A Multiclassifier System to Identify and Subtype Congenital Adrenal Hyperplasia Based on Circulating Steroid Hormones.

CONTEXT: Measurement of plasma steroids is necessary for diagnosis of congenital adrenal hyperplasia (CAH). We sought to establish an efficient strategy for detection and subtyping of CAH with a machine-learning algorithm. METHODS: Clinical phenotype and genetic testing were used to provide CAH diagnosis and subtype. We profiled 13 major steroid hormones by liquid chromatography-tandem mass spectrometry. A multiclassifier system was established to distinguish 11ß-hydroxylase deficiency (11ßOHD), 17α-hydroxylase/17,20-lyase deficiency (17OHD), and 21α-hydroxylase deficiency (21OHD) in a discovery cohort (n = 226). It was then validated in an independent cohort (n = 111) and finally applied in a perspective cohort of 256 patients. The diagnostic performance on the basis of area under receiver operating characteristic curves (AUCs) was evaluated. RESULTS: A cascade logistic regression model, we named the "Steroidogenesis Score", was able to discriminate the 3 most common CAH subtypes: 11ßOHD, 17OHD, and 21OHD. In the perspective application cohort, the steroidogenesis score had a high diagnostic accuracy for all 3 subtypes, 11ßOHD (AUC, 0.994; 95% CI, 0.983-1.000), 17OHD (AUC, 0.993; 95% CI, 0.985-1.000), and 21OHD (AUC, 0.979; 95% CI, 0.964-0.994). For nonclassic 21OHD patients, the tool presented with significantly higher sensitivity compared with measurement of basal 17α-hydroxyprogesterone (17OHP) (0.973 vs 0.840, P = 0.005) and was not inferior to measurement of basal vs stimulated 17OHP (0.973 vs 0.947, P = 0.681). CONCLUSIONS: The steroidogenesis score was biochemically interpretable and showed high accuracy in identifying CAH patients, especially for nonclassic 21OHD patients, thus offering a standardized approach to diagnose and subtype CAH.

Assessment of Facial Morphologic Features in Patients With Congenital Adrenal Hyperplasia Using Deep Learning.

Importance: Congenital adrenal hyperplasia (CAH) is the most common primary adrenal insufficiency in children, involving excess androgens secondary to disrupted steroidogenesis as early as the seventh gestational week of life. Although structural brain abnormalities are seen in CAH, little is known about facial morphology. Objective: To investigate differences in facial morphologic features between patients with CAH and control individuals with use of machine learning. Design, Setting, and Participants: This cross-sectional study was performed at a pediatric tertiary center in Southern California, from November 2017 to December 2019. Patients younger than 30 years with a biochemical diagnosis of classical CAH due to 21-hydroxylase deficiency and otherwise healthy controls were recruited from the clinic, and face images were acquired. Additional controls were selected from public face image data sets. Main Outcomes and Measures: The main outcome was prediction of CAH, as performed by machine learning (linear discriminant analysis, random forests, deep neural networks). Handcrafted features and learned representations were studied for CAH score prediction, and deformation analysis of facial landmarks and regionwise analyses were performed. A 6-fold cross-validation strategy was used to avoid overfitting and bias. Results: The study included 102 patients with CAH (62 [60.8%] female; mean [SD] age, 11.6 [7.1] years) and 59 controls (30 [50.8%] female; mean [SD] age, 9.0 [5.2] years) from the clinic and 85 controls (48 [60%] female; age, <29 years) from face databases. With use of deep neural networks, a mean (SD) AUC of 92% (3%) was found for accurately predicting CAH over 6 folds. With use of classical machine learning and handcrafted facial features, mean (SD) AUCs of 86% (5%) in linear discriminant analysis and 83% (3%) in random forests were obtained for predicting CAH over 6 folds. There was a deviation of facial features between groups using deformation fields generated from facial landmark templates. Regionwise analysis and class activation maps (deep learning of regions) revealed that the nose and upper face were most contributory (mean [SD] AUC: 69% [17%] and 71% [13%], respectively). Conclusions and Relevance: The findings suggest that facial morphologic features in patients with CAH is distinct and that deep learning can discover subtle facial features to predict CAH. Longitudinal study of facial morphology as a phenotypic biomarker may help expand understanding of adverse lifespan outcomes for patients with CAH.

