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Introduction: Until recently no major epidemiological research of primary hyperparathyroidism (PHPT) has been conducted in the Russian Federation, this led to the creation of the Russian online registry. The objective of this study is to estimate the clinical and biochemical profile, classical and non-classical complications, surgical intervention and medical therapy of the patients with different forms of PHPT in the Russian Federation. Materials and methods: The cross-sectional, observational, continuous study was conducted at the Endocrinology Research Centre (Moscow). The present study explored retrospective data from 6003 patients submitted to the Registry between 12.12.2016 and 25.10.2022 from 81 regions of the Russian Federation (http://pgpt.clin-reg.ru/). Results: The median age was 59 [60; 66] years with a female:male ratio of 11.7:1. Symptomatic PHPT was observed in 74.3% while asymptomatic form - only in 25.7% of cases. Bone pathology was the predominant clinical manifestation in 62.5% of cases (n=2293), mostly in combination with visceral complications 45.7% (n=1676). The majority of patients (63.3%) had combined visceral disorders including kidney damage in 51.8% and gastroduodenal erosions/ulcers in 32.3% of patients. Symptomatic patients were older (60 [53; 67] vs. 54 [45; 62] years, p<0.001) and had more severe biochemical alterations of calcium-phosphorus metabolism. Cardiovascular disease (СVD) was recorded in 48% of patients, among them the most frequent was arterial hypertension (up to 93.9%). A genetic test was conducted in 183 cases (suspicious for hereditary PHPT) revealing the mutations in MEN1, CDC73, RET genes in 107, 6 and 2 cases, respectively. Surgery was performed in 53.4% of patients with remission achievement in 87%, the relapse/persistence were recorded in 13% of cases. Histological examination revealed carcinoma in 4%, atypical adenoma in 2%, adenoma in 84% and hyperplasia in 11% of cases. Drug therapy was prescribed in 54.0% of cases, most often cholecalciferol. Conclusion: The detection rate of PHPT has increased in the Russian Federation in recent years. This increase is associated with the start of online registration. However, the majority of patients remain symptomatic with significant alterations of phosphorus-calcium metabolism that indicates delayed diagnosis and requires further modifications of medical care.
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Adenoma , Hiperparatireoidismo Primário , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Cálcio , Estudos Retrospectivos , Hiperparatireoidismo Primário/complicações , Hiperparatireoidismo Primário/epidemiologia , Hiperparatireoidismo Primário/genética , Estudos Transversais , Sistema de Registros , Cálcio da Dieta , Adenoma/complicações , FósforoRESUMO
BACKGROUND: The registry is the main source of information about patients with acromegaly for assessing the quality of medical care, effectiveness of treatment, determining the compliance of real clinical practice with existing standards and patient management protocols. AIMS: To evaluate epidemiological, demographic and clinical characteristics of acromegaly in Russian Federation and effectiveness of treatment modalities. MATERIALS AND METHODS: The object of the study was the database of the united Russian registry of patients with pituitary tumors with specific analysis of patients with acromegaly only. We analyzed the data of 4114 patients with acromegaly stored on the online system in February 2019. RESULTS: Based on the data 32% of patients had complete clinical and laboratory remission of acromegaly; the percentage of patients with no remission was 68%, among them 22.5% had significant improvements in clinical symptoms and a decrease in growth hormone (GH) and insulin-like growth factor-1 (IGF-1) without IGF-1 normalization. The average age of patients at the onset of the disease was 42.7 years and at diagnosis – 45.8 years. The ratio of men to women was 1:2.6. In patients with acromegaly hypopituitarism was registered in 14.7% of cases and among them hypothyroidism (66%) and hypogonadism (52%) were registered more often. Among other complications the leading were diabetes mellitus (15.7%) and acromegalic arthropathy (15%). The proportion of patients receiving neurosurgical treatment increased from 35.7% to 49.6% in 2012–2019; the portion of patients undergoing radiation therapy decreased significantly from 17.7% in 2012 to 0.8% in 2019. Remission was achieved in 40.47% after neurosurgery and 28.95% after medical treatment as a first line therapy p<0.01. The number of patients receiving medical treatment at the time of the study was 1209. Among them 51% of patients treated with long-acting lanreotide and 24% receiving long-acting octreotide achieved remission (p<0.0001) CONCLUSIONS: The remission rate of acromegaly remains suboptimal despite increased surgical activity, which corresponds to global trends. Long-acting lanreotide was significantly superior versus long-acting octreotide in the rate of acromegaly remission, which does not correspond with clinical trials.
