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Margaret De Castro - One of the best experts on this subject based on the ideXlab platform.
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Clinical, Molecular, Functional, and Structural Characterization of CYP17A1 Mutations in Brazilian Patients with 17-Hydroxylase Deficiency.
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme, 2020Co-Authors: Fernanda Borchers Coeli-lacchini, Lucila Leico Kagohara Elias, Livia M Mermejo, Aline Faccioli Bodoni, Wilson Araújo Silva, Sonir R Antonini, Ayrton C Moreira, Margaret De CastroAbstract:17-Hydroxylase-deficiency (17OHD) is a rare form of congenital adrenal hyperplasia. The aim of the work was to study clinical, biochemical, and the follow up of 17OHD patients and evaluate the function and structure of CYP17A1 mutations. Brazilian patients (three 46, XX and four 46, XY; 17±1.9 years) with combined 17-hydroxylase/17,20-lyase deficiency were evaluated. CYP17A1 gene was sequenced. Functional analysis was performed transfecting COS7 cells, which were exposed to progesterone or 17α-hydroxypregnolone substrates. Hormones were determined by RIA or LC-MS/MS. Three-dimensional structural modeling was performed by Modeller software. All patients presented prepubertal female external genitalia, primary amenorrhea, hypergonadotrophic hypogonadism, hypokalemic hypertension, decreased cortisol, and increased ACTH and corticosterone levels. Five patients presented previously described mutations: p.W406R/p.W406R, IVS2-2A>C/p.P428L, and p.P428L/p.P428L. Two patients presented the compound heterozygous p.G478S/p.I223Nfs*10 mutations, whose CYP17A1 activity and the three dimensional structural modeling are originally studied in this paper. CYP17A1 activity of p.G478S was 13 and 58% against progesterone and 17-Hydroxypregnenolone, respectively. The p.I223Nfs*10 caused a truncated inactive protein. Three-dimensional p.G478S structural modeling showed different internal hydrophobic interaction with W313 and created an additional chain side contact with L476 residue. Due to the rarity of 17OHD, the long term follow up (15.3±3.1 years) of our patients will help endocrinologists on the management of patients with 17OHD. The mutation p.G478S/pI223Nfs*10 led to severe 17OHD and impaired CYP17A1 structure and function. The integration of in silico and in vitro analysis showed how the amino acid changes affected the CYP17A1 activity and contributed to clarify the molecular interactions of CYP17A1.
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refining hormonal diagnosis of type ii 3β hydroxysteroid dehydrogenase deficiency in patients with premature pubarche and hirsutism based on hsd3b2 genotyping
The Journal of Clinical Endocrinology and Metabolism, 2005Co-Authors: Livia M Mermejo, Berenice B. Mendonca, Suemi Marui, Lucila Leico Kagohara Elias, Ayrton Custódio Moreira, Margaret De CastroAbstract:Congenital adrenal hyperplasia due to 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4)-isomerase (3betaHSD), a rare autosomal recessive disorder that affects both sexes, has a heterogeneous clinical presentation ranging from the severe salt-wasting to the non-salt-wasting forms and results from mutations in the HSD3B2 gene. The hormonal criteria for diagnosing the mild variant of 3betaHSD deficiency have been controversial because the initial studies were not based on genetic evidence. We investigated the relationship between the hormonal phenotype and HSD3B2 genotype in 22 patients with clinical and/or biochemical features suggestive of 3betaHSD2 deficiency, including nine female children with premature pubarche, 12 hirsute females, and one boy with salt-wasting and ambiguous genitalia. Serum 17-Hydroxypregnenolone (Delta5-17P), cortisol (F), 17-hydroxyprogesterone, dehydroepiandrosterone, and androstenedione levels were determined by RIA and were compared with Tanner pubic hair stage-matched control groups. The genomic DNA was extracted, and the entire HSD3B2 gene was amplified by PCR followed by automatic sequencing. Besides two different mutations previously observed in three patients (T259M and G129R/P222Q mutations), we observed the P222Q mutation in the male patient with salt-wasting form of 3betaHSD2 deficiency. Basal and ACTH-stimulated Delta5-17P levels (nanomoles per liter) ranged from 4-41 (-0.2 to 14 sd) and 36-97 (3.5-15.5 sd), respectively, in patients without mutation in HSD3B2 and from 69-153 (25-57 sd) and 201-351 (36-65 sd), respectively, in patients with mutation in HSD3B2. Basal and ACTH-stimulated Delta5-17P to F ratios ranged from 11-159 (0.5-25 sd) and 42-122 (2.4-11.3 sd), respectively, in patients without mutation in HSD3B2 and from 181-1700 (29-282 sd) and 487-1523 (52-167 sd), respectively, in patients with mutation in HSD3B2. The hormone findings in the genotype-proven patients suggest that the following hormonal criteria are compatible with 3betaHSD2 deficiency in children with premature pubarche: ACTH-stimulated Delta5-17P and Delta5-17P to F ratios at or greater than 201 and 487 nmol/liter, respectively, equivalent to or greater than 36 and 52 sd above matched control mean. Basal and ACTH-stimulated Delta5-17P and Delta5-17P to F ratios in all genotype-proven patients in childhood were unequivocally higher than the levels of either genotype-normal patients. All the other parameters overlapped between the patients with and without mutations in the HSD3B2 gene. In conclusion, genotyping more patients in the present study, we confirm that patients with mutations in the HSD3B2 gene have extremely elevated basal and ACTH-stimulated Delta5-17P levels and Delta5-17P to F ratios. Therefore, these data refine the hormonal criteria proposed to predict more accurately 3betaHSD2 deficiency.
