of CYP21A2 mutations was evaluated for 21-hydroxylase deficiency patients from a single center. This study provides limited data on mutation spectrum and genotype-phenotype correlation of 21-hydroxylase deficiency in Korea.


Subject(s)
Adrenal Hyperplasia, Congenital , Alleles , Ambulatory Care Facilities , Female , Genetic Association Studies , Genetic Testing , Genotype , Humans , Introns , Korea , Male , Medical Records , Phenotype , Retrospective Studies , Steroid 21-Hydroxylase
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