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1.
Methods Mol Biol ; 2546: 451-457, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36127612

RESUMO

Congenital adrenal hyperplasia (CAH) is a group of autosomal-recessive disorders due to deficiency of 11- or 21-hydroxylase. The analysis of cortisol, androstenedione, 17-hydroxyprogesterone (OHPG), dehydroepiandrosterone (DHEA), 11-deoxycortisol, and testosterone is generally performed in the diagnosis and/or follow-up of CAH. Analysis of specific steroids is also performed in other disorders such as evaluation of hirsutism or infertility in females and hypogonadism in males. Cortisol is generally analyzed by immunoassays, whereas other hormones are preferably assayed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). A multiple reaction monitoring, positive mode atmospheric pressure chemical ionization, LC-MS/MS method is described for the simultaneous quantification of androstenedione, 17-hydroxyprogesterone, DHEA, 11-deoxycortisol and testosterone. The method involves addition of labeled internal standards to serum samples and extraction of steroids in methyl tert-butyl ether. The extract is evaporated under stream of nitrogen, and the residue is reconstituted in methanol and analyzed by LC-MS/MS.


Assuntos
Androstenodiona , Cortodoxona , 17-alfa-Hidroxiprogesterona , Androgênios , Cromatografia Líquida/métodos , Desidroepiandrosterona , Feminino , Humanos , Hidrocortisona , Masculino , Metanol , Esteroide 21-Hidroxilase , Esteroides , Espectrometria de Massas em Tandem/métodos , Testosterona
2.
J Steroid Biochem Mol Biol ; 222: 106156, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35882282

RESUMO

Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency is an autosomal-recessive disorder caused by mutations in the CYP21A2 gene. The aim of the study was to analyze the molecular data of 155 21-OHD patients and retrospectively investigated the common allelic mutations of CYP21A2 in 1442 Chinese 21-OHD patients. Clinical features and mutations of CYP21A2 gene in 155 unrelated 21-OHD patients were examined. Of the 155 patients, 103 cases were salt-wasting (SW) forms, 38 were simple virilizing (SV) forms and 14 were non-classical (NC) forms. In general, two types of mutations including common allelic mutations (281/310, 90.6%) and rare mutations (29/310, 9.4%) were detected, among them four novel variants c.835G>T, c.1081C>T, c.1423C>T and c.651 + 2 T > G were identified. In 1442 Chinese 21-OHD patients, the most frequently mutations were I2G (36.2%), large deletion/conversion (20.7%) and p.I173N (17.8%), while p.V282L has the lowest frequency. In this study, we provided detailed clinical data and mutation spectrum in Chinese 21-OHD patients. Moreover, four novel CYP21A2 variants (c.835G>T, c.1081C>T, c.1423C>T and c.651 +2 T > G) were identified and computational structural modeling indicated that these novel variations probably affect structural stability. Our findings improve the understanding of CYP21A2 mutational spectrum and contribute to the precise diagnosis and prenatal counseling.


Assuntos
Hiperplasia Suprarrenal Congênita , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/genética , China , Genótipo , Humanos , Mutação , Fenótipo , Estudos Retrospectivos , Esteroide 21-Hidroxilase/genética
3.
J Clin Endocrinol Metab ; 107(9): 2433-2438, 2022 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-35857714

RESUMO

CONTEXT: Congenital generalized lipodystrophy, type 1 (CGL1), due to biallelic pathogenic variants in AGPAT2, is characterized by the near total loss of body fat from the face, trunk, and extremities. Patients develop premature diabetes, hypertriglyceridemia, hepatic steatosis, and polycystic ovary syndrome. However, sparing of the facial fat and precocious pubertal development has not been previously reported in CGL1. CASE DESCRIPTION: We report a 21-year-old woman of European descent with CGL1 who had sparing of the facial fat and premature thelarche at birth with premature pubarche and menstrual bleeding at age 3 years. Her serum 17-OH progesterone level rose to 1000 ng/dL (30.26 nmol/L) after cosyntropin stimulation test, suggestive of nonclassical congenital adrenal hyperplasia (NCAH) due to 21-hydroxylase deficiency. Hydrocortisone replacement therapy from age 3.5 to 10 years resulted in cessation of menstruation and growth of pubic hair, and a reduction of breast size. Sanger and whole-exome sequencing revealed compound heterozygous variants c.493-1G>C; p.(Leu165_Gln196del), and c.del366_588+534; p.(Leu123Cysfs*55) in AGPAT2 plus c.806G>C; p.(Ser269Thr) and c.844G>T; p.(Val282Leu) in CYP21A2. She developed diabetes at age 13 requiring high-dose insulin and had 7 episodes of acute pancreatitis due to extreme hypertriglyceridemia in the next 5 years. Metreleptin therapy was initiated at age 18 and after 3 years, she had remission of diabetes and hypertriglyceridemia; however, menstrual irregularity and severe hirsutism did not improve. CONCLUSION: Concomitant NCAH in this CGL1 patient was associated with precocious pubertal development and sparing of facial fat. Metreleptin therapy drastically improved her hyperglycemia and hyperlipidemia but not menstrual irregularity and hirsutism.


