Genetic defects of the CYP21A2 gene in girls with premature adrenarche

Skordis, Nicos; Shammas, Christos; Phedonos, Alexia; Kyriakou, Andreas; Toumba, Meropi; Neocleous, Vassos; Phylactou, Leonidas A.

doi:10.1007/s40618-014-0223-1

Cited by 13 publications

(9 citation statements)

References 34 publications

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“…Additionally, 3 children belonging to the SV group exhibited GnRH independent precocious puberty. At this time, more than 200 mutations in the CYP21A2 gene have been reported in numerous studies and there is a good concordance between the clinical phenotype and the patient genotypic findings [13,16,17,21,[37][38][39][40]. The genetic population profile of CAH and endocrinopathies in the Cypriot population is characterized by low consanguinity rates and by similarities to what is observed regarding these disorders in the Eastern Mediterranean countries [41,42].…”

Section: Discussionmentioning

confidence: 64%

“…Since 2007 our group has extensively studied the genetic implication of CYP21A2 in Cypriot patients with CAH. These included the true carrier frequency in the general population of Cyprus [10], the genotype-phenotype association with the various forms of CAH [14][15][16][17][18], the impact of heterozygosity in female patients with hyperandrogenemia [19,20], and the implication of variants in the untranslated 5′UTR region of the CYP21A2 gene [21]. In the present update, we present the molecular genetic features of the disease in patients of Cypriot descent over the last 11 years.…”

Section: Introductionmentioning

confidence: 99%

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The Spectrum of Genetic Defects in Congenital Adrenal Hyperplasia in the Population of Cyprus: A Retrospective Analysis

et al. 2019

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Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is caused by mutations in the CYP21A2 gene. The study refers to CAH patients of Greek-Cypriot ancestry between years 2007 and 2018. One hundred and twenty patients with various degrees of CAH were categorized and genotyped. The patients were categorized in 4 mutation groups based on their clinical and biochemical findings. The majority of patients (85.0%) belonged to the non-classic (NC)-CAH form and the disorder was more often diagnosed in females (71.7%). The most severe classic salt-wasting (SW) form was identified in 11 neonates (9.2%). Seven (5.8%) children were also identified with the simple virilizing (SV) form and a median presentation age of 5 years [interquartile range (IQR) 3.2–6.5]. In the 240 nonrelated alleles, the most frequent mutation was p.Val281Leu (60.0%) followed by c.655 A/C>G (IVS2–13A/C>G) (8.8%), p.Pro453Ser (5.8%), DelEx1–3 (4.6%), p.Val304Met (4.6%), and p.Gln318stop (4.2%). Other less frequent mutations including rare deletions were also identified. Following our recent report that the true carrier frequency of CYP21A2 in Greek-Cypriots is 1:10, this study reports that the CAH prevalence is predicted around 1.7 cases per 10 000 people. Therefore, the up-to-date 120 CAH patients identified by our group make only the 6.9% of the ones estimated (approximately 1750) to exist in the Greek Cypriot population. The compiled data from a coherent population such as the Greek-Cypriot could be valuable for the antenatal diagnosis, management and genetic counselling of the existing and prospect families with CAH.

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Section: Discussionmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 99%

The Spectrum of Genetic Defects in Congenital Adrenal Hyperplasia in the Population of Cyprus: A Retrospective Analysis

et al. 2019

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“…Numerous studies in the Mediterranean Basin, including research from our group, have confirmed as the most predominant genetic defects, the mutations IVS2-13A/C>G, p.Gln318 ∗ , p.Val281Leu, and c.329_336del (8bpdelE3) [12, 13, 33, 34]. Compared to normal female individuals, female carriers for 21-OHD frequently demonstrate an increased secretion of the 21-OH precursors 17-hydroxyprogesterone (17-OHP) and progesterone (P4) [35–43] and lower levels of 11-deoxycorticosterone [37] as expected.…”

Section: Introductionmentioning

confidence: 87%

Variations in the 3′UTR of theCYP21A2Gene in Heterozygous Females with Hyperandrogenaemia

