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Genetics and clinical presentation of nonclassic (late-onset)

congenital adrenal hyperplasia due to 21-hydroxylase
deficiency
Author: Lynnette K Nieman, MD
Section Editors: André Lacroix, MD, Benjamin A Raby, MD, MPH
Deputy Editor: Kathryn A Martin, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2020. | This topic last updated: Oct 17, 2018.

INTRODUCTION

Defective conversion of 17-hydroxyprogesterone to 11-deoxycortisol accounts for more than 90

percent of cases of congenital adrenal hyperplasia [1-3]. This conversion is mediated by 21-
hydroxylase, or in current terminology, CYP21A2.

The most severely affected individuals with classic congenital adrenal hyperplasia due to CYP21A2
deficiency present during the neonatal period and early infancy with adrenal insufficiency with or
without salt wasting, or later, with virilization. Females have genital ambiguity.

"Nonclassic," or late-onset CYP21A2 deficiency, does not manifest with neonatal genital ambiguity;
rather, it presents later in life with signs of androgen excess. Clinical features in late childhood include
premature pubarche, acne, and accelerated bone age; adolescent and adult females present with
acne, hirsutism, and menstrual irregularity [4-10].

The pathophysiology, genetics, and clinical manifestations of the nonclassic form of congenital
adrenal hyperplasia due to CYP21A2 deficiency are reviewed here. The diagnosis and treatment of
late onset CP21A2 deficiency, and the classic form of CYP21A2 deficiency are reviewed separately.
(See "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-
hydroxylase deficiency" and "Diagnosis of classic congenital adrenal hyperplasia due to 21-
hydroxylase deficiency in infants and children" and "Genetics and clinical presentation of classic
congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Treatment of classic
congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults" and "Treatment of classic
congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children".)

PREVALENCE

Based upon neonatal screening studies that detect classic congenital adrenal hyperplasia, CYP21A2
deficiency is a common inherited disorder. The prevalence based upon such studies has been
estimated to be about 1 in 14,200 live births, ranging from 1 in 28,000 in the Chinese to 1 in 280 in
Yupik Eskimos. (See "Genetics and clinical presentation of classic congenital adrenal hyperplasia due
to 21-hydroxylase deficiency", section on 'Prevalence'.)

The nonclassic form (late-onset) is one of the most common autosomal recessive diseases, and the
frequency is ethnic-specific. Among whites, the prevalence of the nonclassic form may be as high as
1 in 1000 to 1 in 100 [11-13], with the prevalence being even higher among Mediterraneans,
Hispanics, and Eastern European Jews [1,14]. Most patients with the nonclassic form will not be
identified by the neonatal screening studies, which are based upon detection of very high levels of 17-
hydroxyprogesterone [15].

Women with the nonclassic form typically present with oligomenorrhea and hyperandrogenism and,
therefore, may be indistinguishable from polycystic ovary syndrome (PCOS). The prevalence of
congenital adrenal hyperplasia in women who present with apparent PCOS is variable, depending
upon the population studied. As an example, in two different regions of Turkey, the prevalence ranged
from 9.5 to 66 percent [16,17]. In the United States, the disorder occurs in about 1 to 4 percent of
white women with clinical evidence of androgen excess [1,18,19]. (See "Clinical manifestations of
polycystic ovary syndrome in adults".)

The frequency of heterozygote carriers has been reported to be about 1 in 60 to 80 in some studies
[11,20], but closer to 1 in 10 in another study using mutation analysis in a European population [21].

In children who present with premature pubarche (premature development of pubic hair), the
prevalence of nonclassic CYP21A2 deficiency has been reported to be very low [22], or as high as 30
percent, in high-risk ethnic groups [23]. In an unselected population of 31 such patients, none were
found to have the disorder [24].

The prevalence in men with idiopathic oligospermia is not established. However, in one study of
Jewish men presenting to an infertility clinic, there were no cases found in either 222 subjects with
abnormal semen analysis or a concurrent control group of 262 men with normal semen analysis [25].
PATHOPHYSIOLOGY

The defective conversion of 17-hydroxyprogesterone to 11-deoxycortisol in patients with CYP21A2

deficiency results in decreased cortisol synthesis and therefore increased corticotropin (ACTH)
secretion (figure 1). The resulting adrenal stimulation leads to increased production of androgens.
The severity of disease relates to the degree to which the mutations compromise enzyme activity. In
patients with the nonclassic form, enzymatic activity is reduced but sufficient to maintain normal
glucocorticoid and mineralocorticoid production, at the expense of excessive androgen production.

