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.

Consideraciones en el manejo del adulto con Hiperplasia Suprarrenal congénita clásica por déficit de 21-Hidroxilasa / Management considerations for the adult with congenital adrenal hyperplasia due 21-hydroxylase deficiency

La Hiperplasia Suprarrenal Congénita (HSRC) corresponde a un grupo de defectos genéticos en la síntesis de cortisol. El 95% de ellas son debidas al déficit de 21-hidroxilasa por lo que nos referiremos solo a esta deficiencia. La hiperplasia suprarrenal congénita clásica (HSRC-C) debuta en recién nacidos o lactantes con insuficiencia suprarrenal primaria, diferentes grados de hiperandrogenismo clínico en mujeres y puede coexistir con hipotensión, hiperkalemia e hiponatremia si hay un déficit clínico de aldosterona. El objetivo de este artículo es actualizar el conocimiento y enfoques sugeridos para el manejo de la HSRC-C desde el inicio de sus controles en la etapa adulta. El diagnóstico diferencial en retrospectiva de la HSRC-C y la no clásica (HSRC-NC) a veces resulta difícil ya que esta enfermedad es un espectro fenotípico continuo. La insuficiencia suprarrenal y la dependencia a terapia corticoidal son los eventos principales para diferenciar estas dos patologías que tienen enfoques terapéuticos diferentes. El tratamiento de la HSRC-C en adultos abarca 2 objetivos primarios: la adecuada sustitución de la falla suprarrenal y el control de hiperandrogenismo mediante el uso de corticoides en sus dosis mínimas efectivas. En la mujer existen terapias complementarias para el control del hiperandrogenismo como anticonceptivos y otras que se encuentran en diferentes fases de investigación. Esto permite disminuir las dosis de corticoides en algunos casos. Es importante a la vez abordar tres objetivos secundarios: controlar el riesgo cardiometabólico propio de la enfermedad, evitar el sobre tratamiento corticoidal y manejar la infertilidad. La correcta monitorización del tratamiento en adultos tomando en cuenta los objetivos descritos permite una mejor calidad de vida en estos pacientes. Finalmente el consejo genético debe realizarse en todos los pacientes con HSRC que deseen fertilidad y en sus parejas. El estudio requiere de secuenciación del gen CYP21A2 y debe realizarse en un laboratorio de experiencia.

Congenital Adrenal Hyperplasia (CAH) are a group of genetic defects characterized by impaired cortisol synthesis. 95% of them are due to 21-hydroxylase deficiency. We will discuss only this enzyme's deficiency. Classic congenital adrenal hyperplasia (CAH-C) debuts in newborns or infants with primary adrenal insufficiency, some degree of clinical hyperandrogenism in newborn females, and can coexist with hypotension, hyperkalemia, and hyponatremia if there is a clinical aldosterone deficiency. The objective of this article is to update the knowledge and suggested approaches for the management of CAH-C from the beginning of its controls in the adult stage. The retrospective differential diagnosis of CAH-C and non-classical (CAH-NC) is sometimes difficult because this disease is a continuous phenotypic spectrum. Adrenal insufficiency and dependence on corticosteroid therapy are the main events to differentiate these two pathologies that have different therapeutic approaches. In adults, the treatment of CAH-C must include 2 primary objectives: adequate the replacement of adrenal failure and control of hyperandrogenism, through the use of corticosteroids in their minimum effective doses. In women there are complementary therapies for the control of hyperandrogenism, such as contraceptives and others that are in different phases of research. This makes it possible to reduce the doses of corticosteroids in some cases. It is important at the same time to address three secondary objectives: control the cardiometabolic risk of the disease secondary to corticosteroid treatment, avoid corticosteroid overtreatment and manage infertility. The correct monitoring of treatment in adults and taking in to account the objectives described, allows a better quality of life in these patients. Finally, genetic counseling must be carried out in all patients planning for children, with any type of CAH and in their partners. The study requires sequencing of the CYP21A2 gene and must be performed in a certified laboratory.

