Clinical And Molecular Spectrum Of Patients With 17β-hydroxysteroid Dehydrogenase Type 3 (17-β-hsd3) Deficiency [espectro Clínico E Molecular De Pacientes Com Deficiência De 17β-hidroxiesteroide Desidrogenase Tipo 2 (17-β-hsd3)]

The enzyme 17β-hydroxysteroid dehydrogenase type 3 (17-β-HSD3) catalyzes the conversion of androstenedione to testosterone in the testes, and its deficiency is a rare disorder of sex development in 46,XY individuals. It can lead to a wide range of phenotypic features, with variable hormonal profiles. We report four patients with the 46,XY karyotype and 17-β-HSD3 deficiency, showing different degrees of genital ambiguity, increased androstenedione and decreased testosterone levels, and testosterone to androstenedione ratio G novel mutation, and c.277+4A>T mutation, both located within the intron 3 splice donor site of the HSD17B3 gene, were identified in case 3. In addition, homozygosis for the missense p.Ala203Val, p.Gly289Ser, p.Arg80Gln mutations were found upon HSD17B3 gene sequencing in cases 1, 2, and 4, respectively. © ABEM todos os direitos reservados.568533539Andersson, S., Moghrabi, N., Physiology and molecular genetics of 17beta-hydroxysteroid dehydrogenases (1997) Steroids, 62, pp. 143-147Lukacik, P., Kavanagh, K.L., Oppermann, U., Structure and function of human 17beta-hydroxysteroid dehydrogenases (2006) Mol Cell Endocrinol, 248, pp. 61-71Labrie, F., Luu-The, V., Lin, S.X., Labrie, C., Simard, J., Breton, R., The key role of 17 beta-hydroxysteroid dehydrogenases in sex steroid biology (1997) Steroids, 62, pp. 148-158George, M.M., New, M.I., Tem, S., Sultan, C., Bhangoo, A., The clinical and molecular heterogeneity of 17aHSD3 enzyme deficiency (2010) Horm Res Paediatr, 74, pp. 229-240Boehmer, A.L., Brinkmann, A.O., Sandkuijl, L.A., Halley, D.J., Niermeijer, M.F., Andersson, S., 17beta-hydroxysteroid dehydrogenase-3 deficiency: Diagnosis, phenotypic variability, population genetics, and worldwide distribution of ancient and de novo mutations (1999) J Clin Endocrinol Metab, 84, pp. 4713-4721Mendonça, B.B., Inacio, M., Arnhold, I.J., Costa, E.M., Bloise, W., Martin, R.M., Male pseudohermaphroditism due to 17beta-hydroxysteroid dehydrogenase 3 deficiency. 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46,xx Dsd And Antley-bixler Syndrome Due To Novel Mutations In The Cytochrome P450 Oxidoreductase Gene [dds 46,xx E Síndrome De Antley-bixler Causada Por Novas Mutações No Gene Da Enzima P450 Oxidorredutase]

Deficiency of the enzyme P450 oxidoreductase is a rare form of congenital adrenal hyperplasia with characteristics of combined and partial impairments in steroidogenic enzyme activities, as P450 oxidoreductase transfers electrons to CYP21A2, CYP17A1, and CYP19A1. It results in disorders of sex development and skeletal malformations similar to Antley-Bixley syndrome. We report the case of a 9-year-old girl who was born with virilized genitalia (Prader stage V), absence of palpable gonads, 46,XX karyotype, and hypergonadotropic hypogonadism. During the first year of life, ovarian cyst, partial adrenal insufficiency, and osteoarticular changes, such as mild craniosynostosis, carpal and tarsal synostosis, and limited forearm pronosupination were observed. Her mother presented