Clinical and Molecular Characterization of a Cohort of 161 Unrelated Women with Nonclassical Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency and 330 Family Members

Bidet, Maud; Bellanné‐Chantelot, Christine; Galand-Portier, Marie-Béatrice; Tardy, Véronique; Billaud, L; Laborde, Kathleen; Coussieu, Christiane; Morel, Yves; Vaury, Chantal; Golmard, Jean‐Louis; Claustre, Aurélie; Mornet, Étienne; Chakhtoura, Zeina; Mowszowicz, Irène; Bachelot, Anne; Touraine, Philippe; Kuttenn, Frédérique

doi:10.1210/jc.2008-1582

Cited by 185 publications

(182 citation statements)

References 37 publications

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“…Basal and ACTH-stimulated 17OHP levels were significantly higher in NC genotype A/C than C/C. These findings are in accordance with other series that included a significant number of NC patients (2,20,40).…”

Section: European Journal Of Endocrinologysupporting

confidence: 92%

Molecular CYP21A2 diagnosis in 480 Brazilian patients with congenital adrenal hyperplasia before newborn screening introduction

Carvalho¹,

Miranda²,

Gomes³

et al. 2016

European Journal of Endocrinology

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Background: Most congenital adrenal hyperplasia (CAH) patients carry CYP21A2 mutations derived from conversion events involving the pseudogene, and the remaining carry new mutations. Objective: To review causal mutations and genotype-phenotype correlation in 480 Brazilian patients. Methods: DNA was extracted from 158 salt-wasters (SWs), 116 simple virilizing (SV), and 206 nonclassical (NC) patients. Fourteen point mutations were screened by allele-specific PCR, large rearrangements by Southern blotting/ MLPA, and sequencing was performed in those with incomplete genotype. The gene founder effect was analyzed by microsatellite studies. Patients were divided into six genotypes (Null; A: <2%; B: 3-7%; C: >20% of residual enzymatic activity (EA); D: unknown EA; E: incomplete genotype). Results: Targeted methodologies defined genotype in 87.6% of classical and in 80% of NC patients and the addition of sequencing in 100 and 83.5%, respectively. The most frequent mutations were p.V281L (26.6% of alleles), IVS2-13A/C>G (21.1%), and p.I172N (7.5%); seven rare mutations and one novel mutation (p.E351V) were identified. Gene founder effect was observed in all but one (p.W19X) mutation. Null, A, B, and C genotypes correlated with SW (88%), SW (70%), SV (98%), and NC forms (100%), respectively. In group D, the p.E351V mutation correlated with classical form and group E comprised exclusively NC-patients. ACTH-stimulated 17OHP level of 44.3 ng/mL was the best cutoff to identify NC-patients carrying severe mutations. Conclusions: We identified a good genotype-phenotype correlation in CAH, providing useful data regarding prediction of disease´s severity; moreover, we suggest that ACTH-stimulated 17OHP levels could predict carrier status for severe mutations. Sequencing is essential to optimize molecular diagnosis in Brazilian CAH patients.

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Section: European Journal Of Endocrinologysupporting

confidence: 92%

Molecular CYP21A2 diagnosis in 480 Brazilian patients with congenital adrenal hyperplasia before newborn screening introduction

Carvalho¹,

Miranda²,

Gomes³

et al. 2016

European Journal of Endocrinology

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“…A study of the phenotype/genotype relationship in 330 family members revealed 9 symptomatic affected individuals, 42 clinically asymptomatic affected individuals, 242 heterozygotic carriers, and 37 unaffected individuals [51]. As found in this study, affected males are generally asymptomatic and usually identified following the diagnosis of a female family member.…”

Section: Clinical Featuressupporting

confidence: 69%

“…In a multicenter study, the most common symptoms among adolescent and adult women were hirsutism (59%), oligomenorrhea (54%), and acne (33%) [50]. Presenting symptoms in 161 women with NCAH were hirsutism (78%), menstrual dysfunction (54.7%), and decreased fertility (12%) [51].…”

Section: Clinical Featuresmentioning

confidence: 99%

“…Correlation of hormone concentrations with genetic analyses has suggested 6 International Journal of Pediatric Endocrinology that mutations are likely to be identified on both alleles when the ACTH-stimulated 17-OHP value exceeds 1500 ng/dL, although a few NCAH patients, particularly if older, will demonstrate ACTH-stimulated 17-OHP levels between 1000 and 1500 ng/dL. In one study, among 123 women with NCAH confirmed by molecular CYP21A2 analysis, mean basal 17-OHP and mean ACTH-stimulated 17-OHP concentrations were 1300 ± 1420 ng/dL and 4080 ± 2040 ng/dL, respectively [51].…”