Clinical and research progress of congenital adrenal hyperplasia with adrenal rest tumor / 中华内分泌代谢杂志

Adrenal rest tumor ( ART ) is a well-known complication in congenital adrenal hyperplasia (CAH),which may occur in all age groups, especially in adolescence and adulthood. Tumors that occur in the testicular known as testicularadrenal rest tumor ( TART ) , in the ovarian and parovarian tissue known as ovarian adrenal rest tumor ( OART) . ART is one of the major causes of reproductive dysfunction in adult with CAH. Early prevention and treatment is the key to avoid irreversible damage to gonadal function. In the past, we paid more attention to TART in children, while ignored TART and OART in adults. This article will review the origin of tumor cells, pathogenesis, epidemiology, diagnosis, treatment and prognosis of CAH associated with ART, which aims to guide clinical work through the profound understanding of CAH with ART.

Clinical and research progress of congenital adrenal hyperplasia with adrenal rest tumor / 中华内分泌代谢杂志

Adrenal rest tumor (ART) is a well-known complication in congenital adrenal hyperplasia (CAH), which may occur in all age groups, especially in adolescence and adulthood. Tumors that occur in the testicular known as testicularadrenal rest tumor (TART), in the ovarian and parovarian tissue known as ovarian adrenal rest tumor (OART). ART is one of the major causes of reproductive dysfunction in adult with CAH. Early prevention and treatment is the key to avoid irreversible damage to gonadal function. In the past, we paid more attention to TART in children, while ignored TART and OART in adults. This article will review the origin of tumor cells, pathogenesis, epidemiology, diagnosis, treatment and prognosis of CAH associated with ART, which aims to guide clinical work through the profound understanding of CAH with ART.

Hiperplasia adrenal congénita en forma clásica virilizante simple / Congenital adrenal hyperplasia in simple classical virilizing form

El déficit de 21-hidroxilasa es la forma más frecuente de hiperplasia adrenal congénita, que forma parte de los desórdenes de la diferenciación sexual. Se presentan 3 casos. El primero, un recién nacido de 19 días que es llevado a consulta por presentar desórdenes de los genitales externos. Al examen físico presentaba un clítoris aumentado de tamaño, con orificio uretral en su base y engrosamiento de los rodetes labioescrotales. El diagnóstico se realizó por ultrasonido ginecológico, cromatina sexual, estudios hormonales y cariotipo. El segundo caso, un recién nacido de 15 días que también es llevado a consulta por desórdenes de los genitales externos, con examen físico similar al primer caso, y se le realizaron los mismos complementarios para su diagnóstico. El tercer caso, un lactante de 2 meses de edad, que es llevado a consulta por igual motivo, y que al examen físico se encontró hiperplasia del clítoris, con orificio en su base, y engrosamiento de los labios mayores que estaban fusionados en la línea media. Se le indicaron iguales complementarios. Se diagnosticó en los 3 casos una hiperplasia adrenal virilizante, y se realizó tratamiento sustitutivo hormonal y cirugía reconstructiva de los genitales externos.

Steroid 21-hydroxylase is the most frequent form of congenital adrenal hyperplasia that is part of the sexual differentiation disorders. This article reported 3 cases. The first one was a 19 days-old infant who was taken to the doctor´s because of external genitalia disorders. The physical exam revealed augmented clitoris with urethral orifice in its basis and thickening of the labioscrotal swellings. The patient was diagnosed by means of gynecological ultrasound, sexual chromatin, hormonal studies and karyotype. The second case was a 15 days-old newborn, who was also taken to the doctor´s for external genitalia disorders. The physical exam was similar to that of the first case and the same complementary tests were performed for diagnosis. The third case was a 2 months-old infant who was taken to the medical service for the same reasons, and his physical exam showed clitoris hyperplasia, orifice in its base and thickening of labia majora that fused in the midline. The same complementary tests were indicated. The final diagnosis in these three cases was virilizing adrenal hyperplasia. They were all treated with hormone replacement therapy and reconstructive surgery of their external genitalia.

