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BACKGROUND: Congenital hypogonadotropic hypogonadism (CHH) is a rare disease, triggered by defective GnRH secretion, that is usually diagnosed in late adolescence or early adulthood due to the lack of spontaneous pubertal development. To date more than 30 genes have been associated with CHH pathogenesis with X-linked recessive, autosomal dominant, autosomal recessive and oligogenic modes of inheritance. Defective sense of smell is present in about 50-60% of CHH patients and called Kallmann syndrome (KS), in contrast to patients with normal sense of smell referred to as normosmic CHH. ANOS1 and FGFR1 genes are all well established in the pathogenesis of CHH and have been extensively studied in many reported cohorts. Due to rarity and heterogenicity of the condition the mutational spectrum, even in classical CHH genes, have yet to be fully characterized. METHODS: To address this issue we screened for ANOS1 and FGFR1 variants in a cohort of 47 unrelated CHH subjects using targeted panel sequencing. All potentially pathogenic variants have been validated with Sanger sequencing. RESULTS: Sequencing revealed two ANOS1 and four FGFR1 mutations in six subjects, of which five are novel and one had been previously reported in CHH. Novel variants include a single base pair deletion c.313delT in exon 3 of ANOS1, three missense variants of FGFR1 predicted to result in the single amino acid substitutions c.331C > T (p.R111C), c.1964 T > C (p.L655P) and c.2167G > A (p.E723K) and a 15 bp deletion c.374_388delTGCCCGCAGACTCCG in exon 4 of FGFR1. Based on ACMG-AMP criteria reported variants were assigned to class 5, pathogenic or class 4, likely pathogenic. Protein structural predictions, the rarity of novel variants and amino acid conservation in case of missense substitutions all provide strong evidence that these mutations are highly likely to be deleterious. CONCLUSIONS: Despite the fact that ANOS1 and FGFR1 are classical CHH genes and were thoroughly explored in several CHH cohorts we identified new, yet undescribed variants within their sequence. Our results support the genetic complexity of the disorder. The knowledge of the full genetic spectrum of CHH is increasingly important in order to be able to deliver the best personalised medical care to our patients.
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Proteínas da Matriz Extracelular/genética , Hipogonadismo/genética , Síndrome de Kallmann/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Adolescente , Sequência de Aminoácidos , Feminino , Variação Genética/genética , Humanos , Hipogonadismo/diagnóstico , Síndrome de Kallmann/diagnóstico , MasculinoRESUMO
BACKGROUND: dsd-LIFE is a comprehensive cross-sectional clinical outcome study of individuals with disorders/differences of sex development (DSD). This study focuses on various rare genetic conditions characterized by impaired gonadal or adrenal functionality. METHODS/DESIGN: The study aims to assess quality of life (QoL) as a measure of psychosocial adaptation, psychosexual and mental health aspects as major outcomes. Health status and functioning, medical and surgical therapies, participants' views on health care, psychological and social support, sociodemographic factors and their interrelations will be investigated as factors associated with the outcomes. In addition, ethical considerations in the field of DSD are addressed and previous experiences with health care were gathered. One thousand and forty participants with different DSD conditions were recruited by 14 study centres in 6 European countries (France, Germany, the Netherlands, Poland, Sweden and the United Kingdom) from February 2014 until September 2015. The conditions included were: Turner syndrome (n = 301); 45,X0/46,XY conditions (n = 45); Klinefelter syndrome (n = 218); 47,XYY (n = 1); 46,XY gonadal dysgenesis/ovotestes (n = 63); complete androgen insensitivity (CAIS) (n = 71); partial androgen insensitivity (PAIS) (n = 35) and androgen synthesis disorders (n = 20); severe hypospadias (n = 25); other or non-classified 46,XY DSD (n = 8); 46,XX congenital adrenal hyperplasia (CAH) (n = 226); 46,XX gonadal dysgenesis/ovotestis (n = 21); and 46,XX in males (n = 6). For an add-on study, 121 46,XY male-assigned individuals with CAH due to 21-hydroxylase deficiency were recruited. Mean age of participants' was 32.4 (+/- 13.6 years). DISCUSSION: Participation was high in conditions not commonly described as DSD, such as Turner and Klinefelter syndromes or CAH. Recruitment of individuals with XY DSD conditions proved to be more difficult. The data collection of PROs resulted in high data quality. Within medical and physical examination data, more missings and/or inaccurate data were found than expected. The European dsd-LIFE study recruited and evaluated the largest cross-sectional sample of individuals with different conditions classified under the term DSD. The data from this large sample will provide a sufficient basis for evidence-based recommendations for improvement of clinical care of individuals affected by a DSD condition. TRIAL REGISTRATION: German Clinical Trials Register DRKS00006072 .
