Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (21-OHase) deficiency is inherited as an autosomal recessive trait. Patients can present with the salt wasting, simple virilizing or a non-classical form of the disease. The gene for P450C21, the enzyme carrying 21-OHase activity, has been mapped to the major histocompatibility complex on chromosome 6p. Using molecular hybridisation techniques we have studied the genetic defect in 27 families with one or more affected offspring diagnosed and treated at the University Hospital of Essen. DNA samples were digested with restriction endonuclease TaqI, PvuII, BglII, and EcoRI and analysed by Southern blot hybridisation with the cDNA probe pC21/3c. Eleven of 40 haplotypes associated with the salt wasting form were found to have a large deletion of 30 kb affecting the 5' end of the active 21-OHase gene and the 3' end of the closely linked pseudogene. Results in another 11 cases are compatible with gene conversion; 18 cases were not informative. The 30 kb deletion was associated with a combination of the HLA antigens Bw47 and DR7 in 7 of 11 cases. In the haplotypes with gene conversion, no linkage disequilibrium to HLA antigens was found. No apparent gene alterations were detected in simple virilizing and non-classical haplotypes. The direct detection of the genetic defect in 55% of the salt wasting haplotypes may help to improve predictive testing in families with CAH.
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PMID:Molecular detection of genetic defects in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: a study of 27 families. 136 34

A total of 33 Italian 21-hydroxylase (21-OH) deficiency families were investigated using a combination of short and long range restriction mapping of the CYP21/C4 gene cluster. The analyses revealed that large-scale length polymorphism in this gene cluster strictly conformed to a compound variable number of tandem repeats (VNTR) plus insertion system with between one and four CYP21 + C4 units and seven BssHII restriction fragment length polymorphisms (RFLPs) (75 kb, 80 kb, 105 kb, 110 kb, 135 kb, 140 kb and 180 kb). A total of 9/66 disease haplotypes, but only 1/61 non-disease haplotypes, showed evidence of gene addition by exhibiting three or more CYP21 + C4 repeat units. Of these, two were identified in one 21-OH deficiency patient who has a total of eight CYP21 + C4 units, being homozygous for the HLA haplotype DR2 DQ2 B5 A28. This haplotype carries four CYP21 + C4 units, three of which contain CYP21A-like genes and one of which contains a CYP21B-like gene that presumably carries a pathological point mutation. Of the other gene addition haplotypes associated with 21-OH deficiency, four show three CYP21 + C4 units flanked by HLA-DR1 and HLA-B14 markers. Although such haplotypes have commonly been associated with non-classical 21-OH deficiency, three examples in the present study are unexpectedly found in two salt-wasting patients, who are respectively homozygous or heterozygous for this haplotype. Only 7/66 disease haplotypes showed evidence of a CYP21B gene deletion.
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PMID:CYP21/C4 gene organisation in Italian 21-hydroxylase deficiency families. 155 57

Ninety-nine Caucasian patients with ultrasonically detected polycystic ovaries (PCO) were typed for human leucocyte (HLA) antigens. Fifty patients with congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency were similarly typed. Among the patients with PCO, there was a significant increase in the frequency of HLA DRW6 (P = 0.0027) compared with that found in a control population, which remained significant (P = 0.027) when corrected for the number of antigens tested. This difference was reduced, but remained significant (P = 0.006), when the patients with CAH and PCO were added. There was also a significant decrease in the frequency of HLA DR7 (P = 0.017) among the patients with PCO compared with a control population, but there was no distortion of the frequencies of HLA A, B or Cw antigens. Among the patients with CAH, previously well documented associations of HLA B14 and DR1 with non-classical disease were confirmed. The frequency of HLA Bw47 was increased among the whole group of CAH patients (P = 0.05) but was not increased among those with classical salt-wasting (SW) or simple virilizing (SV) disease. Family studies were performed in close female relatives of 16 of the PCO patients and 21 of the CAH patients but no evidence for genetic linkage between HLA and PCO status could be found. These data suggest that there is no significant component of disturbed adrenal steroid 21-hydroxylase activity to account for the PCO morphology, although there may be some other genetic factor, more proximal to the centromere on chromosome 6, affecting the development of polycystic ovaries.
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PMID:HLA associations in patients with polycystic ovaries and in patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency. 234 91