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Refining Hormonal Diagnosis of Type II 3β-Hydroxysteroid Dehydrogenase Deficiency in Patients with Premature Pubarche and Hirsutism Based on HSD3B2 Genotyping
The Journal of clinical endocrinology and metabolism, 2004Co-Authors: Lívia Mara Mermejo, Berenice B. Mendonca, Suemi Marui, Lucila Leico Kagohara Elias, Ayrton Custódio Moreira, Margaret De CastroAbstract:Congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase (3βHSD), a rare autosomal recessive disorder that affects both sexes, has a heterogeneous clinical presentation ranging from the severe salt-wasting to the non-salt-wasting forms and results from mutations in the HSD3B2 gene. The hormonal criteria for diagnosing the mild variant of 3βHSD deficiency have been controversial because the initial studies were not based on genetic evidence. We investigated the relationship between the hormonal phenotype and HSD3B2 genotype in 22 patients with clinical and/or biochemical features suggestive of 3βHSD2 deficiency, including nine female children with premature pubarche, 12 hirsute females, and one boy with salt-wasting and ambiguous genitalia. Serum 17-Hydroxypregnenolone (Δ5-17P), cortisol (F), 17-hydroxyprogesterone, dehydroepiandrosterone, and androstenedione levels were determined by RIA and were compared with Tanner pubic hair stage-matched control groups. The genomic DNA was...
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mutations in the type ii 3β hydroxysteroid dehydrogenase hsd3b2 gene can cause premature pubarche in girls
Clinical Endocrinology, 2000Co-Authors: Suemi Marui, Ivo J. P. Arnhold, Margaret De Castro, Ana Claudia Latronico, Lucila Leico Kagohara Elias, Ayrton Custódio Moreira, Berenice B. MendoncaAbstract:OBJECTIVE Most previous studies have failed to demonstrate any mutations in the type II 3β hydroxysteroid dehydrogenase (HSD3B2) gene in patients satisfying the hormonal criteria of nonclassic 3β-hydroxysteroid dehydrogenase deficiency, suggesting that a mutant 3β-hydroxysteroid dehydrogenase protein is not the cause of this disorder. We screened the HSD3B2 gene for mutations in girls with premature pubarche and a hormonal diagnosis of 3β-hydroxysteroid dehydrogenase deficiency. DESIGN From 30 girls with premature pubarche, we selected 9 whose ACTH-stimulated 17-Hydroxypregnenolone levels were elevated (≥6 SD) and screened the HSD3B2 gene for mutations. MEASUREMENTS All patients were submitted to a standard ACTH stimulation test. Serum steroids were measured and compared to the mean level of pubertal stage matched control subjects. The four exons and exon-intron boundaries of the HSD3B2 gene were amplified by polymerase chain reaction and screened for mutations by denaturing gradient gel electrophoresis. The fragments with abnormal migration on denaturing gradient gel electrophoresis were directly sequenced. RESULTS A homozygous T259M mutation was identified in one girl and a new compound heterozygous G129R/P222H mutation was identified in two sisters. The highest ACTH-stimulated 17-Hydroxypregnenolone levels, 147, 339 and 351 nmol/l, were found in those patients with mutations in the HSD3B2 gene. In the patients without mutations, ACTH-stimulated 17-Hydroxypregnenolone ranged from 48 to 111 nmol/l. ACTH-stimulated dehydroepiandrosterone levels had an overlap among the girls with and without mutations and the normal controls. CONCLUSIONS Premature pubarche can be caused by mutations in the type II 3β hydroxysteroid dehydrogenase gene.