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Acromegalia , Neoplasias Hipofisárias , Acromegalia/tratamento farmacológico , Adulto , Feminino , Humanos , Masculino , Octreotida , Neoplasias Hipofisárias/epidemiologia , Sistema de Registros , Federação Russa/epidemiologiaRESUMO
Corticotropinomas and adrenocorticotropic hormone (ACTH)-secreting neuroendocrine tumors exhibit differential levels of some microRNAs (miRs) compared to normal tissue. Because miRs can be released from tissues into circulation, they offer promise as novel disease biomarkers. Objective: To evaluate whether miRs are differentially detected in plasma samples of patients with ACTH-dependent Cushing's syndrome (CS). Design: Case-control study. Methods: Morning fasting plasma samples were collected from 41 consecutive patients with confirmed ACTH-dependent CS and 11 healthy subjects and stored at -80°C. Twenty-one miRs previously reported to be differentially expressed in ACTH-secreting tumors vs. healthy tissue samples were quantified in plasma by qPCR. Results: Among enrolled subjects, 28 were confirmed to have Cushing's disease (CD), 13 had ectopic ACTH secretion (EAS) and 11 were healthy controls. We found statistically significant differences in the circulating levels of miR-16-5p [45.04 (95% CI 28.77-61.31) in CD vs. 5.26 (2.65-7.87) in EAS, P < 0.001; q = 0.001], miR-145-5p [0.097 (0.027-0.167) in CD vs. undetectable levels in EAS, P = 0.008; q = 0.087] and differences in miR-7g-5p [1.842 (1.283-2.400) in CD vs. 0.847 (0.187-1.507) in EAS, P = 0.02; q = 0.14]. The area under the receiver-operator (ROC) curve was 0.879 (95% CI 0.770-0.987), p < 0.001, when using miR-16-5p to distinguish between CD and EAS. Circulating levels of miR-16-5p in the healthy control group differed from that of both the CD and EAS groups. Conclusions: Plasma miR levels differ in patients with CD and EAS. In particular, miR-16-5p, miR-145-5p and miR-7g-5p are promising biomarkers for further research to differentiate ACTH-dependent CS.
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Síndrome de ACTH Ectópico/diagnóstico , Biomarcadores/sangue , MicroRNA Circulante/genética , Síndrome de Cushing/diagnóstico , MicroRNAs/genética , Síndrome de ACTH Ectópico/sangue , Síndrome de ACTH Ectópico/genética , Adulto , Estudos de Casos e Controles , Síndrome de Cushing/sangue , Síndrome de Cushing/genética , Diagnóstico Diferencial , Feminino , Seguimentos , Humanos , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Prognóstico , Curva ROCRESUMO
Hypoparathyroidism and pseudohypoparathyroidism are rare endocrine disorders, characterized by low serum calcium due to inappropriate parathyroid hormone (PTH) levels or resistance to its action. There is little epidemiological information regarding chronic hypoparathyroidism in Russia. This study aims to build a registry database of Russian patients with chronic hypoparathyroidism who were referred for hospital treatment in order to conduct initial analysis of clinical presentations and hospital management. The Italian registry model was taken to be able to integrate our data in the future. Two hundred patients with hypoparathyroidism (n = 194) and pseudohypoparathyroidism (n = 6) were enrolled over 2 years (2017-2019). The most frequent cause of hypoparathyroidism was neck surgery (82.5%, mostly females), followed by idiopathic hypoparathyroidism (10%), syndromic forms of genetic hypoparathyroidism (4.5%) and forms of defective PTH action (3%). Calcium supplements and alfacalcidol were prescribed in most cases. However, a minority of patients (n = 6) needed to receive teriparatide as the only way to maintain calcium levels and to prevent symptoms of hypocalcemia. Consequently, substitution treatment with parathyroid hormone should be available in certain cases of hypoparathyroidism. This database will be useful to estimate the potential requirement for recombinant PTH in Russia and standards for clinical and therapeutic approaches.
