Genetic analysis of a case with 11β hydroxylase deficiency caused by CYP11B2/CYP11B1 chimeric gene / 中华医学遗传学杂志

OBJECTIVE@#To analyze a child with 11β hydroxylase deficiency (11β-OHD) due to CYP11B2/CYP11B1 chimeric gene.@*METHODS@#Clinical data of the child who was admitted to Henan Children's Hospital on August 24, 2020 were retrospectively analyzed. Peripheral blood samples of the child and his parents were collected and subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. RT-PCR and Long-PCR were carried out to verify the presence of chimeric gene.@*RESULTS@#The patient, a 5-year-old male, had featured premature development of secondary sex characteristics and accelerated growth, and was diagnosed with 21 hydroxylase deficiency (21-OHD). WES revealed that he has harbored a heterozygous c.1385T>C (p.L462P) variant of the CYP11B1 gene, in addition to a 37.02 kb deletion on 8q24.3. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.1385T>C (p.L462P) was rated as a likely pathogenic variant (PM2_Supporting+PP3_Moderate+PM3+PP4). The results of RT-PCR and Long-PCR suggested that CYP11B1 and CYP11B2 genes have recombined to form a CYP11B2 exon 1~7/CYP11B1 exon 7~9 chimeric gene. The patient was diagnosed as 11β-OHD and effectively treated with hydrocortisone and triptorelin. A healthy fetus was delivered following genetic counseling and prenatal diagnosis.@*CONCLUSION@#11β-OHD may be misdiagnosed as 21-OHD due to the potential CYP11B2/CYP11B1 chimeric gene, which will require multiple methods for the detection.

Progress on genetic basis of primary aldosteronism / 浙江大学学报·医学版

It has been proven that familial aldosteronism type I is related to 11-beta hydroxylase (CYP11B1)/aldosterone synthase (CYP11B2) chimeric genes. In recent years, accumulated evidences indicate that the genetic basis of primary aldosteronism may involve chromosome 7p22 candidate genes, polymorphisms of CYP11B1 and CYP11B2 genes, mutations of ion channel- related KCNJ5, ATP1A1, CACNA1D genes. The article reviews the progress on genetic basis of primary aldosteronism.

Genetic Analyses of the Chimeric CYP11B1/CYP11B2 Gene in a Korean Family with Glucocorticoid-Remediable Aldosteronism

Glucocorticoid-remediable aldosteronism (GRA) is an autosomal-dominant inheritable form of hyperaldosteronism with early onset hypertension. GRA is caused by unequal crossing-over of the steroid 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes. As a result of chimeric gene duplication, aldosterone is ectopically synthesized in the adrenal zona fasciculata under the control of adrenocorticotropin. Here, we describe three cases of GRA in a Korean family. The proband-a 21-yr-old female-was incidentally found to have high blood pressure (170/108 mmHg). Her 46-yr-old father had been treated twice for cerebral hemorrhage at the ages of 29 and 39 yr. Her 15-yr-old brother had a 2-yr history of hypertension; however, he was never treated. Their laboratory test results showed normokalemia, hyporeninemia, hyperaldosteronism, and a high plasma aldosterone concentration-to-plasma renin activity ratio. Normal saline loading failed to suppress aldosterone secretion. However, dexamethasone administration effectively suppressed their plasma aldosterone concentrations. Following genetic analyses with PCR and direct sequencing to document the chimeric gene and crossover site, respectively, we identified CYP11B1/CYP11B2 and determined the breakpoint of unequal crossover to be located between intron 2 of CYP11B1 and exon 3 of CYP11B2.

A novel missense mutation, GGC(Arg454) --> TGC(Cys), of CYP11B1 gene identified in a Chinese family with steroid 11beta-hydroxylase deficiency / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Steroid 11beta-hydroxylase deficiency (11beta-OHD), an autosomal recessive inherited disease, accounts for 5% - 8% of congenital adrenal hyperplasia. It was scarcely reported in China. This article reports two Chinese girls with 11beta-OHD.</p><p><b>METHODS</b>The two patients were sisters and presented with hypertrichosis, skin pigmentation, laryngeal prominence and virilization of external genitalia. The patients were followed up for their clinical symptoms and signs, hormone profile, and adrenal image. The genomic deoxyribonucleic acids of the patients and their parents were isolated. 11beta-hydroxylase gene (CYP11B1) was amplified by polymerase chain reaction and directly sequenced.</p><p><b>RESULTS</b>Hormone tests showed that serum cortisol was in the low limit of normal range, whereas the concentrations of adrenocorticotropic hormone, testosterone and progesterone were much higher than those of normal adult females. There were obvious adrenal hyperplasia and advance of bone age. After 11 months of treatment with dexamethasone, the skin pigment became regressed; the breast, uterus and ovary gradually developed and normal menstrual cycle started while the manifestations of virilization did not change. A single point mutation of CYP11B1 (R454C, GGC --> TGC) in all the members of this family was detected. The sisters were homozygous and their parents were heterozygous.</p><p><b>CONCLUSIONS</b>The clinical manifestation of 11beta-OHD is complicated. The manifestation of virilization could not regress after treatment with dexamethasone. The novel missense mutation of CYP11B1 (R454C, GGC --> TGC) is the pathogenesis of 11beta-OHD at least in some Chinese patients.</p>

