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

Kurnaz, Erdal; Baykan, Emine Kartal; Türkyılmaz, Ayberk; Yaralı, Oğuzhan; Abalı, Zehra Yavaş; Turan, Serap; Bereket, Abdullah; Çayır, Atilla; Güran, Tülay

doi:10.1159/000515079

Cited by 12 publications

(9 citation statements)

References 38 publications

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“…Patients aged < 14 years (n = 25) presented with genital abnormality (n = 6; clitoromegaly in 2 and palpable gonads in 4), hypertension, and/or hypokalemia (n = 19), and poor secondary sexual characters (n = 1). Serum gonadotropins were elevated in all patients aged ≥ 14 years, except in a patient with biallelic KISS1R pathogenic variant [ 14 ]. Elevated (>10 mIU/mL) gonadotropins were noted as early as 4 years of age.…”

Section: Resultsmentioning

confidence: 99%

17α-Hydroxylase/17,20-Lyase Deficiency in 46,XY: Our Experience and Review of Literature

Maheshwari

Arya

Lila

et al. 2022

Journal of the Endocrine Society

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Objective To describe 46,XY patients with 17α-hydroxylase/17,20-lyase deficiency (17OHD) from our center and perform literature review. Design Retrospective analysis and literature review Patients and measurements: We retrospectively analyzed genetically-proven index cases of 17OHD from our 46,XY disorders of sex development cohort and reviewed similar cases from the literature (n=150). Based on the phenotype, 17OHD probands were classified into combined severe deficiency (n=128), and combined partial deficiency (n=16). Additionally, patients with the apparent isolated 17,20-lyase deficiency (n=7, from 6 families) were noted. Residual enzyme activities with the observed mutant enzymes were arbitrarily divided in two categories as <1% and ≥1%, each for hydroxylase and lyase. Results We present four index cases of 46,XY 17OHD with a complete spectrum of undervirilization and two novel variants in CYP17A1. In the review, the combined severe deficiency was the most common form, with more frequent female sex of rearing, hypertension, hypokalemia, suppressed renin, higher plasma corticotropin, lower serum cortisol and androgens, and higher proportion had <1%/<1% enzyme activity as compared to combined partial deficiency. Immunoassay-measured serum aldosterone was frequently (68.2%) unsuppressed (>5ng/dl). Elevated serum progesterone had high sensitivity for the diagnosis of combined 17OHD, even in combined partial deficiency (83.3%). Among patients with clinical phenotype of combined severe deficiency, 11.5% of patients had partial 17α-hydroxylase and complete 17,20-lyase deficiency (>1%/<1%) and had significantly higher serum cortisol than group with <1%/<1% activity. Conclusion We report the first monocentric case series of Asian-Indian 46,XY patients with 17OHD. We propose that a phenotype of severe undervirilisation with milder cortisol deficiency may represent a distinct subtype of combined severe 17OHD with residual 17α-hydroxylase activity but severe 17,20-lyase deficiency (>1%/<1%), which needs further validation.

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Section: Resultsmentioning

confidence: 99%

17α-Hydroxylase/17,20-Lyase Deficiency in 46,XY: Our Experience and Review of Literature

Maheshwari

Arya

Lila

et al. 2022

Journal of the Endocrine Society

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“…mutations in NR5A1 , StAR , CYP11A1 or HSD3B2 ). Multi-steroid profiling by LC-MS/MS has also been shown to be highly effective in detecting CYP17A1 deficiency early ( 27 ) but was not available. Given the consanguineous background of our siblings, concomitant mutations in other genes causing adrenal insufficiency might have contributed to the phenotype, a rare possibility that we were not able to address.…”

Section: Discussionmentioning

confidence: 99%

The broad phenotypic spectrum of 17α-hydroxylase/17,20-lyase (CYP17A1) deficiency: a case series

