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Uncommon congenital adrenal hyperplasias

Author: Richard J Auchus, MD, PhD

Section Editor: Lynnette K Nieman, MD
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: Dec 2017. | This topic last updated: Dec 04, 2017.

INTRODUCTION — Congenital adrenal hyperplasia (CAH) refers to several disorders characterized by genetic defects in
the proteins and enzymes involved in cortisol biosynthesis (figure 1). The decrease in cortisol production releases the
feedback inhibition of cortisol on the pituitary and increases the production of corticotropin (ACTH). High ACTH causes
adrenal hyperplasia and drives excessive accumulation of cortisol precursors and/or overproduction of ACTH-dependent
adrenal steroids along other pathways. The clinical manifestations of the different disorders are due to diminished
production of cortisol and, depending upon the site of block, decreased or increased production of mineralocorticoids
and/or androgens. (See "Adrenal steroid biosynthesis".)

Treatment aims to replace steroid deficiencies and reduce the production or block the action of steroid excess. The most
common cause of CAH worldwide, accounting for >90 percent of cases, is 21-hydroxylase deficiency (21OHD) [1]. The
prevalence of other forms of CAH varies geographically, largely due to founder mutations that are often isolated in
specific regions. All forms of CAH are inherited as autosomal recessive traits. This topic review will discuss the clinical
and biochemical characteristics of the other forms of CAH, including:

● CYP17A1 deficiencies (combined 17-hydroxylase/17,20-lyase deficiency [17OHD] and isolated 17,20-lyase

deficiency [ILD])

● 3-beta-hydroxysteroid dehydrogenase type 2 deficiency

● CYP11B1 deficiency (11-hydroxylase deficiency [11OHD])

● Cytochrome P450-oxidoreductase (POR) deficiency (ORD)

● Hexose-6-phosphate-dehydrogenase deficiency (apparent cortisone reductase deficiency [ACRD])

● Phosphoadenosine phosphosulfate synthase type 2 (PAPSS2) deficiency (apparent dehydroepiandrosterone [DHEA]

sulfotransferase deficiency)

● Lipoid congenital adrenal hyperplasia (LCAH) (see 'Lipoid congenital adrenal hyperplasia' below)

ACRD and PAPSS2 deficiency are not strictly CAH disorders, since these conditions lack cortisol deficiency. In the lipoid
CAH diseases, production of all steroids is low.

CYP17A1 DEFICIENCIES — The cytochrome P450 17A1 enzyme (CYP17A1) catalyzes both the 17-hydroxylase
reaction, which forms 17-hydroxysteroids, and the 17,20-lyase reaction, which cleaves 21-carbon 17-hydroxysteroids to
19-carbon 17-keto androgen precursors (figure 2) [2]. Most defects in CYP17A1 impair both enzymatic activities and
cause combined 17-hydroxylase/17,20-lyase deficiency (17OHD), which can be complete or partial [3]. The prevalence
appears to be highest in Brazil [4,5]. Isolated 17,20-lyase deficiency (ILD) is extremely rare [6,7], with only approximately
six cases described.
CYP17A1 is expressed both in the human adrenal and gonads [8], and thus, these deficiencies are forms of CAH that
impair both adrenal and gonadal function. ILD, in contrast, does not significantly lead to adrenal hyperplasia and is more
a form of gonadal insufficiency.

Pathophysiology — The hallmarks of 17OHD, first described in 1966 [3], include hypertension and hypokalemia due to
the accumulation of cortisol precursors with mineralocorticoid activity upstream of the block, plus sexual infantilism due to
inability to synthesize androgens and estrogens. Unlike most other forms of CAH, mineralocorticoid excess and high
corticosterone production [9] mitigate the clinical consequences of cortisol deficiency, and symptomatic adrenal
insufficiency is rare [4,10-16].

CYP17A1 metabolizes pregnenolone, progesterone, and their 17-hydroxy derivatives early in the steroidogenic cascades
(figure 2) [11]. Consequently, 17OHD eliminates the synthesis of most steroids and limits steroidogenesis to
progesterone, 11-deoxycorticosterone (DOC), corticosterone, and 18-oxygenated derivatives (table 1) [12,13]. DOC binds
with high affinity to the mineralocorticoid receptor and is not a substrate for 11-beta-hydroxysteroid dehydrogenase type
2. DOC excess causes volume expansion, hypertension, and kaluresis despite suppressed renin and aldosterone
production.

The lack of 17,20-lyase activity precludes conversion of 21-carbon steroids to 19-carbon androgen precursors in both
17OHD and ILD (figure 2). In ILD, 17-hydroxylation is largely preserved, and DOC and corticosterone accumulation are
limited; hence, hypertension and hypokalemia as clinical manifestations of 17OHD are not found. Low 19-carbon steroid
production, however, causes variable degrees of genital ambiguity in affected 46,XY males with a tendency for
gynecomastia during puberty, as occurs in many states of low testosterone synthesis. Affected girls develop only sparse
pubic hair and can have dysmenorrhea [14].

Clinical presentation — The classic presentation of severe 17OHD in phenotypic females (who can have 46,XX or
46,XY karyotype) includes [3,9,10]:

● Hypertension

● Primary amenorrhea

● Absence of secondary sexual characteristics

● Minimal body hair

The hypertension, which is typically detected in early adulthood [17], may be present much earlier [18] and can be severe
[19] but may be normalized with treatment [20]. (See 'Treatment' below.)

In partial forms of 17OHD, 46,XY patients are often identified in infancy due to ambiguous genitalia with intraabdominal
or inguinal testes and a blind vaginal pouch similar to androgen insensitivity syndrome. Genotypic females have a small
uterus and ovaries that may develop large cysts in adolescence due to high gonadotropins and progesterone. Since
estrogens derive from androgens, estrogen synthesis is secondarily impaired, but since estradiol is an extremely potent
inducer of breast development, particularly when androgens are low, some breast development may be seen.
Biochemical evidence of a partial 17-hydroxylation defect may be observed without clinical manifestations of hypertension
or hypokalemia [21].

ILD is generally diagnosed in males with undervirilization, gynecomastia, and failure to develop secondary sexual
characteristics due to the testicular enzyme deficiency [6,7]. Females with ILD have been identified only in families with
affected males; they present with delayed pubarche and oligomenorrhea [14].

Diagnosis — The diagnosis of 17OHD is established by demonstrating an elevated precursor-to-product ratio in serum at
baseline or under cosyntropin stimulation [4]. In general, the diagnosis is established by showing elevated DOC (>100
ng/dL [>3 nmol/L]) and corticosterone (>4000 ng/dL [>116 nmol/L]) with low cortisol (<5 mcg/dL [<138 nmol/L]),
androgens, and estrogens. Progesterone is also elevated [22], while aldosterone and renin are suppressed (table 1).
Gonadotropins and corticotropin (ACTH) are elevated even in children. The characteristic feature of ILD is the elevated
17-hydroxyprogesterone (17OHP)/androstenedione ratio (>50) [6], with all downstream (19-carbon) steroids reduced and
17-hydroxysteroids at or near normal.

Differential diagnosis — The differential diagnosis of ACTH-dependent mineralocorticoid excess is shown in the
table (table 1). Most of these other conditions are distinguished from 17OHD in that DOC is not elevated, and 11-
hydroxylase deficiency (11OHD) is distinguished by the presence of low versus high androgens in 17OHD and 11OHD,
respectively. The differential diagnosis of undervirilization in males is one of the most difficult in pediatric endocrinology
and is discussed separately. (See "Diagnosis and treatment of disorders of the androgen receptor", section on
'Diagnosis'.)

P450 oxidoreductase (POR) deficiency (ORD) [23] can be difficult to distinguish from 17OHD and ILD [24] clinically and
biochemically (figure 3) (see 'P450 oxidoreductase deficiency (apparent combined CYP17A1 and CYP21A2 deficiency)'
below). Urinary steroid profiling by gas chromatography-mass spectrometry (GC-MS) and molecular diagnostics are
extremely useful methods for confirming the diagnosis [25,26] but are not routinely available. In 17OHD, metabolites of
DOC and corticosterone are elevated, while 17OHP and 19-carbon steroid metabolites are low; in ORD, metabolites of
both 17OHP and corticosterone are characteristically elevated due to combined 21- and 17-hydroxylation defects, and
19-carbon steroids are also reduced. Progesterone is elevated in both conditions.

Genetics — As expected with an autosomal recessive inheritance, some patients were offspring of consanguineous
marriages, and obligate heterozygotes have mild defects in 17-hydroxylation, which can be revealed by ACTH stimulation
[27-29].

Approximately 100 different mutations in the CYP17A1 gene, which is located on chromosome 10q24.3 [30], have been
defined [2,15].