Prenatal diagnosis of the "classical" forms of congenital adrenal hyperplasia (CAH) which is a result of 21-hydroxylase (21-OH) deficiency either complete, with salt-wasting or incomplete without salt wasting, is performed in two ways: by measuring concentration of 17-hydroxyprogesterone (17-OHP) and androstendione (delta 4) in amniotic fluid and by HLA typing of fetal cells from amniotic fluid. Having ones own normal values is the basic condition for the safe prenatal diagnosis of CAH 21-OH deficiency by measuring steroid concentration in amniotic fluid. Normal concentrations of 17-OHP in amniotic fluid achieved by amniocentesis in 85 pregnant women from 16-23 gestation week have been measured, as well as concentrations of delta 4 in 66 pregnant women in the same period of gestation. It has been proved that there are no differences between the concentrations of delta 4 in amniotic fluid regarding the sex. As far as 17-OHP is concerned, the same was confirmed earlier. The results of 9 prenatal diagnosis in 8 families, having already one child with "classical" form of CAH with salt-wasting, have been presented. It was achieved by combination of two methods: by measuring concentration of 17-OHP and delta 4 in amniotic fluid and HLA typing of fetal cells from amniotic fluid. In 8 fetuses at risk the birth of healthy children was correctly predicted, which was confirmed after the birth in three cases by HLA typing and measuring concentration of 17-OHP and delta 4 and from the blood of newborn babies.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Prenatal diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase enzyme deficiency]. 263 7

During our investigations of polymorphisms at, and in the immediate chromosomal vicinity of, the 21-hydroxylase locus in families with 21-hydroxylase deficiency, three families were found to show marked discordance in clinical features of HLA identical subjects. In one family, there is discordance between a boy with the simple virilising form of 21-hydroxylase deficiency and his two younger sisters, who are both HLA identical to their brother, but who have additional salt wasting features. In the other two families, one subject is severely affected and has very high 17-hydroxyprogesterone levels, but has an HLA identical sib who is asymptomatic and shows only slightly raised 17-hydroxyprogesterone levels. In all cases, HLA identity, as indicated by protein polymorphism studies (HLA-A, B, DR, C4A, C4B, and Bf typing), has been verified at the gene organisation level using 21-hydroxylase and complement C4 DNA probes. An HLA-Bw47 bearing haplotype in one of the latter families has not been transmitted to the affected child and appears to carry a normal 21-OHB allele and two genes which specify C4A allotypes.
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PMID:21-hydroxylase deficiency families with HLA identical affected and unaffected sibs. 278 76

Prenatal treatment with dexamethasone starting with gestation week 5 has been proposed to prevent virilization of female fetuses with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. We report dexamethasone treatment in a mother during her third pregnancy; this treatment could not be started before the 12th week of gestation. The second child (index case) had a simple virilizing 21-hydroxylase deficiency CAH and Prader IV genitalia. Because after amniocentesis a normal female karyotype and HLA identity with the index case were found, the dexamethasone treatment (3 x 0.5 mg/die) was continued until delivery.-In contrast to patients with salt-wasting CAH, the 17-alpha-hydroxyprogesterone level in the amniotic fluid was within the normal range. Decreased maternal plasma and urine estriol concentrations, as well as the plasma cortisol values, demonstrated adequate suppression of the fetal and maternal adrenal gland. No side effects were found in the mother as a result of the dexamethasone treatment. The newborn had virilization of the external genitalia according to Prader III but without hypertrophy of the clitoris. The degree of rugated scrotum was less marked in relation to the index case and the sinus urogenitalis was more distally shifted. Thus, surgery on the clitoris could be avoided. The conditions for further surgery (vaginoplasty) could probably be improved. Therefore, dexamethasone treatment of a mother with a female CAH fetus due to 21-hydroxylase deficiency seems to be justified starting at the 12th week of gestation. However, the optimal beginning of therapy is in early pregnancy.
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PMID:[The effect of maternal dexamethasone treatment after the 12th week of pregnancy on fetal genital development in adrenogenital syndrome with 21-hydroxylase deficiency]. 278 92