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Transtornos do Desenvolvimento Sexual/fisiopatologia , Desenvolvimento Sexual , Adulto , Protocolos Clínicos , Transtornos do Desenvolvimento Sexual/psicologia , Humanos , Saúde Mental , Satisfação do Paciente , Qualidade de VidaRESUMO
Leydig cell number and function decline as men age, and low testosterone is associated with all "Western" cardio-metabolic disorders. However, whether perturbed androgen action within the adult Leydig cell lineage predisposes individuals to this late-onset degeneration remains unknown. To address this, we generated a novel mouse model in which androgen receptor (AR) is ablated from â¼75% of adult Leydig stem cell/cell progenitors, from fetal life onward (Leydig cell AR knockout mice), permitting interrogation of the specific roles of autocrine Leydig cell AR signaling through comparison to adjacent AR-retaining Leydig cells, testes from littermate controls, and to human testes, including from patients with complete androgen insensitivity syndrome (CAIS). This revealed that autocrine AR signaling is dispensable for the attainment of final Leydig cell number but is essential for Leydig cell maturation and regulation of steroidogenic enzymes in adulthood. Furthermore, these studies reveal that autocrine AR signaling in Leydig cells protects against late-onset degeneration of the seminiferous epithelium in mice and inhibits Leydig cell apoptosis in both adult mice and patients with CAIS, possibly via opposing aberrant estrogen signaling. We conclude that autocrine androgen action within Leydig cells is essential for the lifelong support of spermatogenesis and the development and lifelong health of Leydig cells.
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Síndrome de Resistência a Andrógenos/patologia , Androgênios/farmacologia , Apoptose/efeitos dos fármacos , Células Intersticiais do Testículo/patologia , Receptores Androgênicos/fisiologia , Testículo/patologia , Adolescente , Adulto , Síndrome de Resistência a Andrógenos/tratamento farmacológico , Síndrome de Resistência a Andrógenos/metabolismo , Animais , Comunicação Autócrina , Western Blotting , Células Cultivadas , Criança , Humanos , Técnicas Imunoenzimáticas , Células Intersticiais do Testículo/efeitos dos fármacos , Células Intersticiais do Testículo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Substâncias Protetoras/farmacologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Espermatogênese/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testículo/metabolismo , Adulto JovemRESUMO
BACKGROUND: Until now, there are no established norms for prostate size in children. Prostate volume during development has been analyzed in small study groups. In diagnostic imaging, transabdominal ultrasound and magnetic resonance imaging are used. AIMS: To establish prostate volume norms for individuals aged 1-17 years using transabdominal ultrasound. STUDY DESIGN: Between 2021 and 2023, transabdominal prostate ultrasound was performed on 482 Caucasian boys, aged 1-17 years, who were patients of the urology clinic. Normative data were based on results of 345 boys with normal lower urinary tract, urethral and penile structures. Patients with abnormal external genitalia, Prune Belly Syndrome, Myelomeningocele, chromosomal disorders, or prostate abnormalities found in ultrasound were excluded from the study. Patient eligibility was determined based on medical records and physical examinations. During ultrasound, height, anterior-posterior dimension, and width of prostate were assessed. Prostate volume was calculated using the ellipsoid formula VH x L(AP) x W x 0.523. Measurements were correlated with age, weight, and height. Results were analyzed using descriptive statistics, statistical significance tests for means, and correlation methods. After estimating preliminary results, taking into account the development periods, patients were divided into age groups: 1-4 years (n = 70), 5-10 years (n = 124), 11-12 years (n = 43), 13-15 years (n = 65), and 16-17 years (n = 43). RESULTS: The table and nomogram shows prostate volumes based on age. Prostate size remains stable up to the age of 8. We noticed a transitional phase at the age of 8-11 years. A significant increase in volume occurs over 11 years of age. There was a statistically significant relationship between prostate size, age, height, and weight. DISCUSION: Established norms can serve as a reference for prostate analysis in patients with defects of the genitourinary system. An interesting analysis would be a prostate size assessment in relation to stage of development on Tanner scale. CONCLUSION: Transabdominal ultrasound, being a non-invasive, painless, and readily accessible examination, allows assessment of prostate size even in boys aged 1 year old. A statistically significant relationship was found between prostate size, weight, and height. Norms for prostate size in boys were established according to age.
