scholarly journals Genotype-phenotype associations in non-classical steroid 21-hydroxylase deficiency

2000 ◽  
pp. 397-403 ◽  
Author(s):  
N Weintrob ◽  
C Brautbar ◽  
A Pertzelan ◽  
Z Josefsberg ◽  
Z Dickerman ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
Phenotypic Expression ◽  
Ethnic Origin ◽  
Stepwise Logistic Regression ◽  
Compound Heterozygous ◽  
Significant Variable ◽  
Hydroxylase Deficiency ◽  
Severe Mutation ◽  
Group B ◽  
21 Hydroxylase Deficiency

OBJECTIVE: To evaluate whether genotype differences can explain the clinical variability of non-classical steroid 21-hydroxylase deficiency (NC21-OHD) and to determine if genotype is related to ethnic origin. DESIGN: Genotyping for mutations in the steroid 21-hydroxylase (CYP21) gene was performed in 45 unrelated Israeli Jewish patients (nine males) with NC21-OHD (60min 17-hydroxyprogesterone (17-OHP), 45-386nmol/l) who were referred for evaluation of postnatal virilization or true precocious/early puberty. Eleven siblings diagnosed through family screening were genotyped as well. METHODS: Patients were divided by genotype into three groups: (A) homozygous or compound heterozygous for the mild mutations (V281L or P30L) (n=29; eight males); (B) compound heterozygous for one mild and one severe mutation (Q318X, I2 splice, I172N) (n=12; no males); (C) mild mutation detected on one allele only (n=4; one male; peak 17-OHP 58-151nmol/l). We then related the genotype to the ethnic origin, clinical phenotype and hormone level. Since group C was very small, comparisons were made between groups A and B only. RESULTS: At diagnosis, group B tended to be younger (5. 8+/-3.0 vs 8.1+/-4.3 years, P=0.09), had greater height SDS adjusted for mid-parental height SDS (1.6+/-1.1 vs 0.7+/-1.4, P=0.034), tended to have more advanced bone age SDS (2.9+/-1.5 vs 1.7+/-2.1, P=0.10) and had a higher peak 17-OHP level in response to ACTH stimulation (226+/-92 vs 126+/-62nmol/l, P<0.01). Group B also had pubarche and gonadarche at an earlier age (5.1+/-2.4 vs 7.4+/-2.2 years, P<0.01 and 7.4+/-1.8 vs 9.9+/-1.4 years, P<0.001, respectively) and a higher rate of precocious puberty (50 vs 17%, P=0.04). Stepwise logistic regression analysis (excluding males) yielded age at gonadarche as the most significant variable differentiating the two groups, with a positive predictive value of 86% for a cut-off of 7.5 years. CONCLUSIONS: The findings suggest that genotype might explain some of the variability in the phenotypic expression of NC21-OHD. Compound heterozygotes for one mild and one severe mutation have a higher peak 17-OHP associated with pubarche and gonadarche at an earlier age and more frequent precocious puberty. Hence, the severity of the enzymatic defect might determine the timing and pattern of puberty.

scholarly journals Predicting Phenotype in Steroid 21-Hydroxylase Deficiency? Comprehensive Genotyping in 155 Unrelated, Well Defined Patients from Southern Germany

2000 ◽  
Vol 85 (3) ◽  
pp. 1059-1065 ◽  
Author(s):  
Nils Krone ◽  
Andreas Braun ◽  
Adelbert Anton Roscher ◽  
Dietrich Knorr ◽  
Hans Peter Schwarz
Keyword(s):  
Splice Site ◽  
Splice Site Mutation ◽  
Compound Heterozygous ◽  
Site Mutation ◽  
Hydroxylase Deficiency ◽  
Salt Wasting ◽  
Severe Mutation ◽  
Heterozygous Form ◽  
21 Hydroxylase Deficiency ◽  
Intron 2