severe virilization during pregnancy. The molecular analysis of P450 oxidoreductase gene revealed compound heterozygosis for the nonsense p.Arg223*, and the novel missense p.Met408Lys, inherited from the father and the mother, respectively. © ABEM todos os direitos reservados.568578585Miller, W.L., Minireview: Regulation of steroidogenesis by electron transfer (2005) Endocrinology, 146, pp. 2544-2550Scott, R.R., Gomes, L.G., Huang, N., Van Vliet, G., Miller, W.L., Apparent manifesting heterozygosity in P450 oxidoreductase deficiency and its effect on coexisting 21-hydroxylase deficiency (2007) J Clin Endocrinol Metab, 92, pp. 2318-2322Auchus, R.J., Lee, T.C., Miller, W.L., Cytochrome b5 augments the 17,20-lyase activity of human P450c17 without direct electron transfer (1998) J Biol Chem, 273, pp. 3158-3165Flück, C.E., Tajima, T., Pandey, A.V., Arlt, W., Okuhara, K., Verge, C.F., Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome (2004) Nat Genet, 36, pp. 228-230Arlt, W., Walker, E.A., Draper, N., Ivison, H.E., Ride, J.P., Hammer, F., Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: Analytical study (2004) Lancet, 363, pp. 2128-2135Scott, R.R., Miller, W.L., Genetic and clinical features of P450 oxidoreductase deficiency (2008) Horm Res, 69, pp. 266-275Polusani, S.R., Kar, R., Riquelme, M.A., Masters, B.S., Panda, S.P., Regulation of gap junction function and connexin 43 expression by cytochrome P450 oxidoreductase (CYPOR) (2011) Biochem Biophys Res Commun, 411, pp. 490-495Tomalik-Scharte, D., Maiter, D., Kirchheiner, J., Ivison, H.E., Fuhr, U., Arlt, W., Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency (2010) Eur J Endocrinol, 163, pp. 919-924(2012) Human Gene Mutation Database, , http://www.hgmd.cf.ac.uk/ac/index.php, Available at, Accessed on: Nov 17Flück, C.E., Pandey, A.V., Clinical and biochemical consequences of P450 oxidoreductase deficiency (2011) Endocr Dev, 20, pp. 63-79Krone, N., Reisch, N., Idkowiak, J., Dhir, V., Ivison, H.E., Hughes, B.A., Genotype-phenotype analysis in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency (2012) J Clin Endocrinol Metab, 97, pp. E257-E267Sambrook, J., Fristsch, E.F., Maniatis, T.E., (1989) Molecular Cloning: A laboratory manual, , Cold Spring Harbor, NY: Cold Spring Harbor Laboratory PressXia, C., Panda, S.P., Marohnic, C.C., Martásek, P., Masters, B.S., Kim, J.J., Structural basis for human NADPH-cytochrome P450 oxidoreductase deficiency (2011) Proc Natl Acad Sci U S A, 108, pp. 13486-13491Idkowiak, J., O'Riordan, S., Reisch, N., Malunowicz, E.M., Collins, F., Kerstens, M.N., Pubertal presentation in seven patients with congenital adrenal hyperplasia due to P450 oxidoreductase deficiency (2011) J Clin Endocrinol Metab, 96 (3), pp. E453-E462Hamdane, D., Xia, C., Im, S.C., Zhang, H., Kim, J.J., Waskell, L., Structure and function of an NADPH-cytochrome P450 oxidoreductase in an open conformation capable of reducing cytochrome P450 (2009) J Biol Chem, 284 (17), pp. 11374-11384Xia, C., Hamdane, D., Shen, A.L., Choi, V., Kasper, C.B., Pearl, N.M., Conformational changes of NADPH-cytochrome P450 oxidoreductase are essential for catalysis and cofactor binding (2011) J Biol Chem, 286, pp. 16246-16260Herkert, J.C., Blaauwwiekel, E.E., Hoek, A., Veenstra-Knol, H.E., Kema, I.P., Arlt, W., A