Assuntos
Hiperplasia Suprarrenal Congênita , Hiperinsulinismo , Hiperlipidemias , Hipertrigliceridemia , Lipodistrofia Generalizada Congênita , Pancreatite , Puberdade Precoce , Doença Aguda , Adolescente , Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Hiperplasia Suprarrenal Congênita/genética , Adulto , Criança , Pré-Escolar , Feminino , Hirsutismo/complicações , Humanos , Hiperinsulinismo/complicações , Hiperlipidemias/complicações , Hipertrigliceridemia/complicações , Recém-Nascido , Lipodistrofia Generalizada Congênita/complicações , Lipodistrofia Generalizada Congênita/diagnóstico , Lipodistrofia Generalizada Congênita/genética , Distúrbios Menstruais/complicações , Puberdade Precoce/complicações , Esteroide 21-Hidroxilase , Adulto Jovem
4.
Endocrinol Metab (Seoul) ; 37(4): 587-598, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35799332

RESUMO

A plethora of negative long-term outcomes have been associated with congenital adrenal hyperplasia (CAH). The causes are multiple and involve supra-physiological gluco- and mineralocorticoid replacement, excess adrenal androgens both intrauterine and postnatal, elevated steroid precursor and adrenocorticotropic hormone levels, living with a congenital condition as well as the proximity of the cytochrome P450 family 21 subfamily A member 2 (CYP21A2) gene to other genes. This review aims to discuss the different long-term outcomes of CAH.


Assuntos
Hiperplasia Suprarrenal Congênita , Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/genética , Humanos , Esteroide 21-Hidroxilase/genética
5.
Hum Gene Ther ; 33(15-16): 801-809, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35838129

RESUMO

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder caused by steroidogenic enzymes containing monogenetic defects. Most steroidogenic enzymes are cytochrome P450 groups that can be categorized as microsomal P450s, including 21-hydroxylase and 17α-hydroxylase/17,20 lyase, and mitochondrial P450s, including 11ß-hydroxylase. It has been shown that ectopic administration of Cyp21a1 ameliorates steroid metabolism in 21-hydroxylase-deficient mice. However, the effectiveness of this approach for mitochondrial P450 has not yet been evaluated. In this study, primary fibroblasts from patients with 21-hydroxylase deficiency (CYP21A2D) (n = 4), 17α-hydroxylase/17,20 lyase deficiency (CYP17A1D) (n = 1), and 11ß-hydroxylase deficiency (CYP11B1D) (n = 1) were infected with adeno-associated virus type 2 (AAV2) vectors. Steroidogenic enzymatic activity was not detected in the AAV2-infected CYP11B1D fibroblasts. Induced pluripotent stem cells (iPSCs) of CYP11B1D were established and differentiated into adrenocortical cells by induction of the NR5A1 gene. Adrenocortical cells established from iPSCs of CYP11B1D (CYP11B1D-iPSCs) were infected with an AAV type 9 (AAV9) vector containing CYP11B1 and exhibited 11ß-hydroxylase activity. For an in vivo evaluation, we knocked out Cyp11b1 in mice by using the CRISPR/Cas9 method. Direct injection of Cyp11b1-containing AAV9 vectors into the adrenal gland of Cyp11b1-deficient mice significantly reduced serum 11-deoxycorticosterone/corticosterone ratios at 4 weeks after injection and the effect was prolonged for up to 12 months. This study indicated that CYP11B1D could be ameliorated by gene induction in the adrenal glands, which suggests that a defective-enzyme-dependent therapeutic strategy for CAH would be required. Defects in microsomal P450, including CYP21A2D and CYP17A1D, can be treated with extra-adrenal gene induction. However, defects in mitochondrial P450, as represented by CYP11B1D, may require adrenal gene induction.


