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La pesquisa neonatal de hiperplasia suprarrenal congénita se realiza mediante la determinación de 17 hidroxiprogesterona (17OHP) en gotas de sangre seca en papel de filtro. Los bebés prematuros presentan valores más elevados que los bebés de término, siendo de utilidad contar con límites de corte apropiados. Nuestro objetivo fue actualizar los valores de corte de 17OHP ajustados por edad gestacional para la metodología en uso a nivel nacional por las jurisdicciones asistidas por el "Programa Nacional de Fortalecimiento de la Detección Precoz de Enfermedades Congénitas". La 17OHP se determinó utilizando el kit comercial de enzimo-inmunoanálisis (ELISA competitivo), Elizen Neonatal 17OHP Screening (Zentech, Bélgica). Se obtuvieron límites de corte utilizando percentiles de la distribución de los valores de 17OHP para cada edad gestacional. La sensibilidad obtenida fue 100%, especificidad 98,76 %, tasa de falsos positivos 1,24 % y el valor predictivo positivo 1,12 %. Destacamos la importancia de disponer de límites de corte adecuados a la población. La armonización de los mismos permitirá resultados comparables entre los programas regionales de pesquisa neonatal (AU)
Newborn screening for congenital adrenal hyperplasia is performed by the measurement of 17-hydroxyprogesterone (17OHP) in dried blood spots on filter paper. Premature infants have higher values than full-term infants, and appropriate cutoff values are useful. Our aim was to update the cut-off values of 17OHP adjusted for gestational age for the methodology used at a national level in regions assisted by the "National Program for Strengthening the Early Detection of Congenital Diseases". 17OHP was determined using the commercial enzyme-linked immunosorbent assay (competitive ELISA) kit, Elizen Newborn 17OHP Screening (Zentech, Belgium). Cut-off values were obtained using percentiles of the distribution of 17OHP values for each gestational age. Sensitivity was 100%, specificity 98.76%, false positive rate 1.24%, and positive predictive value 1.12%. It is important to have cut-off values that are adjusted to the population. Harmonization will allow for the comparison of results among regional newborn screening programs (AU)
Subject(s)
Humans , Infant, Newborn , Predictive Value of Tests , Gestational Age , Neonatal Screening/methods , Adrenal Hyperplasia, Congenital/diagnosis , Adrenal Hyperplasia, Congenital/blood , 17-alpha-Hydroxyprogesterone/bloodABSTRACT
ABSTRACT Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is an autosomal recessive disorder caused by CYP21A2 gene mutations, and its molecular diagnosis is widely used in clinical practice to confirm the hormonal diagnosis. Hence, considering the miscegenation of the Brazilian population, it is important to determine a mutations panel to optimise the molecular diagnosis. The objective was to review the CYP21A2 mutations' distribution among Brazilian regions.Two reviewers screened Brazilian papers up to February 2020 in five databases. The pair-wise comparison test and Holm method were used in the statistical analysis. Nine studies were selected, comprising 769 patients from all regions. Low proportion of males and salt-wasters was identified in the North and Northeast regions, although without significant difference. Large gene rearrangements also had a low frequency, except in the Center-West and South regions (p < 0.05). The most frequent mutations were p.I172N, IVS2-13A/C>G, p.V281L and p.Q318X, and significant differences in their distributions were found: p.V281L was more frequent in the Southeast and p.Q318X in the Center-West and Northeast regions (p < 0.05). Thirteen new mutations were identified in 3.8%-15.2% of alleles, being more prevalent in the North region, and six mutations presented a founder effect gene. Genotype-phenotype correlation varied from 75.9%-97.3% among regions. The low prevalence of the salt-wasting form, affected males and severe mutations in some regions indicated pitfalls in the clinical diagnosis. The good genotype-phenotype correlation confirms the usefulness of molecular diagnosis; however, the Brazilian population also presents significant prevalence of novel mutations, which should be considered for a molecular panel.