Gender identity in congenital adrenal hyperplasia secondary to 11-hydroxylase deficiency

The psychoendocrinology of the development of gender identity in patients with congenital adrenal hyperplasia [CAH] is poorly understood. Prenatal androgen exposure, postnatal hormonal influence, degree of external genitalia virilization, genital appearance, social rearing and other biological factors, are all thought to have an effect on gender identity development. [1-6] Late diagnosis and referral, which are common problems in our country, might have an adverse effect on normal gender identity development in female patients with CAH [7]. We describe two genetically female sisters with CAH secondary to 11-hydroxylase deficiency who were raised as boys and referred at the age of puberty to our clinic. We believe that the gender identity development in these two patients, who had the same medical and social background, was related to the extent of external genitalia virilization

11-Beta Hydroxylase Deficiency: a clinical study about seven cases

11 beta-hydroxylase deficiency is a rare recessive autosomal disorder. The aim of this report was to describe among a retrospective study of seven cases, different clinical pictures, problems in diagnosis and management. The frequency of 11 beta-hydroxylase deficiency was 17.5% of congenital adrenal hypererplasia etiology in our study. Consanguinity was found in all cases. The sex ratio was 5 boys/2 girls. Median age on diagnosis was 4.3 years. Five cases were revealed with precocious puberty associated with hypertension. One patient had sexual ambiguity, Prader IV stage, hypertension appears later. One patient developed heterosexual precocious puberty and hypertension at five years of age. One patient had bilateral testicular adrenal rests. Hypertension was diagnosed early in 4 cases and secondarly in the other 3 cases. Hypertension was severe complicated by convulsions, facial paralysis and epistaxis. Hypo kaliemia was identified in six cases. Hormonal investigations confirmed diagnosis in all cases. The secondary sexual characteristics were controled by glucocorticoid substitution. Antihypertensive treatment was necessary initially and prolonged only in three cases Prognosis of final height of patients with late diagnosis was particularly compromised

Relationship between the microsatellite polymorphism of CYP11 alpha gene and the pathogenesis of hyperandrogenism of polycystic ovary syndrome in Chinese / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To explore the association between the microsatellite polymorphism in the promoter region of CYP11 alpha gene and hyperandrogenism of polycystic ovary syndrome (PCOS).</p><p><b>METHODS</b>Eighty-six cases of PCOS and 50 normal women as controls were studied. Polymerase chain reaction and electrophoresis on polyacrylamide gel were employed to detect the polymorphism of CYP11 alpha gene and its frequency distribution. At the same time, the relationships of CYP11 alpha alleles to serum testosterone levels in PCOS were compared.</p><p><b>RESULTS</b>Four different CYP11 alpha (tttta)n alleles were identified, corresponding to 4, 6, 8 and 9 repeat-units alleles. The frequency distribution profiles were 0.17, 0.31, 0.39, 0.13 and 0.22, 0.35, 0.33, 0.10 in PCOS group and control group respectively, showing no statistically significant difference between the two groups. There were no correlations between the polymorphism of CYP11 alpha gene and the serum testosterone levels of PCOS patients.</p><p><b>CONCLUSION</b>Micro-satellite polymorphism (tttta)n of gene CYP11 alpha exists in Chinese women and the polymorphism does not relate to the pathogenesis of hyperandrogenism in women with PCOS.</p>

Bases moleculares da hiperplasia adrenal congênita / Molecular bases of congenital adrenal hyperplasia