Abstract Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders. CAH is most often caused by deficiency of steroid 21-hydroxylase. The frequency of CYP21-inactivating mutations and the genotype-phenotype relationship were characterized in 155 well defined unrelated CAH patients. We were able to elucidate 306 of 310 disease-causing alleles (diagnostic sensitivity, 98.7%). The most frequent mutation was the intron 2 splice site mutation (30.3%), followed by gene deletions (20.3%), the I172N mutation (19.7%) and large gene conversions (7.1%). Five point mutations were detected that have not been described in other CAH cohorts. Genotypes were categorized in 4 mutation groups (null, A, B, and C) according to their predicted functional consequences and compared to the clinical phenotype. The positive predictive value for null mutations (ppvnull) was 100%, as all patients with these mutations had a salt-wasting phenotype. In mutation group A (intron 2 splice site mutation in homozygous or heterozygous form with a null mutation), the ppvA to manifest with salt-wasting CAH was 90%. In group B predicted to result in simple virilizing CAH (I172N in homozygous or compound heterozygous form with a more severe mutation), ppvB was 74%. In group C (P30L, V281L, P453S in homozygous or compound heterozygous form with a more severe mutation), ppvC was 64.7% to exhibit the nonclassical form of CAH, but 90% when excluding the P30L mutation. Thus, in general, a good genotype-phenotype relationship is shown in patients with either the severest or the mildest mutations. A considerable degree of divergence is observed within mutation groups of intermediate severity. As yet undefined factors modifying 21-hydroxylase gene expression and steroid hormone action are likely to account for these differences in phenotypic expression.

scholarly journals CYP21 Genotype, Adult Height, and Pubertal Development in 55 Patients Treated for 21-Hydroxylase Deficiency

2003 ◽  
Vol 88 (12) ◽  
pp. 5680-5688 ◽  
Author(s):  
Antonio Balsamo ◽  
Alessandro Cicognani ◽  
Lilia Baldazzi ◽  
Michela Barbaro ◽  
Federico Baronio ◽  
...  
Keyword(s):  
Early Diagnosis ◽  
First Year ◽  
Compound Heterozygous ◽  
Target Height ◽  
Hydroxylase Deficiency ◽  
Genotypic Analysis ◽  
Group A ◽  
Group B ◽  
21 Hydroxylase Deficiency ◽  
First Year Of Life

Abstract In a retrospective study we evaluated long-term growth, pubertal developmental patterns to final height (FH), and medication in 55 patients (35 females) affected by 21-hydroxylase deficiency. The patients were classified into 3 groups according to predicted mutation severity: group A (11 women and 9 men), homozygous or compound heterozygous for null or In2 splice mutations [residual enzymatic activity (RA), &lt;1%]; group B (11 women and 4 men), homozygous for I172N or R341P or R426H mutations (RA, ∼2–3%) or compound heterozygous with any of the group A or B mutations; and group C (13 women and 7 men), homozygous for P30L or V281L or P453S mutations (RA, &gt;30%) or compound heterozygous with any of the group A, B, or C mutations. Three patients showed unclassifiable genotypes. FH was similar in the female groups, whereas male patients in group B were shorter than males in groups A and C. Fifty-five percent of patients in group A, 33% in group B, and 40% in group C reached an FH within 0.5 sd of target height. Four of the 7 patients diagnosed via neonatal screening achieved an FH equal to or above the target height. In the entire group, early diagnosis (&lt;1 yr) improved height outcome. Early diagnosed CAH patients who received lower cortisol equivalent doses during the first year of life reached a better FH. Our results underline the importance of mineralocorticoid therapy, as CAH subjects in groups A and B who did not receive this treatment showed reduced FH. Early diagnosis, the use of more physiological cortisol equivalent dosages during the first year of life, and the extension of mineralocorticoid therapy to all classical patients are shown to improve the auxological outcome. Genotypic analysis helped to interpret the height results of our cases and prospectively may represent a useful tool for improving the therapeutic choice and the height outcome.

