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      Genotypic Sex and Severity of the Disease Determine the Time of Clinical Presentation in Steroid 17α-Hydroxylase/17,20-Lyase Deficiency

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          Context: Steroid 17α-hydroxylase/17,20-lyase deficiency (17OHD) is characterized by decreased sex steroids and cortisol, and excessive mineralocorticoid action. The clinical symptoms of hypocortisolemia are subtle. Aim: The clinical, biochemical, and molecular characteristics of patients with 17OHD were evaluated to determine the factors influencing the time of diagnosis and the management. Patients and Methods: Clinical data, steroid profiles by liquid chromatography-tandem mass spectrometry, and Sanger sequencing of the CYP17A1 gene was evaluated in 12 patients with 17OHD diagnosed between 2004 and 2020. Results: Median age of diagnosis was 13.9 (range: 0.04–29.5) years. Ten of 12 patients had 46,XY karyotype. Except for one boy with partial 17OHD, all patients had female external genitalia hence raised as females. The clinical presentation of 17OHD was earlier (median age: 7 years) in patients, who presented with severe hypertension, atypical genitalia, or positive family history ( n = 6, 50%) than those without (median age: 15.3 years; p = 0.0005). The latter group presented with amenorrhea ( n = 6, 50%). Steroid profile of patients uniformly showed a typical pattern of 17OHD regardless of the age at diagnosis. Serum gonadotropin concentrations were elevated in patients >12 years ( n = 7), normal in pre-adolescents ( n = 4), and low in a patient, who had a digenic inheritance of homozygous CYP17A1 and KISS1R mutations. Conclusions: Early clinical presentation and diagnosis in 17OHD are associated with symptomatic hypertension in both 46,XX and 46,XY patients or inadequate virilization of external genitalia in 46,XY partial 17OHD. In the absence of these, the clinical presentation is at late pubertal ages at which time amenorrhea and elevated gonadotropins are the hints for diagnosis.

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          Most cited references 39

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          Human cytochrome b5 requires residues E48 and E49 to stimulate the 17,20-lyase activity of cytochrome P450c17.

          Cytochrome P450c17 (CYP17) catalyzes both the 17alpha-hydroxylase and 17,20-lyase reactions in human steroid biosynthesis. Cytochrome b5 (b5) stimulates the rate of the 17,20-lyase reaction 10-fold with little influence on 17alpha-hydroxylase activity. Studies with apo-b5 suggest that stimulation of 17,20-lyase activity results from an allosteric action on the hCYP17 x POR complex, rather than electron transfer by b5. We hypothesized that specific residues on b5 interact with the hCYP17 x POR complex and that targeted mutation of surface-exposed residues might identify b5 residues critical for stimulating 17,20-lyase activity. We constructed, expressed, and purified 14 single plus 3 double b5 mutations and assayed their ability to stimulate 17,20-lyase activity. Most mutations did not alter the capacity of b5 to stimulate 17,20-lyase activity or appeared to modestly alter the affinity of b5 for the hCYP17 x POR complex. In contrast, mutation of E48, E49, or R52 reduced the maximal stimulation of 17,20-lyase activity. In particular, b5 mutation E48G + E49G lost over 95% of the capacity to stimulate 17,20-lyase activity, yet this mutation retained normal electron transfer properties. In addition, mutation E48G + E49G did not impair stimulation of 17,20-lyase activity by wild-type b5, suggesting that the mutation binds poorly to the site of the hCYP17 x POR complex occupied by b5. These data suggest that a specific allosteric binding site on b5, which includes residues E48, E49, and possibly R52, mediates the stimulation of 17,20-lyase activity.
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            Identification of a novel large CYP17A1 deletion by MLPA analysis in a family with classic 17α-hydroxylase deficiency.

            Steroid 17α-hydroxylase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia caused by mutations in the 17α-hydroxylase ( CYP17A1) gene. CYP17A1 is a key enzyme in the biosynthesis of adrenal and gonadal steroid hormones facilitating both 17α-hydroxylase and 17,20-lyase activities. We characterized a partial CYP17A1 deletion in a Kurdish family with 17OHD by multiplex ligation-dependent probe amplification (MLPA). The index patient presented with amenorrhea and lack of pubertal development. Investigations established the diagnosis of 46,XY disorder of sex development (DSD). She is the daughter of consanguineous parents and has 2 sisters with similar clinical presentation. All patients showed biochemical signs of primary adrenal and gonadal insufficiency. The molecular genetic analysis by PCR suggested a deletion spanning exons 1–6 of the CYP17A1 gene. MLPA analysis confirmed the large partial CYP17A1 deletion in patients and parents in homozygous and heterozygous state, respectively. This is the first report employing MLPA for mutation analysis to detect a deletion of CYP17A1 spanning multiple exons in 3 patients with classic 17OHD. Therefore, it is important to consider large partial CYP17A1 deletions in 17OHD in addition to point mutations in cases where no segregation analysis is possible to determine the correct genotype.
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              Puberty in a case with novel 17-hydroxylase mutation and the putative role of estrogen in development of pubic hair.

              17-Hydroxylase/17,20-lyase deficiency (17OHD) results from mutations in the CYP17A1 gene, leading to failure to synthesize cortisol, adrenal androgens, and gonadal steroids. Adrenarche is a consequence of the increased production of adrenal androgens. Here, we report a case carrying novel R239Q mutation causing complete functional loss of CYP17A1, and thus absence of adrenal and gonadal sex hormone production. The patient has had unexpected pubic hair development and insufficient breast development with estrogen replacement therapy. Possible mechanisms leading to pubic hair development and breast underdevelopment are discussed.

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                April 2021
                29 March 2021
                : 93
                : 9-10
                : 558-566
                aDepartment of Pediatric Endocrinology and Diabetes, Erzurum Regional Research and Training Hospital, Erzurum, Turkey
                bDepartment of Internal Medicine, Division of Endocrinology and Metabolism, Erzurum Regional Research and Training Hospital, Erzurum, Turkey
                cDepartment of Medical Genetics, Erzurum Regional Research and Training Hospital, Erzurum, Turkey
                dDepartment of Paediatric Endocrinology and Diabetes, Marmara University, School of Medicine, Istanbul, Turkey
                515079 Horm Res Paediatr 2020;93:558–566
                © 2021 S. Karger AG, Basel

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                Page count
                Tables: 3, Pages: 9
                Research Article


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