Mutations causing 17OHD map to all regions of the protein and are predicted to impair substrate binding, heme
incorporation, and protein folding [7,24,31-44]. In Brazil, the founder mutations R362C and W406R account for >80
percent of affected alleles and, in part, explain the unusually high prevalence of the disease in this country, with only half
of patients from consanguineous families [5]. New mutations continue to be identified in all regions of the gene [45-48],
and recurring mutations include F53 deletion, R96W or Q, R239Q or X, Y329D or X or ins/del, H373D or N or L, P406R, a
CATC duplication at I479, D487-F489 deletion, and D487-S488 duplication [15].

In general, the severity of the clinical phenotype correlates with the degree of impairment of enzymatic activity
demonstrated in heterologous assay systems [11,38,49,50]. However, these assays do not explain occasional differences
in clinical presentation despite the same CYP17A1 genotype. In vitro assays with mutations causing ILD convincingly
demonstrate very low, but not absent, 17,20-lyase activity, despite partially preserved 17-hydroxylase activity [51].

Treatment — The goals of treatment in classic 17OHD are to mitigate the effects of mineralocorticoid excess, prevent
glucocorticoid deficiency, and restore desired secondary sexual characteristics with attendant benefits such as improved
bone mineral density (BMD). This is achieved by mineralocorticoid blockade and physiologic replacement of cortisol and
sex steroids, rather than by supraphysiologic suppressive doses of glucocorticoid.

For patients reared as female, spironolactone is the drug of choice to block the mineralocorticoid receptor. Medications
are titrated based on monitoring blood pressure, DOC, and electrolytes; renin suppression can persist for years, despite
adequate therapy, in some cases [12,52].

Puberty is induced with low-dose estrogen at the expected time of pubarche. Cyclical withdrawal bleeding is only required
for 46,XX females with an intact uterus. Androgen replacement has not been studied in this disorder. (See "Diagnosis and
treatment of delayed puberty", section on 'Estrogen therapy'.)

A few cases of in vitro fertilization and a live birth in a 46,XX patient with incomplete 17OHD have been described [53].
The approach included ovulation induction with gonadotropin stimulation, egg retrieval, and freezing of embryos. During
the ovarian stimulation, adrenal and ovarian progesterone secretion were suppressed with dexamethasone and
gonadotropin-releasing hormone (GnRH) agonist administration. Estradiol valerate was then given to prepare the
endometrium and the frozen-thawed embryo transfer was performed.
Treatment for 46,XY patients with a disorder of sex development (DSD) due to ILD and partial 17OHD is much more
complex and incorporates attention to genital surgery for hypospadias or clitoral reduction for those being reared as
females. Testosterone replacement may be given to stimulate penile growth in childhood and then resumed in
adolescence and adulthood. (See "Management of the infant with atypical genitalia (disorder of sex development)",
section on 'Long-term management'.)

3-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 2 DEFICIENCY — 3-beta-hydroxysteroid dehydrogenase type

2 (HSD3B2) deficiency is a rare form of congenital adrenal hyperplasia (CAH) in which synthesis of all active steroid
hormones is impaired. This very rare disorder, like combined 17-hydroxylase/17,20-lyase deficiency (17OHD), impairs
both adrenal and gonadal steroid production [54]. Paradoxically, both male and female infants are born with genital
ambiguity for reasons explained below. Mutations throughout the HSD3B2 gene have been identified, with a few founder
mutations in isolated populations [55-67].

Characteristic features — HSD3B2 catalyzes the reactions that establish the 3-keto-delta-4 A-ring structure found in the
major endogenous progestins, mineralocorticoids, glucocorticoids, and androgens, including the precursors of
dihydrotestosterone. Consequently, all are deficient, and since androgens are precursors to estrogens, estrogen
biosynthesis is also impaired (figure 4) [54]. The resulting corticotropin (ACTH) excess drives the production of the 3-
beta-hydroxy-delta-5-steroids pregnenolone, 17-hydroxypregnenolone, and dehydroepiandrosterone (DHEA), as well as
their sulfates (figure 4). Unlike 17OHD, the accumulating precursor steroids do not compensate for cortisol deficiency,
and newborns suffer from hypotension and hyperkalemia as in 21-hydroxylase deficiency (21OHD).

Testosterone deficiency results in genital ambiguity in 46,XY newborns and persists throughout adulthood. In contrast,
girls are born with mild-to-moderate clitoromegaly but little labioscrotal fusion (Prader scores II to III) (figure 5), suggesting
androgen excess late in gestation [55]. Undiagnosed girls proceed to develop androgen excess, including precocious
pubarche, acne, and hirsutism with menstrual disturbances. The apparent paradox of androgen deficiency in males and
androgen excess in girls is possible because the concentrations of androgens necessary to cause mild clitoral
enlargement, hirsutism, and acne in girls (total testosterone approximately 200 ng/dL [7 nmol/L]) are well below normal
for a fetal or adult male (approximately 500 ng/dL [17 nmol/L]).

The formation of active androgens in girls occurs because a second enzyme, HSD3B1, is abundant in liver and skin [56],
and this enzyme converts circulating DHEA to androstenedione. The markedly elevated output of precursor steroids leads
to relatively high amounts of testosterone in girls but fails to compensate fully for the defect in testicular testosterone
synthesis in boys [68].

A "nonclassic" form of HSD3B2 deficiency that causes hirsutism, menstrual irregularity, or both in adolescent or young
adult women was previously suggested [69], based on exaggerated serum delta-5 steroid production after cosyntropin
stimulation. However, most of these patients do not have genetic HSD3B2 deficiency, but rather a form of polycystic ovary
syndrome (PCOS), as the HSD3B2 gene is normal [57,58,70,71]. True nonclassic HSD3B2 deficiency is very rare, and
patients should not be given this diagnosis unless 17-hydroxypregnenolone elevation is >10 standard deviations (SDs)
above the normal mean (ie, >5000 ng/dL or 150 nmol/L) [55,57]. (See 'Hormonal criteria for diagnosis' below.)

Clinical and biochemical phenotype — Much like 21OHD, most patients present as neonates or in early infancy with
clinical manifestations of both cortisol and aldosterone deficiency, with feeding difficulties, vomiting, volume depletion,
hyponatremia, and hyperkalemia [54,59].

Newborn males are undervirilized in proportion to the severity of the enzymatic deficiency, but this disease is a rarely
found in boys with idiopathic hypospadias. In one study, only 2 of 90 boys with hypospadias had evidence of subtle
molecular abnormalities in the HSD3B2 gene [72].

Newborn females often have mild virilization and clitoromegaly due to peripheral conversion of adrenal-derived DHEA to
testosterone by the type 1 enzyme. Unlike 21OHD, this disease is not part of neonatal screening programs, and rare
patients may have severe deficiency but few symptoms and escape diagnosis until they are evaluated for delayed
puberty [73,74]. Premature pubarche with exaggerated serum 17-alpha-hydroxypregnenolone responses to ACTH has
been described in three girls with missense mutations of the gene [75].
The primary biochemical abnormalities are greatly increased ratios of delta-5 to delta-4 steroids in serum (best obtained
after cosyntropin stimulation) or in urine, such as a high ratio of delta-5-17-hydroxypregnenolone to delta-4-17-
hydroxyprogesterone (17OHP) in serum or a high ratio of pregnanetriol to pregnanediol in urine (figure 4). As described
above, serum delta-5 steroid concentrations are extremely elevated, whereas the corresponding delta-4 steroids are often
normal or slightly elevated, still yielding a high ratio.

The markedly increased delta-5 steroids distinguish this condition from the other diseases in the differential diagnosis,
which include 11-beta-hydroxylase deficiency (11OHD), 21OHD, and ORD. (See '11-beta-hydroxylase deficiency' below
and "Diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children" and
'P450 oxidoreductase deficiency (apparent combined CYP17A1 and CYP21A2 deficiency)' below.)

Heterozygous carriers cannot be distinguished from normals based on steroid measurements, even after cosyntropin
stimulation [71].

Hormonal criteria for diagnosis — Conclusive hormonal criteria for the diagnosis of HSD3B2 deficiency have been
derived from a study of 55 adolescent and adult patients whose clinical presentation suggested HSD3B2 deficiency [57].
Of these 55, eight were homozygous for deleterious HSD3B2 mutations, and the other 47 carried normal HSD3B2 genes.
Genotypically normal women had cosyntropin-stimulated serum delta-5-pregnenolone concentrations as high as 5000
ng/dL (150 nmol/L). The minimum serum concentrations of delta-5-17-hydroxypregnenolone in patients with genetically
proven HSD3B2 deficiency derived from this study vary with age:

● Neonates ≥12,600 ng/dL (378 nmol/L)

● Tanner stage I children ≥5490 ng/dL (165 nmol/L)

● Children with premature pubarche ≥9790 ng/dL (294 nmol/L)

● Adults ≥9620 ng/dL (289 nmol/L)

These approximate values have been corroborated in another series [58], such that only stimulated delta-5-17-
hydroxypregnenolone values >5000 ng/dL (150 nmol/L) or more should be considered consistent with the diagnosis. (See
"Evaluation of the response to ACTH in adrenal insufficiency", section on 'Congenital adrenal hyperplasia'.)

