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Congenital adrenal hyperplasia describes a group of inherited autosomal recessive disorders characterized by an enzymatic defect in cortisol biosynthesis, compensatory increases in corticotropin secretion, and adrenocortical hyperplasia. 21-Hydroxylase deficiency is responsible for more than 95% of cases and is one of the most common known autosoma...
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... Center, National Institutes of Health [NIH], Bethesda, Maryland): Congenital adrenal hyper- plasia due to 21-hydroxylase deficiency is one of the most common known autosomal recessive disorders (1). In this condition, impaired cortisol production leads to a lack of negative glucocorticoid feedback on the pitu- itary, hypothalamus, and suprahypothalamic centers, re- sulting in an increase in corticotropin, a buildup of cor- tisol precursors, and androgen excess (Figure 1). The carrier frequency of the classic or severe form of 21- hydroxylase deficiency is approximately 1 in 60 persons (2). ...
Citations
... 5 The goals of treatment include ensuring normal growth, puberty, and avoiding complications. 5,218,219 GC replacement in CAH has challenges as it should replicate the natural cortisol circadian rhythm, which peaks in the early morning. 17,220 Moreover, it should adapt to stress 221 and regulate ACTH to control adrenal androgen excess. ...
Congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency accounts for 95% of all CAH cases and is one of the most common inborn metabolic conditions. The introduction of life-saving glucocorticoid replacement therapy 70 years ago has changed the perception of CAH from a paediatric disorder into a lifelong, chronic condition affecting patients of all age groups. Alongside health problems that can develop during the time of paediatric care, there is an emerging body of evidence suggesting an increased risk of developing co-morbidities during adult life in patients with CAH. The mechanisms that drive the negative long-term outcomes associated with CAH are complex and involve supraphysiological replacement therapies (glucocorticoids and mineralocorticoids), excess adrenal androgens both in the intrauterine and postnatal life, elevated steroid precursors and adrenocorticotropic hormone levels. Alongside a review of mortality outcome, we discuss issues that need to be addressed when caring for the CAH patient including female and male fertility, cardio-metabolic morbidity, bone health and other important long-term outcomes of CAH.
... Treatment of classic CAH is intended to replace both glucocorticoid and if necessary, mineralocorticoid hormones to prevent adrenal and salt-wasting crisis and to reduce excessive corticotropin driving adrenal androgen secretion (134). Clinical goals are normal growth and development and pubertal maturation from birth to adolescence, and prevention of adrenal crisis, virilization, and other long-term complications discussed below (134,328,329). The levels of evidence for management guidelines are detailed in The Endocrine Society's Clinical Practice Guideline published in 2018 (134) and are not repeated here. ...
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting cortisol biosynthesis. Reduced activity of an enzyme required for cortisol production leads to chronic overstimulation of the adrenal cortex and accumulation of precursors proximal to the blocked enzymatic step. The most common form of CAH is caused by steroid 21- hydroxylase deficiency due to mutations in CYP21A2. Since the last publication summarizing CAH in Endocrine Reviews in 2000 there have been numerous new developments. These include more detailed understanding of steroidogenic pathways, refinements in neonatal screening, improved diagnostic measurements utilizing chromatography and mass spectrometry coupled with steroid profiling, and improved genotyping methods. Clinical trials of alternative medications and modes of delivery have been recently completed or are under way. Genetic and cell-based treatments are being explored. A large body of data concerning long-term outcomes in patients affected by CAH, including psychosexual well-being, has been enhanced by the establishment of disease registries. This review provides the reader with current insights in congenital adrenal hyperplasia with special attention to these new developments.
... Congenital adrenal hyperplasia (CAH) is a group of inherited autosomal recessive disorders characterized by a defect in enzymes involved in biosynthesis of cortisol, aldosterone or both (1) . The commonest type is 21hydroxylase (21-OH) deficiency accounting for 90 to 95%. ...
... CYP21A2 mutations block the synthesis of aldosterone and cortisol and causes a shift to the androgen production in the presence of 17α-hydroxyprogesterone (Clayton et al., 2002;Merke et al., 2002;New, 2003). CYP11B1 mutations causes increased cortisol precursors for androgen synthesis (New, 2003;Peter, 2002). ...