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Próstata , Ultrassonografia , Humanos , Masculino , Adolescente , Criança , Lactente , Estudos Prospectivos , Ultrassonografia/métodos , Próstata/diagnóstico por imagem , Pré-Escolar , Tamanho do Órgão , Valores de Referência , PolôniaRESUMO
Introduction: Congenital hypogonadotropic hypogonadism results from a dysfunction of the hypothalamic-pituitary-gonadal axis, which is essential for the development and function of the reproductive system. It may be associated with anosmia, referred to as Kallmann syndrome, or a normal sense of smell. Numerous studies have proven that hypogonadotropic hypogonadism is not simply a monogenic Mendelian disease, but that more than one gene may be involved in its pathogenesis in a single patient. The oligogenic complex architecture underlying the disease is still largely unknown. Material and methods: Targeted next-generation sequencing (NGS) was used to screen for DNA variants in a cohort of 47 patients with congenital hypogonadotropic hypogonadism. The NGS panel consists of over 50 well-known and candidate genes, associated with hypogonadotropic state. Results: Here we report the identification of new oligogenic variants in SPRY4/SEMA3A, SRA1/SEMA7A, CHD7/SEMA7A, CCDC141/POLR3B/POLR3B, and PROKR2/SPRY4/NSMF. These genes are known to contribute to the phenotype of hypogonadotropic hypogonadism, yet our results point to potential new "partners" underlying digenic and trigenic patterns. Conclusions: The finding supports the importance of oligogenic inheritance and demonstrates the complexity of genetic architecture in hypogonadotropic hypogonadism. It also underlines the necessity for developing fine-tuned guidelines to provide a tool for adequate and precise sequence variant classification in non-Mendelian conditions.
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MELAS syndrome (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) is a genetically determined disease caused by mutations in mitochondrial DNA. We present a girl who was suspected of MELAS syndrome during the diagnostic evaluation of short stature. The patient suffered from symptoms potentially indicating mitochondrial disease, such as muscular weakness, cranial nerve VI palsy, headaches, retinitis pigmentosa, sensory-neural hearing loss, and elevated lactic acid. T2-weighted brain MRI showed hyperintense lesions in the white matter. Muscular biopsy revealed ragged red fibres. Genetic evaluation did not detect the most common mutations in the MT-TL1 gene and MT-ND5 gene. Endocrine tests led to the confirmation of growth hormone deficiency, and so replacement treatment was started. After 1 year of recombinant growth hormone therapy the patient was diagnosed with diabetes. At the age of 14 years the LH-RH test showed prepubertal values. Endocrine disorders may be one of the first manifestations of MELAS syndrome. In differential diagnosis of short stature, less common causes, such as mitochondrial diseases, should be taken into consideration.
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Doenças do Sistema Endócrino , Síndrome MELAS , Acidente Vascular Cerebral , Adolescente , DNA Mitocondrial , Doenças do Sistema Endócrino/complicações , Doenças do Sistema Endócrino/diagnóstico , Feminino , Humanos , Síndrome MELAS/complicações , Síndrome MELAS/diagnóstico , Síndrome MELAS/tratamento farmacológico , MutaçãoRESUMO
INTRODUCTION: Patients with disorders/differences of sex differentiation/development (DSD) are exposed to physical and mental suffering. The aim of the study was to assess the following: the mental health status and the risk of mental problems in adult DSD patients, their dependence on therapeutic procedures, and to identify groups of disorders that require particular psychological support. MATERIAL AND METHODS: The study involved 59 patients with DSD (gonadal dysgenesis - GD, androgen insensitivity syndrome - AIS, 5-alpha reductase deficiency, ovotestis), and with the Y chromosome in the karyotype, aged 16-65 years. All completed the General Health Questionnaire (GHQ-28) for the assessment of their mental health status. Raw results were converted into sten scores using norms for the Polish adult population to assess the risk of mental problems. RESULTS: A high risk of mental problems was identified in 24% of individuals (26% men, 21% women). Women, when compared with men, displayed a significantly higher mean level of anxiety and insomnia (7.3 vs. 4.6 scores) and somatic symptoms (7.4 vs. 5.5), and worse general mental health status (25.6 vs. 18.8). The most disturbing symptoms were observed among patients with complete and partial AIS, and complete GD (general mental health status: 39.5, 24.3, and 24.2, respectively), women lacking a vagina (27.2), and without an enlarged clitoris (27.5). Patients after genital surgery had significantly fewer somatic symptoms (5.4 vs. 7.8; p < 0.05) and better general mental health status in comparison to those without surgery (20.1 vs. 24.9; p < 0.05). No significant differences were observed between patients using hormone replacement therapy and those who were not. CONCLUSIONS: The individuals with DSD and Y chromosome in the karyotype have increased risk of developing mental problems in comparison to the general Polish population. The risk factors seem to be as follows: female gender, the lack of a vagina, the lack of virilisation (no enlarged clitoris), and no genital operations performed. In some cases, sex hormone replacement therapy may be also the risk of mental problems. Particularly vulnerable groups are CAIS, PAIS, and CGD. The psychological support and an individual approach to particular needs of these patients is necessary.
