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)

Congenital adrenal hyperplasia, caused by any one of a number of inborn errors of steroidogenesis in which cortisol is not sufficiently produced by the adrenal cortex, is in most cases due to a deficiency of the enzyme steroid 21-hydroxylase. Classic 21-hydroxylase deficiency occurs in about 1 in 14,000 live births. In classic 21-hydroxylase deficiency, the most common cause of genital ambiguity in females, prenatal exposure to excess androgens results in virilization of the female fetus. Newborn males have normal genitalia. Postnatally, untreated females as well as males present with signs of androgen excess. Three fourths of classic 21-hydroxylase deficiency cases do not effectively synthesize aldosterone and are salt-wasting, a condition that is potentially fatal. An allelic variant of classic 21-hydroxylase deficiency, termed nonclassic 21-hydroxylase deficiency, is associated with a milder enzymatic defect and no genital ambiguity at birth, but postnatal virilization may be seen. The 21-hydroxylase enzyme, a cytochrome P450 hemeprotein (cytochrome P450c21), is encoded by the gene CYP21, which has a closely neighboring homologous pseudogene, CYP21P. Mutations in the CYP21 gene, causing 21-hydroxylase deficiency, are common and occur owing to two mechanisms: gene deletion and apparent gene conversion. Prenatal diagnosis is important to identify a fetus affected with 21-hydroxylase deficiency. Genital ambiguity in affected females can be prevented by proper administration of dexamethasone to the pregnant mother. Postnatally, the treatment of 21-hydroxylase deficiency is lifelong hormonal replacement. With carefully supervised medical treatment, congenital adrenal hyperplasia patients have the capacity for normal puberty and fertility.
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PMID:Steroid 21-hydroxylase deficiency (congenital adrenal hyperplasia). 782 36

Congenital adrenal hyperplasia (CAH) is an inherited metabolic disease caused by the deficiency of one of the enzymes necessary for cortisol synthesis. Deficiency of 21-hydroxylase (21-OH) accounts for 95% of affected patients There are two forms of the disease. The first is classic, which may be incomplete (simple virilizing) or complete (salt wasting). The second is nonclassic, which may be symptomatic or asymptomatic. In classic 21-OH deficiency which occurs in 1:10000-15000 live births, prenatal exposure to excess androgens results in virilisation of female fetus. Newborn males have normal genitalia. Postnatally, untreated females as well as males present with signs of androgen excess. Three fourths of classic 21-OH deficiency cases do not effectively synthesize aldosterone and are salt wasting, a condition that is potentially fatal. Nonclassic 21-OH deficiency, allelic variant of classic 21-OH deficiency is associated with a milder enzymatic defect and no genital ambiguity at birth, but postnatal virilization may be seen. A subset of individuals with nonclassic 21-OH deficiency are asymptomatic, despite high levels of androgens (cryptic form of disease). The 21-OH enzyme, a cytochrome P450 hemoprotein (cytochrome P450 c21) is encoded by the gene CYP21, which has a closely neighboring homologous pseudogene, CYP21P. Mutations in the CYP21 gene, causing 21-OH deficiency, are common and occur owing to two mechanisms: gene deletion and apparent gene conversion. Prenatal diagnosis is important to identify a fetus affected with 21-OH deficiency. Genital ambiguity in affected females can be prevented by proper administration of dexamethasone to pregnant mother. Postnatally, the treatment of 21-OH deficiency is lifelong hormonal replacement. With carefully supervised medical treatment. CAH patients have the capacity for normal puberty and fertility.
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PMID:[Congenital adrenal hyperplasia due to 21-hydroxylase enzyme deficiency]. 875 1

The molecular genetics of congenital adrenal hyperplasia due to 21-hydroxylase deficiency are reviewed. In Sweden, mutation detection based on allele-specific PCR has been used for genetic diagnosis of this disease since 1993. Around 400 affected 21-hydroxylase genes have been analysed so far. An update of the spectrum of mutations among the Swedish patients shows that nine common pseudogene-derived mutations are responsible for the disease in around 95% of alleles. A total of 13 rare, mostly population-specific mutations have been characterized among the remaining 5%. The mutations can be divided into different groups according to severity. This makes it possible to predict clinical outcome in affected subjects based on genotyping. The risk of salt-wasting and prenatal virilization can be estimated, and over-treatment can be avoided in mildly affected cases.
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PMID:Molecular genetics of congenital adrenal hyperplasia (21-hydroxylase deficiency): implications for diagnosis, prognosis and treatment. 951 1

An update on the molecular genetics of congenital adrenal hyperplasia due to 21-hydroxylase deficiency is given. In Sweden, direct mutation detection has been used for genetic diagnosis of this disease since 1990. Around 400 affected 21-hydroxylase genes have been analyzed so far. Mutations that have arisen by interaction with the adjacent pseudogene, including gene deletion and nine smaller sequence aberrations, are responsible for the disease in around 95% of alleles. A total of 13 rare, mostly population-specific mutations have been characterized among the remaining 5%. Some of these rare mutations are present in the pseudogene at a low frequency, indicating that they have started to spread at a low rate in the population. The mutations can be divided into different groups according to severity. This makes it possible to predict clinical outcome in affected subjects based on genotyping. The risk of salt-wasting and prenatal virilization can be estimated, and overtreatment can be avoided in mildly affected cases.
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PMID:An update on the molecular genetics of congenital adrenal hyperplasia: diagnostic and therapeutic aspects. 982 8

