The presence of the 21-hydroxylase deficiency carrier status in hirsute women: phenotype-genotype correlations

Escobar-Morreale, Héctor F.; Millán, José L. San; Smith, Rhonda R.; Sancho, José; Witchel, Selma F.

doi:10.1016/s0015-0282(99)00317-9

Cited by 68 publications

(40 citation statements)

References 31 publications

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“…On the one hand, this can be valuable under conditions in which hormone determinations are possible but access to genetic testing is limited due to financial restrictions of health care systems or health insurances. Since heterozygosity of CYP21A2 gene mutations has to be considered in the differential diagnosis of hyperandrogenism (7,8,9,10) and since the ACTH test is often performed in these clinical situations (24, 7), calculation of ((17OHPC 21S)/F!1000) provides important additional information for test interpretation and diagnostic workup.…”

Section: Discussionmentioning

confidence: 99%

LC–MS/MS based determination of basal- and ACTH-stimulated plasma concentrations of 11 steroid hormones: implications for detecting heterozygote CYP21A2 mutation carriers

Kulle

Riepe

Hedderich

et al. 2015

European Journal of Endocrinology

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Objective: Heterozygosity in 21-hydroxylase deficiency (21OHD) has been associated with hyperandrogenemic symptoms in children and adults. Moreover, the carrier status is mandatory for genetic counseling. We aimed at defining a hormonal parameter for carrier detection by mass spectrometry. Design: Eleven basal and ACTH-stimulated steroid hormones of heterozygous carriers of CYP21A2 mutations and control individuals were compared. Method: Hormones were determined in plasma samples by liquid chromatography tandem mass spectrometry (LC-MS/MS) in 58 carriers (35 males, 23 females, age range 6-78 years) and 44 random controls (25 males, 19 females, age range 8-58 years). Results: Heterozygotes could be identified best applying the 17-hydroxyprogesteroneC21-deoxycortisol/cortisol!1000 ((17OHPC21S)/F!1000) equation 30 min after ACTH injection. An optimal cut-off value of 8.4 provided 89% sensitivity and specificity. Considering this data and a published frequency of heterozygotes of 1/50 to 1/61, the positive predictive value (PPV) of this cut-off is 12%. Of note, the negative predictive value (NPV) excluding heterozygosity in a given patient is 99.8%. Conclusion: Considering only marginal biochemical effects anticipated from heterozygosity, the stimulated ((17OHPC21S)/ F!1000) identifies and excludes heterozygotes remarkably well. Nevertheless, LC-MS/MS cannot replace genetic testing, since sensitivity and specificity did not reach 100%. However, due to the considerably high NPV of the optimal cut-off and to a specificity of even 100% applying a cut-off higher than 14.7, hormonal assessment of heterozygosity can be of significant aid in conditions with limited access to genetic testing, as in some health care systems. The ((17OHPC21S)/F!1000) equation can guide diagnostic considerations in the differential diagnosis of hyperandrogenism.

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Section: Discussionmentioning

confidence: 99%

LC–MS/MS based determination of basal- and ACTH-stimulated plasma concentrations of 11 steroid hormones: implications for detecting heterozygote CYP21A2 mutation carriers

Kulle

Riepe

Hedderich

et al. 2015

European Journal of Endocrinology

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“…Tanulmányukban szintén kimutatták, hogy az elhízással kapcsolatos gének (mint az FTO és a melanocortin receptor 4 gén -MC4R) szintén magasabb BMI-értékhez vezet PCOS-ben, de nem játszanak fontos szerepet a szindróma kialakulásában. Mivel a PCOS és elhízás között szoros kapcsolat van, érdemes lehet más, zsírmennyiséget befolyásoló gének eltérései-nek a vizsgálata, keresése, amelyek szerepet játszhatnak a PCOS kialakulásában [15][16][17][18][19].…”