Assuntos
Hiperplasia Suprarrenal Congênita , Células-Tronco Pluripotentes Induzidas , Hiperplasia Suprarrenal Congênita/genética , Hiperplasia Suprarrenal Congênita/terapia , Animais , Dependovirus/genética , Dependovirus/metabolismo , Modelos Animais de Doenças , Fibroblastos/metabolismo , Terapia Genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Mutação , Esteroide 11-beta-Hidroxilase/genética , Esteroide 11-beta-Hidroxilase/metabolismo , Esteroide 17-alfa-Hidroxilase/genética , Esteroide 21-Hidroxilase/genética
6.
Eur J Endocrinol ; 187(2): 315-322, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35699971

RESUMO

Introduction: Osilodrostat is a new 11ß-hydroxylase inhibitor with a mode of action analogous to Metyrapone. The objective of this study was to compare steroidogenic profiles in patients treated with either Osilodrostat or Metyrapone for adrenocorticotrophic hormone (ACTH)-dependent Cushing's syndrome (CS). Methods: Patients followed up at Cochin hospital Endocrinology department between March 2019 and December 2021 for an ACTH-dependent CS, controlled by either Osilodrostat or Metyrapone, were included. A serum profile of five steroids (cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, androstenedione and testosterone) was determined using UPLC- tandem mass spectrometry (UPLC-MS/MS). Results: Nineteen patients treated with Osilodrostat, eight patients treated with Metyrapone and six patients treated with consecutive Metyrapone then Osilodrostat were included. Hypocortisolism (basal cortisol <100 nmol/L) was found in 48% of patients treated with Osilodrostat and 7% of patients treated with Metyrapone. 11-deoxycortisol and androstenedione levels were higher in patients treated with Metyrapone (80.9 (2.2-688.4) and 14.9 (2.5-54.3) nmol/L, respectively) than in patients treated with Osilodrostat (10.3 (0.5-71.9) and 4.0 (0.3-13.3) nmol/L) (P = 0.0009 and P = 0.0005). Testosterone level in women was also higher in Metyrapone group (3.3 (0.93-4.82) nmol/L vs 1.31(0.13-5.09) nmol/L, P = 0.0146). CYP11B1 activity (11-deoxycortisol/cortisol) was not significantly different between the two groups. CYP21A2 activity (17OHprogesterone/11-deoxycortisol) and CYP17A1 activity (17OHprogesterone/androstenedione) were significantly decreased in Osilodrostat group (P < 0.0001). Conclusion: In patients with ACTH-dependent CS, the use of CYP11B1 inhibitors in routine care suggests that Osilodrostat has a less specific effect on the inhibition of steroidogenic enzymes than Metyrapone. This might explain a smaller increase in 11-deoxycortisol and androgen levels in patients treated with Osilodrostat.


Assuntos
Síndrome de Cushing , Metirapona , Hormônio Adrenocorticotrópico , Androstenodiona , Cromatografia Líquida , Cortodoxona , Síndrome de Cushing/tratamento farmacológico , Feminino , Humanos , Hidrocortisona , Imidazóis , Metirapona/farmacologia , Metirapona/uso terapêutico , Piridinas , Esteroide 11-beta-Hidroxilase , Esteroide 21-Hidroxilase , Espectrometria de Massas em Tandem , Testosterona
7.
Clin Chem ; 68(7): 927-939, 2022 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-35714169

RESUMO

BACKGROUND: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder that has been included in newborn screening programs. Current approaches to gene testing for CAH are facing challenges because of the complexity of the CYP21A2 locus and genetic heterogeneity of the disease. METHODS: A comprehensive analysis of CAH (CACAH) combining long-range locus-specific PCR and long-read sequencing (LRS) was developed to perform full sequence analysis of 5 common CAH candidate genes, including CYP21A2, CYP11B1, CYP17A1, HSD3B2, and StAR. In a blind retrospective study, the clinical utility of CACAH was evaluated in 37 samples by comparing to standard CAH testing using multiplex ligation-dependent probe amplification (MLPA) plus Sanger sequencing. RESULTS: Of the 37 clinical samples, a total of 69 pathogenic variants were identified, comprising 65 CYP21A2 variants, 2 HSD3B2 variants, and 2 CYP17A1 variants. For CYP21A2, the most frequent variant was c.518T > A (29.2%), followed by c.293-13C/A > G (21.5%). Compared with the current CAH testing using MLPA plus Sanger sequencing, the CACAH assay showed 100% specificity and 100% sensitivity, and precisely determined the junction sites of deletions/insertions and cis-trans configuration of multiple variants without analyzing family samples. Moreover, CACAH identified a case carrying 2 copies of CYP21A1 with the c.1451_1452delinsC variant on the same chromosome, which was not confirmed by MLPA plus Sanger sequencing. CONCLUSION: LRS-based CACAH can determine all genotypes of CAH accurately and reliably in one assay, presenting a comprehensive approach for CAH genetic diagnosis and carrier screening.


