Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042755 (masculinization)
 2,562 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deficiency of 21-hydroxylase is the most common form of congenital adrenal hyperplasia (CAH-21OH). We determined by allele-specific PCR the frequency of microconversion in the CYP21A2 gene in 50 Brazilian patients with the classical (salt wasting: SW and simple virilizing: SV) forms and nonclassical (NC) form of CAH-21OH and correlated genotype with phenotype. Genotypes were classified into three mutation groups (A, B, and C) based on the amount of enzymatic activity in in vitro studies using adrenal cells. In 94 unrelated alleles, we diagnosed 76% of the affected alleles after screening for 7 microconversions. The most frequent point mutations observed in this series were I172N (19%), V281L (18%), and IVS2,A/C>G,-12 (15%). In the SW form, the most frequent mutation was IVS2,A/C>G,-12 (38%), in the SV form it was I172N (53%), and in the NC form it was V281L (57.7%). We observed a good correlation between genotype and phenotype. Discordance between genotype and phenotype was found in one SV patient with a mild mutation in one of the alleles (R356W/V281L). However, we cannot rule out the presence of an additional mutation in these alleles. We also observed a good correlation of genotype with 17alpha-hydroxyprogesterone, testosterone, and androstenedione levels. The severity of external genitalia virilization correlated with the severity of mutation. In conclusion, the frequencies described in the present study did not differ from worldwide studies, including the Brazilian population. The few differences observed may reflect individual sample variations. This new Brazilian cohort study suggests the presence of new mutations in Brazilian patients with different forms of CAH-21OH.
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PMID:Phenotype and genotype correlation of the microconversion from the CYP21A1P to the CYP21A2 gene in congenital adrenal hyperplasia. 1450 62

Congenital adrenal hyperplasia (CAH) refers to a family of inherited disorders of adrenal steroidogenesis in which each disorder is characterized by a specific enzyme deficiency that impairs cortisol production by the adrenal cortex. The enzymes most commonly affected are 21-hydroxylase (21-OH), 11beta-hydroxylase, 3beta-hydroxysteroid dehydrogenase, and less often, 17alpha-hydroxylase/17,20-lyase and cholesterol desmolase. Many of the corresponding genes for the described enzymes have been isolated and characterized, and specific mutations causing CAH have been identified. In classical CAH (simple virilizing and salt wasting forms), androgen excess causes external genital ambiguity in newborn females and progressive postnatal virilization in both sexes. In nonclassical CAH, 21-OHD is partial and occurs with milder symptoms. A deficiency of 11beta-Hydroxylase deficiency results in ambiguous genitalia in the newborn genetic female and androgen excess and hypertension in both males and females. In 3beta-hydroxysteroid deficiency adrenal and gonadal androgen production is deficient resulting in incomplete genital development in genetic males and limited androgen affect in females. Two less frequent causes of CAH 17alpha-Hydroxylase/17,20-lyase and cholesterol desmolase result in external female genitalia in both sexes. Hormonal diagnosis is described for each disorder.
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PMID:Inborn errors of adrenal steroidogenesis. 1465 79

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder mainly caused by defects in the steroid 21-hydroxylase (CYP21) gene. We have experience of molecular analysis of in the CYP21 gene in 85 unrelated CAH families, in Taiwan for ten years. All ten exons of were analyzed by differential polymerase chain reactions (PCR) followed by single-strand conformation polymorphism (SSCP) analysis and the amplification-created restriction site (ACRS) method. More than 90% of the mutations were due to conversion of DNA sequences into its neighboring homologous pseudogene CYP21P. The most frequent mutation found in CAH patients in Taiwan was intron 2 mutation; the others were exons 8, 4 and 3, respectively, decreasing by frequency. Those were single homozygous mutations. In this report, we present two kinds of special mutations in our molecular research. Four families had their babies coming from combined homozygous mutation of both parents, that is due to both intron 2 (nt656) and 8-bp mutation. Eleven families had their babies coming from paternal codon 172 and maternal intron 2 (nt656) compound heterozygous mutations, that is codon 172 pat/int 2 (nt656) mat mutation. These two mutations had clinical manifestation of virilization, that is, enlarged clitoris only, but neither clinical nor laboratory finding of salt-losing. From our study, we found that autosomal recessive disorders such as simple virilizing CAH in our series could result from either combined homozygous mutations or compound heterozygous mutations. Further molecular study will focus on the salt-losing type in order to correlate the genotype/phenotype with this study.
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PMID:Molecular identification of combined homozygous and compound heterozygous mutations in the CYP21 gene in simple virilizing congenital adrenal hyperplasia in Taiwan. 1498 55