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BACKGROUND: Some laboratory and clinical features are associated with a probability of recurrence after transnasal adenomectomy for Cushing disease (CD). However, there is no consensus on a set of predictors. Rules for prediction of recurrence were not proposed earlier. AIM: To develop prediction model of recurrence/remission after successful neurosurgical treatment for CD. METHODS: Retrospective single-site comparative study included 349 patients (52 men and 297 women) with a verified diagnosis of CD who underwent effective endoscopic transsphenoidal adenomectomy between 2007 and 2014. Clinical and laboratory parameters were evaluated. Laboratory tests were performed using immunochemiluminescent method. Time-to-event analysis and ROC-analysis were applied. Multivariate models were developed using logistic regression and artificial neural network (ANN). RESULTS: Postoperative cortisol and ACTH levels and their combinations cannot be used for prediction of recurrence. ANN for prediction of recurrence within 3 years after successful surgery was developed. Input variables are age, duration of the disease, MRI data on adenoma, morning postoperative levels of ACTH and cortisol, output variable is binary (recurrence/remission). Predictive value for remission is 93%, 95% CI [89%; 96%], and predictive value for recurrence is 85%, 95% CI [71%; 94%]. Web-calculator based on the model is developed and free for use. CONCLUSION: Effective method for prediction of recurrence and long-term remission within 3 years after successful endoscopic transsphenoidal adenomectomy is proposed.
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Hipersecreção Hipofisária de ACTH/patologia , Hipersecreção Hipofisária de ACTH/cirurgia , Adolescente , Hormônio Adrenocorticotrópico/sangue , Adulto , Idoso , Feminino , Humanos , Hidrocortisona/sangue , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Procedimentos Neurocirúrgicos , Hipersecreção Hipofisária de ACTH/sangue , Neoplasias Hipofisárias/sangue , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/cirurgia , Curva ROC , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: To evaluate the response of bone to chronic long-term growth hormone (GH) and insulin-like growth factor-1 (IGF1) excess by measuring the expression of selected mRNA and microRNA (miR) in bone tissue samples of patients with active acromegaly. DESIGN: Case-control study. METHODS: Bone tissue samples were obtained during transsphenoidal adenomectomy from the sphenoid bone (sella turcica) from 14 patients with clinically and biochemically confirmed acromegaly and 10 patients with clinically non-functioning pituitary adenoma (NFPA) matched by sex and age. Expression of genes involved in the regulation of bone remodeling was studied using quantitative polymerase chain reaction (qPCR). RESULTS: Of the genes involved in osteoblast and osteoclast activity, only alkaline phosphatase (ALP) mRNA was 50% downregulated in patients with acromegaly. GH excess caused increased expression of the Wnt signaling antagonists (DKK1) and agonists (WNT10B) and changes in the levels of miR involved in mesenchymal stem cell commitment to chondrocytes (miR-199a-5p) or adipocytes (miR-27-5p, miR-125b-5p, miR-34a-5p, miR-188-3p) P < 0.05; q < 0.1. Relevant compensatory mechanisms were found through the changes in miR involved in osteoblastogenesis (miR-210-5p, miR-135a-5p, miR-211, miR-23a-3p, miR-204-5p), but the expression of TWIST1 was 50% downregulated and RUNX2 was unchanged. CONCLUSIONS: Acromegaly had minimal effects on tested mRNAs specific to osteoblast or osteoclast function except for downregulated ALP expression. The expressions of miR known to be involved in mesenchymal stem cell commitment and downregulated TWIST1 expression suggest acromegaly has a negative effect on osteoblastogenesis.