Sun

Mueller

Gilligan

et al. 2021

European Journal of Endocrinology

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Context: 17α-hydroxylase/17,20-lyase deficiency (17OHD) caused by mutations in the CYP17A1 gene is a rare form of congenital adrenal hyperplasia typically characterized by cortisol deficiency, mineralocorticoid excess and sex steroid deficiency. Objective: To examine the phenotypic spectrum of 17OHD by clinical and biochemical assessment and corresponding in silico and in vitro functional analysis. Design: Case series Patients and Results: We assessed eight patients with 17OHD, including four with extreme 17OHD phenotypes: two siblings presented with failure to thrive in early infancy and two with isolated sex steroid deficiency and normal cortisol reserve. Diagnosis was established by mass spectrometry-based urinary steroid profiling and confirmed by genetic CYP17A1 analysis, revealing homozygous and compound heterozygous sequence variants. We found novel (p.Gly111Val, p.Ala398Glu, p.Ile371Thr), and previously described sequence variants (p.Pro409Leu, p.Arg347His, p.Gly436Arg, p.Phe53/54del, p.Tyr60IlefsLys88X). In vitro functional studies employing an overexpression system in HEK293 cells showed that 17,20-lyase activity was invariably decreased while mutant 17α-hydroxylase activity retained up to 14% of wild-type activity in the two patients with intact cortisol reserve. A ratio of urinary corticosterone over cortisol metabolites reflective of 17α-hydroxylase activity correlated well with clinical phenotype severity. Conclusion: Our findings illustrate the broad phenotypic spectrum of 17OHD. Isolated sex steroid deficiency with normal stimulated cortisol have not been reported before. Attenuation of 17α-hydroxylase activity is readily detected by urinary steroid profiling and predicts phenotype severity.

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“…Consequently, 46,XY fetuses are severely undervirilized while 46,XX sexual development is unaffected at birth ( 33 ). The typical presentation of this form of CAH is a phenotypic girl or adolescent with pubertal failure, including lack of breast development and primary amenorrhea, hypertension and hypokalemia ( 45 ). Alternatively, like in all other forms of DSD of adrenal origin, 46,XY individuals may present with ambiguous genitalia and testes present in the inguinal canals or intra-abdominally.…”

Section: Dsd Associated With Adrenal Disordersmentioning

confidence: 99%

“…The distinctive feature of P450c17D is the elevation of pregnenolone, progesterone, DOC and corticosterone, associated to normal/low aldosterone and normal/low plasma renin activity, and decreased levels of steroids downstream P450c17 activity, i.e. 17-hydroxypregnenolone, 17-hydroxyprogesterone, 11-deoxycortisol and cortisol, as well as DHEA and androstenedione ( 33 , 45 ). ACTH stimulation test may be necessary to evidence an increase in pregnenolone/17-hydroxypregenolone and progesterone/17-hydroxyprogesterone ratios ( 44 ).…”

Section: Dsd Associated With Adrenal Disordersmentioning

confidence: 99%

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Disorders of Sex Development of Adrenal Origin

et al. 2021

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Disorders of Sex Development (DSD) are anomalies occurring in the process of fetal sexual differentiation that result in a discordance between the chromosomal sex and the sex of the gonads and/or the internal and/or external genitalia. Congenital disorders affecting adrenal function may be associated with DSD in both 46,XX and 46,XY individuals, but the pathogenic mechanisms differ. While in 46,XX cases, the adrenal steroidogenic disorder is responsible for the genital anomalies, in 46,XY patients DSD results from the associated testicular dysfunction. Primary adrenal insufficiency, characterized by a reduction in cortisol secretion and overproduction of ACTH, is the rule. In addition, patients may exhibit aldosterone deficiency leading to salt-wasting crises that may be life-threatening. The trophic effect of ACTH provokes congenital adrenal hyperplasia (CAH). Adrenal steroidogenic defects leading to 46,XX DSD are 21-hydroxylase deficiency, by far the most prevalent, and 11β-hydroxylase deficiency. Lipoid Congenital Adrenal Hyperplasia due to StAR defects, and cytochrome P450scc and P450c17 deficiencies cause DSD in 46,XY newborns. Mutations in SF1 may also result in combined adrenal and testicular failure leading to DSD in 46,XY individuals. Finally, impaired activities of 3βHSD2 or POR may lead to DSD in both 46,XX and 46,XY individuals. The pathophysiology, clinical presentation and management of the above-mentioned disorders are critically reviewed, with a special focus on the latest biomarkers and therapeutic development.

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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

Cited by 12 publications

References 38 publications

17α-Hydroxylase/17,20-Lyase Deficiency in 46,XY: Our Experience and Review of Literature

17α-Hydroxylase/17,20-Lyase Deficiency in 46,XY: Our Experience and Review of Literature

The broad phenotypic spectrum of 17α-hydroxylase/17,20-lyase (CYP17A1) deficiency: a case series

Disorders of Sex Development of Adrenal Origin

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