Endocrine development最新文献

Rickets is a condition in which there is failure of the normal mineralisation (osteomalacia) of growing bone. Whilst osteomalacia may be present in adults, rickets cannot occur. It is generally caused by a lack of mineral supply, which can either occur as a result of the deficiency of calcium (calciopaenic rickets, now known as parathyroid hormone-dependent rickets) or of phosphate (phosphopaenic rickets, now called FGF23-dependent rickets). Renal disorders may also interfere with the process of mineralisation and cause rickets. Only parathyroid hormone-dependent rickets and distal renal tubular disorders will be discussed in this chapter. The most common cause of rickets is still vitamin D deficiency, which is also responsible for other problems. Disorders of vitamin D metabolism or responsiveness may also cause similar issues. Distal renal tubular acidosis may also be caused by a variety of metabolic errors similar to those of osteoclasts. One form of distal renal tubular acidosis also causes a type of osteopetrosis. This chapter describes these conditions in detail and sets out a logical approach for treatment.

Medullary thyroid carcinoma (MTC) originates from thyroid parafollicular C cells, and it accounts for 5% of thyroid malignancies. MTC is sporadic in approximately 80% and hereditary in 20% of cases. When hereditary it can be associated with other benign endocrine neoplasias and/or typical nonendocrine diseases, thus configuring the multiple endocrine neoplasia syndromes (type 2, MEN2/familial MTC, FMTC). Sporadic MTC is usually diagnosed in adult life. Children with clinically evident MTC are belonging to MEN2 families, particularly MEN2A and MEN2B. Children belonging to families with FMTC are usually identified by RET genetic screening shortly after birth or during childhood but they likely develop MTC later in adult life. A genotype-phenotype correlation has been observed between RET mutations and MEN2 syndromes. As for adults, the diagnosis of childhood MTC is based on serum calcitonin (Ct) and neck ultrasound with fine-needle aspiration if a thyroid nodule is present. The standard treatment is total thyroidectomy and central neck node dissection but, according to recent evidence, if the basal Ct is <30 pg/ml or following the institutional cutoff the neck node dissection can be avoided. For advanced metastatic cases, vandetanib has been demonstrated to be effective in children as well as adults.

The early steps of thyroid development that lead to its function in the human fetus and subsequently the further maturation that allows the human fetus to secrete thyroxine (T4) in a significant amount are reviewed here. We underline the importance of the transfer of T4 from the pregnant woman to her fetus, which contributes at all stages of the pregnancy to fetal thyroid function and development. In the first trimester of pregnancy, the temporal and structural correlation of thyroid hormone synthesis with folliculogenesis supported the concept that structural and functional maturations are closely related. Human thyroid terminal differentiation follows a precisely timed gene expression program. The crucial role of the sodium/iodine symporter for the onset of thyroid function in the human fetus is shown. Fetal T4 is detected by the eleventh week of gestation and progressively increases throughout. The pattern of thyroid hormones and thyroid-stimulating hormone levels in the course of pregnancy is given from fetal blood sampling data, and the mechanisms governing this maturation in the human fetus are discussed. Finally an example of primary human fetal thyroid dysfunction, such as in Down syndrome, is given. The understanding of the physiology of the human fetal thyroid function is the basis for fetal medicine in the field of thyroidology.

Sexual differentiation is a tightly regulated series of events which transform the indifferent gonads and genitalia into sex-specific structures. This is driven by hormones produced by the fetal testes, primarily testosterone (T). However, masculinization of each structure does not occur synchronously and, until recently, it was presumed that androgens also control this masculinization over a broad period of fetal life, coincident with the period of fetal T production. However, a common fetal masculinization programming window (MPW) has been identified in male and female rodent models in which androgens must act to masculinize all components of the reproductive tract and allow their later complete development. Impaired androgen action only within this MPW can induce cryptorchidism and hypospadias. This MPW is likely to occur between 8-14 weeks' gestation in humans. Studies in transgenic mice have begun to investigate some of the underlying mechanisms involved. Anogenital distance is predictive of the incidence of disorders, such as azoospermia, hypospadias and cryptorchidism, and could provide a noninvasive, lifelong indicator of androgen action within this MPW, useful in clinical assessment of patients with disorders of sexual development. In addition, several diagnostic characteristics of the external genitalia are also useful in investigating this MPW.