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ABSTRACT Objective: Herein, we compared ambulatory blood pressure (ABP) between young adults with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase enzyme (21OHase) deficiency and a control group. Additionally, we analyzed correlations between the glucocorticoid dose and androgen levels and ABP parameters. Subjects and methods: This case-control study included 18 patients (6 males and 12 females) and 19 controls (8 males and 11 females) matched by age (18-31 years). ABP monitoring was used to estimate blood pressure (BP) over a 24-h period. Results: No difference was noted between patients and controls in terms of systolic BP (males, 115.5 ± 5.6 vs. 117.0 ± 9.3, P = 0.733; and females, 106.4 ± 7.9 vs. 108.4 ± 7.6, P = 0.556, respectively) and diastolic BP during 24 h (males, 62.8 ± 7.5 vs. 66.2 ± 5.6, P = 0.349; and females, 62.7 ± 4.9 vs. 62.3 ± 4.9, P = 0.818, respectively). Systolic and diastolic BP and pulse pressure during daytime and nocturnal periods were similar between patients and controls. Furthermore, no differences were detected in the percentage of load and impaired nocturnal dipping of systolic and diastolic BP between patients and controls during the 24-h period. Additionally, the glucocorticoid dose (varying between r = −0.24 to 0.13, P > 0.05) and androgens levels (varying between r = 0.01 to 0.14, P > 0.05) were not associated with ABP parameters. Conclusion: No signs of an elevated risk for hypertension were observed based on ABP monitoring in young adults with CAH attributed to 21OHase deficiency undergoing glucocorticoid replacement therapy.
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Previously the diseases of pediatric hyperandrogenism were mainly diagnosed and evaluated by testing traditional androgens such as testosterone and androstenedione.However, clinical application has revealed a poor correlation between traditional androgens and the clinical manifestations of hyperandrogenism in some patients.It has been proposed that adrenal-derived 11-oxygenated androgen may also be involved in the course of this type of disease.The concentrations of 11-oxygenated androgen are elevated in androgen excess diseases, and they fulfill a variety of roles in human physiology and disease.This article discusses three aspects of the synthesis process, activity and content of 11-oxygenated androgen and their application in three androgen excess diseases: congenital adrenocortical hyperplasia, premature adrenarche and polycystic ovary syndrome, in order to help clinicians expand their clinical understanding and investigative thoughts on 11-oxygenated androgen.
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【Objective】 To explore a new treatment of primary bilateral macronodular adrenal hyperplasia (PBMAH) and its efficacy. 【Methods】 Clinical data of 20 PBMAH patients treated in our hospital during Mar.2010 and Apr.2021 were retrospectively analyzed. All patients underwent laparoscopic subcutaneous displacement of vascularized adrenal. The clinical symptoms, plasma free cortisol, adrenocorticotrophic hormone (ACTH), and 24 h urinary free cortisol were regularly monitored after surgery. 【Results】 Of all 20 patients, 19 were followed up for 18 to 120 months (median 60 months). Three months after surgery, reexamination showed 1 patient had decreased plasma free cortisol and increased ACTH, but had no symptoms of low corticosteroids. After another 3 months, the plasma free cortisol and ACTH returned to normal. After 4 to 48 months, the parameters recovered in all patients and the clinical symptoms disappeared. 【Conclusion】 Laparoscopic vascularized adrenal displacement is a new and effective method for the treatment of PBMAH. It can alleviate the Cushing syndrome with no obvious adverse reactions.
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Objective:To summarize initial experience of applying nanopore third-generation sequencing detection method (nanopore sequencing) for genetic diagnosis of non-classical 21 hydroxylase deficiency (NC 21-OHD), and to explore its performance and application prospects.Methods:Clinical data of the two NC 21-OHD patients, who were hospitalized at the First Affiliated Hospital of Zhengzhou University in May 2019, were collected. Peripheral venous blood was collected and genome DNA extracted. Genetic variants was detected by nanopore sequencing and underwent bioinformatic analysis. Pathogenetic mutations in CYP21A2 gene were validated with PCR-sanger sequencing in the two patients and their parents.Results:The average reads length and sequence depth in the patient one was 12, 792 bp and 27.19×. The average reads length and sequence depth in the patient two was 13, 123 bp and 21.34×. Compound variants of c.293-13C>G/c.844G>T (p.Val282Leu) and c.332_339delGAGACTAC (p.Gly111Valfs)/c.844G>T (p.Val282Leu) were detected in these two patients, which were consistent with clinical phenotype of NC 21-OHD. Further analysis showed that c.293-13C>G mutation was inherited from her father and c.844G>T (p.Val282Leu) mutation was inherited from her mother for the patient one. The c.844G>T (p.Val282Leu) mutation was inherited from her father and c.332_339delGAGACTAC (p.Gly111Valfs) mutation from her mother.Conclusions:The heterozygous mutations in CYP21A2 gene are the cause of NC 21-OHD in these two patients. Nanopore sequencing technique is a reliable new detection method for patients with NC 21-OHD.
