Influence of different genotypes on 17‐hydroxyprogesterone levels in patients with nonclassical congenital adrenal hyperplasia due to 21‐hydroxylase deficiency

Bachega, Tânia A. S. S.; Billerbeck, Ana Elisa C.; Marcondes, José Antônio Miguel; Madureira, Guiomar; Arnhold, Ivo Jorge Prado; Mendonca, Berenice B.

doi:10.1046/j.1365-2265.2000.00995.x

Cited by 77 publications

(73 citation statements)

References 33 publications

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“…On the other hand, the lowest value of ACTH-stimulated 17OHP levels in LO patients, in whom mutations in both alleles were determined, was 17 ng/ml. These data suggest that the cutoff value of 10 ng/ml for stimulated 17OHP levels might have overestimated the diagnosis of the non-classical form of CAH-21OH (27). Genotyping patients with the LO form will support the definition of a new cutoff value for ACTHstimulated 17OHP levels.…”

Section: Resultsmentioning

confidence: 91%

21-Hydroxylase deficiency in Brazil

Bachega

Billerbeck

Madureira

et al. 2000

Braz J Med Biol Res

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We determined the frequency of large rearrangements and point mutations in 130 Brazilian patients with 21-hydroxylase deficiency and correlated genotype with phenotype. The frequency of CYP21 deletions was lower (4.4%) than in most of the previous series described, whereas the frequency of large gene conversions was similar to the frequency reported in the literature (6.6%). The most frequent point mutations were I2 splice (41.8% in salt wasting -SW), I172N (32.6% in simple virilizing -SV) and V281L (40.2% in the late onset form -LO). The frequency of the nine most common point mutations was similar to that reported for other countries. The 93 fully genotyped patients were classified into 3 mutation groups based on the degree of enzymatic activity (A<2%, B @ 2%, C>20%). In group A, 62% of cases presented the SW form; in group B, 96% the SV form, and in group C, 88% the LO form. We diagnosed 80% of the affected alleles after screening for large rearrangements and 15 point mutations. To diagnose these remaining alleles we sequenced the CYP21 gene of one patient with the SV form and identified a heterozygous G®A transition in codon 424. This mutation leads to a substitution of glycine by serine in a conserved region and was also found in a compound heterozygous state in 4 other patients. The mutation G424S presented a linkage disequilibrium with CYP21P and C4A gene deletions and HLA DR17, suggesting a probable founder effect. Search for the G424S mutation in other populations will reveal if it is restricted to the Brazilian patients or if it has a wider ethnic distribution.

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Section: Resultsmentioning

confidence: 91%

21-Hydroxylase deficiency in Brazil

Bachega

Billerbeck

Madureira

et al. 2000

Braz J Med Biol Res

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“…The diagnosis may be missed if only a baseline 17-OHP concentration is measured. The ACTH stimulating test is the most useful diagnostic test; patients with nonclassical 21-OHD have 17-OHP concentrations greater than 30 nmol/l at 60 min after injection of ACTH [6,15,16]. Therefore, neonatal mass screening is not sufficient for detecting nonclassical CAH, and most nonclassical patients are found after puberty because of symptoms of androgen excess or in the course of family studies [6].…”

Section: Discussionmentioning

confidence: 99%

Clinical Course of Patients with Nonclassical 21-hydroxylase Deficiency (21-OHD) Diagnosed in Infancy and Childhood

et al. 2008

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Abstract. We report four cases of nonclassical 21-hydroxylase deficiency (21-OHD) diagnosed in neonate or early childhood. The four patients comprised a 6-year, 5-month-old male (case 1); a 3-year, 10-month-old female (case 2); a 13-year, 11-month-old female (case 3) and a 17-year, 1-month-old male (case 4). Cases 3 and 4 were siblings. None had any signs of virilization or salt wasting at birth. 21-OHD was diagnosed using ACTH loading test and other adrenal steroid evaluations. Mutations of the CYP21 gene were detected in all patients. Three patients (cases 1, 3 and 4) had positive results in neonatal mass screening. Cases 1 and 2 showed no apparent signs of virilizaton and were observed without conventional treatment. In cases 3 and 4, because of increased growth velocity and accelerated bone maturation, hydrocortisone administration was initiated from their late infantile period. In spite of hydrocortisone treatment, in case 4, the final height of 159.7 cm was less than his predicted final height. Besides he revealed adrenal insufficiency at the age of 9 years and 2 months old caused by viral infection. Hydrocortisone supplementation therapy may cause adrenal insufficiency in nonclassical patients due to suppression of the hypothalamus-pituitary-adrenal axis. The clinical courses in these cases were various, and it was difficult to predict the appearance of any symptoms of virilization. Careful observation is necessary.