Hiperplasia adrenal congênita (HAC) é uma doença autossômica recessiva decorrente da alteraçäo de enzimas que participam da síntese do cortisol. As manifestações podem ser causadas pela deficiência do cortisol e, em alguns casos, aldosterona e pelo acúmulo de precursores. O objetivo desta revisäo é apresentar os mecanismos moleculares dos principais defeitos enzimáticos envolvidos na etiopatogênese da HAC. A deficiência da 21-hidroxilase (210H) ocorre em 95 por cento dos casos de HAC. Existem dois genes que codificam o P450c21: um ativo, CYP21, e um pseudogene CYP27P. Ambos säo altamente homólogos (98 por cento), o que favorece o emparelhamento desigual dos cromossomos homólogos durante a meiose, levando a duplicações e/ou deleções ou conversões desses genes. Adicionalmente, foram também descritas mutações de ponto, muitas delas presentes no pseudogene sugerindo microconversões. Mutações no gene CYP 1181 causam HAC por deficiência da 11 Rhidroxilase, forma esta que corresponde a 5 por cento dos casos. Algumas mutações säo recorrentes, situando-se principalmente entre os exons 6-8 que representaria uma área hot-spot no gene CYP 1781. A deficiência de 17-hidroxilase é causada por mutações no gene CYP77, que codificam uma proteína alterada, levando a deficiência total ou parcial de 17hidroxilaçäo e 17,20-liase ou deficiência isolada de 17,20-Base. Finalmente, deficiência de 3B-HSD é causada por mutações no gene HSD3B2, que codifica a enzima 3B-HSD tipo II e estas mutações têm sido associadas tanto com a forma clássica como com a forma näo clássica da deficiência da 3B-HSD.

Bases clínico moleculares de la hipertensión arterial dependiente de mineralocorticoides / Clinical molecular basis of the mineralocorticoid dependent arterial hypertension

El hiperaldosteronismo primario es una causa potencialmente curable de hipertensión arterial. El uso rutinario de la razón aldosterona/actividad de renina plasmática como test de screenning ha demostrado que existe una alta prevalencia de esta enfermedad, cercana al 10 por ciento de la población de hipertensos. Esta frecuencia es claramente más alta que la clásicamente descrita cuando la hipokalemia es usada como método de screening. Los subtipos más comunes de hiperaldosteronismo primario son el hiperaldosteronismo supresible por glucocorticoides y la hiperplasia adrenal primaria. El diagnóstico de hiperaldosteronismo primario está dirigido en primer lugar a confirmar la autonomía de la secreción de aldosterona del eje renina-angiotensina y posteriormente a diferenciar los tipos subclínicos de la enfermedad. Este artículo es una puesta al día de los nuevos datos acerca de la prevalencia, criterios diagnósticos y describe las características clínicas, bioquímicas y genéticas de los diferentes subtipos de la enfermedad. Además discutimos el diagnóstico diferencial con otros estados de hipermineralocorticoidismo no dependientes de aldosterona como son el déficit de 11ß-hidroxiesteroide deshidrogenasa tipo II, defectos en el canal renal de sodio o las formas hipertensivas de la hiperplasia suprarrenal congénita (11ß-hidroxilasa y 17a-hiroxilasa)

Hiperplasia suprarrenal congénita / Congenital adrenal hyperplasia

La esteroidogénesis suprarrenal es un proceso complejo y secuencial que involucra a una serie de enzimas, las cuales actuando en forma coordinada sobre el colesterol determinan la síntesis de glucocorticoides y mineralocorticoides. El término hiperplasia suprarrenal congénita ha sido tradicionalmente usado para denominar al conjunto de alteraciones en la esteroidogénesis suprarrenal que determinan un decremento en la biosíntesis de cortisol. Este hecho determina una elevación compensatoria de ACTH, la cual, al estimular la síntesis esteroidal, lleva a un aumento de la producción de esteroides localizados antes del bloqueo. El resultado final es una diversidad de cuadros clínicos determinados por el déficit de cortisol y hormonas distales al bloqueo y al exceso de hormonas y metabolitos proximales al bloqueo. Los cuadros más frecuentes de hiperplasia suprarrenal congénita son los déficit de 21 y 11-hidroxilasa, que serán revisados en conjunto con otros déficit enzimáticos de presentación menos frecuente

Report of 285 patients with congenital adrenal hyperplasia and evaluation of approximate prevalence of the disease in Iran

In this study, 285 cases of congenital adrenal hyperplasia who were followed in the Tehran University Hospitals and Institute of Endocrinology and Metabolism are reported. Among these cases, 165 [57.9%] were female and 120 [42.1%], male. The most common type of congenital adrenal hyperplasia in these patients was the salt-losing type of 21-hydroxylase deficiency [57.9%]; 11-hydroxylase deficiency was present in 13.68% of patients. There were only 3 cases with 3-beta hydroxysteroid dehydrogenase deficiency, 2 cases with 17-alphahydroxylase deficiency and one with 20, 22 desmolase deficiency. Presenting complaints were in decreasing order of frequency: ambiguous genitalia, vomiting and dehydration, precocious puberty, hypertension, failure to thrive, hirsutism and primary amenorrhea. The age of patients at the time of diagnosis was between 2 days to 17 years and the most common age was in the first two years of life especially in the neonatal period. A positive family history of the same disease was present in 17 siblings of our patients. [21-OHD = 14 H-OHD = 3]. There were 27 cases of death among these patients [23 male and 4 female that 24 cases had 21-OHD and 2 cases had 3 beta HSD deficiency and one case had 20,22-desmolase deficiency]