Section: Kandidáns Gének Elhízásbanunclassified

Genetikai és epigenetikai faktorok polycystás ovarium szindróma esetén

et al. 2016

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A polycystás ovarium szindróma kialakulásának pontos mechanizmusa a mai napig nem tisztázott, de környezeti, illetve genetikai tényezők nagy valószínűséggel szerepet játszhatnak a kialakulásában. Ezt a megállapítást alátámasztja a gyakran előforduló családi halmozódás is. A praenatalis időszakban elszenvedett teratogén hatások a postnatalis időszakban kialakuló krónikus betegségek kifejlődéséhez vezethetnek. A szerzők polycystás ovarium szindrómában a genetikai és epigenetikai tényezők szerepével foglalkozó, 2016. január 1-jéig publikált szakirodalmi közlemények alapján szakirodalmi kutatást végeztek. Jelen összefoglaló közlemény célja e különleges betegségcsoportra való figyelemfelhívás, valamint e kórképek genetikai és epigenetikai hátterének ismertetése. Orv. Hetil., 2016, 157(32), 1275-1281. Kulcsszavak: polycystás ovarium szindróma, genetika, epigenetika Genetic and epigenetic factors of polycystic ovary syndromeThe development of polycystic ovary syndrome and its exact pathophysiological mechanism is still unclear, but environmental and genetic factors likely play a role. Exposition to teratogenic effects during the prenatal development can lead to chronic diseases in the postnatal period. This finding confirms the common familial aggregation as well. A literature search was conducted up to January 1, 2016 for articles dealing with the genetic or epigenetic factors of polycystic ovary syndrome. This review will discuss the current understanding of the genetic basis and clinical presentation of this disease. Keywords: polycystic ovary syndrome, genetics, epigeneticsHerczeg, Z., Vanya, M., Szili, K., Dézsi, Cs., Nagy, Zs., Szabó, J. [Genetic and epigenetic factors of polycystic ovary syndrome]. Orv. Hetil., 2016, 157(32), 1275-1281. Rövidítések ACTH = adrenokortikotrop hormon; AEPCOS = Androgen Excess and PCOS Society; AR = androgénreceptor; CAG repeat = citozin-adenin-guanin ismétlődés; FSH = folliculus stimulating hormone; FTO = alpha-ketoglutarate-dependent dioxygenase; GnRH = gonadotropin releasing hormone; GWAS = genome-wide association studies; INSR = inzulinreceptor-gén; LH = luteinizáló hormon; NIH = National Institutes of Health; PCOS = polycystás ovarium szindróma; SHBG = szexhormonkötő globulin; SNP = single nucleotide polymorphism; SRDA = szteroid-5-α-reduktáz A polycystás ovárium szindróma (PCOS) definíciója a szindróma 1935-ös, Stein és Leventhal általi leírása óta a gyarapodó ismeretanyag ellenére a mai napig sem tisztá-zott. PrevalenciaA PCOS-t az egyik leggyakrabban előforduló endokrin betegségnek tartják a reproduktív korú nők körében [1][2][3]. Pontos előfordulási gyakoriságát nem egyszerű meg-

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“…O teste de estímulo com ACTH(1-24) discriminou apenas 39% dos heterozigotos, enquanto que o estudo molecular do gene CYP21A2 identificou 100% dos alelos. A freqüência de resposta de 17-OHP maior que o normal, em outras populações, variou de 28 a 89% (35,36).…”

Section: Hirsutismo: Diagnóstico Diferencialunclassified

“…A prevalência de heterozigotos para a forma não clássica de hiperplasia adrenal congênita na população é relativamente alta, da ordem de 5 a 7% (35,37,38). Aproximadamente 50% dos heterozigotos apresentam uma resposta normal da 17-OHP ao estímulo, enquanto que os restantes 50% apresentam uma resposta maior que aquela observada em indivíduos normais.…”

Section: Prof Dr José Antonio Miguel Marcondesunclassified

Hirsutismo: diagnóstico diferencial

Marcondes¹

2006

Arq Bras Endocrinol Metab

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RESUMOO hirsutismo é um dos sinais das síndromes hiperandrogênicas. Uma abordagem prática consiste em dividir as síndromes hiperandrogênicas em virilizantes e não virilizantes, de acordo com a presença ou ausência de sinais de virilização. Um caso de uma paciente com hirsutismo e com uma concentração basal e após estímulo com ACTH(1-24) elevada de 17-OHP é discutido. A ausência de sinais de virilização e a história clínica tornavam pouco prováveis etiologias como neoplasias virilizantes e a hipertecose de ovário. Dentre as causas das síndromes não virilizantes, a presença de distúrbio menstrual e hiperandrogenemia descartou o hirsutismo idiopático. De acordo com o Consenso de Rotterdam, considerouse o diagnóstico de síndrome dos ovários policísticos, procedendo-se à exclusão da forma não clássica da hiperplasia adrenal congênita por deficiência da 21-hidroxilase. A concentração de 17-OHP após estímulo foi de 14 ng/dL, sendo que, na dependência do limite de corte considerado, seria compatível com esta doença. Embora a região promotora do gene não tenha sido estudada, do ponto de vistas prático pode-se considerar que este diagnóstico tenha sido excluído, uma vez que mutações nessa região são raras. Hirsutism is one of the manifestations of the hyperandrogenic syndromes. A practical approach consists of dividing the hyperandrogenic syndromes into virilizing and non-virilizing, in accordance to the presence or absence of virilization symptoms. A case of a patient with hirsutism and a high basal and post-ACTH stimulation concentration of 17-OHP is presented. The absence of virilization and of clinical history discarded as etiology the virilizing neoplasias and hiperthecose of the ovary. Among the causes of non-virilizing syndromes, the presence of the menstrual disturbance and hiperandrogenemia discarded idiopathic hirsutism. In accordance to the Consensus of Rotterdam, the diagnosis of polycystic ovary syndrome was considered. For to exclude the non classic form of congenital adrenal hyperplasia due to 21-hidroxilase deficiency, the patient was submitted to a short ACTH-(1-24) stimulation test. The 17-OHP concentrations after stimuli were 14 ng/dL, being that, in the dependence of the limit of considered cut-off, it would be compatible with this illness. Although the promoter region had not been studied, we can consider that this diagnosis was excluded through the sequencing of CYP21A2 gene, since mutation on the promoter region is a rare event.

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The presence of the 21-hydroxylase deficiency carrier status in hirsute women: phenotype-genotype correlations

Cited by 68 publications

References 31 publications

LC–MS/MS based determination of basal- and ACTH-stimulated plasma concentrations of 11 steroid hormones: implications for detecting heterozygote CYP21A2 mutation carriers

LC–MS/MS based determination of basal- and ACTH-stimulated plasma concentrations of 11 steroid hormones: implications for detecting heterozygote CYP21A2 mutation carriers

Genetikai és epigenetikai faktorok polycystás ovarium szindróma esetén

Hirsutismo: diagnóstico diferencial

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