GENETICS

As with the other forms of congenital adrenal hyperplasia, CYP21A2 deficiency is transmitted as an
autosomal recessive disorder. Humans have two CYP21A genes, a non-functional pseudogene
(CYP21A1 or CYP21P) and the active gene (CYP21A2 or CYP21), both located in a 35-kilobase region
of chromosome 6p21.3 within the major histocompatibility locus.

The two CYP21A genes are more than 90 percent homologous. This high degree of homology
facilitates recombination events during meiosis, with consequent exchanges of segments of DNA
between the two genes.

● Large or unequal cross-over exchanges can result in a large deletion of the active gene, or a non-
functioning hybrid gene. Patients who are homozygous or heterozygous for such mutations have
classic forms of CAH.

● The exchange of smaller amounts of material can result in hybrid CYP21A1/CYP21A2 gene
products with reduced but not absent enzyme activity. A patient who is heterozygous for this and
a typical large gene deletion may have nonclassic CYP21A2 deficiency [26]. (See "Genetics and
clinical presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

Genotype versus phenotype — It is not always possible to predict the phenotype of these patients
from the specific mutation(s) of the CYP21A2 gene, but there are general correlations between
genotype and phenotype. Patients with CYP21A2 mutations can be divided into groups according to
the predicted effect of the mutation on 21-hydroxylase enzymatic activity. (See "Genetics and clinical
presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on
'Genotype versus phenotype'.)

Women with the late-onset form may be either compound heterozygotes (with a classic mutation and
a variant allele) or homozygotes with two variant alleles, allowing for 20 to 60 percent of normal
enzymatic activity (eg, with point mutations leading to conservative amino acid substitutions such as
Val281Leu).

Women who are compound heterozygotes for two different CYP21A2 mutations usually have the
phenotype associated with the less severe of the two genetic defects [27].

Obligate heterozygote carriers (with one normal allele) may have mild biochemical abnormalities [28-
30], but no clinically important endocrine disorder.

Despite these general correlations, the CYP21A2 deficiency phenotype does not always correlate
precisely with the genotype, suggesting that other genes influence the clinical manifestations. (See
"Genetics and clinical presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase
deficiency", section on 'Genotype versus phenotype'.)

Prenatal diagnosis, neonatal screening and genotyping for CYP21A2 deficiency are discussed
separately. (See "Diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase
deficiency in infants and children" and "Genetics and clinical presentation of classic congenital
adrenal hyperplasia due to 21-hydroxylase deficiency".)

CLINICAL PRESENTATIONS

Children — Children with nonclassic congenital adrenal hyperplasia present after the neonatal period
with signs of hyperandrogenism, without adrenal insufficiency. Clinical features may include:

● Premature pubarche. Children with nonclassic CYP21A2 deficiency typically differ from children
with ordinary premature adrenarche in having a bone age advanced more than 2.0 SD for age.
(See "Premature adrenarche", section on 'Virilizing congenital adrenal hyperplasia'.)

● Medication-resistant cystic acne [31].

● Accelerated growth with tall stature as children.

However, these children may enter puberty early, with early epiphyseal closure, leading to short
stature as an adult, although short stature is not a consistent feature [1,10,32]. The management of
children is discussed separately. (See "Treatment of classic congenital adrenal hyperplasia due to 21-
hydroxylase deficiency in infants and children".)

Female reproduction — Adolescent and adult women have acne, hirsutism, and menstrual irregularity
that are indistinguishable from the polycystic ovary syndrome [8,33,34].
In one study of 220 females with nonclassic congenital adrenal hyperplasia the clinical presentation
varied by the age of the patient [34]:

● Nearly all patients younger than 10 years presented with premature pubarche; clitoromegaly and
acne were less common (20 percent).

● The presenting clinical features in adolescents and adult women included hirsutism (59 percent),
oligomenorrhea (54 percent), acne (33 percent), infertility (13 percent), clitoromegaly (10
percent), alopecia (8 percent), and primary amenorrhea (4 percent).

● The prevalence of hirsutism increased significantly with age, from 70 percent in adolescents to
90 percent in 40- to 49-year-old women. When present, the degree of hirsutism was similar at all
ages.

