Endocrine development最新文献

Central congenital hypothyroidism (CCH) is an underdiagnosed disorder poorly described in childhood and adolescence. Congenital defects in thyroid-stimulating hormone (TSH) synthesis, secretion or bioactivity may lead to a state of 'regulatory' hypothyroidism expressed through aberrantly low or normal TSH levels and low thyroxine (T4), a hormonal pattern undetectable by TSH-based neonatal screening programs for congenital hypothyroidism (CH) implemented in most countries worldwide. CCH is more prevalent than previously thought, reaching 1 in 16,000 neonates in countries consistently identifying CCH through T4-based CH screening strategies. Neonatal detection and early treatment of CCH would prevent the risk of developing mental retardation secondary to late diagnosis of infantile hypothyroidism. CCH is frequently associated with other pituitary defects causing life-threatening situations (like e.g. adrenocorticotropic hormone deficiency) which could benefit from the early detection of CCH, avoiding considerable morbidity and mortality. CCH is not easy to identify clinically, and therefore few children are investigated for the disorder. The current knowledge on the genetic bases of CCH is also scarce. At the hypothalamic level no gene defects causing CCH have yet been identified in humans, but pituitary (thyrotrope)-selective genes encoding the TSH-releasing hormone (TRH) receptor (TRHR), the TSH β-subunit (TSHB) and, recently, the immunoglobulin superfamily factor 1 (IGSF1) are genes involved in isolated central hypothyroidism. Moreover, central hypothyroidism is a complex condition where many regulatory signals are implicated and converge to finely modulate the activity of the hypothalamic-pituitary-thyroid axis. This review focuses on novel pathogenic mechanisms and their implications to understand human CCH and improve the identification and the therapeutic handling of this elusive disease in the pediatric age.

The 2006 Consensus Statement on Management of Intersex Disorders describes peer support as integral to a comprehensive model of care for disorders of sex development (DSD). Affected adults and families look to peer support groups (PSG) for informational, emotional and social support to strengthen coping and assist with the process of shared and informed decision making. Peer support for DSD is relatively new and much can potentially be learned from studies examining the relationship between PSG characteristics and their benefits in other medical conditions. Healthcare providers' awareness of and attitudes toward PSG can influence the degree to which families value such support. This chapter begins with a brief history of peer support for DSD, followed by a summary of the evidence-based literature on PSG across varied medical conditions. We then summarize findings from a recently conducted poll of key DSD peer support and advocacy organizations. The chapter concludes with recommendations for further development of DSD-specific PSG, opportunities for more complete integration of peer support in the model of healthcare and the advantages of input of patient stakeholders in establishing clinical research priorities.

Iodine is an essential trace mineral, required for the production of thyroid hormone. Iodine deficiency may result in goiter, hypothyroidism, miscarriage, stillbirth, congenital anomalies, infant and neonatal mortality, and impaired growth. Adequate thyroid hormone is critically important for normal growth and neurodevelopment in fetal life, infancy and childhood. The population iodine status is most commonly assessed using median urinary iodine concentration values, but goiter prevalence (determined by palpation or by ultrasound), serum thyroglobulin levels, and neonatal thyroid-stimulating hormone values can also be used. Universal salt iodization programs have been the mainstay of public health efforts to eliminate iodine deficiency worldwide. However, in some regions targeted fortification of foods such as bread has been used to combat iodine deficiency. Iodine supplementation may be required in areas where dietary fortification is not feasible or where it is not sufficient for vulnerable groups such as pregnant women. Although international public health efforts over the past several decades have been highly effective, nearly one third of children worldwide remain at risk for iodine deficiency, and iodine deficiency is considered the leading preventable cause of preventable intellectual deficits.

Congenital hypothyroidism (CH) is a state of insufficient thyroid hormone supply to the organism, starting in utero. Two forms of permanent primary or thyroidal CH are known. Thyroid dysgenesis (TD) describes a spectrum of defects of thyroid organogenesis. Five monogenetic forms due to mutations in TSHR, PAX8, NKX2-1, FOXE1 and NKX2-5 have been identified so far. Thyroid dyshormonogenesis comprises defects at every step of thyroid hormone synthesis. Mutations in 7 genes are well described causing iodine transport defect (SLC5A5), iodine organification defect (TPO, DUOX2, DUOXA2, SLC26A4), thyroglobulin (TG) synthesis or transport defect or iodotyrosine deiodinase (IYD/DEHAL1) deficiency. The new consensus guidelines for CH recommend genetic counseling for each family with an affected child. Mode of inheritance, recurrence rate and possible associated malformations in the context of syndromic forms should be outlined. Molecular genetic studies should be preceded by a detailed phenotypic description of the patient's thyroid disease and a detailed family history. This review summarizes clinical, biochemical and radiological phenotypes and molecular aspects of the known genetic forms of TD and thyroid dyshormonogenesis relevant for genetic counseling and molecular studies.