Berenice B. Mendonca - One of the best experts on this subject based on the ideXlab platform.
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refining hormonal diagnosis of type ii 3β hydroxysteroid dehydrogenase deficiency in patients with premature pubarche and hirsutism based on hsd3b2 genotyping
The Journal of Clinical Endocrinology and Metabolism, 2005Co-Authors: Livia M Mermejo, Berenice B. Mendonca, Suemi Marui, Lucila Leico Kagohara Elias, Ayrton Custódio Moreira, Margaret De CastroAbstract:Congenital adrenal hyperplasia due to 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4)-isomerase (3betaHSD), a rare autosomal recessive disorder that affects both sexes, has a heterogeneous clinical presentation ranging from the severe salt-wasting to the non-salt-wasting forms and results from mutations in the HSD3B2 gene. The hormonal criteria for diagnosing the mild variant of 3betaHSD deficiency have been controversial because the initial studies were not based on genetic evidence. We investigated the relationship between the hormonal phenotype and HSD3B2 genotype in 22 patients with clinical and/or biochemical features suggestive of 3betaHSD2 deficiency, including nine female children with premature pubarche, 12 hirsute females, and one boy with salt-wasting and ambiguous genitalia. Serum 17-Hydroxypregnenolone (Delta5-17P), cortisol (F), 17-hydroxyprogesterone, dehydroepiandrosterone, and androstenedione levels were determined by RIA and were compared with Tanner pubic hair stage-matched control groups. The genomic DNA was extracted, and the entire HSD3B2 gene was amplified by PCR followed by automatic sequencing. Besides two different mutations previously observed in three patients (T259M and G129R/P222Q mutations), we observed the P222Q mutation in the male patient with salt-wasting form of 3betaHSD2 deficiency. Basal and ACTH-stimulated Delta5-17P levels (nanomoles per liter) ranged from 4-41 (-0.2 to 14 sd) and 36-97 (3.5-15.5 sd), respectively, in patients without mutation in HSD3B2 and from 69-153 (25-57 sd) and 201-351 (36-65 sd), respectively, in patients with mutation in HSD3B2. Basal and ACTH-stimulated Delta5-17P to F ratios ranged from 11-159 (0.5-25 sd) and 42-122 (2.4-11.3 sd), respectively, in patients without mutation in HSD3B2 and from 181-1700 (29-282 sd) and 487-1523 (52-167 sd), respectively, in patients with mutation in HSD3B2. The hormone findings in the genotype-proven patients suggest that the following hormonal criteria are compatible with 3betaHSD2 deficiency in children with premature pubarche: ACTH-stimulated Delta5-17P and Delta5-17P to F ratios at or greater than 201 and 487 nmol/liter, respectively, equivalent to or greater than 36 and 52 sd above matched control mean. Basal and ACTH-stimulated Delta5-17P and Delta5-17P to F ratios in all genotype-proven patients in childhood were unequivocally higher than the levels of either genotype-normal patients. All the other parameters overlapped between the patients with and without mutations in the HSD3B2 gene. In conclusion, genotyping more patients in the present study, we confirm that patients with mutations in the HSD3B2 gene have extremely elevated basal and ACTH-stimulated Delta5-17P levels and Delta5-17P to F ratios. Therefore, these data refine the hormonal criteria proposed to predict more accurately 3betaHSD2 deficiency.