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“…Realizamos o estudo molecular de 58 pacientes que tiveram diagnóstico hormonal da forma NC-21OH (8). As metodologias utilizadas foram: Southern blotting seguido de hibridação com a sonda genômica do gene CYP21A2 para pesquisar grandes rearranjos (deleção do CYP21A2 e grande conversão gênica), e PCR alelo-específico para identificar 11 mutações de ponto.…”

Section: Critérios Diagnósticos Hormonais E Molecularesunclassified

“…Analisando também os valores da 17OHP após-ACTH entre os dois grupos, o grupo A/C teve valores significativamente maiores do que o grupo C/C, 66±27,6ng/mL e 41,6±24,6ng/mL (tabela 3), respectivamente (figura 1). Outros estudos da forma NC-21OH que realizaram a comparação do genótipo com o fenótipo também observaram uma tendência do genótipo A/C apresentar manifestações clínicas de hiperandrogenismo mais precoce do que o grupo C/C (8,(12)(13)(14). Com relação aos valores da 17OHP após-ACTH, todos estes estudos (8,13,14), exceto o de Speiser e cols.…”

Section: Critérios Diagnósticos Hormonais E Molecularesunclassified

Avaliação dos critérios diagnósticos hormonais da forma não clássica da deficiência da 21-hidroxilase através do estudo molecular do gene CYP21A2

Correa

Bachega

2003

Arq Bras Endocrinol Metab

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RESUMOO diagnóstico da forma não clássica da deficiência da 21-hidroxilase (NC-21OH) é realizado na presença de manifestações hiperandrogênicas e valores da 17-hidroxiprogesterona (17OHP) basais >5ng/mL ou pós-ACTH >10ng/mL. Apresentamos os casos de duas crianças com pubarca precoce e com diagnóstico hormonal de forma NC-21OH, cujo estudo molecular do gene CYP21A2 confirmou o diagnóstico em apenas um caso. Isto nos levou a reavaliar o diagnóstico hormonal da forma NC-21OH através do estudo molecular em 58 pacientes com 17OHP pós-ACTH >10ng/mL. Apenas 37 (67%) pacientes tiveram mutações identificadas em ambos os alelos. Nestes, os valores basais da 17OHP foram francamente elevados (>5ng/mL) em 70%, normais em 11% e, nos demais, entre 2 e 5ng/mL. O menor valor da 17OHP pós-ACTH neste grupo foi de 17ng/mL. Ao analisarmos 59 indivíduos heterozigotos obrigatórios para a deficiência da 21-hidroxilase, observamos dois casos com valores da 17OHP pós-ACTH de 11 e 15ng/mL, respectivamente. Estes dados sugerem que o atual critério diagnóstico hormonal da forma NC-21OH possa estar superestimando seu diagnóstico. Diagnosis of the nonclassical form of 21-hydroxylase deficiency (NC-21OH) is based on clinical hyperandrogenism and basal 17-hydroxyprogesterone (17OHP) levels >5ng/mL or >10ng/mL after ACTH-stimulation. We present two children with precocious pubarche and a hormonal diagnosis of NC-21OH, whose molecular study of the CYP21A2 gene confirmed the diagnosis in just one case. After that, we re-evaluated the diagnosis of 58 patients with ACTH-stimulated 17OHP levels >10ng/mL with molecular studies of CYP21A2 gene. Only 37 (67%) of these patients had mutations detected in both alleles: basal 17OHP levels were >5ng/mL in 70%, normal in 11% and between 2 and 5ng/mL in the remaining patients. The lowest ACTH-stimulated 17OHP level in this group was 17ng/mL. We then analyzed 59 obligate carriers for 21-hydroxylase deficiency and found two asymptomatic subjects with ACTH-stimulated 17OHP levels of 11 and 15ng/mL, respectively. Based on these findings, we suggest that the current cut-off value for ACTH-stimulated 17OHP level overestimates the diagnosis of NC-21OH.

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Influence of different genotypes on 17‐hydroxyprogesterone levels in patients with nonclassical congenital adrenal hyperplasia due to 21‐hydroxylase deficiency

Cited by 77 publications

References 33 publications

21-Hydroxylase deficiency in Brazil

21-Hydroxylase deficiency in Brazil

Clinical Course of Patients with Nonclassical 21-hydroxylase Deficiency (21-OHD) Diagnosed in Infancy and Childhood

Avaliação dos critérios diagnósticos hormonais da forma não clássica da deficiência da 21-hidroxilase através do estudo molecular do gene CYP21A2

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