P450c17 Deficiency: Clinical and Molecular Characterization of Six Patients

Rosa, Stephanie; Duff, Cameron; Meyer, Monika; Lang‐Muritano, Mariarosaria; Balercia, Giancarlo; Boscaro, Marco; Topaloğlu, Ali Kemal; Mioni, Roberto; Fallo, Francesco; Zuliani, L.; Mantero, Franco; Schoenle, Eugen J.; Biason‐Lauber, Anna

doi:10.1210/jc.2006-1486

Cited by 62 publications

(46 citation statements)

References 22 publications

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“…The serum steroid profile was comparable to those previously published (8,20,24,25,28) and disclosed marked increases of B, DOC and their 18-hydroxy--derivatives -18OHB and 18OHDOC -, the so-called 17-deoxysteroids (from the "mineralocorticoid pathway") of the zona fasciculata.…”

Section: Discussionsupporting

confidence: 85%

“…Thus, failure to produce sex steroids in these patients results in sexual infantilism and primary amenorrhea in the female (46,XX) and pseudohermaphroditism in the male (46,XY) (17)(18)(19)(20). In addition, impaired production of cortisol − typical of complete 17OHD −, leads to increased ACTH secretion that stimulates overproduction of deoxycorticosterone (DOC) and corticosterone (B) − non-17-hydroxylated steroid intermediates with mineralocorticoid activity −, causing severe hypertension and hypokalemia (2,(21)(22)(23)(24)(25). Although the serum steroid profile has been extensively studied in 17OHD, systematic evaluation of the full urinary steroid metabolite (metabolome) in these patients is limited.…”

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confidence: 99%

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Distinctive profile of the 17-hydroxylase and 17,20-lyase activities revealed by urinary steroid metabolomes of patients with CYP17 deficiency

Neres

Auchus

Shackleton

et al. 2010

Arq Bras Endocrinol Metab

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Section: Discussionsupporting

confidence: 85%

mentioning

confidence: 99%

Distinctive profile of the 17-hydroxylase and 17,20-lyase activities revealed by urinary steroid metabolomes of patients with CYP17 deficiency

Neres

Auchus

Shackleton

et al. 2010

Arq Bras Endocrinol Metab

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“…In a few cases, patients manifested with partial 17a-hydroxylase deficiency, exhibiting regular menses, intermittent hypertension, hypokalemia, and infertility. Genetic testing and in vitro transfection assays have demonstrated that the mutation of c.1418TOC(F453S) and c.990_993del (E331del) retained part of the enzymatic activities, which is consistent with the phenotype of the patients (14,17,19). In this study, we report a complex heterozygous mutation of the CYP17A1 gene in our patient with 46,XY DSD.…”

Section: Discussionsupporting

confidence: 83%

A unique exonic splicing mutation in the CYP17A1 gene as the cause for steroid 17α-hydroxylase deficiency

Qiao¹,

Han²,

Liu³

et al. 2011

European Journal of Endocrinology

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Background: 17a-Hydroxylase/17,20-lyase deficiency (17OHD) caused by a mutation in the CYP17A1 gene is characterized by hypertension, hypokalemia, and abnormal development of the genitalia. The majority of CYP17A1 mutations are located in the coding sequence, and several intronic splicing site mutations have been reported. Objective: A 2.5-year-old girl with 46,XY disordered sex development exhibited a nearly normal basal cortisol level and reduced sexual steroids. This study is aimed to explore the molecular basis and analyze its possible influence on the phenotype of the patient. Methods and results: Mutation analysis revealed compound heterozygous CYP17A1 mutations, with c.985_987delinsAA in one allele and a synonymous substitution (c.1263GOA) in another allele. In vitro expression analysis of the allelic minigene showed that the novel nucleotide variation located in exon 8 induces a splicing signal, which results in an aberrant splicing of CYP17A1 mRNA and a missing portion of exon 8. The translation product includes the deletion of six or seven amino acids from residue position 415 without causing a frameshift. Consistent with the result of molecular modeling, functional studies in transiently transfected HEK-293T cells with the aberrantly spliced enzyme proteins showed that the deleted proteins completely abolished the enzyme activity. However, RT-PCR indicated the existence of a small fraction of normal, functionally intact enzyme, which may explain the partial masculinization of this patient. Conclusion: This is the first description of an exonic splicing mutation in CYP17A1 relevant to the 17OHD phenotype. It also demonstrates the importance of studying synonymous change in such patients with less severe phenotype.

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“…It should be considered in the differential diagnosis of female delayed puberty because delayed diagnosis leads to severe hypertension and reproductive failure (10,14). In this case, elevated progesterone was a clue for further investigation.…”

Section: Discussionmentioning

confidence: 81%

“…3) not (13). Furthermore, an analysis of 6 cases of 17OHD suggested that age of onset and hypertension severity are not consistent (14). Although there are only a few reports of 17,20-lyase activity in patients with 17OHDs with menstruation, these reports indicate that patients with 17OHD that menstruate have retained 17,20-lyase activity (8,10,15).…”

Section: Discussionmentioning

confidence: 98%

Elevated Levels of Plasma Immunoassayable Aldosterone in a Mild Form of 17 Alpha-Hydroxylase/17,20-lyase Deficiency Diagnosed at the Age of 50

Ueda

Usui

Watanabe

et al. 2015

AACE Clinical Case Reports

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Objective: 17 Alpha-hydroxylase/17,20-lyase deficiency (17OHD) is a form of congenital adrenal hyperplasia caused by homozygous or compound heterozygous mutations in the CYP17A1 gene. Impaired activities of 17 alphahydroxylase and 17,20-lyase typically induce hypertension, hypokalemia, and amenorrhea, with the vast majority of patients with 17OHD are diagnosed in adolescence.Methods: We present a case of 17OHD diagnosed at the age of 50 with complete endocrinologic investigations and genetic analysis.Results: The patient had hypokalemia and a low cortisol level. Her dehydroepiandrosterone sulfate (DHEA-S) and androstenedione levels were undetectable, although her adrenocorticotropic hormone (ACTH) level was elevated. She had markedly elevated pregnenolone, progesterone, deoxycorticosterone, and corticosterone levels. In addition, her plasma renin activity and plasma aldosterone concentration were suppressed and elevated, respectively.Rapid ACTH stimulation increased the hormones upstream of 17 alpha-hydroxylase, and overnight 1-mg dexamethasone suppressed them. The patient was thus diagnosed with 17OHD. Genetic testing confirmed the diagnosis, revealing 2 distinct mutations in the CYP17A1 gene, c985_987delTACinsAA and R416C, which have been previously reported.Conclusion: The present case is a mild form of 17OHD that had gone undiagnosed until the age of 50. The R416C genotype seems to relate to a mild phenotype. Mild 17OHD may remain undiagnosed or be misdiagnosed as primary aldosteronism or idiopathic hyperaldosteronism.

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P450c17 Deficiency: Clinical and Molecular Characterization of Six Patients

Cited by 62 publications

References 22 publications

Distinctive profile of the 17-hydroxylase and 17,20-lyase activities revealed by urinary steroid metabolomes of patients with CYP17 deficiency

Distinctive profile of the 17-hydroxylase and 17,20-lyase activities revealed by urinary steroid metabolomes of patients with CYP17 deficiency

A unique exonic splicing mutation in the CYP17A1 gene as the cause for steroid 17α-hydroxylase deficiency

Elevated Levels of Plasma Immunoassayable Aldosterone in a Mild Form of 17 Alpha-Hydroxylase/17,20-lyase Deficiency Diagnosed at the Age of 50

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