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Refining Hormonal Diagnosis of Type II 3β-Hydroxysteroid Dehydrogenase Deficiency in Patients with Premature Pubarche and Hirsutism Based on HSD3B2 Genotyping
The Journal of clinical endocrinology and metabolism, 2004Co-Authors: Lívia Mara Mermejo, Berenice B. Mendonca, Suemi Marui, Lucila Leico Kagohara Elias, Ayrton Custódio Moreira, Margaret De CastroAbstract:Congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase (3βHSD), a rare autosomal recessive disorder that affects both sexes, has a heterogeneous clinical presentation ranging from the severe salt-wasting to the non-salt-wasting forms and results from mutations in the HSD3B2 gene. The hormonal criteria for diagnosing the mild variant of 3βHSD deficiency have been controversial because the initial studies were not based on genetic evidence. We investigated the relationship between the hormonal phenotype and HSD3B2 genotype in 22 patients with clinical and/or biochemical features suggestive of 3βHSD2 deficiency, including nine female children with premature pubarche, 12 hirsute females, and one boy with salt-wasting and ambiguous genitalia. Serum 17-Hydroxypregnenolone (Δ5-17P), cortisol (F), 17-hydroxyprogesterone, dehydroepiandrosterone, and androstenedione levels were determined by RIA and were compared with Tanner pubic hair stage-matched control groups. The genomic DNA was...
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mutations in the type ii 3β hydroxysteroid dehydrogenase hsd3b2 gene can cause premature pubarche in girls
Clinical Endocrinology, 2000Co-Authors: Suemi Marui, Ivo J. P. Arnhold, Margaret De Castro, Ana Claudia Latronico, Lucila Leico Kagohara Elias, Ayrton Custódio Moreira, Berenice B. MendoncaAbstract:OBJECTIVE Most previous studies have failed to demonstrate any mutations in the type II 3β hydroxysteroid dehydrogenase (HSD3B2) gene in patients satisfying the hormonal criteria of nonclassic 3β-hydroxysteroid dehydrogenase deficiency, suggesting that a mutant 3β-hydroxysteroid dehydrogenase protein is not the cause of this disorder. We screened the HSD3B2 gene for mutations in girls with premature pubarche and a hormonal diagnosis of 3β-hydroxysteroid dehydrogenase deficiency. DESIGN From 30 girls with premature pubarche, we selected 9 whose ACTH-stimulated 17-Hydroxypregnenolone levels were elevated (≥6 SD) and screened the HSD3B2 gene for mutations. MEASUREMENTS All patients were submitted to a standard ACTH stimulation test. Serum steroids were measured and compared to the mean level of pubertal stage matched control subjects. The four exons and exon-intron boundaries of the HSD3B2 gene were amplified by polymerase chain reaction and screened for mutations by denaturing gradient gel electrophoresis. The fragments with abnormal migration on denaturing gradient gel electrophoresis were directly sequenced. RESULTS A homozygous T259M mutation was identified in one girl and a new compound heterozygous G129R/P222H mutation was identified in two sisters. The highest ACTH-stimulated 17-Hydroxypregnenolone levels, 147, 339 and 351 nmol/l, were found in those patients with mutations in the HSD3B2 gene. In the patients without mutations, ACTH-stimulated 17-Hydroxypregnenolone ranged from 48 to 111 nmol/l. ACTH-stimulated dehydroepiandrosterone levels had an overlap among the girls with and without mutations and the normal controls. CONCLUSIONS Premature pubarche can be caused by mutations in the type II 3β hydroxysteroid dehydrogenase gene.
Ying Tai Chang - One of the best experts on this subject based on the ideXlab platform.
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carriers for type ii 3β hydroxysteroid dehydrogenase hsd3b2 deficiency can only be identified by hsd3b2 genotype study and not by hormone test