Section: Diagnosismentioning

confidence: 99%

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Non-classic congenital adrenal hyperplasia

Witchel

2013

Steroids

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Nonclassic congenital adrenal hyperplasia (NCAH) due to P450c21 (21-hydroxylase deficiency) is a common autosomal recessive disorder. This disorder is due to mutations in the CYP21A2 gene which is located at chromosome 6p21. The clinical features predominantly reflect androgen excess rather than adrenal insufficiency leading to an ascertainment bias favoring diagnosis in females. Treatment goals include normal linear growth velocity and "on-time" puberty in affected children. For adolescent and adult women, treatment goals include regularization of menses, prevention of progression of hirsutism, and fertility. This paper will review key aspects regarding pathophysiology, diagnosis, and treatment of NCAH.

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“…An 8 AM value .200 ng/dL (6.0 nmol/L) is suggestive of NCCAH, although it is also compatible with recent ovulation or tumoral hyperandrogenism. 72 This cutoff displayed 92% to 98% sensitivity in detecting NCCAH 73,74 and 12% to 25% specificity in discriminating it from PCOS. 75,76 Thus, unless the 17-OHP level achieves a diagnostic level (.1000 ng/dL = 30 nmol/L), an adrenocorticotropic hormone test is recommended to confirm the diagnosis of NCCAH.…”

Section: Figurementioning

confidence: 98%

The Diagnosis of Polycystic Ovary Syndrome in Adolescents

2015

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Consensus has recently been reached by international pediatric subspecialty societies that otherwise unexplained persistent hyperandrogenic anovulation using age-and stage-appropriate standards are appropriate diagnostic criteria for polycystic ovary syndrome (PCOS) in adolescents. The purpose of this review is to summarize these recommendations and discuss their basis and implications. Anovulation is indicated by abnormal uterine bleeding, which exists when menstrual cycle length is outside the normal range or bleeding is excessive: cycles outside 19 to 90 days are always abnormal, and most are 21 to 45 days even during the first postmenarcheal year. Continued menstrual abnormality in a hyperandrogenic adolescent for 1 year prognosticates at least 50% risk of persistence. Hyperandrogenism is best indicated by persistent elevation of serum testosterone above adult norms as determined in a reliable reference laboratory. Because hyperandrogenemia documentation can be problematic, moderate-severe hirsutism constitutes clinical evidence of hyperandrogenism. Moderate-severe inflammatory acne vulgaris unresponsive to topical treatment is an indication to test for hyperandrogenemia. Treatment of PCOS is symptom-directed. Cyclic estrogenprogestin oral contraceptives are ordinarily the preferred first-line medical treatment because they reliably improve both the menstrual abnormality and hyperandrogenism. First-line treatment of the comorbidities of obesity and insulin resistance is lifestyle modification with calorie restriction and increased exercise. Metformin in conjunction with behavior modification is indicated for glucose intolerance. Although persistence of hyperandrogenic anovulation for $2 years ensures the distinction of PCOS from physiologic anovulation, early workup is advisable to make a provisional diagnosis so that combined oral contraceptive treatment, which will mask diagnosis by suppressing hyperandrogenemia, is not unnecessarily delayed.Polycystic ovary syndrome (PCOS) is the most common cause of chronic hyperandrogenic anovulation and the single most common cause of infertility in young women. 1 It is also a risk factor for metabolic syndrome-related comorbidities and for impaired wellbeing and mortality. 2 Considerable evidence suggests that PCOS has diverse causes, arising as a complex trait with contributions from both heritable and environmental factors that affect ovarian steroidogenesis. 3,4 Insulinresistant hyperinsulinism, in part related to coexistent obesity, is the most common nonsteroidogenic factor. The complex interactions generally mimic an autosomal dominant trait with variable penetrance: the disorder is correlated in identical twins 5 ; about half of sisters are hyperandrogenic, and half of these also have oligo-amenorrhea and thus PCOS 6,7 ; and polycystic ovaries appear to be inherited as an autosomal dominant trait. 7,8 Three percent to 35% of mothers have PCOS, 9,10 and metabolic syndrome prevalence is high in parents and siblings. 11-13 The syndrome was first described...

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Clinical and Molecular Characterization of a Cohort of 161 Unrelated Women with Nonclassical Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency and 330 Family Members

Cited by 185 publications

References 37 publications

Molecular CYP21A2 diagnosis in 480 Brazilian patients with congenital adrenal hyperplasia before newborn screening introduction

Molecular CYP21A2 diagnosis in 480 Brazilian patients with congenital adrenal hyperplasia before newborn screening introduction

Non-classic congenital adrenal hyperplasia

The Diagnosis of Polycystic Ovary Syndrome in Adolescents

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