Final height in congenital adrenal hyperplasia: the dilemma of hypercortisolism versus hyperandrogenism / Altura final na hiperplasia suprarrenal congênita: o dilema do hipercortisolismo versus hiperandrogenismo

OBJECTIVE: The purpose of this study was to identify factors that might interfere with reaching the final height in patients with 21-hydroxylase deficiency (21-OHD). SUBJECTS AND METHODS: Thirty-one patients with classical 21-OHD who reached their FH in our Institution were eva­luated in order to compare the Z score for final height (FHZ) with: (1) the target height, (2) the standard height for the population, and (3) the hydrocortisone treatment schedule. RESULTS: The FHZ of -2.13 ± 1.11 had a significant negative correlation with the hydrocortisone doses used throughout the period of study. Patients who reached FH within the normal population range were those who received lower doses of hydrocortisone, as compared to those whose FH remained below -2 SDS. CONCLUSION: We conclude that careful treatment adjustments have a major influence on growth of children with CAH, and that the dose range for hydrocortisone replacement that does not lead to side effects is relatively narrow. The better height outcome was achieved in 21-OHD patients who received lower doses of hydrocortisone.

OBJETIVO: O objetivo do estudo foi a identificação de fatores que podem interferir na aquisição de altura final de pacientes com a deficiência de 21-hidroxilase (21OHD). SUJEITOS E MÉTODOS: A altura final (escore Z: FHZ) de 31 pacientes com a forma clássica da 21OHD, acompanhados em nossa instituição, foi comparada com: (1) a altura alvo, (2) o padrão de referência para a população, e (3) a dose de hidrocortisona durante o acompanhamento. RESULTADOS: Observou-se correlação negativa significativa entre o FHZ de -2,13 ± 1,11 e as doses de hidrocortisona utilizadas durante o período de estudo. Os pacientes que atingiram altura final dentro do padrão de referência para a população usaram doses mais baixas de hidrocortisona quando comparados àqueles que permaneceram abaixo de -2 DP. CONCLUSÃO: O cuidado nos ajustes das doses durante o tratamento da 21OHD tem grande influência sobre o crescimento das crianças. A faixa de variação da dose de reposição da hidrocortisona que não causa efeitos colaterais é relativamente estreita. O melhor resultado estatural foi observado nos pacientes com 21OHD tratados com doses mais baixas de hidrocortisona.

Pregnancy outcomes of eight pregnant women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency / 中华妇产科杂志

ObjectiveTo investigate the clinical features and pregnant outcomes of the pregnant women with congenital adrenal hyperplasia (CAH) 21-hydroxylase deficiency (21-OHD).MethodsThe clinical features,therapies,pregnant outcomes of the pregnant women with 21-OHD were retrospectively reviewed in Peking Union Medical College Hospital,from January 2005 to April 2011.ResultsThere were 8 pregnant womenwith 21-OHD including 5siinplevirilizing patientsand 3nonclassical 21-OHD women.Eightpatientswereacceptedprogestationalandprenatalcontinuallowerglucocorticoid treatment.During the gestational period,the dosage of glucocorticoid was adjusted in one pregnancy.The serum level of 17-alpha hydroxyprogesterone (17-OHP) were elevated after pregnancy [ (70 ± 38 ) versus (24 ±23) nmol/L,P ＜ 0.05].The fertility and offspring rate of 8 patients was 8/12,the fertility and offspring rate of patients who started treatment at preadolescence was significantly increased (4/5 versus 4/7).Four patients were accepted genital reconstructive surgery ( clitorectomy,clitoroplasty,vulvoplasty) before pregnancy.The incidence of GDM was 1/8.All patients selected caesarean at from 37 +6 gestation weeks to 39+6 gestation weeks.The average newborn birth weight was (3210 ± 447 ) g,and height was (48 ±2) cm of 8 neonates,none of them was CAH.Conclusions Medical and surgical therapy provides satisfactory fertility and pregnancy outcomes for women with 21-OHD.It is safe to pregnant women with 21-OHD and their fetus in continual lower glucocorticoid treatment.The dosage of glucocorticoid should be carefully adjusted during the pregnancy individually according to serum level of 17-OHP.