Management — Similar to treatment of 17OHD, therapy must include replacement of both adrenal and gonadal steroid
deficiencies. (See 'CYP17A1 deficiencies' above.)

● In 46,XY children raised as males, replacement doses of glucocorticoid (hydrocortisone) and mineralocorticoid
(fludrocortisone acetate) are sufficient, and suppression of ACTH is unnecessary.

● In children raised as females, somewhat higher doses may be needed to prevent excess production of androgens
derived from adrenal precursors.

● At the time of expected puberty, gender-appropriate replacement of androgens or estrogens with progestins should
be started and advanced slowly to adult regimens. In undervirilized 46,XY males, testosterone therapy may be used
during childhood to augment penile size prior to initiation of puberty. (See "Steroid 5-alpha-reductase 2 deficiency",
section on 'Supplemental testosterone'.)

11-BETA-HYDROXYLASE DEFICIENCY — Deficiency of CYP11B1 (P450 11B1 or 11-beta-hydroxylase) (11OHD),

affects 1 in 100,000 live births and accounts for up to 5 percent of adrenal steroidogenic defects [76]. In Jews of
Moroccan ancestry, 11OHD prevalence is as high as 1 in 5000 due to the R4448H founder mutation [77,78]. The
phenotype of 11OHD is a mix of androgen excess (as in 21-hydroxylase deficiency [21OHD]) with mineralocorticoid
excess as in combined 17-hydroxylase/17,20-lyase deficiency (17OHD), for the reasons described below.

Pathogenesis — Deficiency of 11-beta-hydroxylase activity in the zona fasciculata blocks the conversions of 11-
deoxycorticosterone (DOC) and 11-deoxycortisol to corticosterone and cortisol, respectively. The resulting increase in
corticotropin (ACTH) secretion causes the accumulation of 11-deoxysteroid precursors and adrenocortical hyperplasia.
Since CYP17A1 activities are intact and also stimulated by high ACTH concentrations, some of the upstream steroids are
metabolized to adrenal-derived androgens.

Clinical manifestations — The clinical manifestations of the disorder result from high adrenal production of the
mineralocorticoid DOC and the androgen precursor dehydroepiandrosterone sulfate (DHEAS) (figure 6 and table 1).
Consequently, the two characteristic clinical features are hypertension with hypokalemia, as found in any other form of
mineralocorticoid excess, and androgen excess. Since 11-deoxycortisol has little biological activity and cannot substitute
for cortisol as a glucocorticoid, however, these patients are paradoxically vulnerable to adrenal crises, although they are
relatively protected by mineralocorticoid (DOC) excess.

Classically, female newborns are identified with ambiguous genitalia, including clitoral enlargement and labioscrotal fusion
as in 21OHD (see "Evaluation of the infant with atypical genitalia (disorder of sex development)"). Boys may have
increased penile size, but unless born into a kindred known to carry 11OHD, they are often not diagnosed at birth or by
newborn screening of 17-hydroxyprogesterone (17OHP), which is not as high in this disorder as it is in 21OHD. (See
"Diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children".)

In children who are not diagnosed at birth, 11OHD presents as premature adrenarche, with body odor and axillary and
pubic hair development. Somatic growth and bone age generally advance faster than in idiopathic premature adrenarche,
suggesting the diagnosis of 11OHD.

Untreated children progress into isosexual or contrasexual precocious pseudopuberty. In one series of 25 patients with
11OHD, approximately half had relatively severe genital ambiguity or signs of hyperandrogenism [79]. The remainder
presented in childhood with sexual precocity, early puberty in boys and acne in men, and hirsutism and menstrual
irregularities in adolescent girls and young women.

Hypertension occurs in approximately two-thirds of patients, often early in life [76,80]. Although it is ascribed to DOC
excess, the correlations between blood pressure and serum DOC concentrations [79,81] or severity of the deficiency
based on genotype [82] are poor. A few patients with 11OHD have salt-wasting or hypotensive crises [79,83-85], but the
reasons for this phenotypic heterogeneity are not known. As with 17OHD, hypertension is often accompanied by
hypokalemia with suppression of plasma renin activity and aldosterone due to volume expansion. (See "Pathophysiology
and clinical features of primary aldosteronism".)

The hypertension and hypokalemia distinguish 11OHD from 21OHD and HSD3B2 deficiency, and the androgen excess
distinguishes 11OHD from 17OHD. As in 21OHD, untreated males may experience hyperplasia of adrenal rest tissue,
which often presents as retroperitoneal or testicular masses that regress with treatment [86,87].

As with 21OHD, a milder or nonclassic form featuring androgen excess without hypertension has been described [76,88-
91] (see 'Clinical and biochemical phenotype' above). Nonclassic 11OHD should be considered in children with androgen
excess and in hirsute or oligomenorrheic adolescent and adult women when symptoms began in childhood and 21OHD
has been excluded. In nonclassic 11OHD, 17OHP is elevated but not as high as in 21OHD. Consequently, the evaluation
of hirsute women should begin with 17OHP and only consider cosyntropin-stimulated 11-deoxycortisol to diagnose
nonclassic 11OHD in selected cases. (See "Diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase
deficiency in infants and children".)

Biochemical features — Patients with classic CYP11B1 deficiency have a characteristic set of hormonal findings,
often with hypokalemia:

● High serum concentrations of 11-deoxycortisol, DOC, DHEA and DHEAS, androstenedione, and testosterone, with
low cortisol and corticosterone (figure 6 and table 1).

● Increased urinary excretion of 11-deoxysteroid metabolites, most prominently tetrahydro metabolites of 11-
deoxycortisol and DOC, which are normally present in trace quantities [92]. Urinary excretion of 17-ketosteroids and
of all 19-carbon steroids, which reflects integrated androgen synthesis, is also increased.

Diagnosis and differential diagnosis — In affected neonates, the diagnosis is most efficiently established by high basal
and cosyntropin-stimulated serum 11-deoxycortisol concentrations with low cortisol or by increased urinary excretion of
tetrahydro-11-deoxycortisol with low cortisol metabolites (figure 6) [76,93,94]. In adolescents and young adults, basal
serum 11-deoxycortisol values may be normal, and cosyntropin stimulation testing is often required to establish the
diagnosis [95,96]. The diagnosis of mild or nonclassic 11OHD requires normal or near-normal cortisol plus 11-
deoxycortisol >1800 ng/dL (>52 nmol/L). All diagnoses are preferably confirmed with genetic testing.

Because 17OHP also accumulates above the 11-beta-hydroxylase block, 17OHP is often moderately elevated in 11OHD.
Consequently, the differential diagnosis for a young girl with mild virilization, androgen excess, and moderate 17OHP
elevations includes nonclassic 21OHD, 11OHD, and 3HSD3B2 deficiency. These diagnoses can only be distinguished by
measurement of additional steroids including 11-deoxycortisol, DOC, and delta-5-17-hydroxypregnenolone, to pinpoint
the enzymatic defect (figure 6).

The frequency of nonclassic disease is the highest for 21OHD; it is far less common for 11OHD and rare for HSD3B2
deficiency [97]. Heterozygous carriers of 11OHD have no detectable biochemical abnormalities [98]. (See "Diagnosis and
treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

Genetic findings — The autosomal recessive disorder 11OHD is caused by mutations of the CYP11B1 gene, located on
chromosome 8q21-q22. Most mutations completely abolish the activity of the enzyme and include missense mutations
that reduce enzyme activity [78,99-101], frameshifts [102], and nonsense mutations [103,104] that prevent synthesis of
the enzyme. The founder mutation R448H is by far the most common and explains the high prevalence of 11OHD in Jews
of Moroccan origin [78]. In two patients, the disorder occurred as a result of unequal recombination between the
CYP11B1 and CYP11B2 genes [105,106], which is reminiscent of the genetic event leading to glucocorticoid-remediable
aldosteronism (GRA). (See "Familial hyperaldosteronism", section on 'Familial hyperaldosteronism type I (FH type I) or
glucocorticoid-remediable aldosteronism (GRA)'.)

Treatment approach — The goals of therapy in children with 11OHD are to reduce mineralocorticoid and adrenal
androgen precursor synthesis sufficiently to ameliorate the hypertension, hypokalemia, and androgen excess. (See
"Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children".)