Congenital adrenal hyperplasias (CAH) are inherited defects of cortisol biosynthesis. More than 90% of CAH are caused by 21-hydroxylase deficiency (21-OHD), found in 1:10 000 to 1:15 000 live births. Females with 'classical' 21-OHD, being exposed to excess androgens prenatally, are born with virilized external genitalia. Potentially lethal adrenal insufficiency is characteristic of two-thirds to three-quarters of patients with the classical salt wasting (SW) form of 21-OHD. Non-SW 21-OHD may be diagnosed on genital ambiguity in affected females, and/or later on the occurrence of androgen excess in both sexes. Non-classical 21-OHD, detected in > or =1:100 of certain populations, may present as precocious pubarche in children or polycystic ovarian syndrome in young women. 21-OHD is caused by mutations in the CYP21 gene encoding the steroid 21-hydroxylase enzyme. More than 90% of these mutations result from intergenic recombination between CYP21 and the closely linked CYP21P pseudogene. The degree to which each mutation compromises enzymatic activity is strongly correlated with the clinical severity of the disorder. This close association between genotype and phenotype makes it possible to predict clinical outcome in affected subjects. The risk of SW and prenatal virilization can be estimated, and overtreatment can be avoided in mildly affected cases. Glucocorticoid and mineralocorticoid replacement therapies are the mainstays of treatment, but additional therapies are being developed. A first trimester prenatal diagnosis should be proposed in families in whom molecular studies have been performed previously. The state of heterozygotism can be predicted by hormonal testing and confirmed by molecular studies. Prenatal diagnosis by direct mutation detection in previously genotyped families permits prenatal treatment of affected females in order to avoid or minimize genital virilization. Neonatal screening by hormonal methods identifies affected children before SW crises develop, reducing mortality in this disorder.
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PMID:Recent advances in the diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. 1551 16

Congenital adrenal hyperplasia (CAH) is an autosomal recessive condition characterized by an insufficient production of cortisol and mineraloactive hormones with a consequent hyperstimulation of hypothalamo-pituitary-adrenal feedback and an increase of androgens. Although the lack of different enzymes in adrenal steroidogenesis can be responsible for different forms of the disease, the deficiency of 21-hydroxylase is the more frequent defect. It is caused by mutations in CYP21 gene located on the short arm of chromosome 6 and it causes a heterogeneous phenotype characterized by a classical form (genitalia virilization in female, early onset acute adrenal insufficiency with salt wasting, precocious pseudopuberty, signs of hyperandrogenism), or by a simple virilizing form (presence of signs of hyperandrogenism without salt-loosing crises) or by a non-classic form evidenced only by mild to moderate signs of hyperandrogenism. The diagnosis can be made by 17-hydroxyprogesterone measurement in basal and after ACTH stimulation test. Glucocorticoid and mineraloactive therapy have been proved to reduce the risk of adrenal crisis reducing the levels of androgens and controlling the symptoms of the disease.
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PMID:Congenital adrenal hyperplasia. 1556 8