21-Hydroxylase deficiency which causes congenital adrenal hyperplasia is one of the most common defects of adrenal steroidogenesis. There are two 21-hydroxylase genes in man, A and B, and these have been mapped to the HLA class III region. Only the 21-hydroxylase B gene is thought to be active. To understand the molecular basis of congenital adrenal hyperplasia in a patient with the salt-wasting form of the disease, we cloned and characterized his single 21-hydroxylase B gene. The nucleotide sequence of this gene and a 21-hydroxylase B gene from a normal individual have been determined. Comparison of the two sequences has revealed 11 nucleotide alterations, of which two are in the 5' flanking region, four are in introns, one is in the 3' untranslated region and four are in exons. Two of the differences in exons cause codon changes, with Ser-269 and Asn-494 in the normal 21-hydroxylase B gene being converted to Thr and Ser, respectively. These amino acid substitutions may give an insight into those residues necessary for 21-hydroxylase enzymatic activity. We have also confirmed that the 21-hydroxylase A gene is a pseudogene due to three deleterious mutations in the exons. In addition, comparison of the 21-hydroxylase B gene sequence with other published sequences indicates that this microsomal cytochrome P-450 may be polymorphic.
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PMID:Molecular characterization of the HLA-linked steroid 21-hydroxylase B gene from an individual with congenital adrenal hyperplasia. 303 28

In order to complete the data on human 21-Hydroxylase deficiency, we present a study on HLA markers in 35 Italian families (14 from Northern, eight from Central and 13 from Southern Italy) with one affected child. Three children from the issue of first cousin marriages were homozygous for the whole HLA haplotype. Extended haplotypes shared by unrelated patients were not found, and a total absence of the HLA Bw47 allele among the haplotypes carrying the disease as well as normal haplotypes was observed. The absence of A1 Cw7 B8 BfS C4AQ0 C4B1 DR3 extended haplotype was instead confirmed. Allele frequencies in the different clinical forms were analyzed: BfSO7 allele frequency was significantly increased on haplotypes of the salt-wasting form (p less than 0.01). We noticed two duplications (C4B1-2) of C4B genes, on haplotypes involved in the disease. Allele distribution in the regions studied showed that Bw22 (w55), Cw3 and DR2 were characteristic of Northern patients, while B15 was found in patients from Central Italy.
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PMID:Italian extended HLA haplotypes in congenital adrenal hyperplasia. 326 15

Defective steroid 21-hydroxylation is the most common of the biochemical defects causing hyperplasia of the adrenal cortex. The genetic mode of transmission of all enzyme abnormalities seen in cortisol biosynthesis is autosomal recessive. Steroid 21-hydroxylase deficiency has three currently accepted forms: the simple virilizing and salt-wasting variants of the classical deficiency, and the nonclassical (attenuated) form, which shows a wide clinical range of effects and whose characterization emerged from co-ordinated hormonal testing and family studies. More recent molecular genetic studies have started to identify specific mutations altering 21-hydroxylase activity. Defects in the other enzymes occur more rarely and are less well known, although initial work with abnormal 11 beta-hydroxylase and 3 beta-hydroxylase indicates that allelic gene defects may be correlated with different clinical phenotypes seen for these disorders also. The gene for the enzyme steroid 21-hydroxylase, a cytochrome P-450, is situated within the major histocompatibility complex on the p arm of human chromosome 6, proximal to the HLA-B antigen locus. Linkage disequilibria between certain B and DR alleles and classical and nonclassical 21-hydroxylase deficiency permit the use of HLA genotyping in conjunction with hormonal evaluation for diagnosis of this disorder and for identification of carrier haplotypes in population studies. Test programs have shown the feasibility of neonatal screening for 21-hydroxylase deficiency by blood-spot hormonal assay for elevated 17-hydroxyprogesterone. Prenatal detection of disease currently depends on HLA serotyping of cultured aminocytes jointly with measurement of amniotic 17-hydroxyprogesterone (13-18 week gestation); molecular genetic techniques with more specific nuclear probes will improve the specificity of this test and will in addition permit even earlier definitive fetal genotyping by chorionic villus biopsy (6-10 week gestation).
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PMID:Basic and clinical aspects of congenital adrenal hyperplasia. 332 May 31

Clinical studies in patients with 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH) were designed to ascertain the genetics of the salt-wasting component of the disorder. The gene controlling aldosterone biosynthesis may not be the same gene that controls 21-hydroxylase in the adrenal zona fasciculata. This we infer from the following clinical observations: (1) concordance for salt-wasting is not observed in all HLA-identical sibs with CAH; (2) the defect in aldosterone biosynthesis does not persist throughout life as does the fasciculata defect; (3) there is a significantly increased gene frequency of B40 and Bw47 in salt-wasting CAH; (4) obligate heterozygote parents of patients with salt-wasting CAH do not express a partial defect in aldosterone biosynthesis, as they do in the fasciculata. These observations cast doubt on the accepted concept of the autosomal recessive transmission of the glomerulosa 21-hydroxylase deficiency.
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PMID:Is salt-wasting in congenital adrenal hyperplasia due to the same gene as the fasciculata defect? 348 28


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