Phenotype and genotype analysis of 6 patients with 21-hydroxylase deficiency / 中华全科医师杂志

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.

Complete corporeal preservation clitoroplasty: new insights into feminizing genitoplasty

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.

Precocious puberty due to congenital adrenal hyperplasia. Case report / Pubertad precoz por hiperplasia adrenal congénita. Reporte de caso

Abstract Introduction: Premature pubarche occurs in girls before the age of 8 or boys before the age of 9 and is a sign of precocious puberty associated with increased growth acceleration. Precocious puberty can be caused, among others, by nonclassic congenital adrenal hyperplasia (CAH). Case presentation: This is a case of a 4 1/2-year-old who developed premature pubarche six months before consultation, and whose parents were first-degree cousins. She had advanced bone age, her external genitalia were normal and her height was inconsistent with her mid-parental height. After performing an adrenocorticotropic hormone test (ACTH test) and other hormone tests, it was found that she had high levels of 17-hydroxyprogesterone (17-OHP), which allowed diagnosing her with nonclassic CAH. Based on this diagnosis, glucorticoid therapy was ordered, and after one year of starting the treatment she had a favorable clinical outcome and did not show any secondary sex characteristics or bone age progression. Conclusion: Nonclassic CAH is the most frequent cause of precocious puberty. Considering that this type of hyperplasia may be asymptomatic during the early days or years of life, its diagnosis must be suspected in children with precocious puberty, increased growth acceleration and advanced bone age.

Resumen Introducción. La pubarca antes de los 8 años en niñas y de los 9 años en niños, es una manifestación de la pubertad precoz asociada al aumento en la velocidad de crecimiento. La hiperplasia adrenal congénita (HAC) no clásica es una de las causas de pubertad precoz. Presentación de caso. Paciente femenina de 4 años y medio y con padres consanguíneos (primos hermanos) quien inició pubarca 6 meses antes de ser llevada a consulta. La niña presentaba edad ósea avanzada, talla discordante con la talla media parental y sus genitales externos eran normales. Luego de realizar el test de estimulación con hormona adrenocorticotropa y otros exámenes hormonales, se encontró que sus niveles de 17-hidroxiprogesterona eran elevados, lo que permitió diagnosticarla con HAC no clásica. Con base en este diagnóstico, se inició tratamiento con glucocorticoides y luego de un año de tratamiento la paciente tuvo una buena evolución clínica, ya que no se observó progresión de los caracteres sexuales secundarios ni de la edad ósea. Conclusión. La HAC no clásica es la causa más frecuente de la PPP. Ya que este tipo de hiperplasia puede ser asintomática durante los primeros días o años de vida, se debe sospechar su diagnóstico en la infancia cuando haya pubarca precoz, mayor velocidad de crecimiento y edad ósea avanzada.

Clinical features and molecular genetic analysis of congenital lipoid adrenal hyperplasia caused by steroidogenic acute regulatory protein gene mutation / 中华围产医学杂志

Objective@#To investigate the clinical and molecular genetic features of neonatal congenital lipoid adrenal hyperplasia (CLAH) caused by mutations in steroidogenic acute regulatory protein (StAR) encoding gene.@*Methods@#This study retrospectively analyzed the clinical data of a CLAH neonate admitted to Fujian Provincial Maternity and Children's Hospital, Affiliated Hospital of Fujian Medical University in April 2017. StAR gene was analyzed using high-throughput sequencing and Sanger sequencing. Relevant literature retrieved from databases including China National Knowledge Infrastructure (CNKI), Wanfang and PubMed were reviewed, and the reported cases with relatively complete clinical data and results of serum hormone test and StAR gene mutation analysis were collected.@*Results@#The index patient presented with hyperpigmentation and growth retardation soon after birth. Laboratory tests revealed hyponatremia, hyperkalemia, increased serum adrenocorticotrophic hormone (263.4 pmol/L) and decreased 17-hydroxyprogesterone (0.16 ng/ml), dehydroepiandrosterone (<0.95 μmol/L), androstenedione (<1.0 nmol/L), testosterone (<0.025 ng/ml), progesterone (0.02 ng/ml) and cortisol (1.6 μg/ml). High-throughput sequencing showed that the patient carried a compound heterozygous mutation of p.Thr240fs in exon 6 and p.Gln258X in exon 7, inherited from the father and mother, respectively. Sanger sequencing confirmed the diagnosis of CLAH caused by StAR gene mutation. After steroid replacement therapy, the patient's symptoms resolved and the concentrations of electrolytes returned to normal. The neonate was followed up to two years of age and no abnormality was found in physical or neurological development. Two Chinese and 11 English publications were retrieved and altogether 96 cases of neonatal CLAH, including the index one, were reviewed and 42 of them had detailed clinical data. The most common clinical manifestations were skin pigmentation (85.7%, 36/42). Other manifestations included vomiting (35.7%, 15/42) and growth retardation (14.3%, 6/42). All patients with physical examination records had female external genitalia (100.0%, 35/35). The common laboratory abnormalities included hyponatremia (95.2%, 40/42), hyperkalemia (88.1%, 37/42), elevated serum adrenocorticotrophic hormone (100.0%, 37/37) and decreased 17-hydroxyprogesterone (90.5%, 19/21), cortisol (86.2%, 25/29), testosterone (9/10) and dehydroepiandrosterone (14/14). p.Gln258X was the most common StAR gene mutation in neonates in Eastern Asia, including China. Most cases had a good prognosis after appropriate steroid replacement.@*Conclusions@#CLAH should be considered for neonates with adrenocortical hypofunction, especially with female phenotypes and low 17-hydroxyprogesterone. Karyotyping and StAR gene analysis may be helpful in diagnosis. Timely and appropriate treatment could improve the prognosis.