● Children are generally treated with glucocorticoids only, typically hydrocortisone (10 to 25 mg/m2), which is preferred
over prednisolone (approximately 0.1 mg/kg) or dexamethasone (up to 0.01 mg/kg), to lower ACTH secretion.
Despite the proclivity for hypertension in 11OHD, hypotensive adrenal crises due to glucocorticoid deficiency occur
during significant illness.

● Fludrocortisone acetate is not necessary, and spironolactone is sometimes added to antagonize both androgens and
mineralocorticoids, allowing reduced glucocorticoid dosing, particularly in adults. Given the phenotypic variability in
this disease, treatment must be tailored to minimize the dose of glucocorticoid so as to prevent iatrogenic Cushing's
syndrome. (See "Epidemiology and clinical manifestations of Cushing's syndrome".)

The response to therapy should be monitored both biochemically and clinically:

● Blood pressure should be normal, normokalemia should be restored, and 11-deoxycortisol concentrations should
decrease although not necessarily to normal.

● Serum androstenedione and testosterone concentrations should be brought to age- and gender-specific normal
range. In postpubertal boys and men, a serum androstenedione concentration higher than testosterone indicates that
the androgens are adrenal derived and disease control is poor.

● A measurable plasma renin activity indicates suppression of mineralocorticoid synthesis, which can take months after
starting therapy.

● Clinical monitoring includes assessment of virilization, growth velocity, and skeletal maturation (bone age) with
attention to glucocorticoid-related side effects such as bruising, weight gain, and glucose intolerance. (See
"Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children",
section on 'Monitoring therapy'.)
 ● In adolescent girls, facial hair growth and acne should be examined. Genital malformations in affected females may
require surgical correction with one or more surgeries and vaginal dilation. (See "Treatment 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 'Reconstructive surgery'.)

In adult women with 11OHD, growth and bone age advancement are no longer concerns, but androgen excess and
hypertension remain indications for treatment.

● Spironolactone, 25 to 200 mg/day, treats both the mineralocorticoid-mediated hypertension with hypokalemia and the
androgen excess by blocking both the mineralocorticoid and androgen receptors.

• The main drawbacks of spironolactone are vaginal bleeding or spotting between menses and contraindication
during pregnancy.

• If pregnancy is not desired, spironolactone and an oral contraception pill can be combined with replacement
doses of hydrocortisone as a glucocorticoid-sparing regimen, as in 17OHD.

• There has been one successful pregnancy reported in a woman with 11OHD. A 26 year old who had been
treated with dexamethasone and metformin conceived when clomiphene citrate was added to induce ovulation
[107]. Pregnancy in 11OHD is not as well studied as in 21OHD, but in both cases, a goal of treatment for women
attempting pregnancy is to suppress adrenal-derived progesterone production.

In adult males, at a minimum, replacement doses of hydrocortisone should be administered to avoid the development of
adrenal rest tumors.

Spironolactone can cause gynecomastia and sexual dysfunction in males, whereas eplerenone and the potassium-
sparing diuretics triamterene and amiloride are alternatives. As with other forms of mineralocorticoid excess, the
hypertension may persist even after adequate treatment. (See "Treatment of primary aldosteronism", section on 'Medical
therapy'.)

Prenatal diagnosis of 11OHD may be established by measuring tetrahydro-11-deoxycortisol in amniotic fluid [108] or by
sequencing the CYP11B1 gene amplified from DNA in chorionic villus biopsy samples [109]. As in 21OHD, prenatal
dexamethasone reduces genital virilization in affected girls, but experience is much more limited than in 21OHD. In one
report, a woman with two affected daughters was treated with dexamethasone (20 mcg/kg daily in three divided doses)
from the fifth week of pregnancy to term and delivered a female infant with normal external genitalia [109]. (See
"Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults", section on 'Pregnancy'.)

P450 OXIDOREDUCTASE DEFICIENCY (APPARENT COMBINED CYP17A1 AND CYP21A2 DEFICIENCY) — The
clinical entity of apparent combined partial CYP17A1 and CYP21A2 deficiencies was first described in 1985 [110], while
its genetic cause, cytochrome P450 oxidoreductase enzyme (POR) mutations, was not identified until 2004 [23,25]. The
POR enzyme serves as an electron donor enzyme to cytochrome P450 (CYP) enzymes in the endoplasmic reticulum
(microsomal or type II), which include steroidogenic enzymes (CYP17A1, CYP21A2, and CYP19A1 [aromatase]) and
xenobiotic-metabolizing hepatic P450 enzymes. The biochemical presentation of POR deficiency (ORD) is characterized
by apparent combined partial CYP17A1 and CYP21A2 deficiencies [110], with a large increase in pregnenolone and
progesterone metabolites readily detectable by gas chromatography-mass spectrometry (GC-MS) analysis of a urine
sample (figure 3) [25,111].

Approximately 100 cases of ORD have been reported [23-25,112-116]; a significant number of reported patients had been
previously misdiagnosed with CYP17A1, CYP19A1, and CYP21A2 deficiency, respectively [23,24,117]. Considering the
number of patients reported in recent years, it appears likely that ORD might be the second most common cause of
congenital adrenal hyperplasia (CAH) in some populations, such as Korea and Japan.

Clinical features — ORD has two unique clinical features. First, affected neonates may present with severe
undervirilization in boys and virilization in girls. In addition, patients may present with a complex, predominantly
craniofacial pattern, resembling that previously described by Antley and Bixler [118] and therefore termed Antley-Bixler
syndrome (ABS).
ORD is not associated with mineralocorticoid deficiency, and in some patients, preferential inhibition of 17-hydroxylase
over 21-hydroxylase by specific POR mutants may even result in mineralocorticoid accumulation [119]. Mineralocorticoid-
related hypertension is not a feature of ORD, although two young adults with ORD and coincident arterial hypertension
have been described [23].

In stark contrast to 21-hydroxylase deficiency (21OHD) due to CYP21A2 mutations, sex steroids in patients with ORD are
low normal or decreased as a consequence of concomitant CYP17A1 dysfunction. The clinical presentation of ORD,
however, comprises the entire spectrum of disorders of sex development (DSD) observed in both sexes. This spectrum
includes undervirilization of genetically male individuals (46,XY DSD), varying from borderline micropenis to severe
perineoscrotal hypospadias, and virilization of genetically female individuals (46,XX DSD), varying from mild clitoral
hypertrophy to Prader IV to V virilization (figure 5).

The paradox of maternal virilization during pregnancy and severe neonatal virilization of affected girls with ORD despite
postnatal androgen deficiency has been explained by activation of an alternative pathway towards the synthesis of
dihydrotestosterone in neonatal life but ceasing shortly after birth [25]. In addition, some POR mutants may also affect
aromatase activity [120], in particular R457H, the most frequently found mutation in the Japanese population, which is
invariably associated with 46,XX DSD in homozygous neonates [113,121].

Pubertal development in ORD is not well studied yet. It appears to be dominated by the consequences of sex steroid
deficiency [113]. Cystic ovaries and also larger ovarian cysts at risk of rupture are a common finding during early
adolescence, as a consequence of gonadotropin upregulation due to sex steroid deficiency (similar to findings in 21-
hydroxylase deficiency [17OHD]).

Malformations reported in patients affected by ORD comprise one type of ABS [118]; the other type lacks disordered
steroidogenesis. Skeletal malformations include craniofacial malformations such as midface hypoplasia with low-set ears
and pear-shaped nose. Craniosynostosis in variable severity may require ventriculoperitoneal shunting. Frequently
observed features include arachnodactyly, clinodactyly, and radiohumeral synostosis. In severely affected children, bowed
femora with neonatal fractures and choanal atresia may be observed. The mechanism of ABS malformations probably
derives from concomitant loss of lanosterol demethylase (CYP51A1) activity, an enzyme required for de novo cholesterol
biosynthesis, which also uses POR as a co-factor. The loss of cholesterol synthesis during embryogenesis impairs
signaling molecules important for body patterning and development [113,114,122-126]. POR also serves as co-factor for
enzymes involved in hepatic drug and xenobiotic metabolism, namely CYP1A2, CYP2C9, CYP2C19, CYP2D6, and
CYP3A4. Disease-causing mutations in POR thus variably alter drug metabolism [127-132].

Diagnosis/differential diagnosis — GC-MS is the gold standard for the diagnosis of ORD, and it identifies the
accumulation of pregnenolone and progesterone metabolites, increased 17-hydroxyprogesterone (17OHP) metabolites
and decreased androgen metabolites (figure 3) [111]. Increased pregnenolone and progesterone metabolite excretion
may occur in some heterozygous parents.