Sex determination is a highly sophisticated and ordered process where both male and female gonads develop from a common bipotential gonad depending on different activated signaling pathways. XY gonads develop into a testis promoted by the SRY/SOX9 pathway, whereas XX gonads develop into an ovary through the action of the RSPO1/WNT4/ß-Catenin pathway. R-spondin (Rspo) genes encode one kind of secreted proteins that activate the canonical WNT/β-Catenin pathway by inhibiting the degradation of WNT receptors. After binding to its receptors LGR4/5, RSPO1-LGR4/5 recruit E3 Ubiquitin-Protein Ligases ZNRF3 and RNF43 to release WNT receptors from being degraded by ubiquitination process, therefore WNT/β-Catenin signaling can be activated continuously. Rspo1 is a major regulator of ovary development across species. In the developing mouse gonad, Rspo1 is mainly expressed in the female supporting cells, and Rspo1 XX mutant gonads undergo female-to-male sex reversal by developing into ovotestis, gonads with both male and female characteristics. The molecular and cellular mechanisms behind this partial sex reversal remain unclear. In this work, we have developed a new mouse model allowing a conditional mutation of Rspo1. We have established that the critical window for Rspo1 requirement in the developing XX mouse gonad is around E11.5, and that Rspo1 function is dispensable for ovarian differentiation after this time point. We have shown that ectopic steroidogenesis is an early event in the phenotypic changes of XX Rspo1 mutant gonads. Through pharmacological inhibition of the androgen receptor we have identified androgen signaling pathway as a major player in the female-to-male sex reversal of XX Rspo1 mutant gonads. In the second part of this work we have studied the phenotype of Sox9cKOWnt4KO double mutants where both the male and female pathway are impaired. We have found that XX Sox9cKOWnt4KO gonads develop as ovotestis indicating that the additional deletion of Sox9 did not rescue the female-to-male sex reversal caused by the Wnt4 mutation. We have also shown that XY Sox9cKOWnt4KO double knockout mutants undergo a transient female-like developmental phase before the gonads develop into ovotestis. This result demonstrates that Wnt4 deletion cannot rescue the initial steps of the male-to-female sex reversal caused by the Sox9 mutation. Together, these results reveal the timing of requirement of Rspo1 in ovarian development and highlight the pro-male role of androgen signaling in the XX female-to-male sex reversal process. It also rises new thoughts on the interactions between male and female pathway in mouse sex determination.
... Congenital adrenal hyperplasia (CAH) is a group of rare disorders demonstrated by a failure in one of the five enzymes responsible for cortisol production in autosomal recessive pattern (1). In adrenal glands, Pregnenolone is made from cholesterol which later can be processed to either mineralocorticoids or glucocorticoids or to sex steroids in adrenals and gonads (2). ...
Background:
Congenital adrenal hyperplasia is a rare autosomal recessive disorder where the mutation in P450 family 17 subfamily A member 1 gene (CYP17A1) is involved in its etiology. The disorder represents itself with low blood levels of estrogens, androgens, and cortisol that generally couples with hypertension, Hypokalemia, sexual primary amenorrhea, infantilism and in affected individuals.
Case:
In this study, the CYP17A1 gene in a 14-year-old female was examined. The karyotype of the patient was 46, XX, and the analysis of the CYP17A1 gene by Sanger sequencing revealed a novel homozygous deletion c.1052-1054CCT which led to isolated 17,20-lyase deficiency.
Conclusion:
In conclusion, this study report an in-frame deletion which results in isolated 17, 20-lyase deficiency, and the mutation might be used for diagnosis in other patients with distinctive clinical symptoms.
... Congenital adrenal hyperplasia (CAH) is a group of inherited autosomal recessive disorders characterized by a defect in enzymes involved in biosynthesis of cortisol, aldosterone or both 1 . The commonest type is 21-hydroxylase (21-OH) deficiency accounting for 90 to 95%. ...
... Okrem toho môže dôjsť k vzniku centrálnej predčasnej puberty v dôsledku aktivácie osi hypotalamus-hypofýza-gonády s vysokými hladinami adrenálnych androgénov, ktoré spôsobí predčasné uzavretie rastových štrbín [13]. Nesprávne vedená liečba CAH glukokortikoidmi ako aj nonkompliancia pacienta môže ohroziť konečnú telesnú výšku [14,15]. ...
Combination of Turner syndrome (TS) and classic congenital adrenal hyperplasia (CAH) is rare. Globally, the incidence of CAH, autosomal recessive disorder caused by enzyme defect of steroidogenic pathway, is very low (1 : 10 000-16 000). 90 % of CAH cases are caused by 21-hydroxylase gene mutation (CYP21A2). Globally, the incidencie of Turner syndrome reaches 1 : 2 500. Phenotypically, females with TS may render wide spectrum of clinical features. Dominant symptoms are lowered terminal height and gonadal dysgenesia, ultimately leading to absence of puberty and infertility. Virilisation may be evident among TS women with chromosome Y 45, X/46, XY. We present a 57 year old woman suffering from both TS 45, X/46, XX and 21-hydroxylase deficiency. Based on the intersex, she was misdiagnosed as a male after the birth. Dominant signs were intrauterine growth retardation and Prader 5 virilisation of the external genitalia. Testes were not palpable. Laparoscopy at the age of 6 showed uterus and ovaries. After this examination, clitoroplasty and vaginoplasty was performed. Karyotyping revealed a 45, X/46, XX pattern. The presence of virilising features at the time of puberty however could not be explained with the diagnosis of Turner syndrome. Laboratory tests revealed elevated level of 17-hydroxyprogesterone, dehydroepiandrosterone with low cortisol concentration and elevated ACTH. With the genomic analysis CYP21A2 gene, namely IN2G (IVS 2-13 A/C>G), large deletion/conversion was detected. Glucocorticoid treatment was initiated. Due to increased plasma renin concentration, fludrocortisone therapy was also initiated. Within this therapy, patient´s state improved significantly.Key words: congenital adrenal hyperplasia - CYP21A2 - Turner syndrome - 21-hydroxylase deficiency.
