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Congenital Adrenal Hyperplasia Due to 17-Alpha-Hydoxylase/17,20-Lyase Deficiency Presenting with Hypertension and Pseudohermaphroditism: First Case Report from Oman

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Congenital Adrenal Hyperplasia Due to 17-Alpha-Hydoxylase/17,20-Lyase Deficiency Presenting with Hypertension and Pseudohermaphroditism: First Case Report from Oman Oman Medical Journal (2014) Vol. 29, No. 1:55-59 DOI 10. 5001/omj.2014.12 Case Reports Congenital Adrenal Hyperplasia due to 17-alpha-hydoxylase/17,20-lyase Deficiency Presenting with Hypertension and Pseudohermaphroditism: First Case Report from Oman Waad-Allah S. Mula-Abed, Fathima B. Pambinezhuth, Manal K. Al-Kindi, Noor B. Al-Busaidi, Hilal N. Al-Muslahi, and Mohammad A. Al-Lamki Received: 14 Nov 2013 / Accepted: 02 Dec 2013 © OMSB, 2014 Abstract This is the first report of congenital adrenal hyperplasia (CAH) identify previous studies related to this subtype of CAH. This is due to combined 17α-hydroxylase/17,20 lyase deficiency in an the first biochemically and genetically proven case of CAH due to Omani patient who was initially treated for many years as a case of 17α-hydroxylase/17,20-lyase deficiency in Oman and in the Arab hypertension. CAH is an uncommon disorder that results from a World described in the literature. defect in steroid hormones biosynthesis in the adrenal cortex. The clinical presentation depends on the site of enzymatic mutations and Keywords: Congenital adrenal hyperplasia; 17 α-hydroxylase; the types of accumulated steroid precursors. A 22-year-old woman 17,20-lyase; Hypertension; Pseudohermaphroditism; Adrenal who was diagnosed to have hypertension since the age of 10 years cortex; Oman. who was treated with anti-hypertensive therapy was referred to the National Diabetes and Endocrine Centre, Royal Hospital, Oman. Introduction The patient also had primary amenorrhea and features of sexual infantilism. Full laboratory and radio-imaging investigations were done. Adrenal steroids, pituitary function and karyotyping study Hypertension is uncommon during childhood and adolescence were performed and the diagnosis was confirmed by molecular with its presence usually pointing to an underlying etiology mostly mutation study. Laboratory investigations revealed adrenal steroids of metabolic origin. Of particular importance in its causations and pituitary hormones profile in addition to 46XY karyotype that especially when associated with genital ambiguity or disordered sex are consistent with the diagnosis of CAH due to 17α-hydroxylase development are mutations in the adrenal steroidogenesis mostly deficiency. Extensive laboratory workup revealed low levels of due to ‘congenital adrenal hyperplasia’ (CAH). The deficiency forms serum cortisol (and its precursors 17α-hydroxyprogesterone and of CAH which are associated with male pseudohermaphrodite 11-deoxycortisol), adrenal androgens (dehydroepiandrosterone include 21α-hydroxylase and to a lesser extent 11β-hydroxylase; with sulfate and androstenedione), and estrogen (estradiol); and high female pseudohermaphrodite include 17α-hydroxylase, 17,20 lyase, levels of mineralocorticoids precursors (11-deoxycorticosterone 3β-hydroxysteroid dehydrogenase, and cholesterol 20,22 desmolase; and corticosterone) with high levels of ACTH, FSH and LH. while CAH forms which are associated with hypertension include Mutation analysis revealed CYP17A1-homozygous mutation 17α-hydroxylase and 11β-hydroxylase deficiency.1 Other inherited (c.287G>A p.Arg96Gln) resulting in the complete absence of metabolic disorders that may be associated with monogenic 17α-hydroxylase/17,20-lyase activity. The patient was treated hypertension during childhood and adolescence include apparent with dexamethasone and ethinyl estradiol with cessation of anti- mineralocorticoid excess, glucocorticoid remediable aldosteronism, hypertensive therapy. A review of the literature was conducted to familial hyperaldosteronism type 2, Liddle's syndrome, Gordon's syndrome, activating mutations of the mineralocorticoid receptor, and generalized glucocorticoid resistance.2 Waad-Allah S. Mula-Abed , Manal K. Al-Kindi Department of Chemical Pathology, Royal Hospital, P.O. Box 1331, Seeb 111, Steroidogenesis is an essential pathway for the synthesis Muscat, Sultanate of Oman. of steroid hormones in the adrenal cortex: mineralocorticoids, E-mail: [email protected] glucocorticoids and androgens, mainly dehydroepiandrosterone Fathima B. Pambinezhuth, Noor B. Al-Busaidi, Hilal N. Al-Muslahi, (DHEA), and androstenedione. Cholesterol is the key substrate National Diabetes and Endocrine Centre, Royal Hospital, P.O. Box 1331, Seeb in this pathway which is converted by the rate limiting cholesterol 111, Muscat, Sultanate of Oman. side chain cleavage enzyme (CYP11A1) into pregnenolone, the Mohammad A. Al-Lamki common precursor for all steroid hormones. In the adrenal cortex, Medical Endo-Metabolic Unit, Royal Hospital, P.O. Box 