Assuntos
Hiperplasia Suprarrenal Congênita , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/genética , Humanos , Recém-Nascido , Mutação , Estudos Retrospectivos , Análise de Sequência , Esteroide 11-beta-Hidroxilase/genética , Esteroide 21-Hidroxilase/genética
9.
Cells ; 11(9)2022 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-35563746

RESUMO

Adrenocortical carcinoma is a heterogeneous and aggressive cancer that originates from steroidogenic cells within the adrenal cortex. In this study, we have assessed for the preclinical gold standard NCI-H295 in direct comparison with the more recently established MUC-1 and a here newly reported ACC cell line (TVBF-7) the mutational status of important driver genes (TP53, MEN1, PRKAR1A, CTNNB1, APC, ZNRF-3, IGF-2, EGFR, RB1, BRCA1, BRCA2, RET, GNAS and PTEN), Wnt-signaling specificities (CTNNB1 mutation vs. APC mutation vs. wildtype), steroidogenic-(CYP11A1, CYP17A1, HSD3B2, HSD17B4, CYP21A2, CYP11B1, CYP11B2, MC2R, AT1R) and nuclear-receptor-signaling (AR, ER, GCR), varying electrophysiological potentials as well as highly individual hormone secretion profiles (Cortisol, Aldosterone, DHEA, DHEAS, Testosterone, 17-OH Progesterone, among others) which were investigated under basal and stimulated conditions (ACTH, AngII, FSK). Our findings reveal important genetic and pathophysiological characteristics for these three cell lines and reveal the importance of such cell-line panels reflecting differential endocrine functionalities to thereby better reflect clinically well-known ACC patient heterogeneities in preclinical studies.


Assuntos
Neoplasias do Córtex Suprarrenal , Córtex Suprarrenal , Carcinoma Adrenocortical , Córtex Suprarrenal/metabolismo , Córtex Suprarrenal/patologia , Corticosteroides , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/genética , Aldosterona/metabolismo , Desidroepiandrosterona , Humanos , Esteroide 21-Hidroxilase/metabolismo
10.
J Pediatr Endocrinol Metab ; 35(6): 777-783, 2022 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-35499511

RESUMO

OBJECTIVES: Congenital adrenal hyperplasia (CAH) remains one of the most challenging endocrine disorders to diagnose, manage, and treat, especially in Africa where there is lack of neonatal screening program, and limited access to care. Data on biomolecular anomaly are sparse, therefore type of mutations are unknown, increasing management challenges and genetic counseling. The present study aims to describe clinical, biomolecular aspects of a group of Cameroonian patients. METHODS: We did an observational retrospective study at the pediatric endocrinology unit of the Mother and Child Centre of the Chantal Biya Foundation in Yaounde from May 2013 to December 2019, including all patients diagnosed with CAH. RESULTS: We consecutively included 31 patients aged less than 21 years, diagnosed CAH. Median age at diagnosis was 1.71 years (IQR 0.08-2.57 years). Abnormal genitalia was the main complain in 48.4%(n=15). The most prevalent genetic anomaly found in our study population (n=24) was on CYP11, found in 16 patients (66.6%) followed by CYP21A2 mutation found in 8 patients. Homozygous mutation of p.Q356X was found in half of patients with 11 hydroxylase deficiency. This mutation was mostly found in people from semi-Bantu tribes, declared non consanguineous. CONCLUSIONS: 11 hydroxylase deficiency is the most prevalent form of CAH found in this group of Cameroonian children.


