{"id":9513,"date":"2026-01-24T08:35:20","date_gmt":"2026-01-24T08:35:20","guid":{"rendered":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/2026\/01\/24\/genetic-analysis-does-not-confirm-non-classical-congenital-adrenal-hyperplasia-in-more-than-a-third\/"},"modified":"2026-01-24T08:35:20","modified_gmt":"2026-01-24T08:35:20","slug":"genetic-analysis-does-not-confirm-non-classical-congenital-adrenal-hyperplasia-in-more-than-a-third","status":"publish","type":"post","link":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/2026\/01\/24\/genetic-analysis-does-not-confirm-non-classical-congenital-adrenal-hyperplasia-in-more-than-a-third\/","title":{"rendered":"Genetic analysis does not confirm non-classical congenital adrenal hyperplasia in more than a third of the women followed with this diagnosis"},"content":{"rendered":"
Valeria Alcantara-Aragon,1<\/sup> Silvia Martinez-Couselo,2<\/sup> Diana Tundidor-Rengel,1<\/sup> Susan M. Webb,1,5<\/sup> Gemma Carreras,3<\/sup> Juan J. Espinos,4<\/sup> Ana Chico,1<\/sup> Francisco Blanco-Vaca,2<\/sup> Rosa Corcoy1,6<\/sup> <\/div>\n
1<\/sup>Endocrinology, 2<\/sup>Biochemistry, 3<\/sup>Pediatrics, and 4<\/sup>Gynecology Departments, Hospital de la Santa Creu I Sant Pau, 5<\/sup>CIBERER 747, 6<\/sup>CIBERBBN; Barcelona, Spain <\/div>\n
\n

Dear Sir,<\/p>\n

Non-classical congenital adrenal hyperplasia (NCCAH) due to 21-hydroxylase deficiency is one of the most frequent autosomal recessive diseases, with an estimated prevalence of 1 in 1000. It may manifest at different stages in life. In late childhood, it may present with advanced skeletal maturation, accelerated growth or premature pubarche. In adult women, the disease usually presents with a hyperandrogenic syndrome including hirsutism, acne, androgenic alopecia, anovulation, menstrual dysfunction, and infertility.1,2<\/sup> However, not all individuals with NCCAH are symptomatic and affected males are not usually detected until a female family member is diagnosed.1,2<\/sup><\/p>\n

Individuals with NCCAH may be compound heterozygotes and can carry severe CYP21A2<\/em> allele mutations.2<\/sup> Consequently, genetic testing and counseling is is highly recommended when when planning pregnancy. Our aim was to assess CYP21A2<\/em> allele mutations and review the clinical characteristics in patients with a NCCAH diagnosis attended at the center, irrespective of their need for genetic counseling at short term.<\/p>\n

Patients with a diagnosis of NCCAH were recruited when they came for their regular follow-up visits. Medical records were examined to retrieve data about initial clinical presentation, later signs and symptoms, hormonal work-up [basal and stimulated 17-hydroxyprogesterone (17OHP)], and treatment at diagnosis and follow-up. A standardized database was used. The interpretation of the patients\u2019 hormonal work-up was performed according to Speiser PW et al: basal 17OHP \u22656 and <30 nmol\/L was considered abnormal, while basal or stimulated 17OHP \u226530 and <300 nmol\/l was considered indicative of NCCAH.3<\/sup> Analysis of the CYP21A2 <\/em>gene was performed through polymerase chain reaction, sequencing, and family genetic testing when possible.4<\/sup> Data obtained from descriptive statistic analysis is expressed as percentages and medians (interquartile range). Chi-square and Mann-Whitney tests were used for comparisons among groups. The Institutional Review Board gave special approval for the study.<\/p>\n

Results are summarized in Table 1<\/a>. The audit included 29 women followed at the Pediatrics (N=5), Gynecology & Obstetrics (N= 6) or Endocrinology & Nutrition (N= 18) Departments at our center. The initial clinical diagnosis was made in all of these departments, as well as in the Endocrinology Departments of other centers from 1976 to 2010. Twenty-four patients (82.7%) were index cases. Age at first symptom was 15.8 \u00b1 8 years and the median number of symptoms was 2 (1 to 3). The most common manifestations were hirsutism (69%) and oligomenorrhea (48.3%). Basal 17OHP at diagnosis was available in the clinical records of 22 patients (75.9%) and was 14 nmol\/l (5.75 to 41). Stimulated 17OHP was available in 8 patients (27.6%) and was 142 nmol\/l (38.5 to 177.75). In a substantial subset of patients in follow-up for NCCAH (16, 55.2%), hormonal work-up available in the clinical records was not sufficient to establish a NCCAH diagnosis.<\/p>\n

Genetic analysis is summarized in Table 1<\/a>. Genetic testing of parents or siblings was performed in 10 patients (34.5%) to clarify the genetic diagnosis. The most common mutation (28 out of 45, 62%) was one that is known to be mild: Val281Leu. Globally, 37.9% of the genetic results did not confirm the alleged diagnosis. Other genes were not analyzed, but since 95% of cases are due to a mutation of the CYP21A2 <\/em>gene,3<\/sup> it is unlikely that more than one third of the women had a mutation in a different gene.<\/p>\n