Establishment of an assay for detection of gene mutation in congenital adrenal hyperplasia / 中华检验医学杂志

Objective To establish a method of gene mutation detection for congenital adrenal hyperplasia (CAH) by using sequencing, single nucleotide polymorphisms (SNP) analysis and T-A cloning. Methods The blood samples of 33 patients with 21-hydroxylase deficiency (21-OHD) , 2 patients with 17α-hydroxylase deficiency (17-OHD) , the parents of all the patients and 105 healthy children were collected. Genomic DNA were extracted form the blood samples. To detect the gene mutation of CYP21A2,highly specific primers for CYP21A2 gene were designed according to the sequence differences between CYP21A2 gene and its pseudogene. The whole CYP21A2 gene was amplified and sequenced. SNP analysis and TA cloning of PCR products were also carried out. The molecular diagnosis of 17-OHD was based on the amplification and sequencing of CYP17A1 gene. Results The corresponding gene mutations was determined in all the patients based on the method established in this study. Thirteen mutations of CYP21A2 gene were identified in 33 patients with 21-OHD. The 3 most frequent mutation of CYP21A2 gene were IVS2-13A/C >G, p. I172N and chimeric mutation, which accounted for 32% (21/66) ,27% (18/66) and 15% (10/66) respectively. Ninety-one persent mutations of CYP21A2 gene resulted from pseudogene conversion. In 2 patients with 17-OHD, homozygous mutations of CYP17A1 gene, IVS4-6A > G and p. 487_489del were identified separately. All the gene mutations detected in the patients were inherited from their parents. No mutation of CYP21A2 gene or CYP17A1 gene was found in the healthy children. Conclusion A method of gene mutation detection for CAH has been established. It will be beneficial to clinical diagnosis of CAH.

Estudo da proteína P450 óxido-redutase e dos citocromos hepáticos 2C19 e 3A4 como possíveis moduladores do fenótipo da deficiência da 21-hidroxilase / Study of P450 oxidoreductase protein and hepatic cytochromes 2C19 and 3A4 as a potential modulatory factors in 21-hydroxylase deficiency phenotype

A deficiência da 21-hidroxilase é uma doença genética comum, causada por mutações no gene CYP21A2, que codifica a enzima 21-hidroxilase (P450c21). A deficiência da 21-hidroxilase afeta a síntese de cortisol e aldosterona e promove acúmulo de precursores, que são desviados para a síntese de andrógenos. Observa-se três principais fenótipos: a forma clássica virilizante simples (VS), na qual as meninas nascem com virilização da genitália externa e ambos os sexos apresentam virilização pós-natal; a forma perdedora de sal (PS), na qual além da virilização, ambos os sexos apresentam crise de perda de sal no período neonatal; e a forma não clássica (NC), na qual os sintomas de hiperandrogenismo iniciam-se mais tardiamente, na infância, adolescência ou idade adulta. Os estudos in vitro das mutações do CYP21A2 demonstram que existe uma boa correlação do grau de comprometimento da atividade enzimática conferido pelo genótipo com o fenótipo. Entretanto, existem algumas divergências como: pacientes que apresentam quadro clínico e hormonal de forma não clássica, nos quais mutações não são identificadas em um ou em ambos os alelos do CYP21A2, e pacientes que apresentam o fenótipo mais leve do que o predito pelo genótipo. Essas divergências sugerem a presença de fatores moduladores do fenótipo na deficiência da 21-hidroxilase. A primeira hipótese foi de que houvesse mutações no gene P450 óxido-redutase (POR), que codifica uma flavoproteína que doa elétrons para as enzimas microssomais P450, inclusive a P450c21, passo fundamental para a atividade enzimática das mesmas. A segunda hipótese foi de que outras enzimas P450, que não a P450c21, tivessem a capacidade de realizar a 21-hidroxilação extra-adrenal da progesterona e 17OH-progesterona (17OHP), sendo então capazes de modular o fenótipo da perda de sal e/ou virilização. Os citocromos P450 hepáticos CYP2C19 e CYP3A4, responsáveis pelo metabolismo de drogas, são capazes de realizar 21-hidroxilação da progesterona...