Nouveautés dans l'hyperplasie congénitale des surrénales: New insights in congenital adrenal hyperplasia.

Congenital adrenal hyperplasia is an autosomal recessive disease due to functional abnormalities of adrenal steroid enzymes. The most common form of the disease is due to a 21-hydroxylase deficiency. The classical forms (most severe) are characterized by a deficiency in cortisol and sometimes in aldosterone, which may compromise the vital prognosis of neonates, and by an increase in androgen synthesis, leading to the virilization of girls' external genitalia at birth, followed by clinical signs of hyperandrogenism during childhood and adolescence. Neonatal screening has improved management and reduced morbidity and mortality in the neonatal period, but its performance could be broadly optimised by adjusting the assay techniques or the biomarkers used. The genetic diagnosis is difficult owing to the large genetic heterogeneity of the 6p21.3 region, which contains the CYP21A2 gene, especially with respect to the use of new-generation techniques of sequencing. Prenatal diagnosis is now possible as early as 6 weeks of gestation, but prenatal treatment remains controversial, awaiting results from prospective cohorts evaluating its long-term impact. Since conventional therapies have limitations, new therapies are currently being developed to allow better control of androgen synthesis and a substitutive treatment that respects the physiological rhythm of cortisol secretion, which would limit the development of long-term complications.

Adrenal cortical hyperplasia: diagnostic workup, subtypes, imaging features and mimics.

Adrenal cortical hyperplasia manifests radiologically as a non-malignant growth, or enlargement, of the adrenal glands, specifically the cortex, although the cortex cannot be definitively identified by conventional imaging. Controlled by the pituitary gland, the adrenal cortex drives critical processes, such as the production of cortisol, mineralocorticoid and sex hormones. Any disruption in the multiple enzymes and hormones involved in these pathways may cause serious or life-threatening symptoms, often associated with anatomical changes in the adrenal glands. Diagnosis and treatment of adrenal cortical hyperplasia requires a thorough clinical evaluation. As imaging has become more robust so has its role in the diagnosis and treatment of adrenal conditions. CT has been the primary modality for adrenal imaging owing to reproducibility, temporal and spatial resolution and broad access. MRI serves a complimentary role in adrenal imaging and can be used to further evaluate indeterminate CT findings or serve as an adjunct tool without the use of ionizing radiation. Ultrasound and fluoroscopy (genitography) are most commonly used in children and foetuses to evaluate congenital adrenal hyperplasia. This article will discuss the clinical presentation, laboratory workup and imaging features of adrenal cortical hyperplasia, both congenital and acquired.

Non-Classical Congenital Adrenal Hyperplasia in Childhood.

Congenital adrenal hyperplasia (CAH) is classified as classical CAH and non-classical CAH (NCCAH). In the classical type, the most severe form comprises both salt-wasting and simple virilizing forms. In the non-classical form, diagnosis can be more confusing because the patient may remain asymptomatic or the condition may be associated with signs of androgen excess in the postnatal period or in the later stages of life. This review paper will include information on clinical findings, symptoms, diagnostic approaches, and treatment modules of NCCAH.

Spatial function in adolescents and young adults with congenital adrenal hyperplasia: clinical phenotype and implications for the androgen hypothesis.

Females with the classic form of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency are said to perform better than unaffected female controls on tests of mental rotation or other visuospatial abilities, but findings are conflicting. We studied 31 adolescents and young adults with CAH and 19 unaffected sibling controls, who were given standardized spatial tests and tests of other sexually differentiated cognitive functions (verbal fluency, perceptual speed). The possible role of CAH subtype (salt-wasting or simple-virilizing) was evaluated. Only females with the more severe, salt-wasting form of CAH, but not females with the simple-virilizing form, performed significantly better than sex-matched sibling controls on measures of mental rotation. Subtype differences were not significant for verbal fluency or perceptual speed. Severity of prenatal genital virilization, but not postnatal age when medication was started, predicted accuracy on the Mental Rotations Test. Results are consistent with the possibility of an organizational effect of androgens in the central nervous system that impacts the development of spatial abilities. Implications for the timing of the hypothetical critical period are discussed.

Ten-year evaluation of a Neonatal Screening Program for congenital adrenal hyperplasia.

