scholarly journals Study of a Kindred with Classic Congenital Adrenal Hyperplasia: Diagnostic Challenge due to Phenotypic Variance1

1998 ◽  
Vol 83 (6) ◽  
pp. 1940-1945
Author(s):  
Daisy Chin ◽  
Phyllis W. Speiser ◽  
Julianne Imperato-McGinley ◽  
Naznin Dixit ◽  
Naveen Uli ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Newborn Screening ◽  
Point Mutation ◽  
Phenotypic Expression ◽  
Variable Degree ◽  
Adrenal Hyperplasia ◽  
Cyp21 Gene ◽  
Classic Congenital Adrenal Hyperplasia ◽  
Genital Ambiguity ◽  
21 Hydroxylase Deficiency

We sought to determine the concordance of the phenotype and genotype in a kindred with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. The variation in phenotypic expression within this family underscores the difficulty of establishing the diagnosis in the absence of newborn screening, even with a heightened index of suspicion. Steroidogenic profiles were obtained for the three affected siblings. The available clinical history of the two affected aunts was retrieved. Genotyping was performed on several members of the kindred. Detailed sequencing of the entire CYP21 gene of two clinically dissimilar subjects in this family was undertaken to explore the possibility of other mutations or polymorphisms. PCR with ligase detection reaction analysis of CYP21 revealed that the affected family members III-2, III-3, III-4, II-3, and II-4, all were compound heterozygotes carrying the intron 2 point mutation known to interfere with splicing (nucleotide 656 A to G) and the exon 4 point mutation causing a nonconservative substitution of asparagine for isoleucine at codon 172 (I172N). Detailed sequencing of the gene was performed for the two most phenotypically dissimilar subjects. A single silent polymorphism was found in the third nucleotide for codon 248 in patient II-4, but not in patient III-4, and no additional mutations were found. Classic congenital adrenal hyperplasia remains a difficult diagnosis to make in the absence of newborn screening because of the variability of phenotypic expression. Likewise, the variable degree of genital ambiguity in affected females in this family serves to question universal advocacy of prenatal steroid treatment in pregnancies at risk for congenital adrenal hyperplasia. Extensive molecular exploration did not provide an explanation of the phenotypic heterogeneity and supports the possibility of influences other than the CYP21 gene for the observed divergence.

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.

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 Newborn Screening for Congenital Adrenal Hyperplasia: Review of Factors Affecting Screening Accuracy

2020 ◽  
Vol 6 (3) ◽  
pp. 67 ◽  
Author(s):  
Patrice K. Held ◽  
Ian M. Bird ◽  
Natasha L. Heather
Keyword(s):  
United States ◽  
Congenital Adrenal Hyperplasia ◽  
Newborn Screening ◽  
False Positive ◽  
Primary Care Physicians ◽  
The United States ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
21 Hydroxylase Deficiency ◽  
Screening Accuracy

Newborn screening for 21-hydroxylase deficiency (21OHD), the most common form of congenital adrenal hyperplasia, has been performed routinely in the United States and other countries for over 20 years. Screening provides the opportunity for early detection and treatment of patients with 21OHD, preventing salt-wasting crisis during the first weeks of life. However, current first-tier screening methodologies lack specificity, leading to a large number of false positive cases, and adequate sensitivity to detect all cases of classic 21OHD that would benefit from treatment. This review summarizes the pathology of 21OHD and also the key stages of fetal hypothalamic-pituitary-adrenal axis development and adrenal steroidogenesis that contribute to limitations in screening accuracy. Factors leading to both false positive and false negative results are highlighted, along with specimen collection best practices used by laboratories in the United States and worldwide. This comprehensive review provides context and insight into the limitations of newborn screening for 21OHD for laboratorians, primary care physicians, and endocrinologists.

scholarly journals Congenital Adrenal Hyperplasia in Patients with Disorders of Sexual Differentiation

2020 ◽  
Vol 1 (3) ◽  
pp. 25-30
Author(s):  
Warda Fatima ◽  
Tayyaba Rafiq ◽  
Saqib Mahmood
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Sexual Differentiation ◽  
Tertiary Care ◽  
Female Gender ◽  
Chromosomal Analysis ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Genital Ambiguity ◽  
Disorders Of Sexual Differentiation ◽  
21 Hydroxylase Deficiency

Congenital Adrenal Hyperplasia (CAH) is considered to be the most common cause of genital ambiguity in children. According to World’s literature, 90-95% of this disease is caused by 21-hydroxylase deficiency that impairs the synthesis of cortisol and aldosterone. The consequent excess in androgen production leads to virilization in the affected females. This study was aimed to find the number of cases with CAH (21-hydroxylase deficiency) in the children presented with disorders of sexual differentiation. For this purpose, 100 patients presented to The Children’s hospital for gender assessment were taken and their 17- OH progesterone levels were measured to confirm 21-hydroxylase deficiency, and chromosomal analysis was done to confirm chromosomal sex. Results indicated that out of 100 patients 49 were suffering from CAH. 63.2% of CAH patients were initially presented as males. Out of these, 44.8% were reassigned female gender on chromosomal analysis. So, it is concluded that the majority of patients presented with genital ambiguity in the tertiary care health facility have the ambiguity due to congenital adrenal hyperplasia.

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