Characteristically, mothers carrying a child affected by ORD have low serum estriol, which might be found in the prenatal
triple test; subsequent analysis of maternal urine reveals a characteristic steroid precursor pattern facilitating prenatal
diagnosis [111,133]. Maternal virilization, associated with a high excretion of androgen metabolites and manifesting
around mid-gestation, is frequently but not invariably observed during these pregnancies [25,111,134].

Plasma steroids are less informative than urinary steroid metabolite analysis; in particular, hallmark steroids of 17OHD
and 21OHD may be present in variable combinations, which may result in misdiagnosis of affected patients [117]. As a
consequence of 21-hydroxylase inhibition, serum 17OHP may be elevated but to a much lesser degree than in 21OHD.
As a consequence, only some of the patients are picked up at neonatal CAH screening [113,121]. Serum progesterone is
consistently high and 19-carbon steroids consistently low, but these data by themselves are not diagnostic.

ABS may also occur in individuals with fibroblast growth factor receptor 2 (FGFR2) mutations [135-137]. However, the
FGFR2 gene in patients with ORD is normal [23,25,122], and patients with proven FGFR2 mutations do not present with
disordered steroidogenesis or disordered sex development [136]. Genetic analysis of a cohort of patients with ABS
phenotype revealed clear segregation of FGFR2 and POR mutations [114]. Thus, it is important to recognize that ABS
only serves as a descriptive term for a distinct pattern of bone malformations but is not an alternative term for ORD. ABS
may occur in individuals with POR mutations, in individuals with FGFR2 mutations, and in individuals with hitherto
unknown mutations.

POR mutations — ORD is an autosomal recessive disorder. Most patients are compound heterozygous, and two
completely inactive or deleted alleles have not been reported. A287P is the most frequently reported mutation in
Caucasians [114]. R457H is predominantly found in Japanese populations [112,113,121] and represents a global founder
mutation [138].

Genotype-phenotype correlations are not fully established, yet certain patterns are emerging between specific mutations
and phenotypic expression of ABS [113].

Treatment — The goals of treatment in ORD are to replace glucocorticoid deficiency and to restore desired secondary
sexual characteristics at time of puberty. (See "Treatment of adrenal insufficiency in adults" and "Diagnosis and treatment
of delayed puberty", section on 'Therapy'.)

A cosyntropin stimulation test should be performed to establish the degree of glucocorticoid deficiency as affected
patients may be at risk of a life-threatening adrenal crisis if not adequately replaced [121,136]. (See "Evaluation of the
response to ACTH in adrenal insufficiency", section on 'Interpretation of the serum cortisol response'.)

Some patients may have a normal response to corticotropin (ACTH) and do not require glucocorticoid replacement [25].
Most ORD patients have normal baseline secretion but fail to achieve an appropriate cortisol response [111,113,139]. If
the response is a borderline fail, stress dose cover for intercurrent illness and surgery might be sufficient. However, if the
test is clearly failed, permanent hydrocortisone replacement is needed. As there is no accumulation of androgens, ACTH
suppression is unnecessary, and hydrocortisone replacement should be administered in the lowest dose possible. (See
"Evaluation of the response to ACTH in adrenal insufficiency", section on 'Interpretation of the serum cortisol response'.)

Mineralocorticoid replacement is not required, and blood pressure requires careful monitoring if GC-MS analysis suggests
accumulation of mineralocorticoid precursors. As in 17OHD, spironolactone should be used to control mineralocorticoid
hypertension [23].

There is insufficient information on pubertal development in ORD, but it appears that puberty needs to be induced with
sex steroid therapy in most individuals. (See "Diagnosis and treatment of delayed puberty", section on 'Therapy'.)

ABS malformations require supportive treatment, including orthopaedic and surgical management, which may include
ventriculoperitoneal shunts and tracheostomy. The most severely affected patients may have decreased survival due to
malformation-related complications [133]. However, mildly affected children are likely to achieve normal life expectancy.

HEXOSE-6-PHOSPHATE-DEHYDROGENASE DEFICIENCY (APPARENT CORTISONE REDUCTASE

DEFICIENCY) — Apparent cortisone reductase deficiency (ACRD) is a rare, autosomal recessive disorder that is
characterized by apparently reduced activity of the enzyme 11-beta-hydroxysteroid dehydrogenase type 1 (HSD11B1),
resulting in reduced regeneration of cortisol from cortisone (figure 7). HSD11B1 does not function as a dehydrogenase in
vivo, most likely because it colocalizes with hexose-6-phosphate-dehydrogenase (H6PDH) to face the lumen of the
endoplasmic reticulum [140]. H6PDH generates the NADPH co-factor required for HSD11B1 to perform the reaction in
the cortisone reductase direction preferentially, and this activity is disrupted in ACRD.

ACRD is characterized by an increase in urinary cortisone metabolites, while concurrently cortisol metabolites are
decreased (figure 7). The compensatory increase in corticotropin (ACTH) production stimulates increases in adrenal
androgen precursors [140].

Clinical findings — ACRD clinically presents with hyperandrogenism, manifesting as premature pubarche or with
oligomenorrhea, acne, and hirsutism (similar to nonclassic congenital adrenal hyperplasia [NCCAH]). Genetically
confirmed ACRD has been described in approximately 10 patients [141-147]. Given the lack of clinical signs and
symptoms that would distinguish ACRD from other causes of androgen excess and the added difficulty that urinary
steroid profiling with GC-MS is needed to establish the diagnosis, the true incidence of the disorder might be
underestimated.
GC-MS analysis of urine has a very high sensitivity and characteristically shows an increase in the cortisone metabolite
tetrahydrocortisone (THE) while the cortisol metabolites tetrahydrocortisol (THF) and 5-alpha-tetrahydrocortisol (5a-THF)
are decreased. As a consequence, the ratio of (5a-THF + THF)/THE is reduced, which serves as diagnostic criterion for
ACRD (figure 7).

H6PD mutations — ACRD is an autosomal recessive disorder caused by homozygous and compound heterozygous
hexose-6-phosphate-dehydrogenase (H6PD) mutations [144,148]. Some patients with ACRD also have polymorphic
HSD11B1 sequence variants that are not disease-causing mutations [142,149,150].

Treatment — The main goal of treatment in ACRD is control of androgen excess and related signs and symptoms. This
can be achieved by modest doses of glucocorticoids (dexamethasone <0.25 mg/day, prednisolone <5 mg/day,
hydrocortisone <20 mg/day) to normalize ACTH and thus adrenal androgen production. The clinical and laboratory
assessment for 21-hydroxylase deficiency (21OHD) are used to titrate therapy. (See "Treatment of classic congenital
adrenal hyperplasia due to 21-hydroxylase deficiency in adults".)

PAPSS2 DEFICIENCY (APPARENT DHEA SULFOTRANSFERASE DEFICIENCY) — 3'-phosphoadenosine-5'-

phosphosulfate (PAPS) synthase type 2 (PAPSS2) deficiency is a rare disorder originally described in its severe form as
spondyloepimetaphyseal dysplasia or autosomal recessive brachyolmia in a Pakistani kindred [151]. Subsequently, a
patient of Turkish origin [152] was described with androgen excess and only subtle bone dysplasia. An additional 20 to 30
cases have been identified with variable skeletal features; when performed, careful endocrine evaluations reveal
disordered adrenal steroidogenesis [153].

PAPSS2 deficiency is characterized by apparent inability of the adrenal androgen precursor dehydroepiandrosterone
(DHEA) to be conjugated via the sulfate donor PAPS to its sulfate ester DHEAS (figure 8). Clinically, PAPSS2 deficiency
presents in childhood with androgen excess resulting in premature pubarche that progresses to oligomenorrhea,
secondary amenorrhea, hirsutism, and acne. The sulfonation defect exists in chondrocytes and also affects bone
development, so that patients may present with bone dysplasia and associated malformation phenotype.

Adrenal DHEA is a major androgen precursor in women. Unconjugated DHEA can be metabolized to active androgens,
whereas the conversion of DHEAS to androgens requires initial cleavage of the sulfate group. Most adrenal DHEA is
sulfonated to DHEAS before entering the circulation, and interconversion between DHEA and DHEAS in the body favors
DHEAS, due to high hepatic sulfonation activity. Thus, impaired DHEA sulfonation increases the amount of DHEA
available for conversion to active androgen.

DHEA sulfotransferase (SULT2A1) is the major enzyme responsible for DHEA sulfonation, converting DHEA to DHEAS
mainly in the adrenal glands and the liver (figure 8) [154]. The sulfate donor PAPS is required by all sulfotransferases,
including SULT2A1. In humans, PAPS is synthesized by the two isoforms of PAPS synthase, PAPSS1 and PAPSS2.
PAPSS2 is predominantly expressed in the major sites of DHEA sulfation, adrenal and liver, while PAPSS1 is ubiquitously
expressed [152]. Both PAPS proteins have two domains associated with distinct enzymatic activities: the ATP sulfurylase
domain converting ATP and sulfate to adenosine-5'-phosphosulfate (APS), and the APS kinase domain that generates
PAPS from APS and ATP [154].