scholarly journals Phenotype-Genotype Correlation in 56 Women with Nonclassical Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

2001 ◽  
Vol 86 (1) ◽  
pp. 207-213 ◽  
Author(s):  
Catherine Deneux ◽  
Véronique Tardy ◽  
Anne Dib ◽  
Etienne Mornet ◽  
Line Billaud ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Phenotypic Expression ◽  
Complete Analysis ◽  
Primary Amenorrhea ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Cyp21 Gene ◽  
Severe Mutation ◽  
21 Hydroxylase Deficiency ◽  
Genotype Correlation

Complete analysis of the CYP21 gene was performed in 56 unrelated French women with symptomatic nonclassical congenital adrenal hyperplasia. The mutational spectrum and the phenotype-genotype correlation were examined. The overall predominant mutation was V281L, which was present on 51% of alleles and in 80% of women. Three novel mutations were found: L317M, R435C, and a 5′-end gene conversion. Sixty-three percent of the women were carrying a severe mutation of the CYP21 gene, and hence risk giving birth to children with a classical form of the disease. In such cases, screening for heterozygosity in the partner is crucial. Potential genotype/phenotype correlations were examined by classifying the patients into three groups according to the CYP21 allelic combinations: A (mild/mild), B (mild/severe), and C (severe/severe). Primary amenorrhea was more frequent, and mean basal and stimulated 17-hydroxyprogesterone levels were higher in compound heterozygotes for mild and severe mutations (group B) compared with women with two mild mutations (group A), but there was a considerable overlap for individual values. Surprisingly, in two women, a severe mutation was found on both alleles (group C). Therefore, the phenotype cannot be accurately predicted from the genotype. Variability in phenotypic expression may be conditioned by mechanisms other than genetic heterogeneity at the CYP21 locus.

scholarly journals Functional Consequences of Seven Novel Mutations in the CYP11B1 Gene: Four Mutations Associated with Nonclassic and Three Mutations Causing Classic 11β-Hydroxylase Deficiency

Endocrinology ◽  
2010 ◽  
Vol 151 (2) ◽  
pp. 839-839
Author(s):  
Silvia Parajes ◽  
Lourdes Loidi ◽  
Nicole Reisch ◽  
Vivek Dhir ◽  
Ian T. Rose ◽  
...  
Keyword(s):  
Expression System ◽  
Phenotypic Expression ◽  
Three Dimensional ◽  
Compound Heterozygous ◽  
Three Dimensional Model ◽  
Hydroxylase Deficiency ◽  
Functional Consequences ◽  
Heterozygous Carriers ◽  
21 Hydroxylase Deficiency

ABSTRACT Context: Steroid 11β-hydroxylase (CYP11B1) deficiency (11OHD) is the second most common form of congenital adrenal hyperplasia (CAH). Cases of nonclassic 11OHD are rare compared with the incidence of nonclassic 21-hydroxylase deficiency. Objective: The aim of the study was to analyze the functional consequences of seven novel CYP11B1 mutations (p.M88I, p.W116G, p.P159L, p.A165D, p.K254_A259del, p.R366C, p.T401A) found in three patients with classic 11OHD, two patients with nonclassic 11OHD, and three heterozygous carriers for CYP11B1 mutations. Methods: We conducted functional studies employing a COS7 cell in vitro expression system comparing wild-type (WT) and mutant CYP11B1 activity. Mutants were examined in a computational three-dimensional model of the CYP11B1 protein. Results: All mutations (p.W116G, p.A165D, p.K254_A259del) found in patients with classic 11OHD have absent or very little 11β-hydroxylase activity relative to WT. The mutations detected in patients with nonclassic 11OHD showed partial functional impairment, with one patient being homozygous (p.P159L; 25% of WT) and the other patient compound heterozygous for a novel mild p.M88I (40% of WT) and the known severe p.R383Q mutation. The two mutations detected in heterozygous carriers (p.R366C, p.T401A) also reduced CYP11B1 activity by 23 to 37%, respectively. Conclusion: Functional analysis results allow for the classification of novel CYP11B1 mutations as causative for classic and nonclassic 11OHD, respectively. Four partially inactivating mutations are predicted to result in nonclassic 11OHD. These findings double the number of mild CYP11B1 mutations previously described as associated with mild 11OHD. Our data are important to predict phenotypic expression and provide important information for clinical and genetic counseling in 11OHD.

