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

Sun, Mingxuan; Mueller, Jonathan Wolf; Gilligan, Lorna C; Shaheen, Fozia; Noczyńska, Anna; T’Sjoen, Guy; Denvir, Louise; Shenoy, Savitha; Fulton, Piers; Cheetham, Timothy; Gleeson, Helena; Rahman, Mushtaqur; Krone, Nils; Taylor, Norman; Shackleton, Cedric; Arlt, Wiebke; Idkowiak, Jan

doi:10.1530/eje-21-0152

Cited by 17 publications

(7 citation statements)

References 37 publications

(59 reference statements)

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“…This leads to complete female external genitalia in both sexes when there is complete enzyme deficiency. Therefore, as in our patients and most other case series, the diagnosis of 17OHD before puberty is very rare unless there is a known case in the family [Wang et al, 2012;Chen et al, 2019;Sun et al, 2021;Beştaş et al, 2022]. Clinical findings related to excessive mineralocorticoid effects, such as HT and hypokalemic alkalosis, are important clues for early diagnosis of 17OHD.…”

Section: Discussionmentioning

confidence: 51%

Presentation, Diagnosis, and Follow-Up Characteristics of 17α-Hydroxylase Deficiency Cases with Exon 1–6 Deletion (Founder Mutation) in the CYP17A1Gene: 20-Year Single-Center Experience

Dündar

Akıncı

Çamtosun

et al. 2023

Sex Dev

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Context: 17α-hydroxylase/17,20-lyase deficiency (17OHD) is characterized by decreased sex steroids and cortisol synthesis, as well as an increased mineralocorticoid effect. Aim: This study aimed to evaluate the clinical, biochemical, and molecular characteristics of patients with 17OHD and to discuss the diagnosis, treatment, and follow-up process. Methods: Age, symptoms, anthropometric measurements, blood pressure, and hormonal, biochemical, and chromosomal analysis results of 13 patients diagnosed with 17OHD between 2003 and 2022 were recorded at admission and during follow-up. Whole gene next-generation sequencing was performed for the CYP17A1 gene. Multiplex ligation-dependent probe amplification was used to detect deletions in patients without point mutations in CYP17A1. Results: The median age at diagnosis was 14.0 (3.5–16.8) years. Nine of 13 (69.2%) had 46,XY karyotypes. All patients were phenotypically female and were raised as girls. The most common reasons for admission were the absence of puberty and amenorrhea (n=8, 61.5%), followed by hypertension (n=3, 23.0%) and family screening (n=2, 15.3%). At the time of diagnosis, hypertension was detected in 10 (76.9%) patients, and 11 (84.6%) patients had hypokalemia. Conclusions: 17OHD should be considered in patients with pubertal delay/primary amenorrhea, hypertension, and hypokalemia. Adrenal function should be included in the clinical study of hypergonadotropic hypogonadism, after excluding Turner syndrome, in all 46,XX females. Deletion in the CYP17A1, including exons 1-6, is the founder mutation for Turkey's East and Southeast regions.

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Section: Discussionmentioning

confidence: 51%

Presentation, Diagnosis, and Follow-Up Characteristics of 17α-Hydroxylase Deficiency Cases with Exon 1–6 Deletion (Founder Mutation) in the CYP17A1Gene: 20-Year Single-Center Experience

Dündar

Akıncı

Çamtosun

et al. 2023

Sex Dev

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“…Since then, more than 100 mutations have been reported in the CYP17A1 gene, including point mutations, small deletions or insertions, splice-site alterations and, less frequent, large deletions [14]. Most of these mutations are associated with the classical phenotype of the disease, with only a small number of CYP17A1 missense variants being reported to impair only partially the activity of 17α-hydroxylase/17, 20-lyase activity [15]. Because of the variate degree attenuation of enzymatic activity of 17α-hydroxylase and 17, 20-lyase, the complete or partial deficiency of the two enzymes can occur [14].…”