Assuntos
Hiperplasia Suprarrenal Congênita , Adolescente , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/epidemiologia , Hiperplasia Suprarrenal Congênita/genética , Camarões/epidemiologia , Criança , Humanos , Recém-Nascido , Oxigenases de Função Mista/genética , Mutação , Estudos Retrospectivos , Esteroide 21-Hidroxilase/genética
11.
Eur J Endocrinol ; 187(1): K13-K18, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35550562

RESUMO

Objective: The aim of this study was to assess the prevalence of ovarian and paraovarian adrenal rest tumors (ARTs) in gonadectomy materials of a subgroup of congenital adrenal hyperplasia (CAH) patients. Methods: A total of 20 historical cases with clinical/molecular diagnosis of classical CAH were included in the study. All patients had 46,XX karyotype and underwent gonadectomy because of being raised as male. Results: Median age at diagnosis of CAH was 5.7 years and was markedly delayed. All patients revealed severe virilization. Bone age was significantly advanced, and bone age/chronological age ratio was increased with a median ratio of 1.8. Median age at the time of gonadectomy was 9.2 years. Ovarian and paraovarian ARTs were detected during the pathological evaluation of gonadectomy materials in four patients (20%) (two with simple virilizing 21-hydroxylase and two with 11-beta-hydroxylase deficiency) with previously normal pelvic imaging. In three cases with ARTs, paraovarian area was composed of medium-sized polygonal cells, with round or oval monomorphic nuclei and abundant granular eosinophilic cytoplasm which is characteristic of adrenocortical tissue. The fourth case had bilateral ovarian 'steroid cell tumors, not otherwise specified', and the tumor was accepted as benign. Except for the ARTs, heterotopic prostate and bilateral paratubal epididymis tissue were detected in a patient. Conclusions: Ovarian and paraovarian ARTs might be more common than previously described, especially among patients with excessive and prolonged adrenocorticotropic hormone exposure. These tumors could be detected histopathologically even if not detected by classical imaging methods.


Assuntos
Hiperplasia Suprarrenal Congênita , Tumor de Resto Suprarrenal , Neoplasias Ovarianas , Hiperplasia Suprarrenal Congênita/diagnóstico , Tumor de Resto Suprarrenal/epidemiologia , Tumor de Resto Suprarrenal/cirurgia , Castração , Feminino , Humanos , Masculino , Neoplasias Ovarianas/cirurgia , Esteroide 21-Hidroxilase
12.
J Clin Endocrinol Metab ; 107(7): 1939-1947, 2022 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-35363313

RESUMO

CONTEXT: Congenital adrenal hyperplasia is most commonly caused by 21-hydroxylase deficiency (21-OHD), an autosomal recessive disorder resulting from biallelic pathogenic variants (PVs) in CYP21A2. With a highly homologous pseudogene and various types of single nucleotide and complex structural variants, identification of PVs in CYP21A2 has been challenging. OBJECTIVE: To leverage long-read next-generation sequencing combined with locus-specific polymerase chain reaction (PCR) to detect PVs in CYP21A2 and to determine its diagnostic yield in patients with 21-OHD. METHODS: Forty-eight Thai patients with 21-OHD comprising 38 sporadic cases and 5 pairs of siblings were enrolled. Two previously described locus-specific PCR methods were performed. Amplicons were subject to long-read sequencing. RESULTS: Ninety-six PVs in CYP21A2 in the 48 patients were successfully identified. The combined techniques were able to detect 26 structural chimeric variants (27%; 26/96) in 22 patients with 18 having monoallelic and 4 having biallelic chimeras. The remaining PVs were pseudogene-derived mutations (63%; 60/96), entire gene deletions (2%; 2/96), missense variants (3%; 3/96), a splice-site variant (2%; 2/96), frameshift variants (2%; 2/96), and a nonsense variant (1%; 1/96). Notably, a splice-site variant, IVS7 + 1G > T, which was identified in a pair of siblings, has not previously been reported. CONCLUSIONS: Our approach exploiting locus-specific PCR and long-read DNA sequencing has a 100% diagnostic yield for our cohort of 48 patients with 21-OHD.


Assuntos
Hiperplasia Suprarrenal Congênita , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/genética , Humanos , Mutação , Esteroide 21-Hidroxilase/genética , Esteroides , Tailândia
13.
Ann Endocrinol (Paris) ; 83(3): 181-185, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35489415

RESUMO

21-Hydroxylase deficiency (21OHD) is the most common cause of congenital adrenal hyperplasia. Increased production of adrenal-derived androgens and progesterone in 21OHD women interfere with their reproductive function and their fertility in many different ways, depending on the severity of the disease. Sexuality and fertility in women with classic 21OHD is impaired, due to several issues such as disrupted gonadotropic axis due to androgen and progesterone overproduction, and mechanical, psychological factors related to genital surgery. Fertility and fecundity in these women get better over the years. Subfertility seems contrariwise to be relative in non-classic 21OHD women. Before pregnancy, genotyping the partner and genetic counselling is mandatory.