Clinical features and molecular genetic analysis of congenital lipoid adrenal hyperplasia caused by steroidogenic acute regulatory protein gene mutation / 中华围产医学杂志

Objective To investigate the clinical and molecular genetic features of neonatal congenital lipoid adrenal hyperplasia (CLAH) caused by mutations in steroidogenic acute regulatory protein (StAR) encoding gene.Methods This study retrospectively analyzed the clinical data of a CLAH neonate admitted to Fujian Provincial Matemity and Children's Hospital,Affiliated Hospital of Fujian Medical University in April 2017.StAR gene was analyzed using high-throughput sequencing and Sanger sequencing.Relevant literature retrieved from databases including China National Knowledge Infrastructure (CNKI),Wanfang and PubMed were reviewed,and the reported cases with relatively complete clinical data and results of serum hormone test and StAR gene mutation analysis were collected.Results The index patient presented with hyperpigrnentation and growth retardation soon after birth.Laboratory tests revealed hyponatremia,hyperkalemia,increased serum adrenocorticotrophic hormone (263.4 pmol/L) and decreased 17-hydroxyprogesterone (0.16 ng/ml),dehydroepiandrosterone (＜0.95 μmol/L),androstenedione (＜1.0 nmol/L),testosterone (＜0.025 ng/ml),progesterone (0.02 ng/ml) and cortisol (1.6 μ g/ml).High-throughput sequencing showed that the patient carried a compound heterozygous mutation of p.Thr240fs in exon 6 and p.Gln258X in exon 7,inherited from the father and mother,respectively.Sanger sequencing confirmed the diagnosis of CLAH caused by StAR gene mutation.After steroid replacement therapy,the patient's symptoms resolved and the concentrations of electrolytes returned to normal.The neonate was followed up to two years of age and no abnormality was found in physical or neurological development.Two Chinese and 11 English publications were retrieved and altogether 96 cases of neonatal CLAH,including the index one,were reviewed and 42 of them had detailed clinical data.The most common clinical manifestations were skin pigmentation (85.7％,36/42).Other manifestations included vomiting (35.7％,15/42) and growth retardation (14.3％,6/42).All patients with physical examination records had female external genitalia (100.0％,35/35).The common laboratory abnormalities included hyponatremia (95.2％,40/42),hyperkalemia (88.1％,37/42),elevated serum adrenocorticotrophic hormone (100.0％,37/37) and decreased 17-hydroxyprogesterone (90.5％,19/21),cortisol (86.2％,25/29),testosterone (9/10) and dehydroepiandrosterone (14/14).p.Gln258X was the most common StAR gene mutation in neonates in Eastern Asia,including China.Most cases had a good prognosis after appropriate steroid replacement.Conclusions CLAH should be considered for neonates with adrenocortical hypofunction,especially with female phenotypes and low 17-hydroxyprogesterone.Karyotyping and StAR gene analysis may be helpful in diagnosis.Timely and appropriate treatment could improve the prognosis.

Crecimiento físico de niños con hiperplasia suprarrenal congénita perdedora de sal durante los dos primeros años de vida en el Instituto Nacional de Salud del Niño / Physical growth in children with salt-wasting adrenal hyperplasia during their first two years of life in the Peruvian National Children's Health Institute

Objetivo: Describir el crecimiento físico de niños con hiperplasia suprarrenal congénita (HSC) perdedora de sal durante los dos primeros años de vida, evaluados en el Servicio de Endocrinología del Instituto Nacional de Salud del Niño (INSN), Lima-Perú. Materiales y métodos: Es un estudio observacional, descriptivo y retrospectivo. Se incluyeron 55 niños con HSC que tuvieron seguimiento en el Servicio de Endocrinología del INSN del 2000 al 2016; se recopilaron datos como peso y talla al nacer y cada 6 meses, edad al diagnóstico, dosis de hidrocortisona y fludrocortisona y velocidad de crecimiento. Resultados: Se analizaron 55 niños con HSC perdedora de sal siendo el diagnóstico más precoz en mujeres (mediana: 21 días) que en varones (mediana: 52 días). Al nacimiento, su longitud promedio fue 0,07 + 0,75 DE; a los 6 meses fue -1,67 + 1,33 DE con mayor compromiso en varones (-2,29 + 1,18 DE; p=0,022); a los 12 meses fue -1,84 + 1,27 DE, con recuperación a los 24 meses (-1,51 + 1,10 DE). La velocidad de crecimiento fue -1,03 + 1,62 DE y -0,89 + 1,06 DE en el en el primer y segundo año, respectivamente. Conclusiones: Los niños con HSC perdedora de sal que tuvieron seguimiento en el INSN, tuvieron menor longitud a los 6 y 12 meses de edad y lograron recuperarse a los 24 meses.