Clinical Endocrinology, 2003Co-Authors: Songya Pang, Ying Tai Chang, Goldy Carbunaru, Anzar Haider, Kenneth C Copeland, Chantal Lutfallah, Ian J MasonAbstract:Summary objective We investigated adrenal steroidogenic function relevant to 3β-hydroxysteroid dehydrogenase (HSD3B2) activity in vivo and HSD3B2 genotype in clinically normal family members of patients with HSD3B2 genotype-proven HSD3B2 deficiency congenital adrenal hyperplasia (CAH) to determine whether genotype-proven carriers for HSD3B2 deficiency exhibit decreased enzyme activity analogous to the mildly decreased adrenal 21-hydroxylase activity in the carriers of CYP21 gene mutation. design/patients Nineteen adult family members (ages median/range: 37/19–56 years) including 13 females and six males of six unrelated patients with HSD3B2 genotype-proven HSD3B2 deficiency were studied. measurements All family members had HSD3B2 DNA analysis and an ACTH stimulation test (Cortrosyn 0·25 mg IV bolus) for determination of adrenal HSD3B activity. results Ten of 13 females and five of six males were carriers of a proven or predictably deleterious mutation in one allele of the HSD3B2 gene, which was identified in the probands. ACTH-stimulated levels of 17-Hydroxypregnenolone (Δ5-17P), 17-hydroxyprogesterone (17-OHP), cortisol (F), dehydroepiandrosterone (DHEA) and androstenedione (Δ4-A) and ratios of Δ5-17P to 17-OHP, Δ5-17P to F and DHEA to Δ4-A, as well as increments of Δ5-17P and DHEA values (ACTH-stimulated − baseline) in the genotype-proven female carriers (age, mean ± SD: 36 ± 6·7 years) and male carriers (age, mean ± SD: 37 ± 6·7 years) did not differ significantly from age-matched normal females (35 ± 5·4 years, n = 20) and normal males (35 ± 6 years, n = 10), respectively. There were no significant differences in any of the ACTH-stimulated hormonal levels or ratios between the female carriers with a seriously deleterious genotype (n = 5) and the female carriers with mildly deleterious genotypes (n = 5). These hormonal levels and ratios in three genotype-normal females and one genotype-normal male overlapped with those of the carriers. conclusion These data suggest that normal adrenal HSD3B2 activity is maintained in the genotype-proven carriers because heterodimers of mutant and wild-type HSD3B2 enzymes may be stable and exhibit similar activity compared to homodimers of wild-type enzymes, possibly by a relatively rate-unlimited effect of haplo-wild-type enzyme activity. However, we cannot preclude entirely the possibility of a limited expression of another HSD3B activity under ACTH stimulation contributing to the normal adrenal HSD3B activity in vivo in the HSD3B2 genotype-proven heterozygotes. Which mechanism plays a role in maintaining normal enzyme activity in the heterozygotes remains to be elucidated. The hormone findings in the genotypic-proven carriers for HSD3B2 deficiency also indicate that carriers for this disorder cannot be detected by a hormone test and can only be detected by HSD3B2 genotype study.
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studies of 3 beta hydroxysteroid dehydrogenase genes in infants and children manifesting premature pubarche and increased adrenocorticotropin stimulated delta 5 steroid levels
The Journal of Clinical Endocrinology and Metabolism, 1996Co-Authors: Hala Sakkalalkaddour, Ying Tai Chang, Li Zhang, Xiaojiang Yang, Michael Kappy, Robert S Slover, Verena Jorgensen, Songya PangAbstract:Classic 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) deficiency congenital adrenal hyperplasia (CAH) results from a mutation in the type II 3 beta HSD gene encoding adrenal and gonadal 3 beta HSD. We investigated the type II and type I 3 beta HSD gene sequences in 15 infants and children with premature pubarche (PP; mean/range of age at PP, 4/0.08-9 yr) and elevated ACTH-stimulated delta 5 precursor steroid levels. Compared to Tanner I control subjects of similar age, ACTH-stimulated hormonal levels were at 2.3-10.7 SD for 17-Hydroxypregnenolone (delta 5-17P) in all PP subjects, at 2.2-17 SD for dehydroepi-androsterone (DHEA) and 2.4-5.6 SD for the delta 5-17P/cortisol (F) ratio in all PP subjects except 1 infant, and at 2.3-10 SD for the DHEA/ androstenedione (delta 5-A) ratio in 8 PP subjects. Compared to Tanner II normal children, the hormonal levels were at 3-8 SD for delta 5-17P in all 13 PP children, at 2.3-4.7 SD for the delta 5-17P/F ratio in 6 PP children, and at 2.3-6.5 SD for DHEA and 3.5-9...