Estudo de frequência da hiperplasia adrenal congênita em centros de referência médica do Brasil / Frequency study of congenital adrenal hyperplasia in medical reference centers from Brazil

Hiperplasia adrenal congênita (HAC) é uma condição endócrina incomum. A deficiência de 21-hidroxilase (D21-OH) é o subtipo mais freqüente (1:10.000-15.000 nascidos vivos), seguido pela deficiência de 11beta-hidroxilase (5-8 por cento de todos os casos). Os demais subtipos, incluindo a deficiência de 17 a-hidroxilase (D17 alpha-OH), são considerados muito raros. Como no Brasil não existem dados de freqüência da HAC, fizemos, neste estudo, uma consulta (por carta-resposta, divulgação em revista médica e contato pessoal) aos centros de referência médica do Brasil, inquirindo sobre o número de casos de HAC e o perfil laboratorial utilizado para classificação dos subtipos, além de procurar identificar casos específicos de HAC por D17 alpha-OH para estudo posterior. Colaboraram com o estudo 52 serviços (7,8 por cento), de um total de 669 contatados diretamente por carta-resposta, e mais três outros convidados, além do nosso, sendo repostados 783 pacientes: 713 (91,1 por cento) por D21-OH, 20 (2,6 por cento) por D3beta-HD, 20 (2,6 por cento) por D17 alpha-OH e 17 (2,2 por cento) por D11 beta-OH. Houve significativa variação entre os serviços quanto à realização de dosagens laboratoriais essenciais para o diagnóstico de HAC, de acordo com cada subtipo. Concluímos que a colaboração dos serviços médicos brasileiros em estudos multicêntricos é modesta, mesmo utilizando metodologia de abordagem variada. No Brasil, a HAC por D21-OH é, também, a forma mais comumente reportada. Entre os demais subtipos, a D17 alpha-OH não se mostrou tão infreqüente, apresentando prevalência pelo menos igual à da D11 beta-OH, mesmo considerando a introdução de um viés pela metodologia empregada e os possíveis erros no estabelecimento do diagnóstico das D17 alhpa-OH e D11 beta-OH.

Alteraciones en la enzimología de la producción de aldosterona / Alterations in the enzymology of aldosterone production

El último paso para la producción de aldosterona (11-desoxicorticosterona a aldosterona) en mitocondrias de zona glomerulosa de adrenal de rata es catalizado por la enzima CYP11B2. CYP11B1, en zona fasciculata, transforma 11-desoxicorticosterona en corticosterona o 18-hidroxi-11-desoxicorticosterona. CYO11B1 y CYP11B2 tienen alta homología y sus genes se hallan en tándem en el cromosoma 8q22. Mutaciones en el gen de CYP11B2 y recombinaciones genéticas entre éste y el gen de CYP11B1 serían las responsables de las alteraciones en la enzimología de la producción de aldosterona, dando una nueva denominación y explicación a las deficiencias anteriormente conocidas como de CMOI y CMOII

Diagnóstico e prevalência da hiperplasia adrenal congênita forma näo clássica em uma amostra de 122 pacientes hirsutas / Diagnosis and prevalence of nonclassical congenital adrenal hyperplasia in 122 hirsute patients

OBJETIVOS: Estabelecer o diagnóstico de HAC-NC e a prevalência desta patologia no nosso meio, em pacientes consultando por hirsutismo. PACIENTES E MÉTODOS: Foram avaliadas do ponto de vista clínico e hormonal 122 pacientes hirsutas. A avaliaçao hormonal incluiu a realizaçao sistemática do teste do ACTH em todas as pacientes. Os dados foram comparados com um grupo controle constituído por 13 mulheres normais, nao hirsutas e com um grupo de 5 heterozigóticas obrigatórias para a deficiência da P45Oc21, maes das pacientes. RESULTADOS: Nove pacientes tiveram o diagnóstico de HAC-NC por déficit na P45O-c21 e 1 por deficiência na P45O-c11. O perfil clínico e hormonal apresentou grande variabilidade entre as 9 pacientes, incluindo os níveis basais de 17-hidroxiprogesterona, que foram normais em 2 delas. A paciente com deficiência na P45O-c11 era normotensa, com acne severa e moderadamente hirsuta, sem outros sinais de virilizaçao. Esta paciente apresentou níveis moderadamente elevados de 17-hidroxiprogesterona em resposta ao ACTH e o diagnóstico foi confirmado pela resposta aumentada do 11 deoxi-cortisol ao estímulo corticotrófico. Na amostra estudada de 122 pacientes hirsutas, a prevalência encontrada para a HAC-NC por deficiência da P45O-c21 foi de 7,4 por cento.

