Hyperandrogenism, nonclassic type, due to 21-hydroxylase deficiency

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: CYP21A2 (HGNC:2600)
• Mode(s) of Inheritance: Autosomal Recessive
• Literature Search: 05/09/2018
• Curation Status: Released - Under Revision (1.2.3)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
CYP21A2	N/A (0023601)	201910	Limited Actionability

Actionability Assertion Rationale

• All experts agreed with the assertion computed according to the rubric.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Infertility/subfertility in females / Glucocorticoid therapy	1	3C	1B	2	7CB

Severity of Outcome

Prevalence of the Genetic Condition

Hyperandrogenism is estimated to affect approximately 10% of the female population. Among these women, the prevalence of non-classic congenital hyperplasia (NCCAH) due to 21-hydroxylase deficiency is estimated to range between 1-10% depending on the ethnicity, with a worldwide estimate of 4.2% of hyperandrogenic women. While it is expected that NCCAH would occur equally in men and women, only a few case reports and small series have been reported in men.

Clinical Features (Signs / symptoms)

In NCCAH there is mild deficiency (30-50%) of the activity of the 21-hydroxylase enzyme resulting in androgen excess. These individuals have postnatal onset with signs of hyperandrogenism.Females are not virilized at birth (as in the classic form), though postnatal virilization can occur. Symptoms of androgen excess may include acne, premature development of pubic hair, accelerated growth, advanced bone age, and reduced adult stature due to premature epiphyseal fusion. Other symptoms in females can include hirsutism, frontal baldness, delayed menarche, ovulatory and menstrual dysfunction, and infertility. Polycystic ovarian morphology is a frequent finding in females with NCCAH. Most women with NCCAH will conceive spontaneously; however, between 10-30% of NCCAH women or reproductive age complain of infertility or subfertility, mainly due to anovulation. Affected adult females are more likely to have gender dysphoria, experience less heterosexual interest, and reduced satisfaction with the assignment to the female sex. Data regarding adult males with NCCAH are extremely limited, therefore it appears that the great majority of male patients are asymptomatic with most identified during genetic screening. Males with NCCAH may have early beard growth, gynecomastia, and an enlarged phallus with relatively small testes. Typically, men have normal sperm counts and do not have impaired gonad function. Testicular adrenal rest tumors are quite uncommon but may occur. Males do not show a general alteration in gender identity or sexual orientation. There is limited data to suggest an association with adrenal hyperplasia and adenoma, insulin resistance, obesity, metabolic syndrome, and exercise intolerance, and cardiovascular events with both classic CAH and NCCAH.

Natural History (Important subgroups & survival / recovery)

NCCAH may present any time postnatally. Most children with NCCAH are asymptomatic in the prepubertal years with premature pubarche, menstrual irregularities (females), and gynecomastia (males) often occurring as the first presentation. Women who present with NCCAH symptoms as adults typically present with hirsutism, acne, androgenic alopecia, and/or clitoromegaly.

Likelihood of Outcome

Mode of Inheritance

Autosomal Recessive

Prevalence of Genetic Variants

>1-2 in 100

The vast majority of NCCAH patients seeking medical attention are associated with CYP21A2 pathogenic variants. As such, it can be estimated that the prevalence of CYP21A2 variants resulting in NCCAH is near the population prevalence of the disease cited above.

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

Unknown

Adult Women:

-Overt ovulatory and menstrual dysfunction: 30-50%

-Polycystic ovarian morphology: 24-44%

-Infertility: 10-30%

-Subfertility: ~50%

-Spontaneous miscarriage: 25% of pregnancies

-Hirsutism: 60-80%

-Acne: ~33%

-Clitoromegaly: 6-20%

-Alopecia: 2-8%Adult Men:

-Testicular adrenal rest tumors: Unknown; rare

Tier 3

Expressivity

Because many patients are compound heterozygotes for two or more different mutant CYP21A2 alleles with varying impacts on enzyme function, a wide spectrum of phenotypes may be observed.

Tier 3

The NCCAH phenotype may be highly variable even with a family sharing the same CYP21A2 genotype.

Tier 3

Intervention Effectiveness

Patient Management

The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet algorithm to help clinical decision-making following newborn screening for congenital adrenal hyperplasia (Elevated 17-OHP): https://www.acmg.net/PDFLibrary/Elevated-17-OHP-Algorithm.pdf

Treatment is suggested for NCCAH only in adults with patient-important hyperandrogenism with the option of discontinuing treatment once symptoms resolve.

Tier 2

In adult women with NCCAH, ovarian androgen suppression or peripheral androgen blockade are more effective than glucocorticoids for reducing circulating androgens and their effects. One controlled randomized trial on a series of 30 patients compared the effectiveness of cyproterone acetate (CPA) versus hydrocortisone. Based on the hirsutism score, CPA was more effective than hydrocortisone (hirsutism improved in 54% and 24% patients, respectively). In another randomized trial including 28 patients, CPA associated with ethinylestradiol was found to be superior to dexamethasone (hirsutism improved in 66% and 31% patients, respectively).

Tier 2

Women should be counseled regarding an increased risk of infertility. Treatment is suggested in adults with NCCAH with patient-important infertility. Adult women with NCCAH who have not conceived spontaneously and who demonstrate overt or subclinical ovulatory dysfunction may benefit from glucocorticoids or from ovulation induction. In a recent study of 38 patients who presented with oligo-amenorrhea before treatment, 27 achieved regular menstrual cycles with hydrocortisone treatment (average dose: 17.5 ± 7.5mg/day). Among the 11 patients presenting with amenorrhea before treatment, only three still had amenorrhea after glucocorticoid-only treatment. Plasma testosterone and androstenedione concentrations decreased significantly in all patients. In one study the rate of singleton live birth was higher in NCCAH women diagnosed and treated for their disorder prior to conceiving that in those patients who conceived spontaneously (86% versus 69%); there were no difference in the rate of ectopic pregnancy, preterm birth, stillbirths, twins or multiple pregnancies. Evidence is mixed regarding the continuation of glucocorticoid treatment during pregnancy to potentially reduce pregnancy loss and there are no clear guidelines concerning treatment during pregnancy.

Tier 2

Nature of Intervention

Nature of Intervention

Glucocorticoid overtreatment may cause Cushing syndrome. As such, glucocorticoids are recommended in only a subset of patients with NCCAH and require monitoring.

Context: Adult

Chance to Escape Clinical Detection

NCCAH is often not diagnosed until adolescence when the first symptoms appear. Reduced fertility may be the only symptom of disease.

Context: Adult

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			CYP21A2			201910	0023601

References List

ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 201910, (2016) World Wide Web URL: http://omim.org/

Carmina E, Dewailly D, Escobar-Morreale HF, Kelestimur F, Moran C, Oberfield S, Witchel SF, Azziz R. (2017) Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women. Human reproduction update. 23(5):580-599.

Clayton PE, Miller WL, Oberfield SE, Ritzen EM, Sippell WG, Speiser PW. (2002) Consensus statement on 21-hydroxylase deficiency from the European Society for Paediatric Endocrinology and the Lawson Wilkins Pediatric Endocrine Society. Hormone research. 58(4):188-95.

Congenital adrenal hyperplasia. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=418

S Nimkarn, PK Gangishetti, M Yau, MI New. 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia. (2002) [Updated Feb 04 2016]. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1171/

Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM, Oberfield SE, Ritzen M, White PC. (2010) Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. The Journal of clinical endocrinology and metabolism. 95(9):4133-60.