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Cromossomos Humanos Y , Transtornos do Desenvolvimento Sexual/complicações , Transtornos do Desenvolvimento Sexual/diagnóstico , Transtornos Mentais/diagnóstico , Saúde Mental/estatística & dados numéricos , Adaptação Psicológica , Adolescente , Adulto , Feminino , Humanos , Masculino , Transtornos Mentais/etiologia , Pessoa de Meia-Idade , Polônia , Qualidade de Vida , Diferenciação Sexual , Adulto JovemRESUMO
BACKGROUND: Patients with disorders/differences of sex development (DSD), especially those possessing the Y chromosome, have a higher risk of gonadal germ-cell tumours (GCTs). We aimed to examine the incidence of different types of gonadal neoplasia and associated risk factors. METHODS: A total of 1040 DSD patients aged ≥16 years participated in a cross-sectional multicentre European study (dsd-LIFE). Data on medical history were gathered from the patients' archival medical documents. A web-based questionnaire was filled out individually by the participants. A physical examination was performed in all, while ultrasonography of gonads was carried out in 214 and semen analysis was performed for 53 patients. RESULTS: Germ-cell neoplasia was present in 12 % of patients with DSD and in 14 % of those with XY DSD. The highest risk (36 %) was observed in 46,XY patients with gonadal dysgenesis (GD): complete GD (33 %) and partial GD (23 %), but also in mixed GD (8 %) and complete androgen insensitivity syndrome (AIS) (6%). It was not reported in partial AIS, XX male, 46,XX DSD and congenital adrenal hyperplasia, Turner and Klinefelter syndromes, or in androgen biosynthesis defects. Benign sex cord-stromal tumours (Sertoli- and Leydig-cell tumours) were noted only in patients with complete AIS (3.1 %) and Klinefelter syndrome (14.3 %). A relationship between risk factors for GCT and gonadal neoplasia appearance, other than the Y chromosome, was not found. CONCLUSION: Adult patients with GD and the Y chromosome have the highest risk of GCT and should be kept under thorough medical control and receive special medical follow-up to prevent the development of gonadal tumours.
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Disgenesia Gonadal/complicações , Neoplasias Embrionárias de Células Germinativas/etiologia , Desenvolvimento Sexual/genética , Adolescente , Estudos Transversais , Feminino , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/patologia , Fatores de RiscoRESUMO
Congenital hypogonadotropic hypogonadism (CHH) is caused by dysfunction of hypothalamic gonadotropic-releasing hormone (GnRH) axis. The condition is both clinically and genetically heterogeneous with more than 40 genes implicated in pathogenesis. The goal of the present study was to identify causative mutations in CHH individuals employing 2 step procedure with a targeted NGS panel as first-line diagnostics and subsequently whole exome sequencing in unsolved cases. Known or novel potentially deleterious variants were found in 28 out of 47 tested CHH patients. Molecular diagnosis was reached in 19/47 CHH cases. In 13 cases monogenic variants were identified in ANOS1, FGFR1, GNRHR, CHD7, SOX10, and PROKR2, while 6 patients showed digenic or trigenic inheritance patterns. The achieved diagnostic rate was comparable to other studies on genetics of CHH. By evaluating and reporting more patients with CHH we make progress in unravelling its genetic complexity and move a step closer to personalised medicine.
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Sequenciamento do Exoma/métodos , Estudos de Associação Genética , Heterogeneidade Genética , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Hipogonadismo/genética , Síndrome de Kallmann/genética , Mutação , Adulto , Sequência de Aminoácidos , Criança , DNA/genética , Feminino , Humanos , Hipogonadismo/diagnóstico , Síndrome de Kallmann/diagnóstico , Masculino , Modelos Genéticos , Alinhamento de Sequência , Análise de Sequência de DNA , Homologia de Sequência de AminoácidosRESUMO
Objectives The main cause of hyperandrogenism in children is congenital adrenal hyperplasia, adrenal and gonadal tumors, polycystic ovary syndrome (PCOs) and Cushing's disease. In the last 20 years several descriptions of girls with hyperandrogenism and venous porto-systemic shunts appeared in literature. Case presentation First case is an eleven and a half-year-old girl, was admitted to Department of Endocrinology because of symptoms of hyperandrogenism. Laboratory tests revealed high serum testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEAS). The ammonia concentration was also increased. In the abdominal angio-CT scans persistent umbilical vein which connected portal and femoral vein was found. The second case was a seven-year-old boy with symptoms of precocious puberty. Blood tests also revealed high concentration of testosterone, androstenedione, DHEAS and ammonia. Imaging studies showed persistent ductus venosus. Conclusion Although pathophysiological relation is not clear, porto-systemic shunts should be considered as a cause of hyperandrogenism of unknown origin in children.
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Identification of novel genes involved in sexual development is crucial for understanding disorders of sex development (DSD). Here, we propose a member of the START domain family, the X chromosome STARD8, as a DSD candidate gene. We have identified a missense mutation of this gene in 2 sisters with 46,XY gonadal dysgenesis, inherited from their heterozygous mother. Gonadal tissue of one of the sisters contained Leydig cells overloaded with cholesterol droplets, i.e., structures previously identified in 46,XY DSD patients carrying mutations in the STAR gene encoding another START domain family member, which is crucial for steroidogenesis. Based on the phenotypes of our patients, we propose a dual role of STARD8 in sexual development, namely in testes determination and testosterone synthesis. However, further studies are needed to confirm the involvement of STARD8 in sexual development.