Objective: To describe physical growth features in children with salt-wasting congenital adrenal hyperplasia (CAH) during their first two years of life, in the Endocrinology Service of the Peruvian National Children's Health Institute (CHI) in Lima, Peru. Materials and Methods: This is a retrospective, observational, and descriptive study. Fifty-five children with CAH underwent follow-up in the Endocrinology Service of the CHI from 2000 to 2016; data such as body weight and height were collected at birth time and every six months, as well as age at diagnosis, hydrocortisone and fludrocortisone doses, and growth velocity. Results: Fifty-five children with salt-wasting CAH were assessed, the diagnosis was more promptly made in females (median: 21 days) compared to males (median: 52 days). At birth, their average length was 0.07 ± 0.75 SD; at 6 months it was -1.67 ± 1.33 SD, and male subjects were more affected (-2.29 ± 1.18 SD; p= 0.022); at 12 months, this parameter was -1.84 ± 1.27 SD, and recovery was observed at 24 months (-1.51 ± 1.10 SD). Growth velocity values were -1.03 ± 1.62 SD and -0.89 ± 1.06 SD in the first and second years of life, respectively. Conclusions: Children with salt-wasting CAH who were followed-up at CHI had shorter length at 6- and 12- months of age, and their recovered at 24-monbths.

Detección de la mutación I172N en pacientes cubanos con hiperplasia suprarrenal congénita por insuficiencia de 21 hidroxilasa / Detection of the I172N Mutation in Cuban Patients with Congenital Adrenal Hyperplasia due to 21 Hydroxylase Insufficiency

Resumen Fundamento: la hiperplasia suprarrenal congénita constituye la causa más frecuente de ambigüedad sexual en la infancia y aproximadamente el 95 % de los casos son producto de mutaciones que ocurren en el gen que codifica la enzima 21α-hidroxilasa. El diagnóstico molecular constituye un elemento a considerar para el manejo y asesoramiento genético a pacientes y familiares en riesgo. Objetivo: identificar la mutación I172N, determinar su frecuencia en la población estudiada y su posible relación con los fenotipos clínicos encontrados. Métodos: se realizó un estudio descriptivo, de corte transversal, durante el período 2014-2016 a pacientes cubanos con diagnóstico de hiperplasia suprarrenal congénita por insuficiencia de 21-OH atendidos en el Instituto de Endocrinología de La Habana. El universo de estudio quedó constituido por 32 pacientes. Los resultados se presentaron en tablas o gráficos según fue más factible mostrar la información. Resultados: la mutación I172N fue identificada en individuos de ambos sexos y se estableció su relación con las formas clásicas de la enfermedad. En la población estudiada, se ubicó dentro de las tres mutaciones más frecuentes de las pesquisadas hasta el momento en el Centro Nacional de Genética Médica de la Habana a pacientes con hiperplasia suprarrenal congénita por insuficiencia de 21 OH. Conclusiones: el método estandarizado demostró ser reproducible y confiable para el diagnóstico molecular de los individuos con hiperplasia suprarrenal congénita por insuficiencia de 21-OH. La mutación I172N se ubica dentro de las tres más frecuentes en la población cubana estudiada y se relaciona con las formas clásicas de la enfermedad.

ABSTRACT Background: congenital adrenal hyperplasia is the most frequent cause of sexual ambiguity in childhood. Molecular diagnosis is an element to be considered for the management and genetic counseling of patients and relatives at risk. Objective: to identify the I172N mutation, to determine its frequency in the studied population and its possible relationship with the clinical phenotypes found. Methods: a descriptive, cross-sectional study was conducted during the 2014-2016 period for Cuban patients diagnosed with congenital adrenal hyperplasia due to 21-OH insufficiency treated at the Institute of Endocrinology of Havana. The universe consisted of 32 patients. The variables analyzed were: age, social sex, age at diagnosis, clinical form of hyperplasia, diagnosis by screening program, family history, consanguinity, nonspecific neonatal death, genital crisis of the newborn, previous molecular diagnosis, mutations studied previously, mutation I172N gene CYP21A. The results were presented in tables or graphs as it was more feasible to show the information. Results: the I172N mutation was identified in individuals of both sexes and its relation with the classic forms of the disease was established. In the studied population the three most frequent mutations of the researched ones, so far in the National Center of Medical Genetics of Havana to patients with congenital adrenal hyperplasia due to 21 OH insufficiency. Conclusions: the standardized method proved to be reproducible and reliable for the molecular diagnosis of individuals with congenital adrenal hyperplasia due to 21-OH insufficiency. The I172N mutation is among the three most frequent in the studied Cuban population and is related to the classic forms of the disease.