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (CYP21) deficiency causes symptoms ranging from life-threatening neonatal adrenal crises to minimal virilization in adulthood. The relationship between CYP21 genotype and phenotypic markers in a non-screened population of 73 CAH children (44 female, 29 male; 54 white, 19 Asian) treated at the Royal Manchester Children's Hospital was investigated and ethnic and sex differences assessed. The patients were categorized according to the mutation on the mildest allele. The age at the time of diagnosis differed significantly between the groups (p = 0.02): all 25 Null and 25 of 26 of the I2 splice patients were diagnosed during the neonatal period, whereas 7 of 11 I172N patients were diagnosed late. Degree of female genital virilization, 17-hydroxyprogesterone level at diagnosis, and fludrocortisone requirement during the 1st year of treatment correlated with the genotype, although Asian Null patients required more fludrocortisone than their white counterparts (p = 0.055). There was an equal sex ratio in both the I2 splice (12 female/14 male) and I172N (5 female/6 male) groups. However, in the Null group, the ratio was 4.0 (20 female/5 male; p = 0.003), suggesting that some Null male infants perish before being clinically detected to have CYP21 deficiency. Our findings strongly support the need for implementation of a neonatal screening programme for CAH in the UK which may reduce the male infant mortality.
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PMID:Female preponderance in congenital adrenal hyperplasia due to CYP21 deficiency in England: implications for neonatal screening. 1562 80

We report on a male twin infant who presented with brachy-turri-cephaly, frontal bossing, large anterior fontanelle, low set and malformed ears, and mild arachnodactyly. He had normal male genitalia. There was no evidence for maternal virilization during pregnancy. The pattern of malformations resembled Antley-Bixler-Syndrome (ABS). However, sequencing analysis of the fibroblast growth factor receptor 2 gene (FGFR2) did not reveal mutations. The boy's twin sister did not show any somatic or endocrine abnormalities. In the boy, neonatal screening for congenital adrenal hyperplasia was positive with moderately elevated 17-hydroxyprogesterone. Sequence analysis of his CYP21 gene did not reveal any mutations. The short synacthen test revealed an exaggerated 17-hydroxyprogesterone and a blunted cortisol response. Urinary steroid profiling by gas chromatography-mass spectrometry (GC-MS) revealed a unique steroid metabolome suggestive of impaired activity of both 17-hydroxylase and 21-hydroxylase. Clinical and metabolic findings therefore were compatible with the recently described variant of congenital adrenal hyperplasia, P450 oxidoreductase deficiency (ORD). Subsequently, sequencing analysis of CPR, the gene encoding P450 oxidoreductase (OR), revealed a homozygous mutation in the patient, resulting in an amino acid exchange in position 284 of the OR protein (A284P). Both the female twin sister and the parents were heterozygous for the A284P mutation. P450 oxidoreductase deficiency represents a novel autosomal recessively inherited form of congenital adrenal hyperplasia. Its characteristic steroid metabolome can readily be detected by GC-MS analysis of spot urine. Clinical features may include an ABS phenotype, ambiguous genitalia (virilization in girls, feminization in boys), and glucocorticoid deficiency. If required, hydrocortisone replacement should be provided.
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PMID:A male twin infant with skull deformity and elevated neonatal 17-hydroxyprogesterone: a prismatic case of P450 oxidoreductase deficiency. 1566 53

Malformations surveillance programs of newborn infants have been developed as a method for identifying serious and relatively common birth defects. The virilization of newborn infants with the classic 21-hydroxylase form of congenital adrenal hyperplasia must be identified early if the associated metabolic crisis in the perinatal period is to be prevented. We compared the detection of virilization associated with 21-hydroxylase congenital adrenal hyperplasia in infants by three methods: an 'active' malformations surveillance of medical records at a large urban hospital; routine medical care by examining physicians; and newborn biochemical screening of blood samples. The experience at a large maternity center in Boston, since 1972, showed that pediatricians often recognized affected females (6/6), but not males (0/2); the state newborn screening program, begun in 1990, identified correctly all affected males and females. The Active Malformations Surveillance Program was the least effective screening method, identifying four of six affected females and neither of the affected males. The low rate of detecting affected females by the Surveillance Program was attributed to a failure to sensitize the research assistants to the importance of physicians' notations regarding the signs and symptoms of virilization. The failure of examining physicians, and thereby, the malformations surveillance program, to detect virilized newborn males was due to the lack of consistent associated physical features. These comparisons between these three methods of detection can be used to design and improve malformations surveillance programs.
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PMID:Evaluating the accuracy of Malformations Surveillance Program in detecting virilization due to congenital adrenal hyperplasia. 1573 23