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Cromossomos Humanos X/genética , Proteínas Ativadoras de GTPase/genética , Disgenesia Gonadal 46 XY/genética , Mutação/genética , Processos de Determinação Sexual/genética , Irmãos , Adolescente , Sequência de Bases , Feminino , Gônadas/patologia , Humanos , Lactente , FenótipoRESUMO
STUDY OBJECTIVE: To provide late adolescent and young adult psychosexual follow-up information on a consecutive series of patients with either mixed or partial gonadal dysgenesis. SETTING: Children's Memorial Health Institute (Warsaw, Poland). PARTICIPANTS: 19 patients (age range, 17-26 years), 9 raised as females and 10 raised as males. MEASURES: Clinical interview and psychologic tests were used to evaluate gender identity, gender role, and sexual behavior. RESULTS: All patients raised as male had a normal male gender identity, displayed masculine gender role behavior in childhood, and had a heterosexual sexual orientation. Seven of the 10 male patients had experienced heterosexual intercourse. Two out of nine women did not identify with the female gender. The majority had masculine gender role interests in childhood. The female patients were significantly less likely to have experienced sexual activity with a partner than the male patients. CONCLUSION: Although gender identity differentiated largely in accordance with sex assignment or sex of rearing in our sample, the patients reared as female appeared to have poorer sexual adjustment than the males. Cultural factors may have impacted on this latter outcome.
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Disgenesia Gonadal Mista/psicologia , Desenvolvimento Psicossexual , Sexualidade/psicologia , Adolescente , Adulto , Criança , Educação Infantil/psicologia , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Testes Psicológicos , Qualidade de Vida , Fatores SexuaisRESUMO
UNLABELLED: In males AMH is produced by the testes from fetal life to puberty. The main role of AMH in the male fetus is to cause Müllerian duct regression, in prepubertal boys AMH is involved in testicular development and function. THE AIM OF THIS STUDY was to assess the use of a sensitive assay kit of AMH measurements in the diagnosis and management of children with abnormal sexual differentiation and cryptorchidism. We also compared the serum AMH levels with testosterone levels after hCG stimulation. METHODS: We assessed serum AMH levels in 79 prepubertal patients: gonadal dysgenesis (n=23), partial androgen insensitivity (n=4), scrotal hypospadiasis (n=16), bilateral cryptorchidism (n=20), anorchia (n=10) and unilateral cryptorchidism (n=6). Earlier hCG test was performed (one dose of 2000 IU/m2 i.m.) and testosterone levels were determined. RESULTS: AMH level was not impaired in patients with unilateral cryptorchidism and partial androgen insensitivity (median 350 pmol/l). AMH was normal in most of boys with scrotal hypospadiasis (median 317 pmol/l). Significant differences were observed between AMH levels in boys with hypospadias and patients with gonadal dysgenesis (median 174 pmol/l; p<0,001). In the cryptorchid group AMH level was normal in 50% of boys. There was a significant difference between AMH levels in cryptorchid boys (median 249.5 pmol/l) and patients with anorchia; (p<0,001). AMH levels were almost undetectable in boys with vanishing testes (median 1.0 pmol/l). The basal AMH levels were correlated with testosterone response to hCG. CONCLUSIONS: When testes are non-palpable a single measurement of serum AMH level can distinguish between cryptorchidism and anorchia. AMH determination can help in the diagnosis of intersex conditions. Our data demonstrated that basal AMH measurements correlate with testosterone response to hCG. Serum AMH concentration in prepubertal children is a marker of testicular function. Preoperative measurement of AMH can be useful in the management of children with cryptorchidism and intersex disorders.