Analysis of the Influencing Factors of 17-Hydroxyprogesterone Level and the Correlation between 17-Hydroxyprogesterone Level and the Clinical Parameters Related to Adrenal Cortical Function in Very-Low-Birth-Weight Infants

PURPOSE: 17-Hydroxyprogesterone (17-OHP) screening results are difficult to interpret owing to the many influencing factors, and confirming the test results takes time. In this study, we examined the factors that affected the 17-OHP level in premature infants. We also evaluated the correlation between 17-OHP level and the clinical parameters related to adrenal cortical function. METHODS: From January 2012 to April 2017, 358 very-low-birth-weight infants (VLBWI) born with birth weights of < 1,500 g were included in the study. Their 17-OHP levels were measured in the neonatal screening test after birth and analyzed by considering various factors that may have influenced the values. RESULTS: The 17-OHP levels negatively correlated with gestational age and birth weight. The values of the parameters that affected the 17-OHP levels were significantly higher in the infants with respiratory distress syndrome (RDS). In relation to the clinical parameters, blood pressure measured within 24 hours, 72 hours, and 1 week after birth negatively correlated with the 17-OHP level. Serum sodium and 17-OHP levels 24 hours after birth were found to be positively correlated. Urine outputs in 1 and 3 days after birth showed significant positive correlations with the 17-OHP level. CONCLUSION: The 17-OHP levels of the VLBWIs were higher when gestational age and birth weight were lower, and were influenced by RDS in the VLBWI. In addition, hypotension and urine output values may be useful in the neonatal intensive care unit as a predictor of early adrenal insufficiency.

Manejo con cinco antihipertensivos en paciente con pubertad precoz. Reporte de caso / Management with five antihypertensives in patient with precocious puberty. Case report

RESUMEN Introducción: la hiperplasia suprarrenal congénita por deficiencia de 11-beta-Hidroxilasa es una enfermedad autosómica recesiva poco frecuente, y en estadios avanzados sus complicaciones cardiovasculares exigen un manejo aún más complejo. Presentación del caso: paciente masculino que inicia pubarca a los 2 años de edad, por lo que se diagnostica hiperplasia suprarrenal congénita por deficiencia de 11-beta-Hidroxilasa, y subsecuente hipertensión desde sus 5 años. Consulta a los 8 años de edad por una intoxicación alimentaria que desencadena una insuficiencia adrenal. Adicionalmente se diagnostica pubertad precoz periférica, melanodermia, hipopotasemia e hipertrofia ventricular izquierda. Requiere manejo con hidrocortisona a dosis de estrés y uso de cinco antihipertensivos. Discusión: el tratamiento determina el pronóstico del paciente; al no realizarse el manejo oportuno puede producirse pubertad precoz e hipertensión arterial con complicaciones irreversibles como deterioro de la talla final y la hipertrofia ventricular izquierda respectivamente.

SUMMARY Introduction: Congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency is an infrequent autosomal recessive disease and the associated cardiovascular complications in the advanced stages make the management even more complex. Case presentation: A male patient who starts pubarche at 2 years old, therefore, he is diagnosed with congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency, and subsequent hypertension from age 5. At eight-years-old, he is hospitalized for a foodborne illness that causes adrenal insufficiency. Additionally, he is diagnosed with peripheral precocious puberty, melanoderma, hypokalemia and left ventricular hypertrophy. He required stress dose of hydrocortisone and five antihypertensives. Discussion: Treatment determines a patient's prognosis. Therefore, once precocious puberty and hypertension produce irreversible complications such as deterioration of the final height and left ventricular hypertrophy respectively, the management is extremely difficult.

Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase gene mutation: a case report / 中华围产医学杂志

We hereby reported the clinical manifestations and genetic diagnosis of a rare case of congenital adrenal hyperplasia (CAH) caused by cytochrome P450 oxidoreductase ( POR ) gene mutation. The case was an 11-year-old girl presented with craniofacial and skeletal malformation such as a depressed nasal bridge, radiohumeral synostosis and camptodactyly in feet. Moreover, she was diagnosed with ambiguous genitalia, and her mother had obvious masculine features during pregnancy. Laboratory tests showed that the levels of peripheral blood progesterone, 17-hydroxyprogesterone and adrenocorticotrophic hormone (ACTH) had increased significantly, which were consistent with the symptom of CAH. Genetic testing revealed a complex heterozygous mutation in POR gene of maternally inherited c.744C>G (p.Tyr248Ter) and paternal inherited c.1370G>A (p.Arg457His). Therefore, she was diagnosed with cytochrome P450 oxidoreductase deficiency (PORD), which is a rare type of CAH. The patient received oral glucocorticoid therapy and underwent knee arthroplasty.

Functional Identification of Compound Heterozygous Mutations in the CYP17A1 Gene Resulting in Combined 17α-Hydroxylase/17,20-Lyase Deficiency