The following features may help distinguish nonclassic congenital adrenal hyperplasia and polycystic
ovary syndrome [34,35]:

● Nonclassic congenital adrenal hyperplasia is uncommon in African-American and Hispanic-

Puerto Rican women [36,37].

● Insulin resistance may be more severe, but probably not more common in polycystic ovarian
syndrome [34,35].

● Polycystic ovaries on ultrasound are less common in nonclassic congenital adrenal hyperplasia
(40 versus 70 percent) [34,35].

● Obesity is more common in women with polycystic ovary disease [19].

In a questionnaire-based study, women with nonclassic congenital adrenal hyperplasia show

increased masculinization (defeminization) when compared to normal women [38]. These attributes
were more extreme in women with the classic form of the disease. A second study using interviews
and questionnaires in women with nonclassic and classic 21-hydroxylase deficiency extended these
findings. Among 22 women with the classic disorder, none reported sexual fantasies or actual
experience with same-sex partners, while 19 of 79 women with the nonclassic form reported sexual
fantasies and 3 of 77 had same-sex encounters [39].

Fertility — Women with the classic form of congenital adrenal hyperplasia due to 21-hydroxylase
deficiency have low fertility rates that correlate with the severity of the mutation. (See "Genetics and
clinical presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency",
section on 'Female reproduction'.)
In contrast, subfertility is milder in women with the nonclassic form of 21-hydroxylase deficiency.
Many women conceive spontaneously, while others have anovulatory infertility that responds to
glucocorticoids alone or combined with clomiphene citrate [40]. (See "Ovulation induction with
clomiphene citrate".)

However, the risk of spontaneous abortion (SAB) appears to be high in these women compared to
normal women (≥25 percent versus 10 to 15 percent, respectively) [33,41-45]. Treatment with
glucocorticoids may lower this risk, as illustrated in a study of 85 women with the nonclassic form
who were pursuing pregnancy. Women who had received therapy with glucocorticoids in order to
conceive (n = 36), had a lower risk of SAB than those who had not received glucocorticoids (n = 49;
6.5 versus 26.3 percent, respectively) [44].

Risk of classic CAH in offspring — Women with the late-onset form who seek fertility should be
aware of the potential risk of giving birth to an infant with classic CYP21A2 deficiency. Women who
carry the classic (severe) mutation whose partner also carries the classic mutation are at risk of
having an infant who is homozygous for the severe mutation. This was illustrated in a report of 162
live births in 101 women with the late-onset form [41]. At birth, 4 (2.5 percent) and 24 (15 percent) of
the 162 infants were diagnosed with the classic form and the late-onset nonclassic form,
respectively.

If genetic screening has not been performed by a couple prior to conception, the birth of an affected
infant should prompt consideration of genotyping and consideration of prenatal diagnosis in
subsequent pregnancies.

However, genotyping for CYP21 mutations is not widely available, usually not covered by insurance,
and does not detect all mutations; as a result, recommendations for screening protocols for these
couples have not been established [46].

Prenatal diagnosis, neonatal screening, and genotyping for CYP21A2 deficiency are discussed
separately. (See "Diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase
deficiency in infants and children" and "Genetics and clinical presentation of classic congenital
adrenal hyperplasia due to 21-hydroxylase deficiency".)

Men — In males, it can be difficult to differentiate between simple virilizing forms of "classic"
CYP21A2 deficiency and "non-classic" forms. Both can present in childhood with premature pubarche
or adrenarche and eventual short stature. After puberty, nonclassic men usually present with acne or
infertility. Asymptomatic individuals (obligate heterozygote carriers) may be diagnosed because of an
affected family member.
Boys and men with classic CYP21A2 deficiency often develop testicular masses (testicular adrenal
rest tumors). During adulthood, these are often associated with oligospermia and infertility. Although
most men with the nonclassic form are thought to have normal testicular function and normal fertility,
some do present with testicular adrenal rests and infertility [9,10,47].

In general, treatment is not necessary for men with nonclassic CYP21A2 deficiency who do not desire
future fertility. However, in men with a testicular mass and/or oligospermia, glucocorticoid therapy
should be given until fertility is no longer desired [48]. (See "Diagnosis of classic congenital adrenal
hyperplasia due to 21-hydroxylase deficiency in infants and children" and "Treatment of classic
congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults", section on 'Testicular
adrenal rest tumors'.)