Adrenal 21-hydroxylase deficiency is a common genetic disorder, caused by mutations in the CYP21A2 gene, which encodes the 21-hydroxylase P450c21. The 21-hydroxylase deficiency disrupts cortisol and aldosterone biosynthesis and leads to accumulation of androgen precursors. There are 3 main phenotypes: the simple virilizing (SV) form, in which girls present with virilized external genitalia at birth and both sexes present with precocious pseudopuberty; the salt wasting (SW) form, characterized by additional salt-wasting crisis in the neonatal period in both sexes; and the nonclassic (NC) form, in which the hyperandrogenic signs occur later in life, during childhood, adolescence or adulthood. In vitro studies show a good correlation between the degree of enzymatic impairment determined by genotype and phenotype. However, there are some discrepancies as: patients with clinical and hormonal profiles of nonclassic form in whom mutations are not found in one or both alleles, and patients with milder phenotype than the ones predicted by genotyping. These discrepancies suggest the existence of modulatory factors in 21- hydroxylase deficiency phenotype. The first hypothesis was that there were mutations in P450 oxidoreductase (POR), a gene which encodes a flavoprotein that donates electrons for all microsomal P450s, including P450c21, an essential step for P450s activity. The second hypothesis was that other enzymes that not P450c21 could perform extra-adrenal 21-hydroxylation of progesterone and 17OHprogesterone (17OHP), modulating salt balance and virilization. Hepatic drugmetabolizing P450 enzymes CYP2C19 and CYP3A4 can 21-hydroxylate progesterone; however, this activity was never compared to 21-hydroxylation performed by P450c21, in order to determine the importance of this extra-adrenal activity in vivo. The present cohort consisted of 11 patients with nonclassic form and incomplete genotype and 6 patients with genotype/phenotype discrepancies...

A case of congenital adrenal hyperplasia presenting as adrenal incidentaloma / 대한내과학회지

Congenital adrenal hyperplasia, an autosomal recessive disorder resulting from an enzymatic defect during cortisol biosynthesis (i.e., 21-hydroxylase deficiency), is characterized by impaired production of cortisol with or without impaired production of aldosterone, chronic stimulation of the adrenal cortex by corticotropin, and overproduction of cortisol precursors and androgens. The severity of the hormonal abnormalities and clinical symptoms depend on the degree of enzymatic activity. Phenotypes are classified into the following types: the severe salt-wasting type, the simple virilizing type, and the non-classic type. Despite adequate treatment, patients may be at risk for salt-wasting adrenal crisis, precocious puberty, short stature, infertility, psychosocial problems, and tumor formation, including adrenal incidentaloma. Here we present a case of adrenal incidentaloma in a 14-year-old boy who was eventually diagnosed with congenital adrenal hyperplasia due to a 21-hydroxylase deficiency. The patient had a history of salt-wasting adrenal crisis, but survived without continuous glucocorticoid and mineralocorticoid treatment. Note also that both plasma aldosterone and plasma renin activity were elevated in this case.

Avaliação do crescimento, do controle laboratorial e da corticoterapia em um grupo de pacientes com a forma clássica da deficiência da 21-hidroxilase / Evaluation of growth, laboratorial control and corticotherapy in a sample of patients with the classical form of 21-hydroxylase deficiency

OBJETIVO: Avaliar o padrão de crescimento de pacientes com hiperplasia adrenal congênita com a forma clássica da deficiência da 21-hidroxilase (21-OH), em relação ao controle hormonal e ao uso de corticóide no tratamento. MÉTODOS: Análise retrospectiva dos prontuários de 45 pacientes. Como padrão de crescimento, foi utilizado o ganho ou não de altura, avaliando-se a diferença entre o escore Z da estatura na última consulta (para idade óssea) em relação ao escore Z da estatura no início do tratamento (para a idade cronológica). Foram avaliadas todas as concentrações de 17-OH progesterona (17-OHP), androstenediona e renina, sendo considerados bem controlados os pacientes com 50 por cento ou mais das dosagens normais. Em relação ao corticóide, foram analisados o tipo e a dose. RESULTADOS: A idade na última consulta variou de 2,8 a 26,6 anos (12,6+5,8 anos), sendo 31 do sexo feminino, 30 com a forma perdedora de sal; 62 por cento foram considerados bem controlados para 17-OHP, 75 por cento para androstenediona e 78 por cento para renina. A hidrocortisona foi usada por 41 pacientes (20,2+2,6 mg/m²/dia) e, por 40, em associação com a 9a-fludrocortisona. Encontrou-se 14 pacientes com ganho, 20 com manutenção e 11 com perda estatural. Os pacientes perdedores de sal (p=0,01) e os bem controlados (p=0,0005) para 17-OHP e androstenediona apresentaram associação significativa com o ganho de estatura. CONCLUSÕES: Nesta amostra de pacientes com a forma clássica da deficiência da 21-OHD, o melhor crescimento apresentou associação com o bom controle laboratorial da 17-OHP e da androstenediona e com a forma perdedora de sal.