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Acromegalia/metabolismo , Hormônio do Crescimento Humano/biossíntese , MicroRNAs/biossíntese , RNA Mensageiro/biossíntese , Osso Esfenoide/metabolismo , Acromegalia/diagnóstico , Acromegalia/genética , Adulto , Estudos de Casos e Controles , Estudos Transversais , Feminino , Expressão Gênica , Hormônio do Crescimento Humano/genética , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , RNA Mensageiro/genética , Osso Esfenoide/patologiaRESUMO
BACKGROUND: Primary hyperparathyroidism (PHPT) is a relatively rare disorder among children, adolescents and young adults. Its development at an early age is suspicious for hereditary causes, though the need for routine genetic testing remains controversial. OBJECTIVE: To identify and describe hereditary forms of PHPT in patients with manifestation of the disease under 40 years of age. DESIGN: We enrolled 65 patients with PHPT diagnosed before 40 years of age. Ten of them had MEN1 mutation, and PHPT in them was the first manifestation of multiple endocrine neoplasia type 1 syndrome. METHODS: The other fifty-five patients underwent next-generation sequencing (NGS) of a custom-designed panel of genes, associated with PHPT (MEN1, CASR, CDC73, CDKN1A, CDKN1B, CDKN1C, CDKN2A, CDKN2C, CDKN2D). In cases suspicious for gross CDC73 deletions multiplex ligation-dependent probe amplification was performed. RESULTS: NGS revealed six pathogenic or likely pathogenic germline sequence variants: four in CDC73 c.271C>T (p.Arg91*), c.496C>T (p.Gln166*), c.685A>T (p.Arg229*) and c.787C>T (p.Arg263Cys); one in CASR c.3145G>T (p.Glu1049*) and one in MEN1 c.784-9G>A. In two patients, MLPA confirmed gross CDC73 deletions. In total, 44 sporadic and 21 hereditary PHPT cases were identified. Parathyroid carcinomas and atypical parathyroid adenomas were present in 8/65 of young patients, in whom CDC73 mutations were found in 5/8. CONCLUSIONS: Hereditary forms of PHPT can be identified in up to 1/3 of young patients with manifestation of the disease at <40 years of age. Parathyroid carcinomas or atypical parathyroid adenomas in young patients are frequently associated with CDC73 mutations.
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Context: Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare monogenic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene and characterized by chronic mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency. Comprehensive characterizations of large patient cohorts are rare. Objective: To perform an extensive clinical, immunological, and genetic characterization of a large nationwide Russian APS-1 cohort. Subjects and Methods: Clinical components were mapped by systematic investigations, sera were screened for autoantibodies associated with APS-1, and AIRE mutations were characterized by Sanger sequencing. Results: We identified 112 patients with APS-1, which is, to the best of our knowledge, the largest cohort described to date. Careful phenotyping revealed several additional and uncommon phenotypes such as cerebellar ataxia with pseudotumor, ptosis, and retinitis pigmentosa. Neutralizing autoantibodies to interferon-ω were found in all patients except for one. The major Finnish mutation c.769C>T (p.R257*) was the most frequent and was present in 72% of the alleles. Altogether, 19 different mutations were found, of which 9 were unknown: c.38T>C (p.L13P), c.173C>T (p.A58V), c.280C>T (p.Q94*), c.554C>G (p.S185*), c.661A>T (p.K221*), c.821del (p.Gly274Afs*104), c.1195G>C (p.A399P), c.1302C>A (p.C434*), and c.1497del (p.A500Pfs*21). Conclusions: The spectrum of phenotypes and AIRE mutation in APS-1 has been expanded. The Finnish major mutation is the most common mutation in Russia and is almost as common as in Finland. Assay of interferon antibodies is a robust screening tool for APS-1.
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Predisposição Genética para Doença/epidemiologia , Mutação , Poliendocrinopatias Autoimunes/epidemiologia , Poliendocrinopatias Autoimunes/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Linhagem , Fenótipo , Poliendocrinopatias Autoimunes/diagnóstico , Prevalência , Doenças Raras , Medição de Risco , Federação Russa/epidemiologia , Análise de Sobrevida , Adulto Jovem , Proteína AIRERESUMO
SUMMARY: Parathyroid carcinoma is an extremely rare disorder with little treatment options. It could be misdiagnosed in medical centers with little experience in management of such cases. Our clinical case shows that the initial misdiagnosis of a parathyroid carcinoma in a young woman has led to the development of multiple lung metastases, thus making its treatment hardly possible. Initiation of treatment with sorafenib - a multi-kinase inhibitor approved for treatment of different types of cancer but not parathyroid carcinoma - has led to a significant decrease in the size of lung metastases and has prevented the progression of hyperparathyroidism, which is usually severe in cases of parathyroid carcinoma. The detection of a germline CDC73 mutation in this patient has raised additional concerns about the necessity of periodic screening for early detection of renal, jaw and uterine lesions. LEARNING POINTS: Diagnosis of parathyroid carcinoma may be challenging due to the absence of reliable diagnostic criteria. Thus, thorough histological examination is needed using immunohistochemical staining of resected tissue in suspicious cases. CDC73 genetic testing should be considered in patients with parathyroid carcinoma.Sorafenib may be a promising treatment of patients with parathyroid carcinoma with distant metastases.