... Decreased activity of the sympathetic nervous system causes impairment of lipolysis, thermogenesis, and consequently leads to the excessive accumulation of body fat [68]. In people with the classic form of CAH achievement of decreased androgen production requires the use of higher doses of steroids, which causes additional adverse metabolic events [69]. ...
... Zmniejszona aktywność współczulnego systemu nerwowego powoduje upośledzenie lipolizy i termogenezy i jest odpowiedzialna za nadmierną kumulację tkanki tłuszczowej [68]. U osób z klasyczną postacią choroby osiągnięcie wyhamowania nadmiernej produkcji androgenów wymaga stosowania wyższej dawki steroidów, co dodatkowo powoduje niekorzystny efekt metaboliczny [69]. ...
Changes in sensitivity to insulin occur in the course of a number of endocrine disorders. Most of the hormones through their antagonistic action to insulin lead to increased hepatic glucose output and its decreased utilisation in peripheral tissues. Carbohydrate disorders observed in endocrine diseases result from the phenomenon of insulin resistance, and in some cases also a reduction in insulin secretion is present. Abnormalities of glucose metabolism are observed in acromegaly, but also in growth hormone deficiency, hypercortisolism in the course of Cushing's syndrome, hyper- or hypothyroidism, primary hyperparathyroidism, aldosteronism, pheochromocytoma, congenital hypertrophy of the adrenal glands, polycystic ovaries syndrome, hypogonadism, or other hormonally active neuroendocrine tumours. They are of a secondary nature in relation to impaired hormonal balance. Hyperglycaemia is therefore often reversible, and the most effective method of treatment of impaired insulin sensitivity is successful therapy of specific endocrinopathies. Insulin sensitisers, also with a good effect, are used. Most experiences to date can be attributed to metformin therapy. Attempts have been made at treatment with other agents that are also effective in reducing insulin resistance as incretins or glitazones. In the presented paper, the authors reviewed endocrine diseases in which there is a clinically significant change in insulin sensitivity. Moreover, methods of therapy of concomitant disturbed glucose metabolism were presented.
... Наиболее частая форма ВДКН, встречающаяся в 90-95% случаев, обусловлена дефицитом фермента 21-гидроксилазы [1][2][3]. В свою очередь ВДКН вследствие дефицита 21-гидроксилазы подразделяется на классические (вирильная и сольтеряющая) и неклассическую формы. ...
... Snegirev Archives of Obstetrics and Gynecology. 2017, 4 (2) DOI http://dx.doi.org/10.18821/2313-8726-2017-4-2-88-92 Reviews of literature На втором месте находится гипертоническая форма (ГФ) ВДКН -дефицит 11β-гидроксилазы, которая встречается, по данным литературы, примерно у 1 из 100 тыс. ...
Fertility in women with congenital dysfunction of the adrenal cortex (CDAC) due to the insufficiency of 21-hydroxylase (n21-OH) is presumed to decrease, especially in women with classic salt-losing type. Several factors contribute to the development of subfertility: an excess of androgens, adrenal hypersecretion of progesterone, the consequences of the reconstructive genital surgery, a syndrome of secondary polycystic ovaries and psychosexual factors. Adequate glucocorticoid therapy and the improvement of surgical and psychological care can contribute to the optimization of infertility in CDAC patients, even in classical variant women. This review contains up-to-date information on reproductive outcomes in CDAC women due to n21-OH, infertility and pregnancy problems.
... (81)(82)(83)(84)(85)(86)(87) Finally, the future guidelines and strategies in the management of children with congenital adrenal hyperplasia could prevent the long-term consequences of the disease.(88) ...
Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder resulting from a deficiency of one of the enzymes necessary for cortisol synthesis. As a result, decreased cortisol synthesis, increased adrenocorticotropin (ACTH) hormone via negative feedback system and over production of the hormones prior to the enzymatic defect. It is not a rare disorder in Saudi Arabia, where more than 90% of cases are due to 21-hydroxylase deficiency. Variable clinical forms ranging from the severe classical CAH, associated with complete loss of enzyme function to the milder non-classical forms (NCAH) where encounter.
This review presents an overview of the various types of CAH in Saudi Arabia, particularly the most common type 21-hydroxylase deficiency, highlighting its epidemiology, clinical presentation, diagnosis and management.