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absence of molecular defect in the type ii 3β hydroxysteroid dehydrogenase 3β hsd gene in premature pubarche children and hirsute female patients with moderately decreased adrenal 3β hsd activity
Pediatric Research, 1995Co-Authors: Ying Tai Chang, J I Mason, Li Zhang, H S Alkaddour, Kemming Lin, Xiaojiang Yang, L R Garibaldi, C J Bourdony, L M Dolan, D L DonaldsonAbstract:ABSTRACT: To date the molecular basis and hormonal criteria for inherited mild late-onset 3β-hydroxysteroid dehydrogenase (3β-HSD) deficiency congenital adrenal hyperplasia (CAH) have not been defined. We have thus investigated the presence or absence of mutation in the type II 3β-HSD gene encoding adrenal/gonadal 3β-HSD in each of five premature pubarche children and hirsute female patients manifesting moderately decreased adrenal 3β-HSD activity. ACTH-stimulated hormonal levels in all patients compared with mean levels in pubertal stage-matched normal subjects were between 2.5 and 6.5 SD for 17-Hydroxypregnenolone levels, and between 2.5 and 7 SD for dehydroepiandrosterone levels in all except one patient. 17-Hydroxypregnenolone to cortisol ratios were between 2.5 and 4.3 SD, and dehydroepiandrosterone to androstenedione ratios were between 3 and 8.6 SD. The type II 3β-HSD gene regions of a putative promoter, exons I, II, III, and IV, and exon-intron boundaries in all subjects were amplified by polymerase chain reaction and then sequenced. All patients had normal sequences of the type II 3β-HSD gene in both alleles. Three female patients heterozygotic for severe 3β-HSD deficiency CAH with one allele mutation of the gene demonstrated normal ACTH-stimulated hormone profiles. These data indicate that moderately decreased adrenal 3β-HSD activity resulting in modestly increased Δ5 precursor steroid levels and Δ5 to Δ4 steroid ratios in premature pubarche and hirsute patients is not caused by a mutation in the type II 3β-HSD gene. This suggests that the moderately decreased adrenal 3β-HSD activity in the patient is not due to mild late-onset variants of inherited 3β-HSD deficiency CAH, whereas the carriers for true 3β-HSD deficiency CAH do not express decreased adrenal 3β-HSD activity.
Songya Pang - One of the best experts on this subject based on the ideXlab platform.
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carriers for type ii 3β hydroxysteroid dehydrogenase hsd3b2 deficiency can only be identified by hsd3b2 genotype study and not by hormone test
Clinical Endocrinology, 2003Co-Authors: Songya Pang, Ying Tai Chang, Goldy Carbunaru, Anzar Haider, Kenneth C Copeland, Chantal Lutfallah, Ian J MasonAbstract:Summary objective We investigated adrenal steroidogenic function relevant to 3β-hydroxysteroid dehydrogenase (HSD3B2) activity in vivo and HSD3B2 genotype in clinically normal family members of patients with HSD3B2 genotype-proven HSD3B2 deficiency congenital adrenal hyperplasia (CAH) to determine whether genotype-proven carriers for HSD3B2 deficiency exhibit decreased enzyme activity analogous to the mildly decreased adrenal 21-hydroxylase activity in the carriers of CYP21 gene mutation. design/patients Nineteen adult family members (ages median/range: 37/19–56 years) including 13 females and six males of six unrelated patients with HSD3B2 genotype-proven HSD3B2 deficiency were studied. measurements All family members had HSD3B2 DNA analysis and an ACTH stimulation test (Cortrosyn 0·25 mg IV bolus) for determination of adrenal HSD3B activity. results Ten of 13 females and five of six males were carriers of a proven or predictably deleterious mutation in one allele of the HSD3B2 gene, which was identified in the probands. ACTH-stimulated levels of 17-Hydroxypregnenolone (Δ5-17P), 17-hydroxyprogesterone (17-OHP), cortisol (F), dehydroepiandrosterone (DHEA) and androstenedione (Δ4-A) and ratios of Δ5-17P to 17-OHP, Δ5-17P to F and DHEA to Δ4-A, as well as increments of Δ5-17P and DHEA values (ACTH-stimulated − baseline) in the genotype-proven female carriers (age, mean ± SD: 36 ± 6·7 years) and male carriers (age, mean ± SD: 37 ± 6·7 years) did not differ significantly from age-matched normal females (35 ± 5·4 years, n = 20) and normal males (35 ± 6 years, n = 10), respectively. There were no significant differences in any of the ACTH-stimulated hormonal levels or ratios between the female carriers with a seriously deleterious genotype (n = 5) and the female carriers with mildly deleterious genotypes (n = 5). These hormonal levels and ratios in three genotype-normal females and one genotype-normal male overlapped with those of the carriers. conclusion These data suggest that normal adrenal HSD3B2 activity is maintained in the genotype-proven carriers because heterodimers of mutant and wild-type HSD3B2 enzymes may be stable and exhibit similar activity compared to homodimers of wild-type enzymes, possibly by a relatively rate-unlimited effect of haplo-wild-type enzyme activity. However, we cannot preclude entirely the possibility of a limited expression of another HSD3B activity under ACTH stimulation contributing to the normal adrenal HSD3B activity in vivo in the HSD3B2 genotype-proven heterozygotes. Which mechanism plays a role in maintaining normal enzyme activity in the heterozygotes remains to be elucidated. The hormone findings in the genotypic-proven carriers for HSD3B2 deficiency also indicate that carriers for this disorder cannot be detected by a hormone test and can only be detected by HSD3B2 genotype study.