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Congenital adrenal hyperplasia(CAH) is a group of autosomal recessive disorders caused by deficiency of specific enzymes in the adrenocortical hormone synthesis pathway, resulting in impaired corticosteroid synthesis. 21-hydroxylase deficiency is the most common type of CAH, and the disorder can lead to impaired fertility in patients. Most current studies have focused on fertility problems in female CAH patients. The most common causes of impaired fertility in men with 21-OHD include testicular adrenal rest tumors(TART), low gonadotropin secretion, and inappropriate glucocorticoid therapy. This article reviews the causes of impaired fertility and its treatment in male patients with 21-OHD, with the aim of providing guidance for improving the fertility of male patients with 21-OHD.
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ABSTRACT Adrenal steroid biosynthesis and its related pathology are constant evolving disciplines. In this paper, we review classic and current concepts of adrenal steroidogenesis, plus control mechanisms of steroid pathways, distribution of unique enzymes and cofactors, and major steroid families. We highlight the presence of a "mineralocorticoid (MC) pathway of zona fasciculata (ZF)", where most circulating corticosterone and deoxycorticosterone (DOC) originate together with 18OHDOC, under ACTH control, a claim based on functional studies in normal subjects and in patients with 11β-, and 17α-hydroxylase deficiencies. We emphasize key differences between CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) and the onset of a hybrid enzyme - CYP11B1/CYP11B2 -, responsible for aldosterone formation in ZF under ACTH control, in "type I familial hyperaldosteronism" (dexamethasone suppressible). In "apparent MC excess syndrome", peripheral conversion of cortisol to cortisone is impaired by lack of 11β-hydroxysteroid dehydrogenase type 2, permitting free cortisol access to MC receptors resulting in severe hypertension. We discuss two novel conditions involving the synthesis of adrenal androgens: the "backdoor pathway", through which dihydrotestosterone is formed directly from androsterone, being relevant for the fetoplacental setting and sexual differentiation of male fetuses, and the rediscovery of C19 11-oxygenated steroids (11-hydroxyandrostenedione and 11-ketotestosterone), active androgens and important markers of virilization in 21-hydroxylase deficiency and polycystic ovaries syndrome. Finally, we underline two enzyme cofactor deficiencies: cytochrome P450 oxidoreductase which partially affects 21- and 17α-hydroxylation, producing a combined clinical/hormonal picture and causing typical skeletal malformations (Antley-Bixler syndrome), and PAPSS2, coupled to SULT2A1, that promotes sulfation of DHEA to DHEAS, preventing active androgens to accumulate. Its deficiency results in reduced DHEAS and elevated DHEA and androgens with virilization. Future and necessary studies will shed light on remaining issues and questions on adrenal steroidogenesis.
Subject(s)
Humans , Male , Adrenal Hyperplasia, Congenital/metabolism , Hyperaldosteronism , Steroids , Cytochrome P-450 CYP11B2 , AndrogensABSTRACT
The clinical data of 6 patients with 21-hydroxylase deficiency(21-OHD) diagnosed in The People′s Hospital of Xinjiang Uygur Autonomous Region from 2015 to 2020 were retrospectively analyzed. There were 2 male cases manifesting shorter height, high progesterone level and infertility. And 4 cases were females, manifesting primary amenorrhea, heterosexual precocious puberty, fatigue during emergency, decreased physical strength, dark skin, clitoral hypertrophy and vulva fusion. None of the parents had a history of consanguinity. All but one patient received glucocorticoid replacement therapy. The sequencing of exons and introns of 21CYPA2 gene showed tuat 1 case was homozygous mutation and 5 cases were complex heterozygous mutation. In terms of clinical phenotype, 1 case was non-classical (complex heterozygous mutation) and 5 cases were simple virilizing phenotype.