1331, Seeb 111, Muscat, Sultanate of Oman. this is processed into either glucocorticoids and androgens in zona Oman Medical Specialty Board Oman Medical Journal (2014) Vol. 29, No. 1:55-59 fasciculate and zona reticularis (which contain the microsomal of enzyme block in the steroid synthesis. CAH should be considered enzyme cytochrome P450c17α-hydroxylase: P450c17 and 17,20 in infants, children or adolescents with ambiguous genitalia, lyase) or into mineralocorticoids in zona glomerulosa (which does sexual infantilism, hypogonadism or hypertension, particularly not contain P450c17 and 17,20 lyase, but contains aldosterone when associated with disturbed water, electrolytes and hydrogen synthase, CYP11B2). Because it possesses both 17α-hydroxylase and homeostasis. The most common form is 21α-hydroxylase deficiency 17,20 lyase activities, P450c17 is considered a bifunctional enzyme which may be diagnosed at birth by the presence of virilization in that has a profound impact on the flux through the steroidogenic female infants or by features of salt wasting in both genders.5 The pathway for its selective cellular localization in zona fasciculate 11β-hydroxylase deficiency is uncommon and 17α-hydroxylase and zona reticularis and its absence in zona glomerulosa.1,3 This deficiency is a rare form of CAH which may present much later in enzyme is encoded by the CYP17A1 gene and has been mapped adolescence or adulthood.6,7 to chromosome 10q24-25 in the adrenal cortex (zona reticularis) and gonads.4 The protein is localized in the endoplasmic reticulum, Case Report has both 17α-hydroxylase and 17,20 lyase activities, and is considered as the key enzyme in steroidogenesis for producing: A 22-year-old Omani woman was referred from Nizwa Hospital, progestins, mineralocorticoids, glucocorticoids, androgens and a secondary care regional hospital, to the National Diabetes and estrogens. Specifically, CYP17A1 acts upon pregnenolone and Endocrine Centre, Royal Hospital, a tertiary care hospital in Oman, progesterone to add a hydroxyl group (-OH) at carbon 17 position for expert consultation. She was diagnosed to have hypertension of the steroid D ring, or acts upon 17α-hydroxypregnenolone and at the age of 10 years and was considered to have early essential 17α-hydroxprogesterone to split the nucleus (17,20 lyase activity) hypertension for which she was given antihypertensive therapy. to convert them into C-19 androgen precursors, DHEA and At the time of her consultation at Royal Hospital, she was on androstenedione, respectively. For understanding the biosynthesis three antihypertensive medications: β1 receptor antagonist of adrenals steroids, a scheme of the pathway is presented. (Fig 1) (atenolol), angiotensin-converting enzyme inhibitor (lisinopril) and In CAH, there are various genetic mutations in the enzymes diuretic (thiazide). However, despite this combined therapy, her involved in steroidogenesis. Due to this enzymatic defect, cortisol is hypertension was not well controlled. The patient also had primary under-produced and the negative feedback control on ACTH is lost amenorrhea and features of sexual infantilism and she appeared to with consequently excess ACTH produced in order to normalize have pseudohermaphroditism. She had no past history of hernial cortisol levels resulting in overproduction and accumulation of surgery. The family history was unremarkable. She has 8 siblings (2 steroids precursors prior to the enzyme defect as well as hyperplasia brothers and 6 sisters). of the adrenal cortex. The clinical manifestation depends on the level Figure 1: Major human steroidogenic pathway in the adrenal cortex. Key enzymes are shown as dashed arrows/shaded boxes indicating the chemical reactions. P450scc (cholesterol desmolase) cleaves cholesterol to pregnenolone, the first intermediate in steroid biosynthesis. The steroids in the first row are Δ5-steroids, which constitute the preferred pathway to C19 steroids in human. Not all intermediate steroids, pathways, and enzymes are shown. In CAH due to 17α-hydroxylase deficiency (marked as red X) there is overproduction of the precursors/hormones on the left side of the first column with decreased production of the precursors/hormones on the right side of the second and third columns. 'Adopted from: Nimkarn S, New M. Prenatal diagnosis and treatment of congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Nat Clin Pract Endocrinol Metab 2007 May;3(5):405-413'. Oman Medical Specialty Board Oman Medical Journal (2014) Vol. 29, No. 1:55-59 57 On physical examination, she was quite tall with height Table 1: Plasma steroids and pituitary hormones at time of 173 cm, weight 73 kg, BMI 24.2 kg/m2, BP 145/90 mmHg, presentation using different reporting units (compared with with no secondary sexual characteristics, no pubic or axillary recommended adult reference ranges). hair, Tanner score P1B1, external genitalia of female type, with no goiter. Diagnostic
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