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Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a genetic disease first described in 2 unrelated male infants with severe symptomatic hyponatremia. Despite undetectable arginine vasopressin levels, patients have inappropriately concentrated urine resulting in hyponatremia, hypoosmolality, and natriuresis. Here, we describe and functionally characterize a novel vasopressin type 2 receptor (V2R) gain-of-function mutation. An L312S substitution in the seventh transmembrane domain was identified in a boy presenting with water-induced hyponatremic seizures at the age of 5.8 years. We show that, compared with wild-type V2R, the L312S mutation results in the constitutive production of cAMP, indicative of the gain-of-function NSIAD profile. Interestingly, like the previously described F229V and I130N NSIAD-causing mutants, this appears to both occur in the absence of notable constitutive ß-arrestin2 recruitment and can be reduced by the inverse agonist Tolvaptan. In addition, to understand the effect of various V2R substitutions on the full receptor "life-cycle," we have used and further developed a bioluminescence resonance energy transfer intracellular localization assay using multiple localization markers validated with confocal microscopy. This allowed us to characterize differences in the constitutive and ligand-induced localization and trafficking profiles of the novel L312S mutation as well as for previously described V2R gain-of-function mutants (NSIAD; R137C and R137L), loss-of-function mutants (nephrogenic diabetes insipidus; R137H, R181C, and M311V), and a putative silent V266A V2R polymorphism. In doing so, we describe differences in trafficking between unique V2R substitutions, even at the same amino acid position, therefore highlighting the value of full and thorough characterization of receptor function beyond simple signaling pathway analysis.
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Mutação/genética , Receptores de Vasopressinas/genética , Receptores de Vasopressinas/metabolismo , Pré-Escolar , AMP Cíclico/metabolismo , Transferência Ressonante de Energia de Fluorescência , Células HEK293 , Humanos , Fosfatos de Inositol/metabolismo , Masculino , Microscopia Confocal , Polimorfismo Genético , Ligação Proteica , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , beta-Arrestina 2/genética , beta-Arrestina 2/metabolismoRESUMO
INTRODUCTION: The aims of this study were: (1) to investigate the association of vascular endothelial growth factor isoform A (VEGF-A) concentration in the anterior chamber liquid (ACL) with vascular proliferation in patients with diabetic retinopathy (DR) who had undergone surgical treatment for cataract and neovascular glaucoma; (2) to analyze the association of VEGF-A level in ACL with the cataract surgery outcomes. MATERIALS AND METHODS: Undiluted aqueous fluid samples were obtained from 207 eyes of patients who underwent intraocular surgery, 136 patients with diabetes mellitus (DM) and 22 patients without DM. The ACL samples were obtained during operation. The VEGF-A levels were analyzed by enzyme-linked immunosorbent assay. RESULTS: The lowest VEGF-A levels were in diabetic patients without signs of DR [22.75 pg/mL (10.78; 63.36)]. More severe DR tended to occur in diabetic patients with higher VEGF-A levels in ACL. In diabetic patients with proliferative DR (PDR), VEGF-A levels were significantly higher [336.6 pg/mL (232.3; 410.74)] than in patients without DR P < 0.0001. In patients with terminal stage of DR [neovascular glaucoma (NG)], VEGF-A levels were dramatically higher and attained 1,634.01 pg/mL (610.69; 2657.33). In non-diabetic patients, VEGF-A levels were 95.07 pg/ml (60.92; 129.22). The best visual acuity results in post-operative period were observed in the group of diabetic patients without DR. In the group of patients with PDR, post-operative visual acuity [0.26 (0.1; 0.42)] was similar to visual acuity before operation [0.29 (0.13; 0.44)]. There was no significant increase in visual acuity due to cataract surgery. In 52.4% patients, no complications had occurred by the end of the follow-up period. In 40% patients, retinal laser coagulation was performed, and in 7.6% patients NG had developed. CONCLUSION: VEGF-A level in ACL increases with DR progression and may be of prognostic value in evaluating the potential risk of further neovascularization progression in diabetic patients.