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studies of 3 beta hydroxysteroid dehydrogenase genes in infants and children manifesting premature pubarche and increased adrenocorticotropin stimulated delta 5 steroid levels
The Journal of Clinical Endocrinology and Metabolism, 1996Co-Authors: Hala Sakkalalkaddour, Ying Tai Chang, Li Zhang, Xiaojiang Yang, Michael Kappy, Robert S Slover, Verena Jorgensen, Songya PangAbstract:Classic 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) deficiency congenital adrenal hyperplasia (CAH) results from a mutation in the type II 3 beta HSD gene encoding adrenal and gonadal 3 beta HSD. We investigated the type II and type I 3 beta HSD gene sequences in 15 infants and children with premature pubarche (PP; mean/range of age at PP, 4/0.08-9 yr) and elevated ACTH-stimulated delta 5 precursor steroid levels. Compared to Tanner I control subjects of similar age, ACTH-stimulated hormonal levels were at 2.3-10.7 SD for 17-Hydroxypregnenolone (delta 5-17P) in all PP subjects, at 2.2-17 SD for dehydroepi-androsterone (DHEA) and 2.4-5.6 SD for the delta 5-17P/cortisol (F) ratio in all PP subjects except 1 infant, and at 2.3-10 SD for the DHEA/ androstenedione (delta 5-A) ratio in 8 PP subjects. Compared to Tanner II normal children, the hormonal levels were at 3-8 SD for delta 5-17P in all 13 PP children, at 2.3-4.7 SD for the delta 5-17P/F ratio in 6 PP children, and at 2.3-6.5 SD for DHEA and 3.5-9...
Suemi Marui - One of the best experts on this subject based on the ideXlab platform.
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refining hormonal diagnosis of type ii 3β hydroxysteroid dehydrogenase deficiency in patients with premature pubarche and hirsutism based on hsd3b2 genotyping
The Journal of Clinical Endocrinology and Metabolism, 2005Co-Authors: Livia M Mermejo, Berenice B. Mendonca, Suemi Marui, Lucila Leico Kagohara Elias, Ayrton Custódio Moreira, Margaret De CastroAbstract:Congenital adrenal hyperplasia due to 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4)-isomerase (3betaHSD), a rare autosomal recessive disorder that affects both sexes, has a heterogeneous clinical presentation ranging from the severe salt-wasting to the non-salt-wasting forms and results from mutations in the HSD3B2 gene. The hormonal criteria for diagnosing the mild variant of 3betaHSD deficiency have been controversial because the initial studies were not based on genetic evidence. We investigated the relationship between the hormonal phenotype and HSD3B2 genotype in 22 patients with clinical and/or biochemical features suggestive of 3betaHSD2 deficiency, including nine female children with premature pubarche, 12 hirsute females, and one boy with salt-wasting and ambiguous genitalia. Serum 17-Hydroxypregnenolone (Delta5-17P), cortisol (F), 17-hydroxyprogesterone, dehydroepiandrosterone, and androstenedione levels were determined by RIA and were compared with Tanner pubic hair stage-matched control groups. The genomic DNA was extracted, and the entire HSD3B2 gene was amplified by PCR followed by automatic sequencing. Besides two different mutations previously observed in three patients (T259M and G129R/P222Q mutations), we observed the P222Q mutation in the male patient with salt-wasting form of 3betaHSD2 deficiency. Basal and ACTH-stimulated Delta5-17P levels (nanomoles per liter) ranged from 4-41 (-0.2 to 14 sd) and 36-97 (3.5-15.5 sd), respectively, in patients without mutation in HSD3B2 and from 69-153 (25-57 sd) and 201-351 (36-65 sd), respectively, in patients with mutation in HSD3B2. Basal and ACTH-stimulated Delta5-17P to F ratios ranged from 11-159 (0.5-25 sd) and 42-122 (2.4-11.3 sd), respectively, in patients without mutation in HSD3B2 and from 181-1700 (29-282 sd) and 487-1523 (52-167 sd), respectively, in patients with mutation in HSD3B2. The hormone findings in the genotype-proven patients suggest that the following hormonal criteria are compatible with 3betaHSD2 deficiency in children with premature pubarche: ACTH-stimulated Delta5-17P and Delta5-17P to F ratios at or greater than 201 and 487 nmol/liter, respectively, equivalent to or greater than 36 and 52 sd above matched control mean. Basal and ACTH-stimulated Delta5-17P and Delta5-17P to F ratios in all genotype-proven patients in childhood were unequivocally higher than the levels of either genotype-normal patients. All the other parameters overlapped between the patients with and without mutations in the HSD3B2 gene. In conclusion, genotyping more patients in the present study, we confirm that patients with mutations in the HSD3B2 gene have extremely elevated basal and ACTH-stimulated Delta5-17P levels and Delta5-17P to F ratios. Therefore, these data refine the hormonal criteria proposed to predict more accurately 3betaHSD2 deficiency.
