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.

Malignant melanoma with synchronous thyroid metastases: case report and literature review

SUMMARY Thyroid metastases are rare in clinical practice. We describe the case of an 85-year-old woman who was referred to our department due to a multinodular goiter with compressive symptoms and subclinical hyperthyroidism. The patient was also undergoing evaluation for a polyp in her left nasal cavity, which was then diagnosed as a malignant melanoma of the nasal mucosa. A thoracoabdominal magnetic resonance imaging obtained for cancer staging revealed a > 50% tracheal obstruction caused by the goiter. The patient underwent simultaneous total thyroidectomy and melanoma excision. Histological analysis of the thyroid showed the presence of multiple metastatic foci from the melanoma. Due to the patient’s age, a decision was made to maintain her under surveillance and administer palliative treatment if necessary. Although metastases to the thyroid are rare, they should be considered in the differential diagnosis of thyroid lesions in patients with a known primary tumor. The thyroidectomy, performed in this patient’s case, allowed the diagnosis of the metastases and relief of compressive symptoms caused by the goiter.

Permanent neonatal diabetes by a new mutation in KCNJ11: unsuccessful switch to sulfonylurea

Permanent neonatal diabetes (PNDM) can result from activating heterozygous mutations in KCNJ11 gene, encoding the Kir6.2 subunit of the pancreatic ATP-sensitive potassium channels (KATP). Sulfonylureas promote KATP closure and stimulate insulin secretion, being an alternative therapy in PNDM, instead of insulin. Male, 20 years old, diagnosed with diabetes at 3 months of age. The genetic study identified a novel heterozygous mutation in exon 1 of the KCNJ11 gene – KCNJ11:c1001G>7 (p.Gly334Val) – and confirmed the diagnosis of PNDM. Therefore it was attempted to switch from insulin therapy to sulfonylurea. During glibenclamide institution C-peptide levels increased, however the suboptimal glycemic control lead us to restart an intensive insulin scheme. This new variant of KCNJ11 mutation had a phenotypic lack of response to sulfonylurea therapy. Age, prior poor metabolic control and functional change of KATP channel induced by this specific mutation may explain the observed unsuccessful switch to sulfonylurea. Interestingly, C-peptide levels raise during glibenclamide administration support some degree of improvement in insulin secretory capacity induced by the treatment. Understanding the response to sulfonylurea is crucial as successful treatment may be life-changing in these patients.

Ovarian Leydig cell tumor in a post-menopausal patient with severe hyperandrogenism / Tumor ovariano de células de Leydig em paciente em pós-menopausa com hiperandrogenismo grave

Leydig cell tumors are rare ovarian steroid cell neoplasms. More than 75% of patients show signs of virilization due to overproduction of testosterone. We report a case of an 8-year-old woman with progressive signs of virilization, and presenting vaginal bleeding. Clinical analyses revealed high levels of serum testosterone, delta 4-androstenedione and estradiol, and also inappropriate low levels of gonadotrophins for a post-menopausal woman. Transvaginal ultrasound showed no evidence of ovarian tumor, but pelvic and abdominal computerized axial tomography imaging revealed a left ovarian solid nodule, and no evidence of alteration in the adrenal glands. Total hysterectomy and bilateral salpingoophorectomy were performed. Histopathology and immunohistochemistry confirmed the diagnosis of Leydig cell tumor. After surgery, androgen levels returned to normal, and there was regression of the signs of virilization.