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Transtornos do Desenvolvimento Sexual/sangue , Transtornos do Desenvolvimento Sexual/fisiopatologia , Glicoproteínas/sangue , Puberdade Tardia/sangue , Puberdade Precoce/sangue , Hormônios Testiculares/sangue , Testículo/fisiopatologia , Hormônio Antimülleriano , Biomarcadores , Pré-Escolar , Gonadotropina Coriônica , Criptorquidismo/sangue , Criptorquidismo/patologia , Transtornos do Desenvolvimento Sexual/patologia , Humanos , Masculino , Testículo/fisiologia , Testosterona/sangueRESUMO
BACKGROUND: Insulin resistance--a key element of the metabolic syndrome--is observed in children with simple obesity. Adipose tissue is producing bioactive substances called adipocytokines. Some of them may play a role in the development of insulin resistance. AIM OF THE STUDY: Estimation of the frequency of insulin resistance and its correlation with leptin, adiponectin and resistin levels in children with simple obesity. MATERIAL AND METHODS: The 53 children (BMI>97 centile), mean age 13.57 years. Mean BMI was +4.04 SDS. Oral glucose tolerance test (OGTT) was performed. Insulin levels at 0' < or = 15 microIU/mL and/or insulin peak during OGTT < or = 150 microIU/mL and/or peak at 120' < or =75 microIU/mL were established as normal values. Homa ratio was calculated. Patients were divided into groups depending on the presence or absence of hyperinsulinemia / insulin resistance. Concentrations of adiponectin, leptin, resistin were measured. RESULTS: In 13.23 % children various types of hyperglycemia were diagnosed and hyperinsulinemia in OGTT was noted in 83.02 %. Severe insulin resistance (HOMA>3) was diagnosed in 71.82 %. In the hyperinsulinemia group higher glucose levels in OGTT were stated comparing to the non hyperinsulinemia group. In children with insulin resistance, higher BMI and SD BMI were observed. In this paper results of correlations of adipocytokines levels and anthropometric parameters or carbohydrates metabolism in children with / without insulin resistance are presented. CONCLUSIONS: In children with severe insulin resistance adiponectin concentrations correlate negatively with glucose levels, there is a positive correlation of adiponectin and glucose and insulin in a group without severe insulin resistance. In patients with insulin resistance leptin concentrations correlate positively with the degree of obesity and insulin levels in OGTT.
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Adiponectina/sangue , Hormônios Ectópicos/sangue , Resistência à Insulina/fisiologia , Leptina/sangue , Obesidade/sangue , Resistina/sangue , Tecido Adiposo/metabolismo , Adolescente , Índice de Massa Corporal , Criança , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Masculino , Análise de Regressão , Sensibilidade e Especificidade , Estatística como AssuntoRESUMO
INTRODUCTION: In patients with Y-chromosome in the karyotype, partial gonadal dysgenesis and disorders of male reproductive sex organs development are usually resected in childhood because of the high risk of germ cell tumours (GCT). In patients with Y-chromosome, complete gonadal dysgenesis and female genitalia gonadectomy is performed markedly later. However, due to the relatively low number of adult patients with preserved dysgenetic gonads, the true risk of neoplasm is unknown. The aim of the study was to evaluate the prevalence of neoplasia in dysgenetic gonads of children and adults with Y-chromosome in a retrospective study. MATERIAL AND METHODS: A review of medical documentation of 94 patients with disorders of sex development (DSD), Y-chromosome and gonadal dysgenesis (GD), aged 1.2-32 years (47 prepubertal, 1.2-10 years; 47 pubertal/adult, 13-32 years), was conducted. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone were determined. Bilateral gonadectomy was performed in 73.4% of patients, and unilateral gonadectomy with biopsy of the contralateral gonad in 26.4%. All gonadal tissues were subjected to immunohistochemical evaluation with antibodies against PLAP and OCT3/4 (markers of malignant germ cells, but also foetal multipotent germ cells), while gonads of prepubertal patients were examined by c-KIT, as well. RESULTS: Streak gonads were identified on both sides (complete GD) in 30.8%, a streak gonad on one side and an underdeveloped testis on the other (asymmetric GD) in 38.3%, and underdeveloped testicular structure on both sides (partial GD) in 30.8% of cases. Germ cell neoplasia was found in 53.2% of patients (51.1% in children, 55.3% in pubertal/adults). Invasive GCT were identified in 11.7% of cases, of which 90.9% were in pubertal/adult patients. Other neoplastic lesions included gonadoblastoma (16% prevalence) and testicular carcinoma in situ (25.5%). In younger patients FSH serum levels were increased in 81% of cases (mean 2.82 ± 2.18 IU/L), while LH in 58% (mean 1.82 ± 1.69 IU/L). Hypergonadotropic hypogonadism was diagnosed in most of the pubertal/ /adult patients (mean FSH 54.2 ± 23.3 IU/L, mean LH 21.7 ± 12.1 IU/L, mean testosterone 5.5 ± 4.5 nmol/L). CONCLUSIONS: Dysgenetic gonads in patients with Y chromosome have a high risk of germ cell neoplasia (ca. 50%). If they are preserved until puberty/early adulthood, they may develop overt, invasive GCT. The gonads also have poor hormonal activity (hypergonadotropic hypogonadism) in most of the pubertal/adult patients. Each of these cases must be considered individually and a decision to remove the gonad or not should be based on the comprehensive analysis of the phenotype by a multidisciplinary team of specialists in consultation with the patient and the parents. If dysgenetic gonads are not resected in childhood, these patients need careful ongoing follow-up examination, including biopsy and histopathological evaluation.