OBJECTIVE: Evaluate the Neonatal Screening Program (NSP) for congenital adrenal hyperplasia (CAH) of the Department of Health of the State of Santa Catarina (Secretaria de Estado da Saúde de Santa Catarina, SES/SC), and provide information to improve the program. SUBJECTS AND METHODS: Descriptive, retrospective study of 748,395 children screened between January 2001 and December 2010. We analyzed the coverage of the NSP-SES/SC prevalence of CAH, child's age when the first sample for 17-hydroxyprogesterone (17OHP) measurement was collected, levels of 17OHP, mean age at treatment onset and main clinical manifestations. RESULTS: The NSP-SES/SC covered 89% of the live newborns in the State. It diagnosed 50 cases of CAH, yielding an incidence of 1:14,967. Mean age at collection of the first sample was 7.3 days and mean level of 17OHP was 152.9 ng/mL. The most frequent manifestations were virilized genitalia with nonpalpable gonads, clitoromegaly and genital hyperpigmentation. In three girls, the genre established at birth was incorrect. The salt-wasting form was present in 74% of the cases. There was no occurrence of shock or death. Mean age at treatment onset in the salt-wasting form was 17.4 days compared with 54.9 days in those without the salt-wasting form of the disease. All children were treated with hydrocortisone, and those with salt-wasting CAH were also treated with fludrocortisone. CONCLUSIONS: The incidence of CAH was 1 case to 14,967 live newborns. Collection of the first sample occurred outside the recommended time, resulting in delays in treatment onset.

Ten-year evaluation of a Neonatal Screening Program for Congenital Adrenal Hyperplasia / Avaliação de dez anos de um Programa de Triagem Neonatal para Hiperplasia Adrenal Congênita

Objective Evaluate the Neonatal Screening Program (NSP) for congenital adrenal hyperplasia (CAH) of the Department of Health of the State of Santa Catarina (Secretaria de Estado da Saúde de Santa Catarina, SES/SC), and provide information to improve the program. Subjects and methods Descriptive, retrospective study of 748,395 children screened between January 2001 and December 2010. We analyzed the coverage of the NSP-SES/SC prevalence of CAH, child’s age when the first sample for 17-hydroxyprogesterone (17OHP) measurement was collected, levels of 17OHP, mean age at treatment onset and main clinical manifestations. Results The NSP-SES/SC covered 89% of the live newborns in the State. It diagnosed 50 cases of CAH, yielding an incidence of 1:14,967. Mean age at collection of the first sample was 7.3 days and mean level of 17OHP was 152.9 ng/mL. The most frequent manifestations were virilized genitalia with nonpalpable gonads, clitoromegaly and genital hyperpigmentation. In three girls, the genre established at birth was incorrect. The salt-wasting form was present in 74% of the cases. There was no occurrence of shock or death. Mean age at treatment onset in the salt-wasting form was 17.4 days compared with 54.9 days in those without the salt-wasting form of the disease. All children were treated with hydrocortisone, and those with salt-wasting CAH were also treated with fludrocortisone. Conclusions The incidence of CAH was 1 case to 14,967 live newborns. Collection of the first sample occurred outside the recommended time, resulting in delays in treatment onset. .

Objetivo Avaliar o Programa de Triagem Neonatal da Secretaria de Estado da Saúde de Santa Catarina (PTN-SES/SC) em relação à hiperplasia adrenal congênita (HAC) e fornecer subsídios que possibilitem seu aperfeiçoamento. Sujeitos e métodos Estudo descritivo e retrospectivo de 748.395 crianças triadas no período de janeiro de 2001 a dezembro de 2010, sendo analisados a cobertura do PTN-SES/SC, a prevalência da HAC, a idade na coleta da primeira amostra para 17-hidroxiprogesterona (17OHP), os níveis de 17OHP, a idade média de início de tratamento e as principais manifestações clínicas. Resultados A cobertura do PTN-SES/SC foi de 89% dos recém-nascidos vivos no Estado. Foram diagnosticados 50 casos de HAC, com incidência de 1:14.967. A média de idade na coleta da primeira amostra foi de 7,3 dias e a de 17OHP, de 152,9 ng/mL. As manifestações mais frequentes foram genitália virilizada sem gônadas palpáveis, clitoromegalia e hiperpigmentação genital. Em três meninas ocorreu erro no estabelecimento de gênero ao nascimento. A forma perdedora de sal foi encontrada em 74% dos casos. Nenhum caso de choque ou óbito foi verificado. A média de idade no início do tratamento nos perdedores de sal foi de 17,4 dias e nos não perdedores, de 54,9 dias. Todas as crianças foram tratadas com hidrocortisona e, nos casos com a forma perdedora de sal, associou-se fludrocortisona. Conclusões A incidência de HAC foi de 1 caso para 14.967 recém-nascidos vivos. A coleta da primeira amostra ainda ocorreu fora do tempo preconizado, acarretando atraso no início do tratamento. .

Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency.

Over the last two decades, we have extensively studied the genetics of congenital adrenal hyperplasia caused by 21-hydroxylase deficiency (CAH) and have performed 8,290 DNA analyses of the CYP21A2 gene on members of 4,857 families at risk for CAH--the largest cohort of CAH patients reported to date. Of the families studied, 1,507 had at least one member affected with one of three known forms of CAH, namely salt wasting, simple virilizing, or nonclassical CAH. Here, we report the genotype and phenotype of each affected patient, as well as the ethnic group and country of origin for each patient. We showed that 21 of 45 genotypes yielded a phenotypic correlation in our patient cohort. In particular, contrary to what is generally reported in the literature, we found that certain mutations, for example, the P30L, I2G, and I172N mutations, yielded different CAH phenotypes. In salt wasting and nonclassical CAH, a phenotype can be attributed to a genotype; however, in simple virilizing CAH, we observe wide phenotypic variability, particularly with the exon 4 I172N mutation. Finally, there was a high frequency of homozygous I2G and V281L mutations in Middle Eastern and Ashkenazi Jewish populations, respectively. By identifying the predominant phenotype for a given genotype, these findings should assist physicians in prenatal diagnosis and genetic counseling of parents who are at risk for having a child with CAH.

[Contemporary diagnosis and therapy in women with congenital adrenal hyperplasia]. / Wspólczesna diagnostyka i terapia kobiet z wrodzonym przerostem nadnerczy.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive defect in steroidogenesis, mostly affecting 21-hydroxylase enzyme deficiency. The other seldom cortisol synthesis abnormalities include deficiencies of: 11beta-hydroxylase, 3beta-hydroxysteroid dehydrogenase, 17beta-hydroxylase, 17,20-lase and 11 beta-hydroxysteroid dwehydrogenase type 1. There are three main types, depending on the clinical level of 21-hydroxylase deficiency: (1) classical form--salt-wasting CAH (2) the classical form non- salt-wasting (3) non-classical form. CAH incidence is estimated at 1/14 000-1/10 000, of which about 70% is the classic salt-wasting form. The clinical picture varies considerably depending on the form. In the classic salt-wasting CAH may develop into the a shock. In classic CAH without loss of salt dominates virilization in girls and precocious puberty in boys. A non-classical forms usually presents as hyperandrogenisation and fertility. CAH treatment is mainly based on the use of glucocorticoid therapy, and if necessary supplemented mineralocorticoids. There is also potential to consider prenatal treatment (female fetuses diagnosed as CAH) with the use of dexamethason. However this kind of treatment is related to some medical and ethical controversies.

Molecular testing in congenital adrenal hyperplasia due to 21α-hydroxylase deficiency in the era of newborn screening.

Newborn screening (NBS) identifies the majority of classical [salt-wasting (SW) and simple-virilizing (SV)] cases of congenital adrenal hyperplasia (CAH) due to 21α-hydroxylase (21α-OHase) during the first days of life. Diagnosis of classical CAH is confirmed by follow-up serum 17-hydroxyprogesterone and/or the adrenocorticotropin stimulation test; however, neither test definitively distinguishes between the classical subtypes. After confirmation, all newborns are started on hydrocortisone (glucocorticoid) and fludrocortisone (mineralocorticoid) treatment. While initiating fludrocortisone treatment in classical CAH patients, independent of subtype and before SW signs or symptoms occur, prevents a life-threatening SW crisis, it may later complicate distinguishing between the classical subtypes. Genotype-phenotype correlations in 21α-OHase deficiency are excellent; however, molecular testing is not a regular part of the diagnostic workup. Molecular testing on 39 patients (25 identified by NBS) with an already established diagnosis of CAH identified 11 SW patients (8 identified by NBS) whose mutations suggested further biochemical and clinical reassessment of their subtype. Overall, SW accounted for 57.6% of our classical CAH patients, below the generally accepted figure that >75% of classical CAH are comprised of the SW form. In the era of NBS, molecular testing is a valuable supplemental tool identifying patients who may benefit from reassessment of their salt-retaining ability.