BACKGROUND: We previously reported a patient with congenital adrenal hyperplasia (CAH) with compound heterozygous mutations in the cytochrome P450 17A1 (CYP17A1) gene. One allele had a p.His373Leu and the other a new p.Glu383fsX36 mutation. The aim of this study was to investigate the functional properties of a new allele present in a compound heterozygote of CYP17A1. METHODS: To understand how p.His373Leu and p.Glu383fsX36 affect P450c17 enzymatic activity, wild type and mutant CYP17A1 cDNAs were cloned into flag-tagged pcDNA3 vector and introduced into human embryonic kidney cells 293T (HEK293T) cells. Protein expression levels of CYP17A1 were then analyzed. And the activities of 17α-hydroxylase and 17,20-lyase of CYP17A1 were evaluated by measuring the conversion of progesterone to 17α-hydroxyprogesterone and of 17α-hydroxypregnenolone to dehydroepiandrosterone, respectively. In addition a computer model was used to create the three-dimensional structure of the mutant CYP17A1 enzymes. RESULTS: Production of the p.His373Leu mutant protein was significantly lower than that of the wild type protein, and the p.Glu383fsX36 protein was hardly produced. Similarly the enzymatic activity derived from the p.His373Leu mutant vector was significantly lower than that obtained from the wild type vector, and little activity was obtained from the p.Glu383fsX36 vector. Three-dimensional modeling of the enzyme showed that p.His373 was located in region important for heme-binding and proper folding. Neither the p.His373Leu nor the p.Glu383fsX36 mutant protein formed a heme-binding structure. CONCLUSION: Enzyme activity measured in both mutants disappeared completely in both 17α-hydroxylase and 17,20-lyase. This result accounts for the clinical manifestations of the patient with the compound heterozygous CYP17A1 mutations.

17-hydroxiprogesterone values in healthy preterm infants / Valores de 17-hidroxiprogesterona en recién nacidos prematuros sanos

Abstract Introduction: In preterm newborn, problems with the interpretation of 17-OHP may occur. Objective: Evaluate 17-OHP values in healthy preterm newborns until they reach the corrected gestational age. Methods: Longitudinal study of 36 preterm infants with 17-OHP evaluation using ELISA from heel blood from 3 to 5 days and thereafter every 2 weeks until the corrected gestational age. Values adjusting multiple variables such as gestational age, birth weight and sex, among others were compared. The results were analyzed against 82 healthy full-term infants. Results: In the first week of life, early term infants born within less than 34 months of gestational age show 17-OHP values that are much higher than the full term neonates. After a week, the values decrease and stabilize, but are still higher than those of full term neonates and remain so even at the corrected gestational age. (average difference of 63.0%, CI 95%: 11.8%-115.5%). 33.6% (41 samples) of a total of 122 samples taken from preterm infants were higher than 30 ng/mL. Conclusions: 17-OHP values in early term infants are higher than those in full term neonates and can be related to postnatal adaptive processes. It is suggested that a second screening at the 37th week of corrected age be performed.

Resumen Introducción: En recién nacidos pretérmino se presentan problemas para interpretar la 17-OHP. Objetivo: Evaluar los valores de 17-OHP en recién nacidos sanos pretérmino hasta cuando alcanzan el término de edad gestacional corregida. Métodos: Estudio longitudinal de 36 prematuros con evaluación de la 17-OHP por ELISA en sangre de talón desde los 3-5 días de vida y luego cada dos semanas hasta la edad gestacional de término corregida. Se comparó los valores ajustando múltiples variables como edad gestacional, peso al nacer y sexo, entre otras. Se analizaron los resultados frente a los de 82 recién nacidos a término sanos. Resultados: En la primera semana de vida, los prematuros menores de 34 semanas de edad gestacional tienen valores de 17-OHP muy superiores a los neonatos de término. Al alcanzar la semana 34 de edad gestacional corregida, los valores descienden y se mantienen estables, siempre mayores a los de término, incluso al llegar a edad a término corregida (diferencia promedio de 63.0%, IC 95%: 11.8%-115.5%). El 33.6% (41 muestras) de un total de 122 muestras hechas en los prematuros eran mayores de 30 ng/mL. Conclusiones: Los valores de 17-OHP en recién nacidos pretérmino son más altos que en neonatos a término, pudiendo ser relacionado con los procesos adaptativos postnatales. Se sugiere realizar un segundo tamizaje al llegar a la semana 37 de edad corregida.

Hiperplasia adrenal congénita. Presentación de caso / Congenital adrenal hyperplasia. Case presentation

Fundamento: La hiperplasia adrenal congénita es el desorden adrenal más común en niños, causa frecuente de seudohermafroditismo femenino y de ambigüedad sexual. La deficiencia de la enzima 21 hidroxilasa es la causa más común, ocurre entre un 90 y 95 % de los casos. La incidencia de la enfermedad es de 1:14 000 nacimientos. La determinación de hormona 17 hidroxiprogesterona al quinto día de nacido, facilita el diagnóstico y el adecuado tratamiento. Presentación de caso: Se describe el diagnóstico de un recién nacido femenino, de nueve días, con antecedentes prenatales de alto riesgo obstétrico, sin manifestaciones clínicas de pérdida adrenal, al examen físico discreto grado de virilización (moderada hipertrofia del clítoris) y niveles elevados de 17 hidroxiprogesterona, al cual se le realizó confirmatorio de 17 hidroxiprogesterona en suero a los nueve días, resultó positivo y ante los antecedentes prenatales, se decidió su diagnóstico y tratamiento oportuno. Conclusiones: Se realizó el diagnóstico de una hiperplasia adrenal congénita, en recién nacido femenino de nueve días, se brindó asesoría a sus familiares, se indicó tratamiento médico con hidrocortisona y fluorhidrocortizona, se le siguió por consulta del programa de hiperplasia adrenal congénita y se realizó estudio molecular para precisar déficit enzimático.