The possibility of measuring thyroid hormones from blood dried on filter paper opened the way to identifying neonates with congenital hypothyroidism (CH) already in the first days of life. Consequently the early initiation of adequate replacement therapy opened the way to an effective prevention of mental retardation. Timely and complete specimen collection, transport logistics, rapid analysis and communication of results are key points for the organization of a CH newborn screening program. Close collaboration between laboratory and treating specialists is necessary to ensure an adequate treatment and follow-up of babies identified by CH screening programs. Topics for further investigations remain in the fields of which forms of CH should be identified by screening (only severe or also very mild forms) and on the long-term outcome of the individuals identified by CH screening.

Screening for a disease begins a process that should lead to confirmation of the diagnosis, establishment of the etiology, optimal treatment and documentation of outcome. In newborns referred for an elevated thyroid-stimulating hormone (TSH) level on the screening specimen, a detailed family and personal history should be obtained, and a careful clinical examination should be performed. Hypothyroidism should be confirmed by measuring serum TSH and thyroxine (T4) and the underlying etiology established by sodium pertechnetate scintigraphy. Treatment should be started promptly with an adequate dose of levothyroxine. Clinical and biochemical monitoring should be frequent during the first 3 years of life, when the brain can suffer irreversible damage from hypothyroidism. Except in patients with thyroid ectopy or with true athyreosis, permanence of hypothyroidism should be confirmed after 3 years of age by withholding treatment for at least 4 weeks and measuring serum TSH and T4 off therapy. Growth, psychomotor development and school progression should be documented, especially in children from socially disadvantaged families. Transition to adult care is particularly important for females, who should receive counseling about increased levothyroxine needs during future pregnancies. Cognitive outcome has improved dramatically with screening for overt congenital hypothyroidism, but the benefits from treatment of mild isolated hyperthyrotropinemia remain unproven.

Autoimmune thyroid disease (AITD) is a multifactorial disease in which autoimmunity against thyroid antigens develops against a particular genetic background facilitated by exposure to environmental factors. Immunogenicity of the major thyroid antigens thyroid peroxidase, thyroglobulin (TG) and thyrotropin receptor (TSHR) is increased by genetic polymorphisms, a high number of antigenic peptides available for binding to human leukocyte antigen (HLA), and a high degree of glycosylation. Antigens bound to HLA are presented by antigen-presenting cells to T cell receptors. Further interaction between both cells is required via binding of CD40 ligand to CD40 and of B7-1/2 to CD28 for activation of T cells. Complex regulatory mechanisms serve to prevent an immune response directed against 'self'-antigens in the thymus (central tolerance) and in peripheral tissues (peripheral tolerance) with the help of regulatory T cells. Breakdown of tolerance to thyroid antigens can result in thyroid autoimmunity, which may happen in subjects who have the wrong genes and who are exposed to the wrong environment. Polymorphisms in thyroid genes (TG, TSHR) and immunoregulatory genes (HLA, CTLA4, PTPN22, CD40, FCRL3, IL2RA, FOXP3) would contribute for about 70% to AITD, and environmental exposures (like iodine, smoking, infections, parity) for the remaining 30%. Thyroid-infiltrating activated T cells may lead to cell-mediated immunity, thyroid injury and eventually hypothyroidism, whereas humoral immunity via TSHR-stimulating antibodies may give rise to hyperthyroidism. Pediatric Hashimoto's and Graves' disease are less prevalent than in adults, and the female preponderance is also less marked in children. The discrepancy is probably due to relatively less involvement of environmental insults in children, whereas the prevalence of risk alleles in AITD children is higher than in AITD adults.

Androgens are important for male sex development and physiology. Their actions are mediated by the androgen receptor (AR), a ligand-dependent nuclear transcription factor. The activity of the AR is controlled at multiple stages due to ligand binding and induced structural changes assisted by the foldosome, compartmentalization, recruitment of coregulators, posttranslational modifications and chromatin remodeling, leading to subsequent transcription of androgen-responsive target genes. Beside these short-term androgen actions, there is phenomenological and experimental evidence of long-term androgen programming in mammals and in the human during sensitive programming time windows, both pre- and postnatally. At the molecular level, research into androgen insensitivity syndrome has unmasked androgen programming at the transcriptome level, in genital fibroblasts and peripheral blood mononuclear cells, and at the epigenome level. Androgens are crucial for male sex development and physiology during embryogenesis, at puberty and in adult life. Testosterone and its more potent metabolite, dihydrotestosterone, which is converted from testosterone within the target cell by 5α-reductase II, are the main androgens involved in male sex differentiation. Androgen action is mediated by a single AR. The AR belongs to the nuclear receptor 3 group C, composed of the glucocorticoid receptor (NR3C1), mineralocorticoid receptor (NR3C2), progesterone receptor (NR3C3) and AR (NR3C4), and acts as a ligand-dependent transcription factor.

The risk of malignant transformation of germ cells, leading to germ cell cancer (GCC) in patients with disorders of sex development, is highly heterogeneous and dependent on a number of parameters, of which the presence of Y-chromosomal material is essential. This chapter describes the networks, both protein-coding and regulatory processes, related to normal gonadal development and GCC, with focus on recent advances of molecular markers for early diagnosis.