Congenital adrenal hyperplasia: an Indian experience.

AIMS: Data regarding the presentation and course of patients with congenital adrenal hyperplasia (CAH) is scarce in South Asia. We aimed to fill that gap by collating our experience with CAH and comparing it with findings from few other centres around the world for pertinent differences. METHODS: We retrospectively analysed the records of 86 CAH patients seen at our tertiary care centre in Eastern-India from 1996 to 2010. RESULTS: Forty-five patients (52.3%) had classic disease and 41 (47.7%) had non-classic disease (NC CAH). In the classic CAH group, 18 (20.9%) had salt wasting CAH (SW CAH) while 27 (31.4%) had simple virilising disease (SV CAH). Ten (11.6%) had a 46,XY karyotype. Patients with SW CAH were diagnosed earlier in infancy at a median age of 0.5 year, than those with SV type, who were diagnosed at 9 years (P < 0.05). The NC CAH patients were diagnosed still later, at 20.4 years. In patients with SW CAH, boys were diagnosed at an earlier median age of 0.1 year than girls who were diagnosed at 6.4 years (P < 0.05). Sixteen girls (21% of the girls) underwent vaginoplasty of whom four required additional clitoroplasty. One girl needed bilateral laparoscopic adrenalectomy. One NC CAH patient had a successful assisted pregnancy. Hypothyroidism, found in seven (8.1%) was the commonest coexisting abnormality. CONCLUSION: The skewed male : female ratio suggested that a substantial proportion of males were being missed and consequently may die. Majority of the diagnosed patients (n= 55, 64%) have been lost to follow-up. Remaining patients could be reasonably controlled with standard therapy.

No correlation between androgen receptor CAG and GGN repeat length and the degree of genital virilization in females with 21-hydroxylase deficiency.

CONTEXT: In 21-hydroxylase (CYP21A2) deficiency (21OHD), the level of in vitro enzymatic function allows for classification of mutation groups (null, A, B, C) and prediction of disease severity. However, genital virilization in affected females correlates only weakly with CYP21A2 mutation groups, suggesting the influence of genetic modifiers. OBJECTIVE: The objective of the study was to investigate the influence of the polymorphic CAG and GGn repeats of the androgen receptor (AR) gene on the degree of genital virilization in 21OHD females. DESIGN AND PATIENTS: Design of the study was the determination of CYP21A2 genotype, degree of genital virilization (Prader stage), and X-weighted biallelic mean of AR CAG and GGn repeat length in 205 females with 21OHD. OUTCOME MEASUREMENTS: Correlation of AR CAG and GGn repeat lengths with Prader stages using nested stepwise logistic regression analysis was measured. RESULTS: CYP21A2 mutation groups null and A showed significantly higher levels of genital virilization than groups B and C (P < 0.01). However, Prader stages varied considerably within mutation groups: null, Prader I-V (median IV); A, Prader I-V (median IV); B, Prader I-V (median III); C, 0-III (median I). Mean GGn repeat length of patients was not significantly associated with Prader stages, classified as low (0-I), intermediate (II-III), or severe (IV-V) (odds ratio per repeat: 0.98, 95% confidence interval 0.71-1.35). In contrast, patients with Prader 0-I showed a trend toward longer CAG repeats without reaching statistical significance (P = 0.07, odds ratio per repeat: 0.82, 95% confidence interval 0.65-1.02). CONCLUSION: Neither CAG nor GGn repeat lengths are statistically significant modifiers of genital virilization in females with 21OHD.

Classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency in Croatia between 1995 and 2006.