The rate of non-confirmatory genetic analysis was not significantly different in women with a satisfactory biochemical diagnosis of NCCAH (33.1%) vs those without (50%). Department of origin, the patient\u2019s index condition, age at initial presentation, and number of signs\/symptoms did not differ between women with and without a genetic diagnosis of NCCAH (data not shown). Twenty-six women (89.7%) received drug treatment for NCCAH at some point during follow-up, most frequently corticosteroids (23 women, 79.3%). Similarly, at 314 follow-up visits, 87.9% of the women were receiving drug treatment, most frequently corticosteroids (74.2%). Use of drug treatment did not differ in women with and without a genetic diagnosis of NCCAH (88.9 vs 90.9% at some point during follow-up, ns).<\/p>\n

The main finding of this investigation is that a clinically significant subset of women followed and treated according to a diagnosis of NCCAH did not have a confirmatory genetic diagnosis. Some patients had been referred from other centers and access to lab tests at diagnosis and follow-up was limited. This could partly explain the less than optimal rate of available hormonal work-up at diagnosis. The limited sample size may have contributed to the non-significant differences in the characteristics of women with and without a genetic diagnosis of NCCAH.<\/p>\n

All women included in this series presented symptoms suggestive of NCCAH together with at least an abnormal basal 17OHP at some point that could help understand the assignment of a NCCAH diagnosis. The heterozygote condition was not uncommon. In the literature, the clinical presentation and 17OHP values of the heterozygote carriers may overlap with that of NCCAH.2<\/sup> Other conditions, such as premature adrenarche in childhood or PCOS in young adults, might have been present. For example, Pall et al5<\/sup> reported an elevation of basal 17OHP in up to 25% of patients with PCOS.<\/p>\n

Current guidelines emphasize limiting drug treatment to symptomatic NCCAH patients and avoiding corticosteroids whenever possible, with the exception of women seeking pregnancy.3<\/sup> At present we can only speculate on the potential untoward effects of prolonged treatment for a non-existing NCCAH.<\/p>\n

The results of this audit compel us to reconsider the diagnostic and therapeutic requirements of patients coming to the outpatient clinic with an alleged diagnosis of NCCAH. The fact that a significant percentage of patients attended in different departments with a NCCAH diagnosis did not have a confirmatory genetic analysis suggests that the situation may not be uncommon.<\/p>\n

REFERENCES<\/span><\/p>\n

1. White PC, Speiser PW, 2000 Congenital adrenal hyperplasia due to 21-hydroxylased Deficiency. Endocr Rev 21: 245-291.
2. Witchel SF, 2013 Non-classic congenital adrenal hyperplasia. Steroids 78: 747-750.
3. Speiser PW, Azziz R, Baskin LS, et al, 2010 Congenital Adrenal Hyperplasia Due to Steroid 21-Hyroxylase Deficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 95: 4133-4160.
4. Bidet M, Bellann\u00e9-Chantelot C, Galand-Portier MB, et al, 2009 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. J Clin Endocrinol Metab 94: 1570-1578.
5. Pall M, Azziz R, Beires J, et al, 2010 The phenotype of hirsute women: a comparison of polycystic ovary syndrome and 21-hydroxylase-deficient nonclassic adrenal hyperplasia. Fertil Steril 94: 684-689. <\/p>\n

Address for correspondence:<\/span>
Valeria Alcantara-Aragon, Endocrinology Department, Hospital de la Santa Creu I Sant Pau, Sant Antoni Maria Claret 167, Barcelona 08025, Spain, Tel.: +30 935565661, Fax: +30 935565602, e-mail: VAlcantara@santpau.cat<\/p>\n

Received 03-03-2013, Accepted 14-04-2014 <\/p><\/div>\n

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Valeria Alcantara-Aragon,1 Silvia Martinez-Couselo,2 Diana Tundidor-Rengel,1 Susan M. Webb,1,5 Gemma Carreras,3 Juan J. Espinos,4 Ana Chico,1 Francisco Blanco-Vaca,2 Rosa Corcoy1,6 1Endocrinology, 2Biochemistry, 3Pediatrics, and 4Gynecology Departments, Hospital de la Santa Creu I Sant Pau, 5CIBERER 747, 6CIBERBBN; Barcelona, Spain Dear Sir, Non-classical congenital adrenal hyperplasia (NCCAH) due to 21-hydroxylase deficiency is one of the most Read More<\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[70,2,15],"tags":[1760,1761],"class_list":["post-9513","post","type-post","status-publish","format-standard","hentry","category-volume-13-issue-4","category-journal-articles","category-volume-13","tag-17-alpha-hydroxy-progesterone","tag-non-classical-congenital-adrenal-hyperplasia"],"_links":{"self":[{"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/posts\/9513","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/comments?post=9513"}],"version-history":[{"count":0,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/posts\/9513\/revisions"}],"wp:attachment":[{"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/media?parent=9513"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/categories?post=9513"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/tags?post=9513"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}