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Disgenesia Gonadal/complicações , Disgenesia Gonadal/patologia , Neoplasias Testiculares/complicações , Testículo/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Gonadotropinas/sangue , Humanos , Lactente , Masculino , Estudos Retrospectivos , Fatores de Risco , Neoplasias Testiculares/epidemiologia , Testosterona/sangueRESUMO
CONTEXT: P450 oxidoreductase deficiency (PORD) is a unique congenital adrenal hyperplasia variant that manifests with glucocorticoid deficiency, disordered sex development (DSD), and skeletal malformations. No comprehensive data on genotype-phenotype correlations in Caucasian patients are available. OBJECTIVE: The objective of the study was to establish genotype-phenotype correlations in a large PORD cohort. DESIGN: The design of the study was the clinical, biochemical, and genetic assessment including multiplex ligation-dependent probe amplification (MLPA) in 30 PORD patients from 11 countries. RESULTS: We identified 23 P450 oxidoreductase (POR) mutations (14 novel) including an exonic deletion and a partial duplication detected by MLPA. Only 22% of unrelated patients carried homozygous POR mutations. p.A287P was the most common mutation (43% of unrelated alleles); no other hot spot was identified. Urinary steroid profiling showed characteristic PORD metabolomes with variable impairment of 17α-hydroxylase and 21-hydroxylase. Short cosyntropin testing revealed adrenal insufficiency in 89%. DSD was present in 15 of 18 46,XX and seven of 12 46,XY individuals. Homozygosity for p.A287P was invariably associated with 46,XX DSD but normal genitalia in 46,XY individuals. The majority of patients with mild to moderate skeletal malformations, assessed by a novel scoring system, were compound heterozygous for missense mutations, whereas nearly all patients with severe malformations carried a major loss-of-function defect on one of the affected alleles. CONCLUSIONS: We report clinical, biochemical, and genetic findings in a large PORD cohort and show that MLPA is a useful addition to POR mutation analysis. Homozygosity for the most frequent mutation in Caucasians, p.A287P, allows for prediction of genital phenotype and moderate malformations. Adrenal insufficiency is frequent, easily overlooked, but readily detected by cosyntropin testing.
Assuntos
Hiperplasia Suprarrenal Congênita/genética , NADPH-Ferri-Hemoproteína Redutase/genética , Adolescente , Hiperplasia Suprarrenal Congênita/urina , Insuficiência Adrenal/genética , Insuficiência Adrenal/metabolismo , Insuficiência Adrenal/urina , Adulto , Criança , Estudos de Coortes , Análise Mutacional de DNA/métodos , Transtornos do Desenvolvimento Sexual , Feminino , Estudos de Associação Genética , Genitália/anormalidades , Hormônios Esteroides Gonadais/urina , Humanos , Masculino , Metaboloma , Modelos Biológicos , Modelos Moleculares , Reação em Cadeia da Polimerase Multiplex/métodos , NADPH-Ferri-Hemoproteína Redutase/deficiência , NADPH-Ferri-Hemoproteína Redutase/fisiologia , Adulto JovemRESUMO
CONTEXT: P450 oxidoreductase (POR) is a crucial electron donor to all microsomal P450 cytochrome (CYP) enzymes including 17α-hydroxylase (CYP17A1), 21-hydroxylase (CYP21A2) and P450 aromatase. Mutant POR causes congenital adrenal hyperplasia with combined glucocorticoid and sex steroid deficiency. P450 oxidoreductase deficiency (ORD) commonly presents neonatally, with disordered sex development in both sexes, skeletal malformations, and glucocorticoid deficiency. OBJECTIVE: The aim of the study was to describe the clinical and biochemical characteristics of ORD during puberty. DESIGN: Clinical, biochemical, and genetic assessment of seven ORD patients (five females, two males) presenting during puberty was conducted. RESULTS: Predominant findings in females were incomplete pubertal development (four of five) and large ovarian cysts (five of five) prone to spontaneous rupture, in some only resolving after combined treatment with estrogen/progestin, GnRH superagonists, and glucocorticoids. Pubertal development in the two boys was more mildly affected, with some spontaneous progression. Urinary steroid profiling revealed combined CYP17A1 and CYP21A2 deficiencies indicative of ORD in all patients; all but one failed to mount an appropriate cortisol response to ACTH stimulation indicative of adrenal insufficiency. Diagnosis of ORD was confirmed by direct sequencing, demonstrating disease-causing POR mutations. CONCLUSION: Delayed and disordered puberty can be the first sign leading to a diagnosis of ORD. Appropriate testosterone production during puberty in affected boys but manifest primary hypogonadism in girls with ORD may indicate that testicular steroidogenesis is less dependent on POR than adrenal and ovarian steroidogenesis. Ovarian cysts in pubertal girls may be driven not only by high gonadotropins but possibly also by impaired CYP51A1-mediated production of meiosis-activating sterols due to mutant POR.