AIMS: To evaluate the incidence, gender, symptoms and age at diagnosis of patients with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency in Croatia. METHODS: Data were collected retrospectively for all classical CAH patients born or electively aborted following prenatal diagnosis between January 1, 1995 and December 31, 2006 and were compared with the data of a previously conducted study evaluating CAH patients discovered between 1964 and 1984. RESULTS: During a 12-year period 34 classical CAH patients were born. There were 20 salt-wasting (SW; 12 female/8 male) and 14 simple-virilizing (SV; 7 female/7 male) patients. If 3 female, electively aborted fetuses were added, there would be a total of 37 CAH patients. With 532,942 live births and 34 CAH patients born over this period, the incidence of classical CAH was estimated at 1:15,574 or 1:14,403 if the 3 electively aborted fetuses were included. The lower incidence of SW boys compared to SW girls (8:12) and similar number of SW and SV boys (8:7) indicate that a substantial proportion of SW boys die unrecognized. Owing to better healthcare, the diagnosis was established significantly earlier in SW and SV girls compared to the period of 1964-1984 (p < 0.003). During 1995-2006, none of the patients died following the diagnosis of CAH and there was no erroneous sex assignment. CONCLUSION: Despite improvements in healthcare, the diagnosis of CAH in Croatia is still delayed and some of the patients go unrecognized or die. Therefore, the results of our study support the need to introduce newborn screening.

High frequency of Q318X mutation in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency in northeast Brazil.

OBJECTIVES: Deficiency of 21-hydroxylase is the most common form of congenital adrenal hyperplasia (CAH-21OH). The aim of this study was to determine, by allele-specific PCR, the frequency of microconversions of the CYP21A2, in sixteen patients with the classical forms and in 5 patients with the nonclassical (NC) form of CAH-21OH and correlate genotype with phenotype. METHODS: Genotypes were classified into 3 mutation groups (A, B and C), based on the degree of enzymatic activity. Screening for 7 microconversions by allele-specific PCR diagnosed 74.3% (n=26) of the 35 unrelated alleles. RESULTS: The most frequent mutations were Q318X (25.7%), V281L (17.1%), I2 Splice (14.3%), I172N (14.3%), and R356W (14.3%). Genotype was identified in 57.1% of the patients. We observed correlation between genotype and phenotype in 91.7% of the cases. CONCLUSION: The highest frequency for Q318X (25.7%) when compared to other studies may reflect individual sample variations in this Northeastern population.

High frequency of Q318X mutation in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency in northeast Brazil / Alta freqüência da mutação Q318X em pacientes com hiperplasia adrenal congênita por deficiência da 21-hidroxilase no nordeste do Brasil

OBJETIVES: Deficiency of 21-hydroxylase is the most common form of congenital adrenal hyperplasia (CAH-21OH). The aim of this study was to determine, by allele-specific PCR, the frequency of microconversions of the CYP21A2, in sixteen patients with the classical forms and in 5 patients with the nonclassical (NC) form of CAH-21OH and correlate genotype with phenotype. METHODS: Genotypes were classified into 3 mutation groups (A, B and C), based on the degree of enzymatic activity. Screening for 7 microconversions by allele-specific PCR diagnosed 74.3 percent (n=26) of the 35 unrelated alleles. RESULTS: The most frequent mutations were Q318X (25.7 percent), V281L (17.1 percent), I2 Splice (14.3 percent), I172N (14.3 percent), and R356W (14.3 percent). Genotype was identified in 57.1 percent of the patients. We observed correlation between genotype and phenotype in 91.7 percent of the cases. CONCLUSION: The highest frequency for Q318X (25.7 percent) when compared to other studies may reflect individual sample variations in this Northeastern population.

OBJETIVOS: Deficiência de 21-hidroxilase é a forma mais comum de hiperplasia adrenal congênita (CAH-21OH). O objetivo deste estudo foi determinar, por PCR alelo-específica, a freqüência de microconversões no CYP21A2, em 16 pacientes com a forma clássica e em cinco pacientes com a forma não-clássica (NC) de CAH-21OH e correlacionar o genótipo com o fenótipo. MÉTODOS: Genótipo foi classificado em três grupos de mutações (A, B e C), baseado no grau de atividade enzimática. A técnica de PCR alelo-específico diagnosticou 74,3 por cento (n = 26) dos 35 alelos não relacionados. RESULTADOS: As mutações mais freqüentes foram Q318X (25,7 por cento), V281L (17,1 por cento), I2 Splice (14,3 por cento), I172N (14,3 por cento) e R356W (14,3 por cento). O genótipo foi identificado em 57,1 por cento dos pacientes. Houve correlação genótipo-fenótipo em 91,7 por cento dos casos. CONCLUSÃO: A mais alta freqüência da mutação Q318X (25,7 por cento) comparada a outros estudos pode refletir variações individuais desta população do nordeste.

Male gender identity in an XX individual with congenital adrenal hyperplasia.