The first patient with PAPSS2 deficiency identified due to androgen excess was a girl presenting with premature pubarche
and advanced bone age at age six years, followed by progression to the phenotype observed in NCCAH, including
oligomenorrhea, acne, hirsutism, and eventually secondary amenorrhea at the age of 13 years [152]. Her circulating
androgens, including androstenedione, testosterone, dihydrotestosterone, and DHEA were high, but DHEAS was below
the detection limit of the assay, suggesting that impaired DHEA sulfonation was the cause of androgen excess. Detailed
radiograph analysis of this girl showed mild bone dysplasia in the lumbar and thoracic spine but no involvement of the
long bones; however, she had no clinical symptoms of bone dysplasia. Genetic analysis showed compound heterozygous
mutations in the PAPSS2 gene, which is located on chromosome 10 (10q22-q24): one missense mutation affecting the
APS kinase domain and a nonsense mutation resulting in early truncation of the ATP sulfurylase domain [152].

A family with two postpubertal brothers who are compound heterozygotes for a null frame-shift allele and mutation G270D
has also been described [153,155]. The mother, who is a carrier for the null allele, had chronic anovulation and enhanced
conversion of DHEA to androgens. These findings suggest that heterozygous carriers might have clinical manifestations.
The goal of the treatment in PAPSS2 deficiency is the control of androgen excess and its clinical consequences.
Glucocorticoid in moderate dose to lower adrenal androgens, as for apparent cortisone reductase deficiency (ACRD), is
an option but risks overtreatment. Additional options include antiandrogens and oral contraceptive pills. Boys might not
require treatment upon reaching adulthood, whereas women will likely require chronic therapy. (See 'P450
oxidoreductase deficiency (apparent combined CYP17A1 and CYP21A2 deficiency)' above.)

LIPOID CONGENITAL ADRENAL HYPERPLASIA — Lipoid congenital adrenal hyperplasia (LCAH) is among the rarest
and when complete the most severe form of congenital adrenal steroidogenic defect (table 2 and figure 9).

Pathophysiology and genetics — LCAH is characterized by deficiency of all or nearly all adrenal and gonadal steroid
hormones, increased corticotropin (ACTH) secretion, and marked adrenal hyperplasia with progressive accumulation of
cholesterol esters.

The defect in the majority of patients with LCAH resides in a gene on chromosome 8 that codes for the steroidogenic
acute regulatory protein (StAR) [156,157]. This mitochondrial phosphoprotein normally mediates the acute response to
steroidogenic stimuli by increasing cholesterol transport from the outer to the inner mitochondrial membrane [156,158-
160], resulting in increased conversion of cholesterol to pregnenolone, the first step in steroid biosynthesis (figure 9).
Hence, mutations may decrease all pathways of steroidogenesis. StAR is expressed in the adrenal cortex and
steroidogenic cells of the gonads but not in the placenta, and placental synthesis of progesterone, which requires
CYP11A1, is unaffected in LCAH [61].

The role of StAR has been studied by sequencing the gene in patients with LCAH [157,161-164]. More than 100 patients
and 40 different mutations have been described [165]; the mutated StAR proteins were inactive in functional assays.
Steroidogenic cells that lack StAR are capable of low levels of steroidogenesis but progressively accumulate cholesterol
esters. Experts have concluded that the LCAH phenotype is the result of two separate events:

● An initial defect in steroidogenesis due to the StAR mutation

● A subsequent further defect in steroidogenesis due to cellular damage from accumulated cholesterol esters

The "two hit" hypothesis is supported by clinical data from girls with LCAH, in whom the ovary makes negligible steroids
during fetal life and childhood. At the time of expected puberty, girls with LCAH sometimes develop breasts and even
menses [166], but estrogen production fails over months to years as cholesterol esters accumulate in the steroidogenic
cells of the ovary.

In addition to classic LCAH, a nonclassic form has been described [167]. These patients present with isolated
glucocorticoid deficiency because a much higher quantity of cortisol production is required to fulfill its biologic function
than for other classes of steroids. Thus, these first patients were identified in kindreds with presumed familial
glucocorticoid deficiency (FGD). Mutation R188C, which retains approximately 7 percent activity, is the most common
allele, but others (eg, R192C, G221D, L260P, and F267) have been described [168].

Clinical presentation — Patients with complete LCAH caused by StAR mutations typically have severe adrenal
insufficiency very soon after birth, although they occasionally present later in infancy [169] with vomiting, diarrhea, volume
depletion, hyponatremia, and hyperkalemia. Male infants usually have female external genitalia due to lack of testicular
androgen production. In comparison, female infants are normally developed at birth, and occasional girls undergo
spontaneous partial pubertal development [170].

The transient sparing of ovarian steroid synthesis has been attributed to the dormancy of ovarian steroidogenesis until
puberty, thereby preventing the excess cholesterol accumulation and subsequent damage that the adrenal glands and
testes suffer. The same explanation might account for the detectable, if very low, serum aldosterone concentrations
driven by high plasma renin activity in these patients; the adrenocortical cells destined to become glomerulosa cells are
minimally stimulated in utero [166].

Boys with nonclassic LCAH may present with adrenal insufficiency but have normal male external genitalia.
 Laboratory findings — Patients with LCAH have very low serum cortisol and aldosterone concentrations and very
high plasma ACTH concentrations and plasma renin activity [171-173]. Production of gonadal steroids is also impaired,
and serum gonadotropin concentrations are high (for age) in newborns and in children as young as 4.5 years old [173].

Diagnosis — The diagnosis should be considered in a neonate with any symptoms or signs of adrenal insufficiency and
ambiguous or female genitalia. The diagnosis is confirmed by the absence of demonstrable steroid biosynthetic activity by
either the adrenals or the gonads.

Treatment — Classic LCAH has been fatal during infancy in two-thirds of reported patients [173], but some patients
survive [166,174]. Glucocorticoid and mineralocorticoid deficiency is managed by replacement therapy as in any form of
adrenal insufficiency [173].

Replacement therapy alone is required, as the high ACTH will not cause excess of unwanted steroids [173]. At the time of
puberty, estrogen therapy is provided to complete the development of secondary sexual characteristics, as all patients are
phenotypically female. Surprisingly, one patient with classic LCAH homozygous for the L275P mutation has had two
pregnancies and live births following clomiphene citrate ovulation induction with progesterone support during early
pregnancy [175].

In nonclassic LCAH, glucocorticoid replacement therapy alone is required, at least during childhood. Pubertal
development and fertility in these patients has not been studied adequately.

P450 11A1, CHOLESTEROL SIDE-CHAIN CLEAVAGE ENZYME DEFICIENCY — Before the discovery of steroidogenic
acute regulatory protein (StAR), it was assumed that the defect in lipoid congenital adrenal hyperplasia (LCAH) would
reside in the CYP11A1 gene encoding the cholesterol side-chain cleavage enzyme. However, CYP11A1 is required for
biosynthesis of progesterone, and placental progesterone synthesis from the syncytiotrophoblast, which is fetal tissue, is
believed to be necessary for the maintenance of pregnancy. Therefore, complete CYP11A1 deficiency was thought to be
lethal, and initial reports failed to find CYP11A1 mutations in patients with LCAH [].

Subsequently, two patients with LCAH were shown to have heterozygous mutations of CYP11A1 []. The important
difference from the usual presentation of LCAH is that the adrenals are not lipid laden in P450 11A1 deficiency. In addition
to adrenal insufficiency, 46,XY individuals may have phenotypically female external genitalia at birth [171,176].

Pathophysiology and genetics — P450 11A1, encoded by CYP11A1, catalyzes the conversion of cholesterol to
pregnenolone in mitochondria in steroidogenic cells. Theoretically, complete deficiency of the enzyme should be lethal
because of placental insufficiency, as described above. Among the approximately 30 patients with CYP11A1 deficiency,
the R451W mutation from eastern Turkey is most common [177]. Some patients harbor two null alleles [176], which is
difficult to reconcile with the presumed requirement of progesterone to maintain pregnancy [165]. Affected patients with
apparent haploinsufficiency have been described [171,178].

Clinical presentation and laboratory findings — The clinical presentation is similar to LCAH with more variable onset
of adrenal insufficiency and a spectrum of external genitalia from complete female to normal male [165]. Serum cortisol is
low with high plasma corticotropin (ACTH). Other adrenal and gonadal steroids and gonadotropins vary with the severity
of the disease. The adrenal glands are not markedly enlarged unlike most, but not all, cases of LCAH due to StAR
mutations.