Background: Adrenal hyperplasia, congenital is the most common adrenal disorder in children, a frequent cause of femenine pseudohermaphroditism and sexual ambiguity. The deficiency of the 21 hydroxylase enzyme is the most common cause, occurs between 90 and 95 % of the cases. The incidence of the disease is at about 1:14 000 births. The determination of hormone 17 hydroxyprogesterone on the fifth day of birth facilitates diagnosis and adequate treatment. Case report: We describe the diagnosis of a 9 days old femenine infant with a prenatal history of high obstetric risk, with no clinical manifestations of adrenal loss, a discrete physical examination of virilization (moderate clitoris hypertrophy) and elevated levels of 17 hydroxyprogesterone, which was confirmed with serum hydroxyprogesterone at 9 days, was positive and before the prenatal history, the diagnosis and timely treatment was decided. Conclusion: Adrenal hyperplasia, congenital was diagnosed in a 9-day-old femenine newborn, counseling was given to her relatives, medical treatment with hydrocortisone and fluorhydrocortisone was indicated, followed by consult with the adrenal hyperplasia, congenital program and molecular study was made to determine enzymatic deficit.

Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency: description of a new mutation, R384X / Hiperplasia suprarrenal congénita por déficit de 11-beta-hidroxilasa: descripción de una nueva mutación, R384X

Abstract Case Description: It is presented the phenotype of a new compound heterozygous mutation of the genes R384X and Q356X encoding the enzyme of 11-beta-hydroxylase Clinical Findings: Severe virilization, peripheral hypertension, and early puberty. Treatment and Outcome: Managed with hormone replacement therapy (corticosteroid) and antihypertensive therapy (beta-blocker), resulting in the control of physical changes and levels of arterial tension. Clinical Relevance: According to the phenotypic characteristics of the patient, it is inferred that the R384X mutation carries an additional burden on the Q356X mutation, with the latter previously described as a cause of 11-beta-hydroxylase deficiency. The description of a new genotype, as in this case, expands the understanding of the hereditary burden and deciphers the various factors that lead to this pathology as well as the other forms of congenital adrenal hyperplasia (CAH), presenting with a broad spectrum of clinical presentations. This study highlights the importance of a complete description of the patient's CAH genetic profile as well as their parents' genetic profile.

Resumen Descripción del Caso: Se presenta el fenotipo de una nueva mutación heterocigota compuesta en los genes Q356X y R384X que codifican la enzima 11-beta-hidroxilada Hallazgos Clínicos: Virilización severa, pubertad precoz periférica e hipertensión. Tratamiento y Resultados: Manejo con terapia de reemplazo hormonal con corticoide y antihipertensivo con beta-bloqueador con lo que se logró controlar los cambios físicos y los niveles de tensión arterial. Relevancia Clínica: Según las características fenotípicas del paciente se infiere que la mutación R384X acarrea una carga adicional a la mutación Q356X, esta última descrita como causa de deficiencia de 11-beta-hidroxilasa. La descripción de nuevos genotipos, como en este caso, permite ampliar la comprensión de la carga hereditaria y descifrar los diversos factores que llevan a que esta patología, así como las demás formas de hiperplasia suprarrenal congénita (HSC), se presenten con un amplio espectro de cuadros clínicos. Esto permite resaltar la importancia de una descripción completa del perfil genético del paciente con HSC y de sus padres.

Development of a strategy of physician-patient relationship for improving care for patients with disorders of sex development: a qualitative study / Desenvolvimento de uma estratégia de relacionamento médico-paciente para a melhoria do atendimento aos pacientes com desordens do desenvolvimento do sexo: um estudo qualitativo

ABSTRACT: CONTEXT AND OBJECTIVE: Care for patients with disorders of sex development (DSD) should be provided in integrated-care centers by a multidisciplinary team. Implementation of this project within the teaching clinic routine presents several challenges: 1) difficulties in relationships between the medical team and patients and their families; 2) age, ethnic and cultural differences; 3) DSD-related prejudice; and 4) physicians' anxiety. We report on a psychologist's work strategy that focused on creating arrangements that could contribute towards development of the relationship between the medical team and patients and their families, as a way of preparing the clinical staff to manage treatment of adult DSD patients. DESIGN AND SETTING: Prospective qualitative study. METHODS: Between February 2010 and April 2015, we conducted a qualitative study in the Adrenal Outpatient Clinic of Escola Paulista de Medicina (São Paulo, Brazil), based on interviews, team discussions and group dynamics with resident physicians, postgraduate students and attending physicians. RESULTS: Implementation of the project allowed residents to build a story of differentiated care for their patients, thus facilitating dialog between them and making it possible to address taboo topics. Sequential care provided by the same resident led patients to feel that their doctor cared for them, with individuality, continuity and a sense of interest in their story. CONCLUSION: Presence of a psychologist in the outpatient routine enabled inclusion of subjective factors in the routine of medical consultations, thus broadening the notion of healthcare for patients with DSD, facilitating bonds and providing support for difficulties faced.