rare cause of congenital adrenal hyperplasia: Antley-Bixler syndrome due to POR deficiency (2011) Neth J Med, 69, pp. 281-283Fukami, M., Hasegawa, T., Horikawa, R., Ohashi, T., Nishimura, G., Homma, K., Cytochrome P450 oxidoreductase deficiency in three patients initially regarded as having 21-hydroxylase deficiency and/or aromatase deficiency: Diagnostic value of urine steroid hormone analysis (2006) Pediatr Res, 59, pp. 276-280Flück, C.E., Miller, W.L., P450 oxidoreductase deficiency: A new form of congenital adrenal hyperplasia (2006) Curr Opin Pediatr, 18, pp. 435-441Homma, K., Hasegawa, T., Nagai, T., Adachi, M., Horikawa, R., Fujiwara, I., Urine steroid hormone profile analysis in cytochrome P450 oxidoreductase deficiency: Implication for the backdoor pathway to dihydrotestosterone (2006) J Clin Endocrinol Metab, 91, pp. 2643-2649But, W.M., Lo, I.F., Shek, C.C., Tse, W.Y., Lam, S.T., Ambiguous genitalia, impaired steroidogenesis, and Antley-Bixler syndrome in a patient with P450 oxidoreductase deficiency (2010) Hong Kong Med J, 16, pp. 59-62Iijima, S., Ohishi, A., Ohzeki, T., Cytochrome P450 oxidoreductase deficiency with Antley-Bixler syndrome: Steroidogenic capacities (2009) J Pediatr Endocrinol Metab, 22, pp. 469-475Ko, J.M., Cheon, C.K., Kim, G.H., Yoo, H.W., A case of Antley-Bixler syndrome caused by compound heterozygous mutations of the cytochrome P450 oxidoreductase gene (2009) Eur J Pediatr, 168, pp. 877-880Sahakitrungruang, T., Huang, N., Tee, M.K., Agrawal, V., Russell, W.E., Crock, P., Clinical, genetic, and enzymatic characterization of P450 oxidoreductase deficiency in four patients (2009) J Clin Endocrinol Metab, 94, pp. 4992-5000Adachi, M., Tachibana, K., Asakura, Y., Yamamoto, T., Hanaki, K., Oka, A., Compound heterozygous mutations of cytochrome P450 oxidoreductase gene (POR) in two patients with Antley-Bixler syndrome (2004) Am J Med Genet A, 128, pp. 333-339New, M.I., Nonclassical congenital adrenal hyperplasia and the polycystic ovarian syndrome (1993) Ann NY Acad Sci, 687, pp. 193-205Rosa, S., Duff, C., Meyer, M., Lang-Muritano, M., Balercia, G., Boscaro, M., P450c17 deficiency: Clinical and molecular characterization of six patients (2007) J Clin Endocrinol Metab, 92, pp. 1000-1007Shima, M., Tanae, A., Miki, K., Katsumata, N., Matsumoto, S., Nakajima, S., Mechanism for the development of ovarian cysts in patients with congenital lipoid adrenal hyperplasia (2000) Eur J Endocrinol, 142, pp. 274-279Belgorosky, A., Pepe, C., Marino, R., Guercio, G., Saraco, N., Vaiani, E., Hypothalamic-pituitary-ovarian axis during infancy, early and late prepuberty in an aromatase-deficient girl who is a compound heterozygote for two new point mutations of the CYP19 gene (2003) J Clin Endocrinol Metab, 88, pp. 5127-5131Fukami, M., Horikawa, R., Nagai, T., Tanaka, T., Naiki, Y., Sato, N., Cytochrome P450 oxidoreductase gene mutations and Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis: Molecular and clinical studies in 10 patients (2005) J Clin Endocrinol Metab, 90, pp. 414-426Grondahl, C., Hansen, T.H., Marky-Nielsen, K., Ottesen, J.L., Hyttel, P., Human oocyte maturation in vitro is stimulated by meiosis-activating sterol (2000) Hum Reprod, 15 (SUPPL. 5), pp. 3-1