Congenital adrenal hyperplasia: molecular mechanisms resulting in 21-hydroxylase deficiency

1986 ◽  
Vol 113 (4_Suppl) ◽  
pp. S315-S320 ◽  
Author(s):  
Patricia A. Donohoue ◽  
Cornelis Van Dop ◽  
Nicholas Jospe ◽  
Claude J. Migeon
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Molecular Mechanisms ◽  
Sequence Data ◽  
Phenotypic Expression ◽  
Restriction Pattern ◽  
Class Iii ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Wide Range ◽  
21 Hydroxylase Deficiency

Abstract 21-Hydroxylase deficiency resulting in congenital adrenal hyperplasia (CAH) is a HLA-linked autosomal recessive disorder that has a wide range of phenotypic expression. Two homologous 21-hydroxylase genes (21-OHA and 21-OHB) occur within the Class III region of the major histocompatibility complex, but only one (21-OHB) appears to function in adrenal steroidogenesis. Our restriction maps, and initial sequence data from White et al. (Pediatr Res 20:274A (1986)) for the two human 21-OH genes reveal a high degree of homology between these genes and a reading frame shift mutation in the 21-OHA gene respectively. Among fourteen control subjects, the intragenic restriction patterns of the 21-OHA and 21-OHB genes are invariant. The few restriction fragment length polymorphisms (RFLPs) found in some controls result from polymorphic restriction sites outside the 21-OH genes. In patients with CAH, several different mechanisms for mutation of the 21-OHB gene have been described: 1) deletion of the unique sequences of the 21-OHB gene, 2) conversion of the unique sequences of the 21-OHB gene to those of 21-OHA, and 3) mutations of 21-OHB which do not result in a detectable alteration of restriction pattern (e.g., point mutations). Duplication of the 21-OHA gene has been found in some patients with attenuated CAH; however, the significance of this finding remains unclear.

scholarly journals Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency: late diagnosis and gender reassignment in a two-year-old child

2021 ◽  
Vol 67 (5) ◽  
pp. 53-57
Author(s):  
N. Yu. Raygorodskaya ◽  
E. P. Novikova ◽  
A. N. Tyulpakov ◽  
M. A. Kareva ◽  
N. A. Nikolaeva ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Clinical Case ◽  
Clinical Manifestations ◽  
Autosomal Recessive Disorder ◽  
Compound Heterozygous ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Gender Reassignment ◽  
And Gender ◽  
21 Hydroxylase Deficiency

11β-hydroxylase deficiency is a rare autosomal recessive disorder due to impaired steroidogenesis in the adrenal cortex caused by pathogenic mutations in the CYP11B1 gene. The main clinical manifestations are determined by a deficiency of cortisol, ACTH hyperproduction, excessive androgens secretion and the accumulation of 11-deoxycorticosterone, which leads to the development of arterial hypertension. In the diagnostic search, it is important to take into account the ethnicity of the patient, since the frequency of the disease and the prevalence of mutations differ between ethnic groups. The article presents a clinical case of 11β-hydroxylase deficiency as the result of compound heterozygous mutations in the CYP11B1 gene in a patient of Turkic origin. This case shows the clinical manifestations and the development of complications of 11β-hydroxylase deficiency, the stages of differential diagnosis of patients with 21-hydroxylase deficiency.

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