Tumores ovarianos de células de Leydig são neoplasias raras de células ovarianas esteroidogênicas. Mais de 75% dos pacientes apresentam sinais de virilização devido à produção excessiva de testosterona. Relatamos aqui o caso de uma mulher de 81 anos de idade com sinais progressivos de virilização e ocorrência de sangramento vaginal. As análises clínicas mostraram altos níveis de testosterona sérica, delta 4-androstenediona e estradiol, além de níveis inadequadamente baixos de gonadotrofinas para uma mulher em pós-menopausa. O ultrassom transvaginal não apresentou evidências de tumor ovariano, mas a tomografia axial computadorizada da região pélvico-abdominal mostrou um nódulo sólido no ovário esquerdo e nenhuma evidência de alteração nas adrenais. Foi feita uma histerectomia total e salpingooforectomia bilateral. Os exames histopatológicos e a imuno-histoquímica confirmaram o diagnóstico de tumor de células de Leydig. Após a cirurgia, os níveis de androgênios voltaram ao normal, e os sinais de virilização regrediram.

Ovarian intratumoral 21-hydroxylase deficiency in a postmenopausal hirsute woman / Deficiência de 21-hidroxilase ovariana intratumoral na virilização da mulher pós-menopausa

Virilising ovarian tumours are a rare cause of hyperandrogenism in women, accounting for less than 5% of all ovarian neoplasms. It occurs most often in - and postmenopausal women. We report a case of a 64 year-old woman with signs of virilisation that had started 3 years before. Blood hormone analysis revealed increased levels of testosterone, and 17-hydroxyprogesterone. The tetracosactin test revealed 21-hydroxylase deficiency. Radiological imaging demonstrated a nodule in her left ovary. The patient was submitted to bilateral laparoscopic oophorectomy, and histopathological examination revealed a luteoma of the left ovary. Postoperative serum testosterone level and 17-hydroxyprogesterone returned to normal levels in one month. Virilism regressed within six months. Our patient also showed an elevation in 17-OHP serum levels. Normalization of 17-OHP after oophorectomy suggests a case of intratumoral 21-hydroxylase deficiency. To our knowledge, this is the first description of ovarian intratumoral 21-hydroxylase deficiency in a postmenopausal woman. Arq Bras Endocrinol Metab. 2012;56(9):672-6.

Tumores ovarianos virilizantes são uma causa rara de hiperandrogenismo em mulheres, contabilizando menos de 5% de todos as neoplasias ovarianas. Esses tumores ocorrem mais comumente em mulheres em peri ou pós-menopausa. Relatamos aqui o caso de uma mulher de 64 anos de idade com sintomas de virilização que começaram 3 anos antes. O perfil hormonal revelou níveis aumentados de testosterona e de 17-hidroxiprogesterona (17-OHP). O teste de tetracosactin demonstrou deficiência de 21-hidroxilase. Exames radiológicos mostraram um nódulo no ovário esquerdo. A paciente foi submetida à ooforectomia laparoscópica bilateral e o exame histopatológico revelou um luteoma no ovário esquerdo. A concentração sérica de testosterona e de 17-hidroxiprogesterona após a cirurgia retornou aos níveis normais em um mês. A virilização regrediu em 6 meses. Nossa paciente também revelou uma elevação dos níveis séricos de 17-OHP. A normalização da 17-OHP após a ooforectomia sugere um caso de deficiência de 21-hidroxilase intratumoral. Esta é a primeira descrição de deficiência de 21-hidroxilase intratumoral em uma mulher na pós-menopausa. Arq Bras Endocrinol Metab. 2012;56(9):672-6.

Ectopic Cushing's syndrome caused by a pulmonary ACTH-secreting tumor in a patient treated with octreotide / Síndrome de Cushing ectópico causado por um tumor pulmonar secretor de ACTH em tratamento com octreotide

Ectopic ACTH syndrome is a rare disease often associated with severe hypercortisolism. When feasible, optimal management is surgical excision of the tumor. A 33-year-old male patient was admitted to the hospital in 1993 with clinical manifestations suggestive of Cushing's syndrome. He presented high plasma ACTH and markedly elevated urinary free cortisol excretion that was not suppressed with high-dose dexamethasone administration. Pituitary MRI scan was normal. No central-to-peripheral ACTH gradient was present in bilateral inferior petrosal sinus sampling. Thoracic CT scan showed a 1.7 cm nodule at the left lung. Pulmonary fine needle cytology and immunocytochemical and ultrastructural studies, together with the presence of bone metastases, led to the diagnosis of an ACTH-producing neuroendocrine carcinoma. He was initially submitted to chemotherapy and has been on treatment with octreotide LAR since 1998, having shown a favorable clinical, biochemical and imaging response. We highlight the excellent long-term response to medical therapy with octreotide LAR, without tachyphylaxis, probably due to its antiproliferative effect.