Pediatric thyroid diseases cover a large spectrum of congenital and acquired forms, ranging from congenital primary or central hypothyroidism, autoimmune thyroid disease, iodine deficiency, rare genetic defects of thyroid hormone action, metabolism and cell membrane transport to benign nodules and malignant tumors. The previous 15 papers of the textbook Paediatric Thyroidology gave a systematic overview of the current knowledge and guidelines on all these diseases. In this final paper, the authors collected a series of patient histories from their clinics illustrating frequently encountered clinical problems and providing key learning points and references to each case. Although not fully comprehensive, it aims at providing relevant clinical knowledge on thyroid diseases of the neonate, the child, and the adolescent.

Fertility potential is one of the issues that should be considered by the multidisciplinary team when addressing gender assignment, surgical management, the process of disclosure to patients and their families, and prospective long-term outcomes of individuals with disorders of sex development (DSD). In this article, we review the current evidence of the fertility potential of patients with: (1) dysgenetic DSD, including pure and partial gonadal dysgenesis, asymmetric gonadal differentiation, ovotesticular DSD and 46,XX testicular DSD; (2) 46,XY DSD due to abnormal testicular hormone production or action, including testosterone production deficiencies, dihydrotestosterone deficiency, androgen insensitivity and defects in anti-Müllerian hormone or its receptor, and (3) 46,XX DSD due to excessive androgen exposure in individuals with no testicular tissue, i.e. congenital adrenal hyperplasia and aromatase deficiency.

Transition of medical care is a multifaceted, active process that attends to the medical, psychosocial, educational and vocational needs of adolescents and young adults as they move from child- to adult-centred care. Transition from paediatric to adult services is recognized as an important part of continuous care for young people with disorders of sex development (DSD), just as it is for all young people affected by chronic medical conditions. There is evidence that the medical community is failing to transition young people with DSD safely, the result being that young people are lost to care and not receiving appropriate services into adulthood. To support transition more effectively, healthcare professionals should provide developmentally appropriate care. To accomplish this, healthcare professionals must understand, recognize and address the real-life challenges faced by young people in general, as well as those challenges specific to having DSD. Communication between paediatric and adult services, individual healthcare professionals, young people and their families is necessary for the successful transition of care.

Patients with defects in the steroid biosynthesis and resulting disorders of sex development are the largest group among patients with such disorders. Many of these patients suffer from adrenal insufficiency and have to take either glucocorticoids or a combination of glucocorticoid and mineralocorticoid replacement therapy from birth to avoid life-threatening complications. In this chapter, the physiologic situation of cortisol secretion and the different possibilities of hormone replacement therapy are discussed. Further attention is given to stress-dosing of glucocorticoids, especially hydrocortisone.

The role of feminising surgery in disorders of sex development (DSD) has been a topic of intense discussion for many years. The controversy mainly focuses on the timing of surgery: early (in childhood) or delayed (in adolescence), with clinicians divided in opinion. This conflict between proponents of either treatment approach remains unresolved, and will continue to do so until long-term outcome data from prospective studies become available. A significant recommendation of the Chicago Consensus Statement in 2005 was the need for individuals with DSD to be cared for exclusively in specialised centres within a multidisciplinary setting. Whilst this appears to be widely adopted, it remains to be seen whether other recommendations regarding limiting feminising surgery only to girls with a significant degree of virilisation have been similarly embraced. To reflect the current situation, we will summarise the main arguments in favour of either of the two treatment modalities, i.e. early or late feminising surgery, and conclude with a management proposal.

Congenital thyroid diseases can be explained in the context of the individual ontogenetic development; however, they can also be mirrored in the perspective of the phylogenetic evolution of the thyroid hormone system. The unique feature of the system, e.g., the generation of iodinated tyrosine derivatives by specialized enzymes that are frequently disrupted by mutations in congenital hypothyroidism, occurred very early in plant evolution and can still be demonstrated in algae today. All other components like the thyroid hormone receptors (TRs), the transporter molecules, the regulation by thyroid-stimulating hormone and thyrotropin-releasing hormone--and their respective receptors - as well as the structures that produce thyroid hormone with the human thyroid as the most recent development evolved in the animal kingdom. Already in the earliest animal species like Ciona intestinalis, specialized cells in the so-called endostyle not only iodinate tyrosine residues, but also secrete thyroid hormone itself, which activates TRs in target cells. During the following process of growing complexity of the thyroid system in higher species, pre-existing molecules and functions accumulated new variations, which enabled their assembly in new functional frames of the system and its central regulation. A deeper view into the range of evolutional variabilities and also flexibilities within the thyroid axis will most likely increase our understanding of the molecular defects and their potential treatment in the current human thyroid system.