Adrenal incidentalomas — Although 60 percent of patients with unilateral adrenal incidentalomas,

and even more of those with bilateral incidentalomas, have exaggerated serum 17-
hydroxyprogesterone responses to ACTH stimulation [1], the prevalence of germline CYP21A2
mutations is low. However, unilateral and bilateral adrenal incidentalomas were found in 10 of 12
patients with simple virilizing and five of seven patients with late-onset CAH, as well as 9 of 10
heterozygotic siblings [49]. Most tumors had a diameter of less than 2 cm, but three patients had
masses more than 5 cm in size. Adrenal masses in children with CYP21A2 deficiency are usually
benign [1].  

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around
the world are provided separately. (See "Society guideline links: Classic and nonclassic congenital
adrenal hyperplasia due to 21-hydroxylase deficiency".)

SUMMARY

Nonclassic CYP21A2 deficiency is one of the most common autosomal recessive diseases, and the
frequency is ethnic-specific. (See 'Prevalence' above.) The genetics of this disorder are discussed
above. (See 'Genetics' above.)

● Children may present with precocious pubarche, medication-resistant acne, and accelerated
growth. (See 'Clinical presentations' above.)

● In adolescent girls and adult women, nonclassic CYP21A2 deficiency is characterized by acne,
hirsutism, and menstrual irregularity (oligoovulation) that are indistinguishable from the
 polycystic ovary syndrome. (See 'Children' above and 'Female reproduction' above.)

● Oligo/anovulatory infertility is common in women who are untreated. Most conceive with
ovulation induction (glucocorticoids alone or combined with clomiphene citrate), and the rate of
early pregnancy loss appears to be no higher than normal after treatment begins. (See 'Fertility'
above.)

● Although most men with the nonclassic form are thought to have normal testicular function and
normal fertility, some do present with testicular adrenal rests and infertility. (See 'Clinical
presentations' above.)

DISCLOSURE

The views expressed in this topic are those of the author(s) and do not reflect the official views or
policy of the United States Government or its components.

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Topic 144 Version 10.0

GRAPHICS

Synthetic defect in CYP21A2 (21-hydroxylase) deficiency

Pathways of adrenal steroid synthesis. A synthetic defect in 21-hydroxylase leads to diminished cortisol synthesis,
increased release of corticotropin (ACTH), accumulation of 17-hydroxyprogesterone (particularly after the
administration of ACTH), possible virilization due to increased androgen production, and possible salt-wasting due
to diminished production of aldosterone and deoxycorticosterone.

The numbers at the arrows refer to specific enzymes: 17α: 17α-hydroxylase (P450c17); 17,20: 17,20 lyase which is part of
the P450c17 enzyme; 3β: 3β-hydroxysteroid dehydrogenase; 21: 21-hydroxylase (P450c21); 11β: 11β-hydroxylase;
(P450c11); 18 refers to the two-step process of aldosterone synthase (P450c11as), resulting in the addition of an hydroxyl
group that is then oxidized to an aldehyde group at the 18-carbon position; ?: unclear if pathway functions in vivo; DHEA:
dehydroepiandrostenedione; 17KSR: 17-ketosteroid reductase; and A: aromatase.

Graphic 81907 Version 4.0

Contributor Disclosures
Lynnette K Nieman, MD Grant/Research/Clinical Trial Support: HRA Pharma [Cushing's syndrome
(Metyrapone)]. André Lacroix, MD Grant/Research/Clinical Trial Support: Novartis [Pituitary tumors, Cushing's
syndrome (Pasireotide, octreotide, osilodrostat)]; GLWL Research Inc [Prader-Willi syndrome (GLWL-01)].
Consultant/Advisory Boards: Novartis [Pituitary tumors, Cushing's syndrome (Pasireotide, octreotide,
osilodrostat)]. Speaker's Bureau: Novartis [Cushing's syndrome (Pasireotide, octreotide, osilodrostat)]. Other
Financial Interest: Encyclopedia of Endocrinology [Adrenal (Editor)]; European Journal of Endocrinology [Senior
editor]. Benjamin A Raby, MD, MPH Consultant/Advisory Boards: Sanofi; Genzyme; Regeneron; Teva [Asthma].
Employment (spouse): Parexel [Hematology (CRO)]. Kathryn A Martin, MD Nothing to disclose

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