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Objetivo: Descrever o diagnóstico e manejo clínico da deficiência da 21-hidroxilase (D-21OH), no contexto atual de inclusão da doença nos programas de triagem neonatal, bem como características genéticas, fisiopatológicas e manifestações na infância e adolescência. Fonte de Dados: Revisão integrativa realizada nas bases de dados MEDLINE (PubMed), LILACS (BVS), Scopus, Web of Science nos últimos vinte anos, em língua inglesa e portuguesa; população-alvo: crianças da primeira infância à adolescência; com o uso dos termos "triagem neonatal", "hiperplasia adrenal congênita", "deficiência da 21-hidroxilase", "glucocorticoide" e "polimorfismos do gene NR3C1". Síntese de Dados: A hiperplasia adrenal congênita (HAC) constitui um grupo de doenças caracterizadas por deficiências enzimáticas na esteroidogênese do córtex adrenal. A D-21OH é responsável por 95% dos casos e, se não tratada precocemente, pode levar ao óbito no período neonatal em sua forma clássica. A triagem neonatal para a HAC consiste na dosagem do precursor 17-hidroxiprogesterona (17OHP) no sangue de recém-nascidos, permitindo rápida confirmação diagnóstica e instituição da terapêutica. A implantação da triagem neonatal constitui um avanço, mas o controle dos pacientes pediátricos com D-21OH é complexo e deve ser sempre individualizado. Conclusão: A instituição dos programas de triagem neonatal para HAC tem trazido benefícios para o prognóstico das crianças com D-21OH. Seu manejo é multiprofissional, individualizado e ainda um desafio mesmo para o especialista. Ampla divulgação do conhecimento sobre a doença é desejável para permitir melhor condução dessas crianças, especialmente de meninas com a doença que apresentam genitália atípica.
Objective: To describe the diagnosis and clinical management of 21-hydroxylase deficiency (21OH-D), in the current context of including the disease in neonatal screening programs, as well as genetic, pathophysiological characteristics, and manifestations in childhood and adolescence. Data Source: Integrative review performed in MEDLINE (PubMed), LILACS (BVS), Scopus, Web of Science databases in the last twenty years, in English and Portuguese; target population: children from early childhood to adolescence; with the use of the terms "neonatal screening"; "congenital adrenal hyperplasia"; "21-hydroxylase deficiency"; "glucocorticoid"; "polymorphisms of the NR3C1 gene". Data Synthesis: Congenital adrenal hyperplasia (CAH) is a group of diseases characterized by enzyme deficiencies in adrenal cortex steroidogenesis. 21OH-D is responsible for 95% of cases and, if not treated early, can lead to death in the neonatal period in its classic form. Neonatal screening for CAH consists of measuring the precursor 17-hydroxyprogesterone (17OHP) in the blood of newborns, allowing rapid diagnostic confirmation and institution of therapy. The implementation of neonatal screening is an advance, but the control of pediatric patients with 21OH-D is complex and must always be individualized. Conclusion: The institution of newborn screening programs for CAH has benefits for the prognosis of children with 21OH-D. Its management is multi-professional, individualized and still a challenge even for the specialist. Wide dissemination of knowledge about the disease is desirable to allow better management of these children, especially girls with the disease who have atypical genitalia.