RESUMO: CONTEXTO E OBJETIVO: Pacientes com desordens do desenvolvimento do sexo (DDS) e seus familiares devem ser atendidos em centros de atenção integral, por equipe multidisciplinar. A efetivação desse projeto no cotidiano da clínica-escola apresenta vários desafios: 1) dificuldades nas relações entre equipe médica, paciente e família, 2) diferenças etárias, étnicas e culturais, 3) preconceitos relacionados às DDS, e 4) angústia dos médicos. Relatamos o desenvolvimento de uma estratégia de trabalho do psicólogo, que teve como foco a criação de dispositivos que contribuíssem para o aprimoramento da relação entre equipe médica, paciente e família, preparando o staff clínico para administrar o tratamento de pacientes adultos com DDS. DESENHO E LOCAL: Estudo qualitativo prospectivo. MÉTODOS: De fevereiro de 2010 até abril de 2015, realizamos uma pesquisa qualitativa no Ambulatório de Adrenal da Escola Paulista de Medicina (São Paulo, Brasil), baseada em entrevistas, discussões de equipe e dinâmica de grupo com médicos residentes, pós-graduandos e assistentes. RESULTADOS: A implementação do projeto possibilitou aos residentes construir uma história de atendimento diferenciado com seus pacientes, facilitando o diálogo entre eles e permitindo que temas-tabus fossem abordados. O fato de ter sido atendido seguidamente pelo mesmo residente possibilitou ao paciente a sensação de cuidado, individualidade, continuidade e a sensação de que havia interesse, por parte do médico, sobre a sua história. CONCLUSÃO: A presença do psicólogo no cotidiano do ambulatório permitiu que aspectos subjetivos fossem incluídos na rotina das consultas médicas, ampliando a noção de saúde e cuidado aos pacientes com DDS, facilitando o vínculo e dando suporte para as dificuldades encontradas.

Reduction Clitoroplasty with Preservation of the Dorsal Neurovascular Pedicle in a 6-Year-Old Female: A Case Report

A 6-year-old female presented to our hospital with clitoromegaly. On physical examination, she demonstrated evidence of precocious pubic hair and clitoromegaly. The relaxed clitoris measured 3.7 cm in length. Her uterus was undetectable on diagnostic transvaginal ultrasonography and abdomen-pelvis computed tomography (CT) with otherwise normal-appearing internal female genitalia. We planned reduction clitoroplasty with preservation of the dorsal neurovascular pedicle to maintain sensitivity of the glans clitoris. After surgery, the patient demonstrated good recovery. The parents of the patient were satisfied with the surgical results. The patient was discharged without complications on hospital day 6.

17α-hydroxylase Deficiency Mimicking Hyperaldosteronism by Aldosterone-producing Adrenal Adenoma / 대한내과학회지

17α-hydroxylase deficiency is a rare cause of congenital adrenal hyperplasia and is characterized by primary amenorrhea, delayed puberty and hypertension. Although 17α-hydroxylase deficiency mimics mineralocorticoid-induced hypertension, impaired sexual development can aid in the differential diagnosis of this disease. A 32-year-old woman, who had a history of testicular feminization syndrome, presented with hypertension. Her aldosterone level was elevated whereas plasma renin activity was reduced, and her computed tomography scan showed a left adrenal adenoma, which was thought to be an aldosterone producing adenoma. A left adrenalectomy was performed to treat hypertension; however, the condition did not improve. The hormonal tests revealed high levels of plasma progesterone, mineralocorticoid and adrenocorticotropic hormone, and low levels of 17a hydroxyprogesterone, cortisol and sex hormones. The patient was diagnosed with 17α-hydroxylase deficiency and commenced on prednisolone, which controlled hypertension. Here, we report a case of 17α-hydroxylase deficiency mimicking hyperaldosteronism via aldosterone-producing adrenal adenoma.

Tumores e hiperplasias adrenocorticais: identificação de possíveisdoenças hereditárias / Recognition of hereditary diseases related to adrenocortical tumors andhyperplasias

A alta prevalência de tumores da glândula adrenal deve-se, em parte, ao avanço dos métodos de imagem. Os adenomas, carcinomas e hiperplasias oriundos do córtex adrenal são responsáveis por 80 a 90% dos processos tumorais. Alguns casos são herdados e podem estar associados a efeito compressivo de massa tumoral, hipersecreção de esteroides ou manifestações clínicas em outros órgãos. Considerando as hiperplasias e tumores adrenocorticais, o objetivo desse trabalho foi auxiliar os médicos na identificação de pacientes que apresentem risco para doença hereditária. As neoplasias e hiperplasias adrenocorticais podem ser encontradas em síndromes hereditárias, como a síndrome de Li-Fraumeni, síndrome de Beckwith-Wiedemann, neoplasia endócrina múltipla do tipo I, síndrome de Gardner e no complexo de Carney. A hereditariedade também está associada com doenças adrenocorticais na hiperplasia adrenal congênita, no aldosteronismo primário e/ou na síndrome de Cushing (doença clínica ou subclínica) na hiperplasia adrenal macronodular primária. Essa revisão descreve as características clínicas e os defeitos genéticos responsáveis pelas síndromes hereditárias. Relacionamos também a classificação histopatológica dos processos expansivos com os principais sinais clínicos e os genes relacionados. A identificação de defeitos genéticos em células germinativas nessas doenças familiais permite o conhecimento de alterações somáticas em alguns tipos de processos tumorais adrenocorticais de etiologia esporádica. Considerando a prevalência dos tumores do córtex adrenal, a identificação de predisposição hereditária é essencial para assegurar a conduta clínica correta do paciente e o aconselhamento genético de seus familiares.

