Differences in hormonal levels between heterozygous CYP21A2 pathogenic variant carriers, non-carriers, and females with non-classic congenital hyperplasia

ABSTRACT Objective: CYP21A2 mutation heterozygote carriers seem to have an increased risk of hyperandrogenism. However, the clinical relevance of the heterozygote carrier status and the reliability of hormonal testing in discriminating a carrier from a non-carrier are puzzling questions. We aimed to characterize a population of Portuguese females suspected of having non-classic congenital adrenal hyperplasia (NC-CAH) due to clinical and biochemical criteria and who have undergone CYP21A2 molecular analysis. Subjects and methods: Retrospectively, we have analyzed the clinical records of 131 females (32 girls aged 3-9 and 99 adolescents and premenopausal women aged 13-49) who underwent complete CYP21A2 molecular analysis due to suspicion of NC-CAH. We divided included participants into three groups according to the CYP21A2 molecular analysis: NC-CAH females (46), heterozygous carriers (49), and wild type (36). We then compared clinical signs and symptoms as well as biochemical and molecular data between carriers and NC-CAH individuals and between carriers and wild type females. We measured 17OHP by electrochemiluminescence immunoassay. Results: Clinical features were similar between groups. Heterozygous carriers presented higher basal and post-cosyntropin 17-hydroxyprogesterone (17OHP) than wild type individuals (p < 0.05) and lower basal and stimulated 17OHP levels than NC-CAH patients (p < 0.05). We discovered a considerable overlap between 17OHP levels among groups. The most common pathogenic variant we identified was p.Val282Leu. Conclusion: In this population of hyperandrogenic women and children, heterozygous carriers showed higher basal and stimulated 17OHP than non-carriers although normal basal and stimulated 17OHP responses do not exclude heterozygosity for CYP21A2 pathogenic variants. In this study, only the molecular analysis presented good sensitivity in identifying heterozygotes.

Complete mole in a dichorionic twin pregnancy after intracytoplasmic sperm injection / Mola hidatiforme completa em gravidez bicoriônica após injecção intracitoplasmática de espermatozoides

A dichorionic twin pregnancy with complete hydatidiform mole and coexistent fetus is a rare and challenging situation, whose pathogenesis has not been yet fully understood. We present a case of a 39-year-old woman who underwent intracytoplasmic sperm injection with two embryos transfer. The 12-week gestation ultrasound examination revealed normal fetus and placenta with features of hydatidiform mole, leading to pregnancy termination. Autopsy and histological examinations diagnosed a complete mole coexisting with a normal fetus, and the genetic analysis showed a diploid fetus with biparental genome and molar tissue with paternal diploidy. This case highlighted that complete molar pregnancies may still occur even though pregnancy is achieved after intracytoplasmic sperm injection. A review of the literature was performed by collecting data from the few similar reported cases and by commenting on the pathogenesis of this rare condition.

Uma gravidez bicoriônica com mola hidatiforme completa e feto normal é uma situação rara e desafiadora, cuja patogênese não foi ainda totalmente compreendida. Apresenta-se o caso de uma mulher de 39 anos submetida à injeção intracitoplasmática de espermatozoides com transferência de dois embriões. Na ecografia pré-natal realizada na 12ª semana de gestação, foi identificado um embrião morfologicamente normal e uma placenta com características molares. Esta situação resultou na terminação eletiva da gravidez. A autópsia e o estudo histológico permitiram o diagnóstico definitivo de uma mola hidatiforme completa coexistindo com feto normal. A análise genética mostrou feto diploide com genoma biparental e tecido molar com diploidia paterna. Este caso ressaltou que as gestações com mola hidatiforme completa poderão ainda ocorrer, mesmo que a gravidez seja realizada após uma injeção intracitoplasmática de espermatozoides. Foram realizadas uma revisão dos raros casos descritos na literatura e uma explicação da patogenia desta condição rara.

Recurrent nodules in the calves: A sign of tuberculosis / Recurrent nodules in the calves: A sign of tuberculosis

Aims: To describe a case of erythema induratum of Bazin, classified as a tuberculid, or skin lesion with similar histological features to true cutaneous tuberculosis, in which the relation with Mycobacterium tuberculosis cannot be easily demonstrated.Case Description: A 60-year-old woman presented with recurrent multiple nodules in the legs. Skin examination revealed violaceous painless nodules, some of them ulcerated, with a serous fluid, located on both legs in an asymmetric way, predominantly in the calves. Lesions disappeared spontaneously for brief periods. Skin biopsies revealed septal and lobular panniculitis with epithelioid granulomata and vascular necrosis. Tuberculin skin test was positive. Culture of the cutaneous lesions and polymerase chain reaction to Mycobacterium tuberculosis were negative, but mediastinal lymph nodes collected through mediastinoscopy were cultivated and positive to Mycobacterium tuberculosis. Therapy with isoniazid, rifampicin, pyrazinamide and ethambutol were administered. After two months under therapy the skin lesions healed. The clinical and histopathological features and the strong positive tuberculin skin test have strongly suggested the diagnosis of erythema induratum of Bazin. Positive culture for Mycobacterium tuberculosis and the remission of the lesions with antituberculosis therapy confirmed the diagnosis.Conclusions: Clinicians must be aware of the differential diagnosis of recurrent skin lesions, including the erythema induratum of Bazin. In this case, association with tuberculosis was confirmed by positive culture of mediastinal lymph nodes for Mycobacterium tuberculosis and remission of the lesions with antituberculosis therapy.

Objetivos: descrever um caso de eritema induratum de Bazin, classificado como tubercúlide, lesão cutânea com características histológicas semelhantes à tuberculose cutânea, mas na qual a relação entre o Mycobacterium tuberculosis não é facilmente demonstrada.Descrição do Caso: uma mulher de 60 anos de idade apresentou-se com múltiplos nódulos recorrentes nos membros inferiores. O exame da pele revelou nódulos indolores, violáceos, alguns deles ulcerados, com um líquido seroso, localizados em ambas as pernas, de forma assimétrica e com predomínio nas panturrilhas. As lesões apresentavam um aparecimento paroxístico, com remissão espontânea por breves períodos. Foi realizada biópsia cutânea que revelou paniculite septal e lobular com granulomas epitelióides e necrose vascular. O teste tuberculínico foi positivo. A cultura das lesões cutâneas e a reação em cadeia da polimerase para Mycobacterium tuberculosis foram negativos, mas foi realizada biópsia de linfonodos por mediastinoscopia, cuja cultura foi positiva para Mycobacterium tuberculosis. Foi iniciada terapêutica específica com isoniazida, rifampicina, pirazinamida e etambutol. Após dois meses de tratamento houve remissão das lesões. As características clínicas e histopatológicas e o teste tuberculínico fortemente positivo sugeriram o diagnóstico de eritema indurado de Bazin, sendo este confirmado pela cultura de linfonodos positiva para Mycobacterium tuberculosis e pela remissão das lesões com a terapêutica antituberculose.Conclusões: o clínico precisa estar atento para o diagnóstico diferencial de lesões cutâneas recorrentes, incluindo neste o eritema induratum de Bazin. Neste caso, a associação com a tuberculose ficou confirmada pela cultura dos linfonodos mediastinais positiva para Mycobacterium tuberculosis e remissão das lesões com a terapêutica antituberculose.