Subject(s)
Humans , Male , Female , Child , Adolescent , Steroid 21-Hydroxylase/metabolism , Adrenal Hyperplasia, Congenital/therapy , Polymorphism, Genetic/genetics , Neonatal Screening , Adrenal Hyperplasia, Congenital/diagnosis , 17-alpha-Hydroxyprogesterone/metabolismABSTRACT
RESUMEN Introducción: Las glándulas suprarrenales se dividen en corteza y médula. La corteza secreta tres clases de hormonas diferentes: los glucocorticoides, mineralocorticoides y andrógenos; la médula produce las catecolaminas. Todas ellas intervienen en múltiples funciones corporales. Objetivo: Mostrar diferentes formas de presentación de algunas de las enfermedades de la corteza adrenal. Presentación de los casos: Paciente 1: escolar de 7 años, antecedentes de hipotiroidismo controlado, presenta decaimiento y escaso crecimiento pondoestatural. Cortisol en ayunas 86 nmol/L y ACTH 154 pg/ml. Se diagnostica insuficiencia adrenal primaria. Reingresa a los 9 años, por mantener escaso crecimiento. Edad ósea: 2 años y 8 meses. Test de clonidina: alterado, confirma déficit de hormona del crecimiento. Paciente 2: escolar de 8 años, antecedentes de hiperplasia adrenal congénita por déficit de 21 hidroxilasa, forma virilizante simple. Presenta aceleración del desarrollo genital. Se incumplió tratamiento con hidrocortisona, durante 5 años. Se comprobó elevada la 17 hidroxiprogesterona 189 ng/dl. Se diagnosticó pubertad precoz periférica y virilización de los genitales. Paciente 3: lactante de 5 meses con obesidad de 3 meses de evolución. Tomografía axial computarizada de abdomen contrastado confirma lesión tumoración de 5 cm en proyección de la suprarrenal derecha. Cortisol en ayunas 892 nmol/L, cortisol 11 pm 920 nmol/L. Se realizó cirugía y se diagnosticó síndrome de Cushing por carcinoma adrenal productor de cortisol. Conclusiones: En la práctica clínica diaria podemos encontrar pacientes con síntomas y signos tan comunes como el decaimiento, vómitos o el aumento brusco de peso y ellos ser secundario a enfermedades de la glándula suprarrenal.
ABSTRACT Introduction: The adrenal glands are divided into cortex and marrow. The cortex secretes three different classes of hormones: glucocorticoids, mineralocorticoids and androgens; the marrow produces catecholamines. All of them are involved in multiple corporal functions. Objective: Show different forms of presentation of some of the diseases of the adrenal cortex. Presentation of cases: Patient 1: 7-year-old school boy, history of controlled hypothyroidism, and presenting decay and poor pondostatural growth. Cortisol level in fasting 86 nmol/L and ACTH 154 pg/ml. Primary adrenal insufficiency is diagnosed. Re-admitted at age 9 for maintaining little growth. Bone age: 2 years and 8 months. Clonidine test: altered, it confirms growth hormone deficiency. Patient 2: 8-year-old schoolboy, history of congenital adrenal hyperplasia due to 21 hydroxylase deficiency, simple virilizing form. He presents acceleration of genital development. Hydrocortisone treatment was missed for 5 years. 17 hydroxyprogesterone was found to be elevated to 189 ng/dl. Peripheral precocious puberty and virilization of the genitals were diagnosed. Patient 3: 5-month-old infant with obesity of 3 months of evolution. Contrasted computed axial tomography of the abdomen confirms tumor lesion of 5 cm in projection of the right adrenal. Cortisol level in fasting 892 nmol/L, cortisol 11 pm 920 nmol/L. Surgery was performed and Cushing's syndrome was diagnosed due to cortisol-producing adrenal carcinoma. Conclusions: In daily clinical practice we can find patients with symptoms and signs as common as decay, vomiting or sudden weight gain and they are secondary to diseases of the adrenal gland.
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ABSTRACT Introduction: 46,XX Congenital adrenal hyperplasia (CAH) remains the first cause of genital virilization and current surgical techniques aim to restore female aspect of genitalia while preserving dorsal neurovascular bundle but not at the expense of not preserving erectile tissue. We aim to report our experience with a new surgical technique for clitoroplasty, completely preserving corporeal bodies, neurovascular bundles without dismembering the clitoris, in four patients with over a year follow up. Materials and Methods: After IRB approval four patients with 46,XX CAH and Prader 5 and 3 external genitalia, underwent feminizing genitoplasty. Complete preservation of erectile tissue was accomplished without a need to dissect dorsal neurovascular bundle. Glans size allowed no need for glanular reduction and there was no need to dismember the corporeal bodies. Results: Four patients 12 to 24-months-old underwent complete corporeal preservation clitoroplasty (CCPC), mean age was 18.5 months, mean follow up was 10.25 months. Vaginoplasty was performed in all patients with partial urogenital mobilization (PUM) and Urogenital Sinus flap (UF), only one severely virilized patient required a parasagittal pre-rectal approach to mobilize the vagina. We had no complications until last follow up. Conclusion: To our knowledge, we are introducing the concept of CCPC without the need of disassembling the corporeal bodies, neurovascular bundle and glans. It stands as a new alternative for feminizing genitoplasty with complete preservation of erectile tissue and no dissection of neurovascular bundle. Although there is still lacking long-term follow-up, it represents a new step in conservative reconfiguration of the external virilized female genitalia.