Neocleous

Fanis

Toumba

et al. 2017

International Journal of Endocrinology

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Heterozygosity for CYP21A2 mutations in females is possibly related to increased risk of developing clinical hyperandrogenism. The present study was designed to seek evidence on the phenotype-genotype correlation in female children, adolescents, and women with CYP21A2 mutations and variants in the 3′UTR region of the gene. Sixty-six patients out of the 169 were identified as carriers of CYP21A2 mutations. Higher values of stimulated 17 hydroxyprogesterone (17-OHP) levels were found in the carriers of the p.Val281Leu mutation compared to the carriers of other mutations (mean: 24.7 nmol/l versus 15.6 nmol/l). The haplotype of the ∗52C>T, ∗440C>T, and ∗443T>C in the 3′UTR was identical in all heterozygous patients with p.Val281Leu and the haplotype of the ∗12C>T and ∗52C>T was identical in all heterozygous patients with the p.Gln318∗. In conclusion, hyperandrogenaemic females are likely to bear heterozygous CYP21A2 mutations. Carriers of the mild p.Val281Leu mutation are at higher risk of developing hyperandrogenism than the carriers of more severe mutations. The identification of variants in the 3′UTR of CYP21A2 in combination with the heterozygous mutation may be associated with the mild form of nonclassic congenital adrenal hyperplasia and reveal the importance of analyzing the CYP21A2 untranslated regions for the appropriate management of this category of patients.

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“…The symptoms at presentation are often indistinguishable from adrenarche, so that the diagnosis requires investigations. Studies in children with premature adrenarche have shown that 4-25% were diagnosed with CAH (31,32). Genetic investigations in a cohort of 59 individuals with androgen symptoms showed that 12 had NCAH, 19 were carriers and 18 were heterozygous for a polymorphism previously discussed with regard to causing increased androgen production (32).…”

Section: Clinical Presentationmentioning

confidence: 99%

MANAGEMENT OF ENDOCRINE DISEASE: Diagnosis and management of the patient with non-classic CAH due to 21-hydroxylase deficiency

Nordenström

Falhammar

2019

European Journal of Endocrinology

115

129

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Non-classic congenital adrenal hyperplasia (NCAH) is a relatively common disorder regardless of ethnicity, but most cases are never diagnosed, especially in males. A baseline 17-hydroxyprogesterone measurement may be used for screening, but 17-hydroxyprogesterone measurement after ACTH stimulation is the gold standard. We advocate a CYP21A2 mutation analysis to verify the diagnosis, for genetic counselling and for better prognostic and treatment guidance. Most patients are diagnosed in adolescence and adult life with hirsutism, acne, a PCOS-like picture and fertility issues. Many men with NCAH never seek medical attention and escape diagnosis. Although treatment is somewhat controversial, an early diagnosis and start of treatment may have positive implications on growth and be relevant for preventing and ameliorating the symptoms and consequences of androgen excess that develop over time, including fertility issues. Long-term treatment with glucocorticoids will improve the androgen symptoms but may result in long-term complications, such as obesity, insulin resistance, hypertension, osteoporosis and fractures. The glucocorticoid doses should be kept low. However, complications seen in NCAH, assumed to be caused by the glucocorticoid treatment, may also be associated with long-term androgen exposure. Oral contraceptive pills are a common treatment option for young females with NCAH. Regular clinical monitoring to improve the clinical outcome is recommended. It is important to acknowledge that glucocorticoid treatment will lead to secondary cortisol insufficiency and the need for stress dosing. Studies focusing on the specific difficulties patients with NCAH face, both those with a late clinical diagnosis and those with a neonatal diagnosis obtained by screening, are warranted.

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Genetic defects of the CYP21A2 gene in girls with premature adrenarche

Cited by 13 publications

References 34 publications

The Spectrum of Genetic Defects in Congenital Adrenal Hyperplasia in the Population of Cyprus: A Retrospective Analysis

The Spectrum of Genetic Defects in Congenital Adrenal Hyperplasia in the Population of Cyprus: A Retrospective Analysis

Variations in the 3′UTR of theCYP21A2Gene in Heterozygous Females with Hyperandrogenaemia

MANAGEMENT OF ENDOCRINE DISEASE: Diagnosis and management of the patient with non-classic CAH due to 21-hydroxylase deficiency

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