Treatment — Glucocorticoid and mineralocorticoid deficiency is treated by replacement therapy as described above for
LCAH. Many, but not all, patients require sex steroid therapy at the time of expected puberty, depending on the severity of
the defect. (See "Treatment of adrenal insufficiency in adults".)

SUMMARY AND RECOMMENDATIONS — 21-hydroxylase deficiency (21OHD) is the most frequent cause of congenital
adrenal hyperplasia (CAH), but several less common causes of CAH exist:

● CYP17A1 deficiencies – The cytochrome P450 17A1 enzyme (CYP17A1) catalyzes both the 17-hydroxylase
reaction, which forms 17-hydroxysteroids, and the 17,20-lyase reaction, which cleaves 21-carbon 17-hydroxysteroids
to 19-carbon 17-keto androgen precursors [2]. Most defects in CYP17A1 impair both enzymatic activities and cause
combined 17-hydroxylase/17,20-lyase deficiency (17OHD). These deficiencies impair both adrenal and gonadal
 function. The classic presentation of severe 17OHD includes hypertension, primary amenorrhea, absence of
secondary sexual characteristics, and minimal body hair in phenotypic females, who can have 46,XX or 46,XY
karyotype (table 1 and figure 2). Approximately 100 different mutations in the CYP17A1 gene, which is located on
chromosome 10q24.3, have been identified. (See 'CYP17A1 deficiencies' above.)

● 3-beta-hydroxysteroid dehydrogenase type 2 deficiency (HSD3B2) – This is a rare form of CAH in which
synthesis of all active steroid hormones is impaired. HSD3B2 catalyzes the reactions that establish the 3-keto-delta-4
A-ring structure found in the major endogenous progestins, mineralocorticoids, glucocorticoids, and androgens,
including the precursors of dihydrotestosterone. This disorder impairs both adrenal and gonadal steroid production.
Much like 21OHD, most patients present as neonates or in early infancy with clinical manifestations of both cortisol
and aldosterone deficiency, with feeding difficulties, vomiting, volume depletion, hyponatremia, and hyperkalemia
(figure 4). Girls have mild androgen excess, due to the conversion of delta-5 steroids to active androgens via the type
1 isoenzyme in peripheral tissues. (See '3-beta-hydroxysteroid dehydrogenase type 2 deficiency' above.)

● 11-beta-hydroxylase deficiency – Deficiency of CYP11B1, or 11-beta-hydroxylase deficiency (11OHD), features the

androgen excess of 21OHD and mineralocorticoid excess of 17OHD. The clinical manifestations of the disorder
result from high adrenal production of the mineralocorticoid 11-deoxycorticosterone (DOC) and the adrenal androgen
precursors (figure 6 and table 1). Consequently, the two characteristic clinical features are hypertension with
hypokalemia, as with any other form of mineralocorticoid excess and androgen excess. The autosomal recessive
disorder 11OHD is caused by mutations of the CYP11B1 gene, located on chromosome 8q21-q22. (See '11-beta-
hydroxylase deficiency' above.)

● P450 oxidoreductase deficiency (apparent combined CYP17A1 and CYP21A2 deficiency) is an autosomal
recessive disorder caused by mutations in the flavoprotein co-factor of the enzymes CYP17A1, CYP21A2, and
CYP19A1 (aromatase). The biochemical presentation of P450 oxidoreductase (POR) deficiency (ORD) is
characterized by apparent combined partial CYP17A1 and CYP21A2 deficiencies. This disorder has two unique
clinical features. First, affected neonates may present with severe undervirilization in boys and severe virilization in
girls. In addition, patients may present with a complex, predominantly craniofacial skeletal dysplasias, termed Antley-
Bixler syndrome (ABS). The goals of treatment in ORD are to replace glucocorticoid deficiency and to restore desired
secondary sexual characteristics at the time of puberty (figure 3). (See 'P450 oxidoreductase deficiency (apparent
combined CYP17A1 and CYP21A2 deficiency)' above.)

● Hexose-6-phosphate-dehydrogenase deficiency (apparent cortisone reductase deficiency [ACRD]) is an

autosomal recessive disorder caused by mutations within the H6PD gene, encoding hexose-6-phosphate
dehydrogenase (H6PDH). ACRD clinically manifests with hyperandrogenism, manifesting as premature pubarche or
with oligomenorrhea, acne, and hirsutism (similar to nonclassic 21OHD). (See 'Hexose-6-phosphate-dehydrogenase
deficiency (apparent cortisone reductase deficiency)' above.)

● PAPSS2 deficiency (apparent DHEA sulfotransferase deficiency) is an extremely rare disorder characterized by
apparent inability to convert the adrenal androgen precursor dehydroepiandrosterone (DHEA) to its sulfate ester
DHEAS (figure 8). Clinically, 3'-phosphoadenosine-5'-phosphosulfate synthase type 2 (PAPSS2) deficiency manifests
with androgen excess resulting in premature pubarche and later by oligomenorrhea, secondary amenorrhea,
hirsutism, and acne. However, failure to sulfonate also affects bone development, and patients may present with
bone dysplasia and associated malformation phenotype. This disorder is due to mutations in the PAPSS2 gene,
which is located on chromosome 10 (10q22-q24). (See 'PAPSS2 deficiency (apparent DHEA sulfotransferase
deficiency)' above.)

● Lipoid congenital adrenal hyperplasia (LCAH) – LCAH, when complete, is the most severe form of CAH. Most
cases are due to mutations in the steroidogenic acute regulatory protein (StAR), which increases cholesterol
transport from the outer to the inner mitochondrial membrane. StAR is required for normal steroidogenesis in the
adrenal cortex and gonads (figure 9). Patients typically have severe combined adrenal insufficiency soon after birth,
or occasionally later in infancy. Male infants usually have female external genitalia due to lack of testicular androgen
production. Female patients occasionally undergo spontaneous partial pubertal development, and one patient has
 conceived and carried two normal children to term. A nonclassic form of LCAH with isolated cortisol deficiency also
exists. (See 'Lipoid congenital adrenal hyperplasia' above.)