Assuntos
Hiperplasia Suprarrenal Congênita , Gonadotrofos , Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/genética , Androgênios , Feminino , Fertilidade , Humanos , Gravidez , Progesterona , Esteroide 21-Hidroxilase/genética
14.
Front Endocrinol (Lausanne) ; 13: 834549, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35422767

RESUMO

Adrenal insufficiency in paediatric patients is mostly due to congenital adrenal hyperplasia (CAH), a severe monogenic disease caused by steroid 21-hydroxylase deficiency (21-OHD, encoded by the CYP21A2 gene) in 95% of cases. CYP21A2 genotyping requires careful analyses that guaranty gene-specific PCR, accurate definition of pseudogene-gene chimeras, gene duplications and allele dropout avoidance. A small panel of well-established disease-causing alterations enables a high diagnostic yield in confirming/discarding the disorder not only in symptomatic patients but also in those asymptomatic with borderline/positive results of 17-hydroxyprogesterone. Unfortunately, the complexity of this locus makes it today reluctant to high throughput techniques of massive sequencing. The strong relationship existing between the molecular alterations and the degree of enzymatic deficiency has allowed genetic studies to demonstrate its usefulness in predicting/classifying the clinical form of the disease. Other aspects of interest regarding molecular studies include its independence of physiological variations and analytical interferences, its usefulness in the diagnosis of simple virilizing forms in males and its inherent contribution to the genetic counseling, an aspect of great importance taking into account the high carrier frequency of CAH in the general population. Genetic testing of CYP21A2 constitutes an irreplaceable tool to detect severe alleles not just in family members of classical forms but also in mild late-onset forms of the disease and couples. It is also helpful in areas such as assisted reproduction and preimplantation diagnosis. Molecular diagnosis of 21-OHD under expert knowledge definitely contributes to a better management of the disease in every step of the clinical course.


Assuntos
Hiperplasia Suprarrenal Congênita , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/genética , Alelos , Criança , Feminino , Humanos , Masculino , Esteroide 21-Hidroxilase/genética , Esteroides
15.
Mol Diagn Ther ; 26(3): 293-300, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35476220

RESUMO

The term CAH-X was coined to describe a subset of patients with 21-hydroxylase deficiency displaying a phenotype compatible with the hypermobility type of Ehlers Danlos syndrome. The genetic defect is due to the monoallelic presence of a CYP21A2 deletion extending into the gene encoding tenascin X (TNXB), a connective tissue extracellular matrix protein. The result is a chimeric TNXA/TNXB gene causing tenascin-X haploinsufficiency. The prevalence of CAH-X was estimated to be around 14-15% in large cohorts of patients with 21-hydroxylase deficiency. However, population studies are still scarce and the clinical picture of the syndrome has yet to be fully defined. In this review, we discuss the current knowledge regarding the genetic and clinical profile of the CAH-X syndrome.


Assuntos
Hiperplasia Suprarrenal Congênita , Síndrome de Ehlers-Danlos , Hiperplasia Suprarrenal Congênita/genética , Síndrome de Ehlers-Danlos/epidemiologia , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/metabolismo , Humanos , Mutação , Esteroide 21-Hidroxilase/genética , Tenascina/genética
16.
Front Endocrinol (Lausanne) ; 13: 803226, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35282436

RESUMO

Congenital adrenal hyperplasia (CAH) secondary to 21-hydroxylase deficiency is an autosomal recessive disorder. The 21-hydroxylase enzyme P450c21 is encoded by the CYP21A2 gene located on chromosome 6p21.33 within the HLA major histocompatibility complex. This locus also contains the CYP21A1P, a non-functional pseudogene, that is highly homologous to the CYP21A2 gene. Other duplicated genes are C4A and C4B, that encode two isoforms of complement factor C4, the RP1 gene that encodes a serine/threonine protein kinase, and the TNXB gene that, encodes the extracellular matrix glycoprotein tenascin-X (TNX). TNX plays a role in collagen deposition by dermal fibroblasts and is expressed in the dermis of the skin and the connective tissue of the heart and skeletal muscle. During meiosis, misalignment may occur producing large gene deletions or gene conversion events resulting in chimeric genes. Chimeric recombination may occur between TNXB and TNXA. Three TNXA/TNXB chimeras have been described that differ in the junction site (CH1 to CH3) and result in a contiguous CYP21A2 and TNXB gene deletion, causing CAH-X syndrome. TNXB deficiency is associated with Ehlers Danlos syndrome (EDS). EDS comprises a clinically and genetically heterogeneous group of connective tissue disorders. As molecular analysis of the TNXB gene is challenging, the TNX-deficient type EDS is probably underdiagnosed. In this minireview, we will address the different strategies of molecular analysis of the TNXB-gene, as well as copy number variations and genetic status of TNXB in different cohorts. Furthermore, clinical features of EDS and clinical recommendations for long-term follow-up are discussed.