Section: Discussionmentioning

confidence: 99%

Successful Treatment of Infertility in a Patient with Probable 17 Hydroxylase Deficiency and Particularities of Association with Adrenal Autoimmunity—A Case Report and Review of the Literature

Albu

Iancu²,

Albu

2023

Life

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Congenital adrenal hyperplasia (CAH) due to 17-hydroxylase deficiency (17OHD) is a rare disease accounting for less than 1% of cases of CAH. In female patients, fertility is severely affected mainly due to constantly increased progesterone affecting endometrium receptivity and implantation. The optimal treatment for infertility in these patients is not clearly established, with only a few recent case reports of successful pregnancies available in the literature. Hereby, we present the case of an infertile female patient with 17OHD who obtained pregnancy through an in vitro fertilization (IVF) freeze-all strategy and particularities of association with adrenal autoimmunity. A 32-year-old infertile female patient was referred for infertility evaluation and treatment. She had normal sex development and menstrual history with oligomenorrhea alternating with normal menstrual cycles. During the evaluation, a reduced ovarian reserve and obstruction of the left fallopian tube were identified, and IVF treatment was recommended. During a controlled ovarian stimulation for IVF, increased values of serum progesterone were observed; thus, all the embryos were frozen and additional tests were performed. Increased values of 17-hydroxyprogesteron, 11-deoxycorticosteron, and adrenocorticotropic hormones in association with low basal and stimulated serum cortisol, testosterone, androstenedione, and dehydroepiandrosterone sulfate were found, supporting the presence of 17OHD. She started treatment with oral hydrocortisone given at 20 mg/day but, because follicular phase serum progesterone remained high, hydrocortisone was replaced by an oral dexamethasone treatment of 0.5 mg/day, followed by the normalization of serum progesterone. A thawed blastocyst was transferred after preparation with oral estradiol at 6 mg/day and intravaginal progesterone at 600 mg/day under continuous suppression of endogenous progesterone production with a gonadotropin-releasing hormone agonist and oral dexamethasone. The patient became pregnant and delivered two healthy girls at term. One year after delivery, the presence of 21-hydroxylase antibodies was detected, which might explain the particularities of adrenal steroids in our patient. Our case report demonstrates that a patient with 17OHD can become pregnant through IVF and the transfer of thawed embryos in a subsequent cycle under continuous suppression of adrenal and ovarian progesterone production.

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“…Per-patient data were tabulated to include demographics, geographical region ( https://population.un.org/wpp/DefinitionOfRegions )], clinical findings, hormonal parameters, testicular biopsy findings, genotype, and effects on enzyme activities (in vitro, functional activity as described in the respective study), and treatment details. Patients with the diagnosis of apparent isolated 17,20-lyase deficiency (n = 7, from 6 families) [ 4 , 5 , 12 , 13 ] were noted, whereas others were classified into combined severe deficiency (female external genitalia) and combined partial deficiency (atypical or male external genitalia) based on the clinical parameters. Residual enzyme activities with the observed mutant enzymes were arbitrarily divided in 2 categories as < 1% and ≥ 1%, for each hydroxylase and lyase activity.…”

Section: Methodsmentioning

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

Cited by 17 publications

References 37 publications

Presentation, Diagnosis, and Follow-Up Characteristics of 17α-Hydroxylase Deficiency Cases with Exon 1–6 Deletion (Founder Mutation) in the CYP17A1Gene: 20-Year Single-Center Experience

Presentation, Diagnosis, and Follow-Up Characteristics of 17α-Hydroxylase Deficiency Cases with Exon 1–6 Deletion (Founder Mutation) in the CYP17A1Gene: 20-Year Single-Center Experience

Successful Treatment of Infertility in a Patient with Probable 17 Hydroxylase Deficiency and Particularities of Association with Adrenal Autoimmunity—A Case Report and Review of the Literature

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

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