Enzimología de la biosíntesis de aldosterona: una revisión / Enzymology of the biosynthesis of aldosterone: a review

La última etapa de la biosíntesis de aldosterona (ALDO) involucra la oxidación mitocondrial de 11-desoxicorticosterona (DOC), a través de varios caminos, que comienzan en sus metabolicos corticosterona (B) y 18-hidroxi-11-desoxicorticosterona (18OHDOC). Todas las reacciones de estos caminos son catalizadas por enzimas de la familia de los citocromos P450. El número y la identidad de cada una de ellas han sido objeto de investigaciones en los últimos treinta años. El modelo, actualmente en vigencia, postula que en la adrenal de la vaca todas las reacciones que llevan desde DOC a ALDO son catalizadas por un único citocromo P450-11ß/18 hidroxilasa/aldosintetasa, presente en toda la corteza adrenal. En cambio, en la adrenal de rata, ratón y humano, la catálisis total es llevada a cabo por el citocromo P450 CYP11B2 sólo presente en la zona glomerulosa, mientras que en la zona fasciculata existe el citocromo P450 CYP11B1, que sólo cataliza la transformación de DOC en B o en 18 OH-DOC. Este modelo, avalado por experimentos de bioquímica celular y molecular, no explica, sin embargo, algunos hechos experimentales

Critérios diagnósticos das formas näo-clássicas de hiperplasia adrenal congênita / Diagnostic criteria of non-classic forms of congenital adrenal hyperplasia

A hiperplasia adrenal congênita (HAC) resulta de deficiência herdada em uma das várias enzimas necessárias para a síntese do cortisol. Deficiência na produçao de cortisol é comum a todas as formas de HAC, em decorrência da deficiência enzimática. Devido à existência de um mecanismo de feedback negativo entre a hipófise anterior e a supra-renal, ocorre aumento da secreçao de ACTH. Dependendo da severidade da deficicência enzimática, a concentraçao sérica de cortisol pode ou nao ser normalizada; porém sempre acompanhado de elevaçao dos esteróides precursores, resultando, nas formas clássicas de HAC, de alteraçoes bioquímicas e fenotípicas. O grau do bloqueio determina qual precursor estará elevado, enquanto que a severidade da deficiência enzimática determinará a extensao do comprometimento clínico. A forma nao-clássica da HAC diferencia-se da forma clássica pelo fato de os indivíduos afetados manifestarem sinais e sintomas de excesso androgênico tardiamente, ma infância ou adolescência, através de um espectro clínico variável, como pubarca precoce, acne, hirsutismo, distúrbio menstrual e infertilidade, podendo até mesmo nao manifestar sintomas, na chamada forma críptica da doença. O diagnóstico da forma nao-clássica de HAC, em geral, nao pode ser feito levando-se em consideraçao apenas a concentraçao basal dos hormônios esteróides, uma vez que estes podem se encontrar normais ou em concentraçao similar à das demais síndromes hiperandrogênicas. A dosagem dos hormônios esteróides após estímulo com ACTH sintético é o método que se impoe para o diagnóstico. Entretanto, os critérios diagnósticos ainda nao se encontram estabelecidos.

Circulating cortisol & related steroids following ketoconazole challenge in Cushing's disease.

Circulating levels of cortisol, 17 alpha hydroxy progesterone and delta 4 androstenedione were analysed by specific radioimmunoassays in 11 patients with Cushing's disease before and at 2, 4, 6, 12 and 24# h following an oral dose of 400 mg ketoconazole. A significant fall in cortisol (26 - 79.6%, 59.8 +/- 18.7 SEM), delta 4 androstenedione (21.5 - 63.3%, 47.8 +/- 4.87) with a concomitant rise in 17 alpha hydroxy progesterone (113 - 218%, 116 +/- 11.43) were noted, suggesting inhibition of 17, 20 desmolase and 11 beta-hydroxylase enzymes in cortisol biosynthetic pathway.