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BACKGROUND: Autoimmune polyglandular syndrome type 1 (APS-1) (OMIM 240300) is a rare autosomal recessive disorder associated with three major manifestations: chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency. There are, however, multiple minor components of APS-1 that induce significant phenotype variability. Subsequently, the diagnosis of APS-1 during early stages is often challenging. AIM: We aimed to provide clinical and mutational data for a large number of APS-1 patients in the Russian population. METHODS: We analyzed clinical variations and component prevalence in APS-1 patients. DNA screening for autoimmune regulator (AIRE) gene mutations was performed in established APS-1 patients and in patients with the single components of chronic mucocutaneous candidiasis, hypoparathyroidism, adrenal insufficiency, or alopecia. RESULTS: We identified 46 patients from 42 families with APS-1. Eighteen different components were present in the patients, including very rare conditions - bone dysplasia and retinitis pigmentosa. We identified 10 different mutations, 3 of which were novel (M1T, E298K, c1053_1060del). The common Finnish mutation, R257X, was the most frequent in our population, present in 64/92 (70%) of the alleles. CONCLUSION: We found that the R257X AIRE mutation is common in Russian APS-1 patients. The majority of children with hypoparathyroidism and chronic mucocutaneous candidiasis were carriers of the AIRE mutations.
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Poliendocrinopatias Autoimunes/genética , Poliendocrinopatias Autoimunes/imunologia , Adolescente , Adulto , Autoanticorpos/imunologia , Autoimunidade/imunologia , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Mutação , Fenótipo , Poliendocrinopatias Autoimunes/diagnóstico , Federação RussaRESUMO
AIMS: To determine risk factors, prognostic, value prevention of development of contrast-induced nephropathy (CIN) after percutaneous coronary intervention (PCI) in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: We have retrospectively analyzed the incidence of CIN developed after PCI in 151 patients T2DM and 50 patients without diabetes. All patients were subjected to thorough clinical examination (including serum creatinine level before and 48 hours after intervention). RESULTS: CIN developed more frequently after PCI in patients with T2DM than in patients of the same age without diabetes at the same baseline renal function, volume of contrast media and hydration status. The risk of developing CIN in patients with T2DM is associated with: heart failure, anemia, volume of contrast media, diuretics use in the peri-procedure period, multiple coronary artery disease, need of interventional procedures. TIDM patients with CIN had faster decline of renal function, more often developed cardiovascular diseases and had lower 24 month survival rate. CONCLUSIONS: High risk of CIN development and its prognostic significance in patients with T2DM determine the necessity of individually evaluated risks for preventive measures during contrast media interventions.
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Meios de Contraste/efeitos adversos , Angiografia Coronária/efeitos adversos , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Nefropatias Diabéticas/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Volume SistólicoRESUMO
CONTEXT: Aromatase excess syndrome (AES) is a rare hereditary autosomal dominant disorder characterized by increased extraglandular aromatization of steroids and presented with heterosexual precocity in males and isosexual precocity in females. OBJECTIVE: The objective was to study the molecular basis of AES in a kindred with 16 affected subjects, both males and females. PATIENTS: The propositus, currently a 17-year-old boy, presented with breast enlargement in the first year of life, which persisted thereafter. Investigations at the age of 7.5 yr revealed growth acceleration (height sd score, 2.8), puberty staging Tanner P1B3, testicular volume 6 ml, and bone age 13 yr. The hormonal data were compatible with increased conversion of androgens to estrogens, which was independent of gonadotropin secretion. In the affected adults, there were short stature (height sd score ranged from -3.7 to -2), gynecomastia in males, and macromastia in females. DESIGN: Linkage analysis was performed using a polymorphic tetranucleotide (TTTA) repeat marker at nucleotide position 682 of CYP gene, as well as two additional STS markers, D15S123 (CA)n and D15S209 (CA)n, located within genetic distance of less than 5 cM from CYP19 gene. Using RNA extracted from the breast tissue of the propositus, a 5'-rapid amplification of cDNA ends (RACE) was performed with gene-specific primers corresponding to exon 2 of CYP19 gene. RESULTS: Linkage analysis with (TTTA)n, D15S123 (CA)n, and D15S209 (CA)n markers produced LOD scores 0.85, 1.5, and 1.17, respectively. 5'-RACE revealed a novel untranslated exon 1 composed by exon 1 of TRPM7 gene (Transient Receptor Potential Cation Channel, Subfamily M, member 7), which has ubiquitous expression. CONCLUSIONS: 5'-RACE finding points to a potential rearrangement between CYP19 and TRPM7 genes on chromosome 15q21.2 as a cause of AES.