More than 90% of cases of congenital adrenal hyperplasia (CAH, the inherited inability to synthesize cortisol) are caused by 21-hydroxylase deficiency. Females with severe, classic 21-hydroxylase deficiency are exposed to excess androgens prenatally and are born with virilized external genitalia. Most patients cannot synthesize sufficient aldosterone to maintain sodium balance and may develop potentially fatal "salt wasting" crises if not treated. The disease is caused by mutations in the CYP21 gene encoding the steroid 21-hydroxylase enzyme. More than 90% of these mutations result from intergenic recombinations between CYP21 and the closely linked CYP21P pseudogene. Approximately 20% are gene deletions due to unequal crossing over during meiosis, whereas the remainder are gene conversions--transfers to CYP21 of deleterious mutations normally present in CYP21P. The degree to which each mutation compromises enzymatic activity is strongly correlated with the clinical severity of the disease in patients carrying it. Prenatal diagnosis by direct mutation detection permits prenatal treatment of affected females to minimize genital virilization. Neonatal screening by hormonal methods identifies affected children before salt wasting crises develop, reducing mortality from this condition. Glucocorticoid and mineralocorticoid replacement are the mainstays of treatment, but more rational dosing and additional therapies are being developed.
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PMID:Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. 1085 54

A case of nonclassic (NC) 21-hydroxylase deficiency, with a moderately elevated 17-hydroxyprogesterone level (145 nmol/L in filter paper blood spot), was detected in newborn screening. The newborn's phenotype was female, with no sign of virilization. Confirmatory diagnosis revealed elevated serum levels of 17-hydroxyprogesterone and of 21-desoxycortisol, whereas cortisol, PRA, and electrolytes were normal. Hydrocortisone substitution was considered at the age of 6 months, when virilization became obvious. For clinical reasons, this case had to be classified as late-onset congenital adrenal hyperplasia (CAH) with unusually early manifestation. However, the diagnosis of classic 21-hydroxylase deficiency was obtained by Southern blotting studies, showing that she was homozygous for the 30-kb deletion, including the 3' end of CYP21P pseudogene, the C4B gene, and the 5' end of the functional CYP21 gene. Further studies, using PCR and sequencing, were conducted to explain the discrepancy between this genotype, usually associated with a classic salt-wasting form, and the girl's phenotype. Typically, patients homozygous for the 30-kb deletion encoding classic CAH possess a unique CYP21P/21 hybrid gene with the junction site located after the third exon, yielding a nonfunctional pseudogene. The girl in question, however, was heterozygous for the 8-bp deletion, suggesting that the chimeric pseudogene on one allele had a junction site before the third exon. She was compound heterozygous for a 30-kb deletion encoding classic CAH on the paternal allele, and a 30-kb deletion encoding NC CAH on the maternal allele. This novel maternal CYP21P/21 hybrid gene is characterized by a junction site before intron 2 and differs from the normal CYP21 gene only by the P30L mutation in exon 1 and the promoter region of the CYP21P pseudogene. Because the P30L mutation has been described to result in an enzyme with 30-60% activity of the normal P450c21 enzyme, and the CYP21P promoter reduced the transcription to 20% of normal, this puzzling phenotype of a NC CAH with early onset may be fully explained by the genotype of the patient and considered as an intermediate form between the simple virilizing and NC form.
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PMID:How a patient homozygous for a 30-kb deletion of the C4-CYP 21 genomic region can have a nonclassic form of 21-hydroxylase deficiency. 1113 9

This study attempted an analysis of the mutational spectrum of 21-hydroxylase deficiency in 79 unrelated Austrian patients with classical and nonclassical forms of congenital adrenal hyperplasia and their respective 112 family members. Apparent large gene deletions/conversions were present in 31% of the 158 unrelated congenital adrenal hyperplasia alleles, whereas the most frequent point mutations were intron 2 splice (22.8%), I172N (15.8%), V281L (12%), and P30L (7.6%), in line with the frequencies reported for other countries. In 5 of the 12 congenital adrenal hyperplasia alleles carrying a P30L mutation the aberration is based on a single base substitution, whereas the remaining 7 represent part of a CYP21B conversion (1 allele) or CYP21B/21A hybrid gene (6 alleles), the latter characterized by a junction site before intron 2 as indicated by Southern blot, PCR, and sequence analyses. Previously described mutations were not present in 1.2% of unrelated congenital adrenal hyperplasia alleles, including one female patient presenting with severe genital virilization. Sequence analysis of the complete functional 21-hydroxylase gene revealed an as yet undescribed mutation in exon 10-Arg(426)His, which has not yet been described to represent a common pseudogene sequence. In vitro expression experiments showed the Arg(426)His mutant to exhibit only low enzyme activity toward the natural substrate 17-hydroxyprogesterone corresponding to the degree of disease manifestation in the patient in whom it was found.
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PMID:Mutational spectrum of the steroid 21-hydroxylase gene in Austria: identification of a novel missense mutation. 1160 May 39

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 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


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