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Genetics of Endocrine Disorders and Diabetes Mellitus
Published in George H. Gass, Harold M. Kaplan, Handbook of Endocrinology, 2020
Bess Adkins Marshall, Abby Solomon Hollander
Congenital adrenal hyperplasia (CAH) is a disorder characterized by a deficiency of one of the adrenal enzymes required for cortisol biosynthesis. Cortisol deficiency leads to hypersecretion of adrenocorticotropic hormone (ACTH), resulting in adrenal hyperplasia. The most common etiology of this disorder is deficiency of 21-hydroxylase, the enzyme required to convert 17-hydroxyprogesterone to 11-deoxycortisol. This enzyme deficiency accounts for approximately 90–95% of all cases of CAH.1 21-Hydroxylase deficiency is a common inborn error of metabolism, occurring in about 1 in 15,000 births as an autosomal recessive disorder.2 The genetic basis of this disease has been thoroughly studied. The clinical variants of 21-hydroxylase deficiency, localization of the gene, known mutations, and progress in prenatal diagnosis and treatment will be discussed.
Variation of sex differentiation
Published in Joseph S. Sanfilippo, Eduardo Lara-Torre, Veronica Gomez-Lobo, Sanfilippo's Textbook of Pediatric and Adolescent GynecologySecond Edition, 2019
Anne-Marie Amies Oelschlager, Margarett Shnorhavorian
11β-Hydroxylase deficiency is caused by a mutation in the CYP11B1 gene, which results in increased 11-deoxycortisol and mild elevation in 17-OHP. Presenting 46,XX infants may have mild virilization and later may develop hypertension and hypokalemia.
Developmental abnormalities of the genitalia: intersex, hypospadias, and cryptorchidism
Published in J Kellogg Parsons, E James Wright, The Brady Urology Manual, 2019
11β-hydroxylase deficiency: <5% of CAHNot salt wasting (i.e. no mineralocorticoid deficiency)Presentation: hypertension, hyperpigmentation, virilization (and precocious puberty in males)Diagnosis: will have elevated serum levels of 11-deoxycortisol and 11-deoxycorticosterone.
Osilodrostat for the treatment of Cushing’s disease
Published in Expert Opinion on Pharmacotherapy, 2021
The 22-week LINC2 study included two cohorts; the continuation cohort were 4 of the 12 LINC1 patients who re-enrolled and had a UFC >ULN after being taken off osilodrostat therapy for 15–19 months. The expansion cohort included 15 new patients who had a UFC > 1.5× ULN. After a washout and screening period for both groups, LINC1 patients continued treatment for 22 weeks on the dose that they tolerated in LINC1 with dosing adjustments made if needed. The expansion titration mirrored the LINC1 protocol. After two patients discontinued treatment, 15 patients (88.2%) had normal UFC levels by week 22 in the per protocol analysis, with 15 (78.9%) in the intention-to-treat analysis. Other hormonal changes were similar to those observed in LINC1. Morning serum and salivary cortisol decreased to normal levels while late-night salivary cortisol changes were variable, and levels remained above normal during treatment. ACTH levels increased fourfold at week 22. Overall mean baseline 11-deoxycortisol and 11-deoxycorticosterone levels increased during treatment. Overall mean aldosterone and renin levels decreased. Mean testosterone levels in 9 (75%) females increased to greater than ULN at week 22. Of note, two patients (10.5%) had not undergone prior surgery for management of CD [10].
Drug design strategies for Cushing’s syndrome
Published in Expert Opinion on Drug Discovery, 2019
S. A. Usanov, A. V. Kliuchenovich, N. V. Strushkevich
The selective inhibition of CYP11B1 is a novel strategy to block cortisol production. However, the development of selective and potent CYP11B1 inhibitors is particularly challenging due to high homology to the CYP11B2 isoform. Both CYP11B1 and CYP11B2 belong to the cytochrome P450 family and contain a heme group as a cofactor. CYP11B1 catalyzes the 11β-hydroxylation of 11-deoxycortisol to cortisol. CYP11B2 catalyzes a multistep reaction: the 11β-hydroxylation of 11-deoxycorticosterone (DOC) to corticosterone (B) followed by the 18-hydroxylation of B and 18-oxidation of 18-OH-B to aldosterone. CYP11B1 and CYP11B2 are located in the inner membrane of the mitochondria, share 93% amino acid sequence identity and function within an identical redox-chain which consists of ferredoxin reductase and ferredoxin [11]. However, they are expressed in different zones of the adrenal cortex and, as a result, have different gene regulation. CYP11B1 is expressed in the zona fasciculata/reticularis under control of ACTH [25], while expression of CYP11B2 is restricted to the zona glomerulosa and regulated by angiotensin II, K+ and ACTH [26] . Zonal distribution, the absence of CYP17A1 in the zona glomerulosa and centripetal blood flow in the adrenal cortex ensure different sites of production of mineralocorticoids (aldosterone) and glucocorticoids (cortisol) [26].
Decision-making for adrenocortical carcinoma: surgical, systemic, and endocrine management options
Published in Expert Review of Anticancer Therapy, 2018
Soraya Puglisi, Paola Perotti, Deborah Cosentini, Elisa Roca, Vittoria Basile, Alfredo Berruti, Massimo Terzolo
Aldosterone-producing ACC is rare and is generally associated with severe hypertension and marked hypokalemia [12]. Screening by measuring plasma aldosterone and plasma renin activity (PRA) (or direct renin concentration) is recommended in all hypertensive and/or hypokalemic patients with adrenal masses [13]. In some cases, pseudo-aldosteronism is present, due to increased production of deoxycorticosterone. Pure estrogen excess is rare and may cause gynecomastia, loss of libido and testicular atrophy in men, while in women menstrual irregularities [8]. Hypersecretion of sexual steroids is frequently associated to cortisol excess in ACC patients. Baseline 17-OH progesterone levels are frequently increased, as well as androstenedione and DHEAS, which leads to increased plasma testosterone in females with signs of androgen excess (hirsutism, acne, alopecia) [3]. Measurement of steroid precursors in blood or urine may be exploited for diagnostic purposes. However, the value of increased DHEAS levels to predict malignancy of an adrenal mass is rather low [14]. More recently, it was demonstrated that serum steroid paneling by LC-MS/MS is a useful tool to discriminate ACC from other adrenal tumor lesions. In this study, both the number of steroids secreted in high amounts and the marked elevation of several steroid intermediates without biological activity was characteristic of ACC and useful for the differential diagnosis. The cortisol precursor 11-deoxycortisol was found the most discriminating between ACC and non-ACC adrenal lesions [15].