A secreção ectópica de ACTH é uma síndrome rara associada habitualmente à hipercortisolemia grave. A remoção cirúrgica do tumor é o tratamento de primeira linha, sempre que seja exequível. Homem com 33 anos, internado em 1993 com manifestações clínicas sugestivas de síndrome de Cushing, apresentava valores elevados de ACTH plasmática e excreção urinária de cortisol livre muito aumentada, sem supressão na prova com dose alta de dexametasona; RM hipofisária sem alterações; cateterismo bilateral dos seios petrosos inferiores sem gradiente central-periférico de ACTH. A CT de tórax mostrou um nódulo de 1,7 cm no pulmão esquerdo. O diagnóstico de carcinoma neuroendócrino produtor de ACTH foi feito com base nos resultados citológico, imunocitoquímico e ultraestrutural, juntamente com a presença de metástases ósseas. Foi inicialmente submetido à quimioterapia e encontra-se em tratamento com octreotide LAR desde 1998, apresentando resposta clínica, bioquímica e imagiológica favorável. Destacamos a excelente resposta a longo prazo à terapêutica com octreotide LAR, sem taquifilaxia, provavelmente devido ao seu efeito antiproliferativo.

Importance of 99mTc-sestaMIBI thyroid scan in a case of amiodarone-induced thyrotoxicosis / A importância da cintigrafia tiroidea com 99mTc-sestaMIBI num caso de tireotoxicose induzida pela amiodarona

Amiodarone (AM)-induced thyrotoxicosis (AIT) is a condition with uncertainties from the diagnostic and therapeutic standpoints. A 54-year old male was referred to the hospital due to thyrotoxicosis. He had history of atrial fibrillation medicated with AM. No history of pre-existing thyroid disease was present, thyroid palpation revealed no goiter, and there were no signs of Graves' ophthalmopathy. Thyroid autoantibodies and thyroid-stimulating hormone receptor antibodies (TRABs) were negative. Thyroid and Doppler ultrasounds were normal. 99mTc-sestaMIBI thyroid scan (STS) showed uptake with rapid washout. AM therapy was discontinued, and combined therapy was started. After a long course of glucocorticoid and thionamides, the patient became euthyroid. It is necessary to distinguish between the types of AIT to decide whether or not continue AM treatment; after that, the appropriate therapy should be selected. STS was very important in the diagnosis of the type of AIT.

A tireotoxicose induzida por amiodarona (AIT) é uma condição incerta do ponto de vista de diagnóstico e tratamento. Um homem de 54 anos de idade foi encaminhado ao hospital devido à tireotoxicose. Ele apresentou um histórico de fibrilação atrial medicada com amiodarona (AM). Não havia histórico de doença da tiroide preexistente, a palpação da tiroide não revelou bócio e não havia sinais de oftalmopatia de Graves. Os autoanticorpos contra a tireoide e anticorpos para os receptores de hormônio estimulante da tireoide (TRABs) foram negativos. Os resultados do ultrassom da tiroide e do exame de Doppler foram normais. A cintigrafia da tiroide com 99mTc-sestaMIBI mostrou captação com rápida eliminação. O tratamento com AM foi descontinuado, e se iniciou a terapia combinada. Após um longo tratamento com glicocorticoides e tionaminas, o paciente se tornou eutiroide. É necessário distinguir entre os tipos de AIT para se determinar a continuação ou interrupção do tratamento com AM. Depois disso, o tratamento apropriado deve ser selecionado. A STS é muito importante no diagnóstico do tipo de AIT.