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Genetic Steroid Disorders
Genetic Steroid Disorders, Second Edition targets adult and pediatric endocrinologists, clinical geneticists, genetic counselors, reproductive endocrinologists, neonatologists, urologists, and psychoendocrinologists. It is designed to assist these specialists in the diagnosis and treatment of steroid disorders. This revision includes a new chapter on "Gonadotropins, Obesity and Bone" and new research on non-invasive prenatal diagnosis with cell-free DNA. Chapters are thoroughly updated covering steroid disorders, the genetic bases for the disorder and case presentations, This definitive reference belongs in every medical library! - Presents a comprehensive, translational look at all aspects ...
Hormonal and Genetic Basis of Sexual Differentiation Disorders and Hot Topics in Endocrinology: Proceedings of the 2nd World Conference
Proceedings of the 2nd World Conference – Hormonal and Genetic Basis of Sexual Differentiation Disorders and Hot Topics in Endocrinology. The meeting took place at The Eden Roc Hotel in Miami Beach, Florida, 1/15/10 – 1/17-10. Endocrinology and more specifically, the area of sexual differentiation disorders is an evolving field of medicine. The diagnosis and treatment of Disorders of Sex Development (DSD) is multi-faceted.
Genetic Steroid Disorders
The transformation of Δ5-3β-hydroxysteroids into the corresponding Δ4-3-keto-steroids is an essential step for the biosynthesis of all classes of active steroids: progesterone, mineralocorticoids, glucocorticoids, androgens, and estrogens. These steroid hormones play a crucial role in the differentiation, development, growth, and physiological function of most human tissues. The 3β-HSD deficiency (OMIM +201810), transmitted in an autosomic recessive disorder, is characterized by varying degrees of salt wasting; in genetic males, fetal testicular 3ß-HSD deficiency causes an undervirilized male genitalia (male pseudohermaphroditism); females exhibit either normal sexual differentiation or mild virilization.
Genetic Steroid Disorders
Ambiguous genitalia can be associated with disorders of sex development (DSD). DSD occurs when a person is born with discordant genetic, gonadal, or anatomic sex. Here we discuss typical-appearing external genital appearance in unaffected males and females followed by descriptions of ambiguous genitalia in newborns with 46,XY DSD, 46,XX DSD, syndromes associated with multiple congenital anomalies including, but not limited to, ambiguous genitalia, ovotesticular DSD, and mixed gonadal dysgenesis in newborns who possess a Y chromosome. We provide guidance to proceed with a clinical work-up to differentiation between types of DSD that result in ambiguous genitalia at birth. Finally, we discuss how gender assignments are made for newborns with DSD including ambiguous genitalia.
Genetic Steroid Disorders
Cytochrome P450 oxidoreductase (POR) is an enzyme that is essential for multiple metabolic processes; chiefly among them are reactions catalyzed by cytochrome P450 proteins for metabolism of steroid hormones, drugs, and xenobiotics. Mutations in POR cause a complex set of disorders that often resemble defects in steroid metabolizing enzymes 17-hydroxylase, 21-hydroxylase, and aromatase. Since the initial reports of POR mutations in 2004, more than 70 different mutations and polymorphisms in the POR gene have been identified and tested for their effect on activities of several steroid and drug metabolizing P450 proteins. Mutations in POR may have variable effects on different P450 partner proteins depending on the location of the mutation. The POR mutations that disrupt the binding of cofactors have a negative impact on all partner proteins, while mutations causing subtle structural changes may lead to altered interaction with partner proteins and the overall effect may be different for each partner.
Genetic Steroid Disorders
Glucocorticoid-remediable aldosteronism (GRA) is a heritable form of primary hyperaldosteronism. As a result of a chimeric gene duplication, aldosterone synthase is expressed in the cortisol-producing zona fasciculata of the adrenal cortex and is regulated by adrenocorticotropin (ACTH). Clinically, GRA is characterized by early onset of hypertension, which may be severe and refractory to standard therapies. In the absence of treatment with diuretics, hypokalemia is uncommon. GRA is associated with a high prevalence of intracranial aneurysms and hemorrhagic stroke. Diagnostic testing for the presence of the chimeric gene is available. The mainstay of treatment is glucocorticoid suppression of ACTH, and alternatives include mineralocorticoid receptor antagonism.
Genetic Steroid Disorders
Steroidogenesis begins with internalization of low-density lipoprotein particles and subsequent intracellular processing of cholesterol. Disorders in these steps include adrenoleukodystrophy, Wolman disease, and Niemann–Pick type C disease, which may present as adrenal insufficiency. Cholesterol delivery to the inner mitochondrial membrane is regulated by the steroidogenic acute regulatory protein, StAR, and cholesterol is converted to pregnenolone within mitochondria by the cholesterol side chain cleavage enzyme, P450scc. Severe StAR mutations cause classic congenital lipoid adrenal hyperplasia (CAH), characterized by adrenal insufficiency and 46,XY disorders of sexual development (DSD). ...
Genetic Steroid Disorders
Humans have two isozymes with 11β-hydroxylase activity that are respectively required for cortisol and aldosterone synthesis. CYP11B1 (11β-hydroxylase) converts 11-deoxycortisol to cortisol and 11-deoxycorticosterone to corticosterone, is expressed at high levels and is regulated by ACTH. CYP11B2 (aldosterone synthase) is normally expressed at low levels and is regulated mainly by angiotensin II and potassium levels. The latter enzyme also has 18-hydroxylase and 18-oxidase activities and thus can synthesize aldosterone from deoxycorticosterone. Mutations in the CYP11B1 gene cause steroid 11β-hydroxylase deficiency, a form of congenital adrenal hyperplasia. Mutations in CYP11B2 result in aldosterone synthase deficiency, which can cause hyponatremia, hyperkalemia and hypovolemia in infancy. These are both recessive disorders. Unequal crossing over between the CYP11B genes can generate a duplicated chimeric gene, causing glucocorticoid-suppressible hyperaldosteronism, an autosomal dominant form of hypertension. Frequent polymorphisms in these genes can affect aldosterone secretion and risk of hypertension.
Genetic Steroid Disorders
Surgical treatment of congenital adrenal hyperplasia has undergone dramatic evolution over the past 30 years. This chapter will explore current reconstructive techniques and historic as well as current surgical outcomes. A brief description of surgical technique and its evolution will be described, followed by an analysis of surgical outcomes. The chapter will conclude with a discussion regarding current controversies regarding timing and technique of surgical correction.
Genetic Steroid Disorders
Following development of the fetal bipotential gonad into a testis, male genital differentiation requires testicular androgens. Fetal Leydig cells produce testosterone that is converted to dihydrotestosterone in genital skin, resulting in labioscrotal fusion. An alternative “backdoor” pathway of dihydrotestosterone synthesis that bypasses testosterone has been described in marsupials, but its relevance to human biology has been uncertain. The classic and backdoor pathways share many enzymes, but a 3α-reductase, AKR1C2, is unique to the backdoor pathway. Human AKR1C2 mutations cause disordered sexual differentiation, establishing that both pathways are required for normal human male genital development. These observations show that fetal dihydrotestosterone acts both hormonally and as a paracrine factor, substantially revising the classic paradigm for fetal male sexual development.