Subject(s)
Humans , Male , Female , Infant , Child, Preschool , Adolescent , Adrenal Hyperplasia, Congenital/surgery , Plastic Surgery Procedures , Surgical Flaps , Vagina/surgery , Clitoris/surgery , Genitalia, Female/surgeryABSTRACT
Introducción: La práctica de la cirugía genital es frecuente en infantes y adolescentes diagnosticados de intersexualidad. Una de sus principales consecuencias se refleja en la personalidad del paciente. Existen numerosos estudios en población adulta, pero son escasos en edades pediátricas. El dibujo constituye un instrumento valioso para la exploración psicológica en edades tempranas. Objetivo: Identificar las características psicológicas de infantes y adolescentes con tratamiento quirúrgico de los genitales, y de su desarrollo psicológico en el momento de la valoración. Métodos: Estudio transversal descriptivo y metodología cualitativa. La muestra la integraron 15 participantes entre 6 y 12 años, con hiperplasia adrenal congénita y cirugía genital. De ellos, 4 con asignación al sexo masculino y 11 con asignación femenina. Todos residentes en La Habana, Cuba y captados de las consultas de seguimiento de los servicios de Endocrinología del Instituto de Endocrinología y hospitales pediátricos. Se aplicaron las técnicas psicográficas (dibujo espontáneo, dibujo temático de la familia y dibujo temático "Así soy yo"). Resultados: El desarrollo psicológico se correspondió con la edad cronológica. El 100 por ciento presentó un pensamiento coherente y estructurado. El 50 por ciento presentó indicadores emocionales que aluden a insatisfacción con el propio yo, angustia (40 por ciento), y falta de aceptación del propio cuerpo (70 por ciento); además, expresaron dificultades en la comunicación familiar (60 por ciento). Conclusiones: Los indicadores globales relevantes de los dibujos denotaron daño emocional, dificultades en la aceptación, percepción y representación del esquema corporal y también en la comunicación social y familiar. Resulta impostergable intervenir en las causas del malestar y los problemas psicológicos de los sujetos estudiados para evitar que se desarrollen enfermedades psiquiátricas en la edad adulta(AU)
Introduction: The practice of genital surgery is frequent in infants and adolescents diagnosed with intersex. One of the main consequences is reflected in the patient´s personality. There are numerous studies in the adult population; however, they are rare in pediatric ages. Drawing is a valuable tool for psychological exploration in early ages. Objective: Identify the psychological characteristics of infants and adolescents with surgical treatment of the genitalia, and to characterize their psychological development. Method: Descriptive cross-sectional study and qualitative methodology. The sample was made up of 15 infants and adolescents between 6 and 12 years old with congenital adrenal hyperplasia and genital surgery. 4 of them with male sex assignment and 11 with female assignment, coming from the primary care level, residents in Havana, Cuba, recruited in the follow-up consultations of the endocrinology services of the Institute of Endocrinology and pediatric hospitals. The psychographic techniques (spontaneous drawing, thematic drawing of the family and thematic drawing called "I am like this" were applied). The study complied with the basic ethical aspects of scientific research. Results: Psychological development corresponded with chronological age. 100 percent of the patients presented a coherent and structured thinking. 50 percent presented emotional indicators that allude to dissatisfaction with one's own self, anguish (40 percent), and lack of acceptance of one's own body (70 percent); in addition, they expressed difficulties in family communication (60 percent). Conclusions: The relevant global indicators of the drawings denoted emotional damage, difficulties in the acceptance, perception and representation of the body scheme and also in social and family communication. It cannot be postponed an intervention in the discomfort causes and psychological problems of the patients studied, in order to avoid that psychiatric diseases can be developed in adults ages(AU)