Assuntos
Hiperplasia Suprarrenal Congênita/fisiopatologia , NADPH-Ferri-Hemoproteína Redutase/deficiência , Puberdade/fisiologia , Adolescente , Amenorreia/etiologia , Androgênios/sangue , Androgênios/uso terapêutico , Estudos de Coortes , Feminino , Genitália/anormalidades , Disgenesia Gonadal 46 XY/enzimologia , Disgenesia Gonadal 46 XY/fisiopatologia , Hormônios Esteroides Gonadais/sangue , Terapia de Reposição Hormonal , Humanos , Recém-Nascido , Cariotipagem , Masculino , Menstruação , Cistos Ovarianos/tratamento farmacológico , Cistos Ovarianos/genética , Ovário/patologia , Fenótipo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Esteroides/urina , Adulto JovemRESUMO
CONTEXT: Nijmegen breakage syndrome (NBS) is a severe chromosomal instability disorder characterized by microcephaly, growth retardation, immune deficiency, and predisposition for malignancy. It is caused by hypomorphic mutations in the NBN gene, which product belongs to the protein complex critical for processing DNA double-strand breaks during mitotic and meiotic recombination. Data on gonadal function in patients with NBS are limited. OBJECTIVE: Growth and sexual development, along with hormonal assays, were evaluated in girls and young women with NBS homozygous for c.657_661del5 mutation. STUDY DESIGN AND PATIENTS: The group comprised 37 girls and young women with NBS (ages, 0.17-24.25 yr), followed between 1993 and 2008. Patients were divided into three age groups: 1) 1-3 yr; 2) 4-9 yr; and 3) 10 yr and older. Growth, puberty, concentrations of gonadotropins and 17-beta-estradiol, bone age, and pelvic ultrasound were assessed. RESULTS: None of the patients presented a typical growth spurt; the adult height ranged between the 3rd and 25th centiles. Median bone age was delayed by 4.05 yr. Pubarche reached stadium P2 in eight patients and P3 in two patients. In all but one girl, thelarche did not exceed Th2, with low 17beta-estradiol levels. Gonadotropin levels showed a biphasic pattern, with median FSH values of 55.0, 10.9, and 81.9 IU/liter, and LH of 3.2, 0.8, and 21.0 IU/liter in consecutive age groups. Ultrasound visualized small ovaries or solid streaks and the hypoplastic uterus. CONCLUSIONS: Primary ovarian insufficiency and the associated hypergonadotropic hypogonadism are hallmark manifestations in girls and young women with NBS. Our findings emphasize the need for long-term endocrinological and interdisciplinary supervision of these patients.
Assuntos
Hipogonadismo/epidemiologia , Síndrome de Quebra de Nijmegen/complicações , Insuficiência Ovariana Primária/epidemiologia , Puberdade Tardia/epidemiologia , Adolescente , Análise de Variância , Estatura , Criança , Pré-Escolar , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Hipogonadismo/sangue , Hipogonadismo/complicações , Lactente , Estudos Longitudinais , Hormônio Luteinizante/sangue , Síndrome de Quebra de Nijmegen/sangue , Prevalência , Insuficiência Ovariana Primária/sangue , Insuficiência Ovariana Primária/complicações , Puberdade Tardia/sangue , Puberdade Tardia/complicações , Estatísticas não Paramétricas , Adulto JovemRESUMO
CONTEXT: Undervirilization in males, i.e. 46,XY disordered sex development (46,XY DSD), is commonly caused by either lack of androgen action due to mutant androgen receptor (AR) or deficient androgen synthesis, e.g. due to mutations in 17alpha-hydroxylase (CYP17A1). Like all other microsomal cytochrome P450 (CYP) enzymes, CYP17A1 requires electron transfer from P450 oxidoreductase (POR). OBJECTIVE: The objective of the study was to analyze the clinical and biochemical phenotype in a 46,XY individual carrying concomitant POR and AR mutations and to dissect their impact on phenotypic expression. METHODS: We characterized the clinical and biochemical phenotype, genetic identification, and functional analysis of POR missense mutation by yeast micrososomal coexpression assays for CYP17A1, CYP21A2 and CYP19A1 activities. RESULTS: The patient presented neonatally with 46,XY DSD and was diagnosed as partial androgen insensitivity syndrome carrying a disease causing AR mutation (p.Q798E). She was raised as a girl and gonadectomized at the age of 4 yr. At 9 yr progressive clitoral enlargement prompted reassessment. Urinary steroid analysis was indicative of POR deficiency, but surprisingly androgen production was normal. Genetic analysis identified compound heterozygous POR mutations (p.601fsX12/p.Y607C). In vitro analysis confirmed p.Y607C as a pathogenic mutation with differential inhibition of steroidogenic CYP enzymes. CONCLUSION: Both mutant AR and POR are likely to contribute to the neonatal presentation with 46,XY DSD. Virilization at the time of adrenarche appears to suggest an age-dependent, diminishing disruptive effect of both mutant proteins. This case further highlights the importance to assess both gonadal and adrenal function in patients with 46,XY DSD.