OBJECTIVE: To verify the growth pattern of patients with congenital adrenal hyperplasia (CAH) due to classical 21hydroxylase (21-OH) deficiency in relation to hormonal control and use of corticoid during the treatment. METHODS: Retrospective analysis of data from 45 patients. The growth pattern was analyzed according to height gain or not, using the difference between height Z score (for bone age) at the last visit in relation to the height Z score (for chronological age) in the first visit. Concentrations of 17-OH progesterone (17-OHP), androstenedione and rennin were evaluated, and the patients were considered well-controlled when 50 percent or more of the dosages were normal. Corticoid therapy was analyzed according to type and dose. RESULTS: The age at last visit ranged from 2.8 to 26.6 years (12.6+5.8 years), 31 were females, 30 with salt wasting form; 62 percent were considered well-controlled for 17-OHP, 75 percent for androstenedione and 78 percent for renin. Hidrocortisone was used in 41 patients (20.2+2.6 mg/m²/day) and 40 in association with 9a-fludrocortisone. There were 14 patients with height gain, 20 with maintenance and 11 with loss. Height gain was associated with salt wasting patients (p=0.01) and with patients well-controlled for 17OHP (p=0,0005) and androstenedione (p=0,02). CONCLUSIONS: In this sample of patients with CAH due to classical 21-OH deficiency, better height gain was associated with a good control of 17-OHP and androstenedione and with salt wasting clinical form of the disease.

Hiperplasia adrenal congênita por deficiência da 21-hidroxilase, forma clássica: estudo da freqüência em famílias de indivíduos afetados / Congenital adrenal hyperplasia due to 21-hydroxylase deficiency, classic form: frequency evaluation of families with affected patients

OBJETIVOS: Analisar a freqüência de indivíduos afetados e das formas clínicas da doença, de acordo com o gênero e a taxa de consangüinidade, em famílias com hiperplasia adrenal congênita (HAC) por deficiência da enzima 21-hidroxilase, forma clássica (HAC-D21-OHC). MÉTODOS: A casuística foi composta por 58 famílias com 79 indivíduos afetados (67 vivos e 12 mortos) com pais normais e pelo menos um filho afetado vivo com diagnóstico comprovado da doença. A freqüência de indivíduos afetados foi avaliada pelas técnicas de Haldane e Hogben, com análise por seleção truncada. Também foram avaliadas a história parental de consangüinidade e a freqüência de homozigose de mutações no gene CYP21A2, bem como a forma clínica da doença e a distribuição por gênero. RESULTADOS: Dez famílias apresentaram história de consangüinidade entre os pais e mais cinco com homozigose no estudo molecular. A freqüência de indivíduos afetados nas irmandades avaliadas foi de 23,5 por cento, semelhante à esperada de 25 por cento; no entanto, com distribuição heterogênea. Quanto às formas clínicas, 56 (70 por cento) eram perdedores de sal (25M:31F) e 23 (30 por cento) virilizantes simples (10M:13F), não sendo observada diferença na distribuição entre os gêneros. CONCLUSÕES: Estes dados confirmam que a HAC-D21-OHC apresenta padrão de herança monogênica autossômica recessiva, com freqüência de 23,5 por cento na irmandade de indivíduos afetados, elevada taxa de consangüinidade e proporção semelhante entre os gêneros, porém com distribuição heterogênea no número de casos nas irmandades e predomínio da forma clínica perdedora de sal.