Subject(s)
Humans , Male , Female , Child , Primary Health Care , Adrenal Hyperplasia, Congenital/psychology , Sex Reassignment Surgery/methods , Epidemiology, Descriptive , Cross-Sectional Studies , Psychological TechniquesABSTRACT
ABSTRACT Primary adrenal insufficiency (PAI) is characterized by the inability of the adrenal cortex to produce sufficient amounts of glucocorticoids and/or mineralocorticoids. Addison's disease (AD) and congenital adrenal hyperplasia (CAH) are the most frequent disorders in adults and children, respectively. Despite the diagnostic advances and the availability of glucocorticoid and mineralocorticoid replacements, adrenal crisis (AC) is still a potentially lethal condition contributing to the increased mortality, not only during the first year of life, but also throughout life. Failure in increasing glucocorticoid doses during acute stress, when greater amounts of glucocorticoids are required, can lead to AC and an increase morbimortality rate of PAI. Considering a mortality rate of 0.5 per 100 patient years, up to 1,500 deaths from AC are expected in Brazil in the coming decade, which represents an alarming situation. The major clinical features are hypotension and volume depletion. Nonspecific symptoms such as fatigue, lack of energy, anorexia, nausea, vomiting, and abdominal pain are common. The main precipitating factors are gastrointestinal diseases, other infectious disease, stressful events (e.g., major pain, surgery, strenuous physical activity, heat, and pregnancy), and withdrawal of glucocorticoid therapy. Suspected AC requires immediate therapeutic action with intravenous (iv) hydrocortisone, fluid infusion, monitoring support, and antibiotics if necessary. AC is best prevented through patient education, precocious identification and by adjusting the glucocorticoid dosage in stressor situations. The emergency card, warning about acute glucocorticoid replacement, has high value in reducing the morbidity and mortality of AC.
Subject(s)
Humans , Child , Adult , Addison Disease , Adrenal Insufficiency/etiology , Adrenal Hyperplasia, Congenital , Hydrocortisone , Glucocorticoids/therapeutic useABSTRACT
Congenital lipoid adrenal hyperplasia (CLAH) is a rare autosomal recessive disorder, which is characterized by adrenal insufficiency and 46, XY sex reversal. Two cases of CLAH with 46, XY karyotype exhibited male external genitalia were reported to explore the clinical and genetic features. A retrospective analysis of CLAH with relevant literatures was performed.
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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/therapyABSTRACT
Abstract In the 1960s Guthrie conceived the idea of preventing congenital disease using dried blood spot samples on filter paper to detect them through biochemical tests and then be able to treat environmental factors in time to avoid the devastating effect of the diseases. Uruguay started in 1994 with the detection of congenital hypothyroidism in umbilical cord blood. In 2007 it was extended to Phenylketonuria and Congenital Adrenal Hyperplasia, starting with dried blood spot sample. In 2008, with the incorporation of Mass Spectrometry, a pilot program was started for the detection of aminoacidopathies, beta-oxidation defects and organic acidemias disorders. In the following years, the program expanded to more diseases, reaching a total of 25 disorders that could be detected, 5 of them are investigated on a mandatory basis and others in pilot program. During the 25-year of experience, 974277 umbilical cord blood samples were analyzed and since 2007: 532684 dried blood spot samples. 613 true positive congenital disorders were identified. The coverage has been greater than 98% and the repetition rate for insufficient samples less than 1.9%.