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Refining Hormonal Diagnosis of Type II 3β-Hydroxysteroid Dehydrogenase Deficiency in Patients with Premature Pubarche and Hirsutism Based on HSD3B2 Genotyping
The Journal of clinical endocrinology and metabolism, 2004Co-Authors: Lívia Mara Mermejo, Berenice B. Mendonca, Suemi Marui, Lucila Leico Kagohara Elias, Ayrton Custódio Moreira, Margaret De CastroAbstract:Congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase (3βHSD), a rare autosomal recessive disorder that affects both sexes, has a heterogeneous clinical presentation ranging from the severe salt-wasting to the non-salt-wasting forms and results from mutations in the HSD3B2 gene. The hormonal criteria for diagnosing the mild variant of 3βHSD deficiency have been controversial because the initial studies were not based on genetic evidence. We investigated the relationship between the hormonal phenotype and HSD3B2 genotype in 22 patients with clinical and/or biochemical features suggestive of 3βHSD2 deficiency, including nine female children with premature pubarche, 12 hirsute females, and one boy with salt-wasting and ambiguous genitalia. Serum 17-Hydroxypregnenolone (Δ5-17P), cortisol (F), 17-hydroxyprogesterone, dehydroepiandrosterone, and androstenedione levels were determined by RIA and were compared with Tanner pubic hair stage-matched control groups. The genomic DNA was...
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mutations in the type ii 3β hydroxysteroid dehydrogenase hsd3b2 gene can cause premature pubarche in girls
Clinical Endocrinology, 2000Co-Authors: Suemi Marui, Ivo J. P. Arnhold, Margaret De Castro, Ana Claudia Latronico, Lucila Leico Kagohara Elias, Ayrton Custódio Moreira, Berenice B. MendoncaAbstract:OBJECTIVE Most previous studies have failed to demonstrate any mutations in the type II 3β hydroxysteroid dehydrogenase (HSD3B2) gene in patients satisfying the hormonal criteria of nonclassic 3β-hydroxysteroid dehydrogenase deficiency, suggesting that a mutant 3β-hydroxysteroid dehydrogenase protein is not the cause of this disorder. We screened the HSD3B2 gene for mutations in girls with premature pubarche and a hormonal diagnosis of 3β-hydroxysteroid dehydrogenase deficiency. DESIGN From 30 girls with premature pubarche, we selected 9 whose ACTH-stimulated 17-Hydroxypregnenolone levels were elevated (≥6 SD) and screened the HSD3B2 gene for mutations. MEASUREMENTS All patients were submitted to a standard ACTH stimulation test. Serum steroids were measured and compared to the mean level of pubertal stage matched control subjects. The four exons and exon-intron boundaries of the HSD3B2 gene were amplified by polymerase chain reaction and screened for mutations by denaturing gradient gel electrophoresis. The fragments with abnormal migration on denaturing gradient gel electrophoresis were directly sequenced. RESULTS A homozygous T259M mutation was identified in one girl and a new compound heterozygous G129R/P222H mutation was identified in two sisters. The highest ACTH-stimulated 17-Hydroxypregnenolone levels, 147, 339 and 351 nmol/l, were found in those patients with mutations in the HSD3B2 gene. In the patients without mutations, ACTH-stimulated 17-Hydroxypregnenolone ranged from 48 to 111 nmol/l. ACTH-stimulated dehydroepiandrosterone levels had an overlap among the girls with and without mutations and the normal controls. CONCLUSIONS Premature pubarche can be caused by mutations in the type II 3β hydroxysteroid dehydrogenase gene.