Congenital adrenal hyperplasia due to deficiency of the enzyme 21-hydroxylase (21-OH), a cytochrome P450 enzyme located in the endoplasmic reticulum and which catalyzes the conversion of 17-hydroxyprogesterone to 11-deoxycortisol and progestene to deoxycorticosterone, is distinguished in its classical and non-classical form and is also one of the most common autosomal recessive inherited diseases in humans. The classical form appears in a rate between 1:5000 and 1:15,000 among the live neonates of North America and Europe, while the non-classical form occurs in approximately 0.2% of the general white population. This rate is especially high between the Ahskenazi Jews and a part (ie Italians, Hispanics) of the Mediterranean populations. Three alleles are associated with the 21-OH locus and can be combined in several ways in individuals who are either unaffected, heterozygote carriers, or affected with classical or non-classical disease. Variable signs and symptoms of hyperandrogenism, such as hirsutism, acne, virilization of the external genitalia and/or the body, short stature, menstrual irregularities, are common to both types of the disorder. Among the genes responsible for the synthesis of the enzyme 21-OH and the antigens of HLA system, exist both a proven genetic linkage and a proven genetic linkage disequilibrium. HLA-Bw47, HLAB5 and HLA-B35 are the most common haplotypes usually met in the classical form, while the haplotype HLA-B14DR1 is the most recurrent in the non-classical form of the disease. The significant advances in molecular biology and gene analysis over the past two decades have led to the development of novel sensitive methods of DNA analysis and study, such as polymerase chain reaction and southern blot analysis. Thus, it has been revealed that the synthesis of enzyme 21-OH is controlled by two genes, the active CYP21B gene and the CYP21A pseudogene. All three forms of the disease have a known sequence of gene changes owing to mutations in isolated proteins or whole series of genes due to translocations or deletions of genetic material.
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PMID:21-Hydroxylase deficiency: from molecular genetics to clinical presentation. 1588 69

Congenital adrenal hyperplasia (CAH) is a family of autosomal recessive disorders caused by mutations in genes encoding the enzymes involved in one of the various steps of adrenal steroid synthesis. Steroid 21-hydroxylase deficiency (21-OHD) is responsible for over 95% of the 5 forms of CAH, and results due to enzymatic defect owing to mutation in the CYP21 gene. The disease has two major clinical presentations. The "classical" form is severe, and divided into a salt wasting (SW) and simple virilizing (SV) subgroups. In both, affected female fetuses undergo virilization of the external genitalia prenatally and present at birth with sexual ambiguity. In addition, in both sexes infants with SW CAH are at risk of life-threatening adrenal crisis without treatment. This is why it is so important to make a diagnosis and to counsel the families. The diagnosis is easy by measuring the plasma levels of 17-hydroxyprogesterone (17-OHP) in antenatal (amniotic fluid), or perinatal samples (peripheral blood). Confirmation by molecular genetic analysis is advised. The second form of 21-OHD is called "non classical" because the presentation is much less severe and the onset of clinical expression occurs long after birth, often in the peripubertal period, as non-specific symptoms of hyperandrogeny. The unambiguous diagnosis of the latter requires a simple short ACTH test, with the measurement of 17-OHP at 60 min. In both forms, the mutations on the gene CYP21 responsible for the disease are now well known and can be identified by molecular biology techniques. There is a good correlation between phenotypes and genotypes, due to variable amount of the 21-hydroxylase-enzyme activity left (null to 50-60%). SW, SV and NC forms are associated with distinct mutations or combination of mutations. Nowadays, by combining hormonal and molecular tests, it is possible to predict the clinical form of the disease in a given family in the context of a prenatal diagnosis, which can lead to a prenatal treatment. Therefore, 21-OHD genotyping also appears essential for a new approach of genetic counseling, prediction of clinical form after postnatal screening and to define the post-ACTH 17-OHP values indicating the cut-off lines between NC, heterozygote and normal subjects.
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PMID:21-Hydroxylase deficiency: an exemplary model of the contribution of molecular biology in the understanding and management of the disease. 1598 83


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