Assuntos
Hiperplasia Suprarrenal Congênita , Síndrome de Ehlers-Danlos , Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/genética , Quimera , Colágeno , Variações do Número de Cópias de DNA , Síndrome de Ehlers-Danlos/complicações , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/metabolismo , Feminino , Humanos , Masculino , Mutação , Esteroide 21-Hidroxilase/genética , Tenascina/genética
17.
BMC Endocr Disord ; 22(1): 57, 2022 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-35255871

RESUMO

BACKGROUND: Congenital adrenal hyperplasia (CAH), characterized by defective adrenal steroidogenesis, is transmitted in an autosomal recessive manner. Mutations in the steroid 21-hydroxylase gene CYP21A2 causing steroid 21-hydroxylase deficiency account for most cases of CAH. The c.145l-1452delGGinsC gene mutation is rare, and only one case has been reported, but the form of gene mutation is different from this case, resulting in different clinical phenotype. The most common pathogenic genotype of CAH is a homozygous or compound heterozygous mutation, but CAH patients homozygous for the p.I173N mutation and heterozygous for the c.1451-1452delGGinsC mutation have not been reported previously. We report herein a familial case of CAH, in which both siblings carry the rare homozygous p.I173N mutation and heterozygous c.1451-1452delGGinsC mutation. CASE PRESENTATION: The proband showed amenorrhea, infertility, polycystic ovaries, and increased levels of androgen, rather than the typical clinical manifestations of CAH such as an adrenal crisis or masculine vulva, so was misdiagnosed with polycystic ovary syndrome for many years. Following a correct diagnosis of CAH, she was given glucocorticoid treatment, her menstruation became more regular, and she became pregnant and delivered a healthy baby girl. CONCLUSIONS: The genotypes may be p.I173N homozygous or p.I173N/c.1451-1452delGGinsC heterozygous, both mutations could be pathogenic. This complex combination of mutations has not been reported or studied before. Through the report and analysis of this genotype, the content of CAH gene bank is enriched and the misdiagnosis rate of CAH is reduced.


Assuntos
Hiperplasia Suprarrenal Congênita/genética , Heterozigoto , Homozigoto , Mutação/genética , Esteroide 21-Hidroxilase/genética , Glândulas Suprarrenais/diagnóstico por imagem , Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Adulto , Diagnóstico Diferencial , Feminino , Glucocorticoides/uso terapêutico , Humanos , Infertilidade/etiologia , Infertilidade/terapia , Masculino , Linhagem , Síndrome do Ovário Policístico , Gravidez , Análise de Sequência de DNA , Tomografia Computadorizada por Raios X
18.
Arch Endocrinol Metab ; 66(2): 168-175, 2022 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-35289513

RESUMO

Objective: CYP21A2 mutation heterozygote carriers seem to have an increased risk of hyperandrogenism. However, the clinical relevance of the heterozygote carrier status and the reliability of hormonal testing in discriminating a carrier from a non-carrier are puzzling questions. We aimed to characterize a population of Portuguese females suspected of having non-classic congenital adrenal hyperplasia (NC-CAH) due to clinical and biochemical criteria and who have undergone CYP21A2 molecular analysis. Methods: Retrospectively, we have analyzed the clinical records of 131 females (32 girls aged 3-9 and 99 adolescents and premenopausal women aged 13-49) who underwent complete CYP21A2 molecular analysis due to suspicion of NC-CAH. We divided included participants into three groups according to the CYP21A2 molecular analysis: NC-CAH females (46), heterozygous carriers (49), and wild type (36). We then compared clinical signs and symptoms as well as biochemical and molecular data between carriers and NC-CAH individuals and between carriers and wild type females. We measured 17OHP by electrochemiluminescence immunoassay. Results: Clinical features were similar between groups. Heterozygous carriers presented higher basal and post-cosyntropin 17-hydroxyprogesterone (17OHP) than wild type individuals (p < 0.05) and lower basal and stimulated 17OHP levels than NC-CAH patients (p < 0.05). We discovered a considerable overlap between 17OHP levels among groups. The most common pathogenic variant we identified was p.Val282Leu. Conclusion: In this population of hyperandrogenic women and children, heterozygous carriers showed higher basal and stimulated 17OHP than non-carriers although normal basal and stimulated 17OHP responses do not exclude heterozygosity for CYP21A2 pathogenic variants. In this study, only the molecular analysis presented good sensitivity in identifying heterozygotes.