INTRODUCTION: In spite of significant changes in the management policies of intersexuality, clinical evidence show that not all pubertal or adult individuals live according to the assigned sex during infancy. AIM: The purpose of this study was to analyze the clinical management of an individual diagnosed as a female pseudohermaphrodite with congenital adrenal hyperplasia (CAH) simple virilizing form four decades ago but who currently lives as a monogamous heterosexual male. METHODS: We studied the clinical files spanning from 1965 to 1991 of an intersex individual. In addition, we conducted a magnetic resonance imaging (MRI) study of the abdominoplevic cavity and a series of interviews using the oral history method. MAIN OUTCOME MEASURES: Our analysis is based on the clinical evidence that led to the CAH diagnosis in the 1960s in light of recent clinical testing to confirm such diagnosis. RESULTS: Analysis of reported values for 17-ketosteroids, 17-hydroxycorticosteroids, from 24-hour urine samples during an 8-year period showed poor adrenal suppression in spite of adherence to treatment. A recent MRI study confirmed the presence of hyperplastic adrenal glands as well as the presence of a prepubertal uterus. Semistructured interviews with the individual confirmed a life history consistent with a male gender identity. CONCLUSIONS: Although the American Academy of Pediatrics recommends that XX intersex individuals with CAH should be assigned to the female sex, this practice harms some individuals as they may self-identify as males. In the absence of comorbid psychiatric factors, the discrepancy between infant sex assignment and gender identity later in life underlines the need for a reexamination of current standards of care for individuals diagnosed with CAH.

Caracterización clínica y epidemiológica de una cohorte de pacientes con hiperplasia adrenal congénita / Characterization of a clinical and epidemiological cohort of patients with congenital adrenal hyperplasia

Estudio descriptivo, retrospectivo, basado en historias clínicas de pacientes con hiperplasia adrenal congénita (HAC) evaluados en la consulta de Endocrinología infantil del Hospital Universitario San Vicente de Paúl (HUSVP) en un periodo de cinco años. Se toma una cohorte de 82 pacientes (7 por ciento de la consulta del servicio), siendo diagnosticada la entidad durante el primer año de vida en el 67,4 por ciento de los casos. Las manifestaciones clínicas más frecuentes fueron la crisis salina (43,3 por ciento) y la ambigüedad genital (37,3 por ciento). Estos datos sugieren que la forma de presentación más frecuente de hiperplasia adrenal congénita en nuestro medio es la forma clásica asociada a déficit de la enzima 21 hidroxilasa. Un paciente con genotipo XY presentó ambigüedad genital lo que sugiere una mutación en el gen de la 17 alfa hidroxilasa o de la 3 beta hidroxiesteroide deshidrogenasa. Llama la atención que la mayoría de los padres proceden del Valle de Aburrá (35,5 por ciento) y del Oriente Antioqueño (27,7 por ciento), sugiriendo una desviación poblacional importante de la enfermedad según el número de habitantes de cada región, lo que motiva a hacer estudios de tamización y pruebas piloto en los municipios del Oriente Antioqueño.

Age-specific changes in sex steroid biosynthesis and sex development.

Normal male sex development requires the SRY gene on the Y chromosome, the regression of Müllerian structures via anti-Müllerian hormone (AMH) signalling, the development of the Wolffian duct system into normal male internal genital structures consequent to testosterone secretion by the testicular Leydig cells, and finally, sufficient activation of testosterone to dihydrotestosterone by 5alpha-reductase. All these events take place during weeks 8-12 of gestation, a narrow window of sexual differentiation. Recent studies in human fetal development have demonstrated the early fetal expression of the adrenocorticotrophic hormone (ACTH) receptor and all steroidogenic components necessary for the biosynthesis of cortisol. These findings provide compelling evidence for the assumed pathogenesis of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, diminished feedback to the pituitary due to glucocorticoid deficiency, subsequent ACTH excess, and up-regulation of adrenal androgen production with subsequent virilization. Another CAH variant, P450 oxidoreductase deficiency, manifests with 46,XX disorder of sex development (DSD), i.e., virilized female genitalia, despite concurrently low circulating androgens. This CAH variant illustrates the existence of an alternative pathway toward the biosynthesis of active androgens in humans which is active in human fetal life only. Thus CAH teaches important lessons from nature, providing privileged insights into the window of human sexual differentiation, and particularly highlighting the importance of steroidogenesis in the process of human sexual differentiation.