OBJECTIVE: To analyze the frequency of affected patients, rate of parental consanguinity and clinical forms of the disease, according to sex in families with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, classic form (CAH-21-OHD-C). METHODS: 58 families with 79 patients (67 alive and 12 dead) with non-affected parents and at least one affected live patient with an established diagnosis of the disease by molecular analysis were studied. The frequency of affected siblings was evaluated according to Haldane and Hogben techniques by truncated selection. Data about parental consanguinity, frequency of CYP21A2 homozygosis gene mutation, clinical form of the disease and sex distribution were also evaluated. RESULTS: Ten families had parental history of consanguinity and other five had homozygosis in the molecular analysis. The frequency of affected children in the kindred was 23.5 percent, similar to the 25 percent expected, but the sample showed a heterogeneous distribution. Among the clinical forms, 56 (70 percent) patients had the salt wasting form (25 males and 31 females) and 23 (30 percent) the simple virilizing one (10 males and 13 females) without difference in sex distribution. CONCLUSIONS: These data confirm that CAH-21-OHD-C has an autosomal recessive monogenic inheritance, with a high rate of consanguinity, similar distribution in both sexes, but it has a heterogeneous distribution of cases among the kindred with predominance of the salt wasting form.

Diagnosis and treatment of female pseudohermaphroditism caused by congenital adrenal hyperplasia (report of 4 cases) / 中华泌尿外科杂志

Objective To report the effect of hormone replacement plus orthopedic surgery for 4 patients with female pseudohermaphroditism caused by congenital adrenal hyperplasia. Methods Four patients with female pseudohermaphroditism caused by congenital adrenal hyperplasia were included.On admission their ages were 11,15,14 and 20 years,respectively.The diagnoses were confirmed by medical histories,ultrasonography,serum levels of hormones and chromosome analysis.They all underwent clitoroplasty and vaginoplasty with perineal skin flap. Results After operation the patients received estrogen and progestogen for a short time to adjust the menstrual cycle and hydrocortisone replacement(10 to 20 mg,twice a day) for their lifetime.Normal menstruation and well-developed breasts were observed in all the patients.No constriction occurred in the reconstructed vaginas. Conclusions This disease can be easily misdiagnosed as hypospadias with bilateral cryptorchidism.Therefore,in addition to careful physical examination,the measurement of serum hormones,ultrasonography of the abdomen,and chromosome analysis are necessary.Proper utilization of the perineal skin flap for reconstruction of the clitoris and vagina as well as careful perioperative managements in combination with hormone replacement therapy can greatly contribute to satisfactory results.

Genotype and clinical characteristics of Chinese patients with nonclassical steroid 21-hydroxylase deficiency / 中华内分泌代谢杂志

Objective To investigate the genotype in Chinese patients with nonclassical 21 hydroxylase deficiency (NC 21OHD). Methods Eight patients with NC 21 OHD, 35 patients with classical one and 20 normal controls were studied as followed: CYP21 gene was amplified into fragment 1 (exon1→exon3) and fragment 2 (exon3→exon10) through PCR with specific primers. Second round PCRs were performed using fragment 1 and 2 as template, and PCR products were digested by restrictive endonucleases to analyze mutations by 3% 4% agarose gel electrophoresis. Results (1) The most frequent mutation in 8 cases of Chinese NC 21 OHD was P30L(6/16,37.5%), followed by V281L(4/16,25.0%). NC 21 OHD also carried mutations causing moderate or severe degree of enzymatic compromise, such as i2g (3/16, 18.8%), Q318X and R356W (1/16, 6.3% respectively), and I172N (3/16, 18.8%). (2) In ACTH 1 24 stimulation tests of 8 NC 21 OHD patients, basal 17 OH progesterone level was (23.9?28.4)?g/L and stimulated 17 OH progesterone level was (92.0?83.7)?g/L. (3) Genotype had strong correlation with phenotype in 21 OHD patients. Conclusion (1) As compared with caucasians, the most frequent mutation in Chinese NC 21 OHD is P30L, not V281L. (2) Much more attention should be paid to patients with hyperandrogenism to screen NC 21 OHD.