The adrenal gland tumors are prevalent due in part by the widespread use of imaging studies. Adenomas, carcinomas and hyperplasias, originating from the adrenal cortex, account for 80-90% of adrenal tumoral processes. Some cases are inherited and may be associated with local mass effect, steroid hypersecretion and/or clinical manifestation in other organs. In the context of adrenocortical tumors and hyperplasias, the purpose of this article is to assist physicians in identifying patients who may be at risk of hereditary diseases. Adrenocortical hyperplasias and neoplasias can be found in familial tumor syndromes, such as Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, multiple endocrine neoplasia type 1, Gardner syndrome and Carney complex. Heredity has been also associated with adrenocortical lesions in congenital adrenal hyperplasia, primary aldosteronism and/or Cushing syndrome (overt or subclinical disease) in primary macronodular adrenal hyperplasia (PMAH). This review describes the clinical recognition and genetic defects that have been found to be responsible for these hereditary diseases. Furthermore, we present the histopathologic classification of adrenocortical expansive processes in correlation to the main clinical features and related genes. The identification of germline genetic defects in such familial diseases lead to the identification of somatic alterations in a subgroup of sporadic adrenocortical lesions. Considering the prevalence of adrenocortical tumors, identification of a hereditary predisposition is essential to assure the adequate clinical management of the patient and to offer the genetic counselling to family members.

Cardiovascular risk factors and increased carotid intima-media thickness in young patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

ABSTRACT Objective Increased arterial intima-media thickness has been observed in adults with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD). CAH has also been associated with obesity, insulin resistance, and hypertension. The aim of the present study was to compare youths with CAH with healthy, normal-weight individuals, evaluating carotid intima-media thickness (CIMT) and indicative factors of cardiovascular risk to seek for abnormalities in the CAH group. Subjects and methods Clinical, biochemical, and ultrasonographic evaluations, according to published criteria, were performed in 113 subjects (5 to 20 years old): 40 patients with 21-OHD and 73 healthy individuals matched for gender, pubertal status, and age. Results Most CAH patients were female (80%), salt-losers (72.5%), and pubescent (80%); 10 (25%) patients were overweight. An increase in CIMT was observed both on the right (p = 0.0240) and left (p = 0.0003) sides in 38 CAH patients compared with the healthy individuals. The body mass index, BMI/age Z score, and systolic blood pressure (SBP) were higher in patients compared with controls (p < 0.000 and p = 0.0219, respectively). Conclusions Findings of increased CIMT, BMI, and SBP in young patients with 21-OHD indicate the need for early identification and intervention regarding cardiovascular risk. Validating these findings might result in improved therapeutic approaches for children with 21-OHD in the future. Arch Endocrinol Metab. 2015;59(6):541-7.

Hiperplasia suprarrenal congénita: origen de trastornos del desarrollo y diferenciación sexual / Adrenal hyperplasia congenital: beginning of developmental and sexual differentiation disorders

La hiperplasia suprarrenal congénita es una patología de origen genético que se desarrolla por un déficit enzimático secundario a alteraciones en la síntesis de proteínas. Dicho déficit perturba las vías del metabolismo suprarrenal, específicamente las que ocurren en la corteza de la glándula, es decir, el metabolismo glucocorticoide, mineralocorticoide y de hormonas sexuales. Estas variaciones moleculares traducidas a la clínica se expresan en una variedad de presentaciones posibles, cada una dependiente de la enzima que se encuentre afectada, desde alteraciones electrolíticas, metabólicas, renales o del tracto gastrointestinal, pero hay una que es comúnmente encontrada, trastornos de desarrollo y diferenciación sexual. Dentro de las formas más severas de hiperplasia suprarrenal congénita se observan alteraciones de los caracteres sexuales externos que básicamente traducen en virilización de los genitales durante el desarrollo gestacional, así como también pubertad precoz, amenorreas, infertilidad, entre otros...

Adrenal hyperplasia congenital is a genetic disease that develops from an enzyme deficiency secondary to alterations in protein synthesis. This deficit disturbs the pathways of adrenal metabolism, specifically occurring in the cortex of the gland, such as, the glucocorticoid, mineralocorticoid and the sex hormones metabolism. These molecular variations translated to the clinics are expressed in a variety of possible presentations, each depending of the enzyme that is affected, since electrolyte, metabolic, renal abnormalities or and gastrointestinal tract disturbances, but one of these is commonly for all presentation, the development and sexual differentiation disorders. Among the most severe forms of adrenal hyperplasia congenital alterations of the external sexual characters that basically translate into virilization of the genitals duringgestational development, as well as precocious puberty, amenorrhea, infertility observed, among other...