Assuntos
Hiperplasia Suprarrenal Congênita , Esteroide 21-Hidroxilase , 17-alfa-Hidroxiprogesterona , Adolescente , Hiperplasia Suprarrenal Congênita/genética , Criança , Feminino , Heterozigoto , Humanos , Hiperplasia , Masculino , Mutação/genética , Reprodutibilidade dos Testes , Estudos Retrospectivos , Esteroide 21-Hidroxilase/genética
19.
Internist (Berl) ; 63(1): 43-50, 2022 Jan.
Artigo em Alemão | MEDLINE | ID: mdl-34978615

RESUMO

Congenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive disorders and is characterized by cortisol deficiency. The most common cause of CAH is a mutation in the CYP21A2 gene, resulting in 21-hydroxylase deficiency in the adrenal cortex. The lack of cortisol causes an increase in adrenocorticotropic hormone (ACTH), which in turn results in an excess of adrenal androgens. Aldosterone synthesis may also be impaired. The clinical manifestation of CAH depends on the residual activity of 21-hydroxylase and the subsequent lack of cortisol and adrenal androgen excess. While classic CAH is a potentially life-threatening condition, non-classic CAH is mild to asymptomatic. Therapy of classic CAH consists of glucocorticoid and mineralocorticoid substitution. Despite optimization of therapy, CAH still leads to increased morbidity and mortality in patients. The clinical consequences of androgen excess in affected women range from intrauterine virilisation of external genitalia in classic CAH patients to mild symptoms of hyperandrogenism in non-classic forms. Increased demand for cortisol during illness or physical and psychological stress situations can trigger life-threatening adrenal crises. As current glucocorticoid therapy cannot mimic the physiological circadian rhythm and is usually supraphysiological in dose to control androgen excess, therapy-associated long-term consequences such as decreased bone health and an increased cardiometabolic risk profile are common. The burden of the disease may also lead to impaired quality of life and mental health. For this reason, regular screening and follow-up of patients with CAH should be performed in specialized centers to detect and treat possible comorbidities at an early stage.


Assuntos
Hiperplasia Suprarrenal Congênita , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Feminino , Glucocorticoides/uso terapêutico , Humanos , Morbidade , Qualidade de Vida , Esteroide 21-Hidroxilase/genética
20.
Hormones (Athens) ; 21(2): 241-249, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35079965

RESUMO

PURPOSE: The prevalence of CYP21A2 gene variants and genotype-phenotype correlations are variable among populations. The aim of this study was to characterize CYP21A2 gene variants in adult patients with classical congenital adrenal hyperplasia (CCAH) from southern Poland and to analyze genotype-phenotype correlations. MATERIALS/METHODS: A total of 48 patients (30 women and 18 men) with CCAH were included in the study. Patients were divided into two clinical subgroups, namely, salt-wasting (SW) - 38 patients and simple virilizing (SV) - 10 patients. A genetic analysis MLPA (multiplex ligation-dependent probe amplification) was performed in all of them. In dubious cases, the analysis was complemented by Sanger sequencing. Genotypes were classified into five groups (depending on the residual in vitro enzymatic activity), namely, null, A, B, C, and D, and correlated with the clinical picture. RESULTS: Molecular defects were investigated and identified in 48 patients. The most common variant in the studied group was I2G, followed by whole or partial gene copy deletion, and I172N. One novel variant c.[878G>T] (p.Gly293Val) was found. In nine patients, a non-concordance between genotype and phenotype was observed. Genotype-phenotype correlations measured by positive predictive value (PPV) were as follows: 100% in group null, 90.5% in group A, and 66.7% in group B. CONCLUSIONS: CYP21A2 variants in the studied cohort were similar to values previously reported in other countries of the region. There was a good correlation between genotype and phenotype in the null and A groups, the correlation being considerably lower in group B.


Assuntos
Hiperplasia Suprarrenal Congênita , Hiperplasia Suprarrenal Congênita/genética , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Mutação , Fenótipo , Polônia , Esteroide 21-Hidroxilase/genética
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