ABSTRACT
Introducción: La terapia de reemplazo con glucocorticoides sigue siendo el paradigma de tratamiento en las formas clásicas de la hiperplasia suprarrenal congénita. Sus efectos sobre la mineralización ósea no están totalmente claros. Objetivo: Describir las variables relacionadas con la masa ósea en pacientes con HSC que reciben tratamiento esteroideo sustitutivo. Método: Se realizó un estudio descriptivo transversal que exploró variables clínicas, bioquímicas, hormonales y de mineralización óseaen 25 pacientes con hiperplasia suprarrenal congénita por déficit de 21OHasa y tratamiento esteroideo. Resultados: 21 (84,0 por ciento) femeninas, el mayor grupo correspondió a los adolescentes entre 10 y 19 años (52 por ciento). Predominaron las formas clásicas con 22 pacientes (88,0 por ciento), de ellas 13 (52 por ciento) fueron perdedoras de sal, 9 virilizantes simples (36,0 por ciento) y solo 3 (12,0 por ciento) formas no clásicas. El esteroide más utilizado fue la hidrocortisona en 16 pacientes (64 por ciento), a una dosis media de 22,10±12,00 mg diarios, correspondiendo con 17,09±5,71 mg/m2sc/día y como promedio llevaban 14,02±6,57 años de terapéutica sustitutiva. No se detectaron alteraciones del metabolismo fosfocálcico. La densidad y el contenido mineral óseo en columna y en fémur mostraron valores superiores en las formas no clásicas de la enfermedad, seguidos de la virilizante simple y finalmente los pacientes perdedores de sal, en ninguno de los casos con significación estadística. Conclusiones: Los pacientes con hiperplasia suprarrenal congénita del presente estudio mostraron en su mayoría una masa ósea conservada(AU)
Introduction: Glucocorticoid replacement therapy is still the treatment´s paradigm in the classic forms of congenital adrenal hyperplasia. Its effects on bone mineralization are not entirely clear. Objective: Describe bone mass-related variables in congenital adrenal hyperplasia patients receiving substitute steroid treatment. Method: A cross-sectional descriptive study was conducted exploring clinical, biochemical, hormonal and bone mineralization variables in 25 patients with congenital adrenal hyperplasia caused by 21OHase deficiency and steroid treatments. Results: 21 women (84.0 percent); the largest group was of adolescents between the age of 10 and 19 years (52 percent).Classical forms predominated with 22 patients (88.0 percent), including 13 of them (52 percent) that were salt losers, 9 simple virilizers (36.0 percent) and only 3 (12.0 percent) of non-classical forms. The most commonly used steroid was hydrocortisone in 16 patients (64 percent), at an average dose of 22.10±12.00 mg daily, corresponding to 17.09±5.71 mg/m2sc/day and on average carried 14.02±6.57 years of substitute therapy. No alterations in the phosphocalcic metabolism were detected. Density and bone mineral content in the spinal column and femur showed higher values in non-classical forms of the disease, followed by simple virilizing and finally the salt loser patients, in none of the cases with statistical significance. Conclusions: Patients with congenital adrenal hyperplasia in this study showed mostly preserved bone mass(AU)
Subject(s)
Humans , Female , Child , Adolescent , Calcification, Physiologic/physiology , Hydrocortisone/therapeutic use , Bone Density , Adrenal Hyperplasia, Congenital/therapy , Epidemiology, Descriptive , Cross-Sectional StudiesABSTRACT
ABSTRACT Objective To analyze the morphological and functional characteristics of primary macronodular adrenal hyperplasia (PMAH) nodules carrying or not carrying ARMC5 mutations and the consequences of the presence of mutations in terms of the pattern of macronodule composition and functional state. Subjects and methods The analyses were performed by hematoxylin-eosin staining, immunohistochemistry, microdissection of spongiocyte tissue and RT-qPCR of histological sections from 16 patients diagnosed with PMAH with germline (5) or germline/somatic mutations (5) and without mutations (6) in the ARMC5 gene. Results Hyperplastic nodules were predominantly composed of spongiocytes in mutated and nonmutated sections. ARMC5 mRNA expression in spongiocytes was higher in ARMC5-mutated nodules than in ARMC5-nonmutated nodules, and homogenous ARMC5 protein distribution was observed. The presence of arginine-vasopressin receptor (AVP1AR) and ectopic ACTH production were observed in both cell populations regardless of ARMC5 mutations; the numbers of serotonin receptor (5HT4R)- and proliferating cell nuclear antigen (PCNA)-positive cells were higher in macronodules carrying ARMC5 mutations than in those without mutations. Conclusions Our results suggest that the presence of ARMC5 mutations does not interfere with the pattern of distribution of spongiocytes and compact cells or with the presence of AVP1AR, gastric-inhibitory polypeptide receptor (GIPR) and ectopic ACTH. Nevertheless, the higher numbers of PCNA-positive cells in mutated nodules than in nonmutated nodules suggest that mutated ARMC5 can be related to higher proliferation rates in these cells. In conclusion, our results provide more information about the crosstalk among abnormal GPCRs, ectopic ACTH in steroidogenesis and the ARMC5 gene, which may be relevant in understanding the pathogenesis and diagnosis of patients with PMAH.
Subject(s)
Humans , Armadillo Domain Proteins/genetics , Serotonin , Proliferating Cell Nuclear Antigen , Receptors, Serotonin, 5-HT4 , MutationABSTRACT
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.