● P450 11A1, the cholesterol side-chain cleavage enzyme deficiency – P450 11A1, encoded by CYP11A1,
catalyzes the conversion of cholesterol to pregnenolone in the mitochondria of steroidogenic cells. All patients
described with P450 11A1 deficiency had adrenal insufficiency, and the adrenal glands are not enlarged as in most
cases of LCAH. (See 'P450 11A1, cholesterol side-chain cleavage enzyme deficiency' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Wiebke Arlt, MD, DSc, FRCP,
FMedSci, who contributed to an earlier version of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 2000; 21:245.
2. Yanase T, Simpson ER, Waterman MR. 17 alpha-hydroxylase/17,20-lyase deficiency: from clinical investigation to
molecular definition. Endocr Rev 1991; 12:91.
3. Biglieri EG, Herron MA, Brust N. 17-hydroxylation deficiency in man. J Clin Invest 1966; 45:1946.
4. Kater CE, Biglieri EG. Disorders of steroid 17 alpha-hydroxylase deficiency. Endocrinol Metab Clin North Am 1994;
23:341.
5. Costa-Santos M, Kater CE, Auchus RJ, Brazilian Congenital Adrenal Hyperplasia Multicenter Study Group. Two
prevalent CYP17 mutations and genotype-phenotype correlations in 24 Brazilian patients with 17-hydroxylase
deficiency. J Clin Endocrinol Metab 2004; 89:49.
6. Geller DH, Auchus RJ, Mendonça BB, Miller WL. The genetic and functional basis of isolated 17,20-lyase
deficiency. Nat Genet 1997; 17:201.
7. Sherbet DP, Tiosano D, Kwist KM, et al. CYP17 mutation E305G causes isolated 17,20-lyase deficiency by
selectively altering substrate binding. J Biol Chem 2003; 278:48563.
8. Chung BC, Picado-Leonard J, Haniu M, et al. Cytochrome P450c17 (steroid 17 alpha-hydroxylase/17,20 lyase):
cloning of human adrenal and testis cDNAs indicates the same gene is expressed in both tissues. Proc Natl Acad
Sci U S A 1987; 84:407.
9. Moreira AC, Leal AM, Castro M. Characterization of adrenocorticotropin secretion in a patient with 17 alpha-
hydroxylase deficiency. J Clin Endocrinol Metab 1990; 71:86.
10. Heremans GF, Moolenaar AJ, van Gelderen HH. Female phenotype in a male child due to 17-alpha-hydroxylase
deficiency. Arch Dis Child 1976; 51:721.
11. Auchus RJ, Lee TC, Miller WL. Cytochrome b5 augments the 17,20-lyase activity of human P450c17 without direct
electron transfer. J Biol Chem 1998; 273:3158.
12. Kater CE, Biglieri EG, Brust N, et al. The unique patterns of plasma aldosterone and 18-hydroxycorticosterone
concentrations in the 17 alpha-hydroxylase deficiency syndrome. J Clin Endocrinol Metab 1982; 55:295.
13. Griffing GT, Wilson TE, Holbrook MM, et al. Plasma and urinary 19-nor-deoxycorticosterone in 17 alpha-hydroxylase
deficiency syndrome. J Clin Endocrinol Metab 1984; 59:1011.
14. Simsek E, Ozdemir I, Lin L, Achermann JC. Isolated 17,20-lyase (desmolase) deficiency in a 46,XX female
presenting with delayed puberty. Fertil Steril 2005; 83:1548.
15. Auchus RJ. Steroid 17-hydroxylase and 17,20-lyase deficiencies, genetic and pharmacologic. J Steroid Biochem
Mol Biol 2017; 165:71.
16. Auchus RJ, Miller WL. The principles, enzymes, and pathways of human steroidogenesis. In: Endocrinology: Adult a
nd Pediatric, 6th ed, DeGroot LJ, Jameson JL (Eds), Saunders Elsevier, Philadelphia 2010. Vol 2, p.1783.
17. Biglieri EG. Mechanisms establishing the mineralocorticoid hormone patterns in the 17 alpha-hydroxylase deficiency
syndrome. J Steroid Biochem 1979; 11:653.
18. Dean HJ, Shackleton CH, Winter JS. Diagnosis and natural history of 17-hydroxylase deficiency in a newborn male.
J Clin Endocrinol Metab 1984; 59:513.
19. Morimoto I, Maeda R, Izumi M, et al. An autopsy case of 17 alpha-hydroxylase deficiency with malignant
hypertension. J Clin Endocrinol Metab 1983; 56:915.
20. Peter M, Sippell WG, Wernze H. Diagnosis and treatment of 17-hydroxylase deficiency. J Steroid Biochem Mol Biol
1993; 45:107.
21. Tiosano D, Knopf C, Koren I, et al. Metabolic evidence for impaired 17alpha-hydroxylase activity in a kindred
bearing the E305G mutation for isolate 17,20-lyase activity. Eur J Endocrinol 2008; 158:385.
22. Martin RM, Lin CJ, Costa EM, et al. P450c17 deficiency in Brazilian patients: biochemical diagnosis through
progesterone levels confirmed by CYP17 genotyping. J Clin Endocrinol Metab 2003; 88:5739.
23. Flück CE, Tajima T, Pandey AV, et al. Mutant P450 oxidoreductase causes disordered steroidogenesis with and
without Antley-Bixler syndrome. Nat Genet 2004; 36:228.
24. Hershkovitz E, Parvari R, Wudy SA, et al. Homozygous mutation G539R in the gene for P450 oxidoreductase in a
family previously diagnosed as having 17,20-lyase deficiency. J Clin Endocrinol Metab 2008; 93:3584.
25. Arlt W, Walker EA, Draper N, et al. Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and
human androgen synthesis: analytical study. Lancet 2004; 363:2128.
26. Homma K, Hasegawa T, Nagai T, et al. Urine steroid hormone profile analysis in cytochrome P450 oxidoreductase
deficiency: implication for the backdoor pathway to dihydrotestosterone. J Clin Endocrinol Metab 2006; 91:2643.
27. Winter JS, Couch RM, Muller J, et al. Combined 17-hydroxylase and 17,20-desmolase deficiencies: evidence for
synthesis of a defective cytochrome P450c17. J Clin Endocrinol Metab 1989; 68:309.
28. Wit JM, van Roermund HP, Oostdijk W, et al. Heterozygotes for 17 alpha-hydroxylase deficiency can be detected
with a short ACTH test. Clin Endocrinol (Oxf) 1988; 28:657.
29. D'Armiento M, Reda G, Kater C, et al. 17 alpha-hydroxylase deficiency: mineralocorticoid hormone profiles in an
affected family. J Clin Endocrinol Metab 1983; 56:697.
30. Sparkes RS, Klisak I, Miller WL. Regional mapping of genes encoding human steroidogenic enzymes: P450scc to
15q23-q24, adrenodoxin to 11q22; adrenodoxin reductase to 17q24-q25; and P450c17 to 10q24-q25. DNA Cell Biol
1991; 10:359.
31. Kagimoto M, Winter JS, Kagimoto K, et al. Structural characterization of normal and mutant human steroid 17 alpha-
hydroxylase genes: molecular basis of one example of combined 17 alpha-hydroxylase/17,20 lyase deficiency. Mol
Endocrinol 1988; 2:564.
32. Yanase T, Sanders D, Shibata A, et al. Combined 17 alpha-hydroxylase/17,20-lyase deficiency due to a 7-basepair
duplication in the N-terminal region of the cytochrome P45017 alpha (CYP17) gene. J Clin Endocrinol Metab 1990;
70:1325.
33. Yanase T, Kagimoto M, Suzuki S, et al. Deletion of a phenylalanine in the N-terminal region of human cytochrome
P-450(17 alpha) results in partial combined 17 alpha-hydroxylase/17,20-lyase deficiency. J Biol Chem 1989;
264:18076.
34. Fardella CE, Zhang LH, Mahachoklertwattana P, et al. Deletion of amino acids Asp487-Ser488-Phe489 in human
cytochrome P450c17 causes severe 17 alpha-hydroxylase deficiency. J Clin Endocrinol Metab 1993; 77:489.
35. Biason A, Mantero F, Scaroni C, et al. Deletion within the CYP17 gene together with insertion of foreign DNA is the
cause of combined complete 17 alpha-hydroxylase/17,20-lyase deficiency in an Italian patient. Mol Endocrinol 1991;
5:2037.
36. Rumsby G, Skinner C, Lee HA, Honour JW. Combined 17 alpha-hydroxylase/17,20-lyase deficiency caused by
heterozygous stop codons in the cytochrome P450 17 alpha-hydroxylase gene. Clin Endocrinol (Oxf) 1993; 39:483.
37. Yanase T, Kagimoto M, Matsui N, et al. Combined 17 alpha-hydroxylase/17,20-lyase deficiency due to a stop codon
in the N-terminal region of 17 alpha-hydroxylase cytochrome P-450. Mol Cell Endocrinol 1988; 59:249.
38. Lin D, Black SM, Nagahama Y, Miller WL. Steroid 17 alpha-hydroxylase and 17,20-lyase activities of P450c17:
contributions of serine106 and P450 reductase. Endocrinology 1993; 132:2498.
39. Monno S, Ogawa H, Date T, et al. Mutation of histidine 373 to leucine in cytochrome P450c17 causes 17 alpha-
hydroxylase deficiency. J Biol Chem 1993; 268:25811.
40. Costa-Santos M, Kater CE, Dias EP, Auchus RJ. Two intronic mutations cause 17-hydroxylase deficiency by
disrupting splice acceptor sites: direct demonstration of aberrant splicing and absent enzyme activity by expression
of the entire CYP17 gene in HEK-293 cells. J Clin Endocrinol Metab 2004; 89:43.
41. Yanase T, Waterman MR, Zachmann M, et al. Molecular basis of apparent isolated 17,20-lyase deficiency:
compound heterozygous mutations in the C-terminal region (Arg(496)----Cys, Gln(461)----Stop) actually cause
combined 17 alpha-hydroxylase/17,20-lyase deficiency. Biochim Biophys Acta 1992; 1139:275.
42. Yamaguchi H, Nakazato M, Miyazato M, et al. A 5'-splice site mutation in the cytochrome P450 steroid 17alpha-
hydroxylase gene in 17alpha-hydroxylase deficiency. J Clin Endocrinol Metab 1997; 82:1934.
43. Hegesh E, Hegesh J, Kaftory A. Congenital methemoglobinemia with a deficiency of cytochrome b5. N Engl J Med
1986; 314:757.
44. Giordano SJ, Kaftory A, Steggles AW. A splicing mutation in the cytochrome b5 gene from a patient with congenital
methemoglobinemia and pseudohermaphrodism. Hum Genet 1994; 93:568.
45. Brooke AM, Taylor NF, Shepherd JH, et al. A novel point mutation in P450c17 (CYP17) causing combined 17alpha-
hydroxylase/17,20-lyase deficiency. J Clin Endocrinol Metab 2006; 91:2428.
46. Ergun-Longmire B, Auchus R, Papari-Zareei M, et al. Two novel mutations found in a patient with 17alpha-
hydroxylase enzyme deficiency. J Clin Endocrinol Metab 2006; 91:4179.
47. Turan S, Bereket A, Guran T, et al. Puberty in a case with novel 17-hydroxylase mutation and the putative role of
estrogen in development of pubic hair. Eur J Endocrinol 2009; 160:325.
48. Wu C, Fan S, Qian Y, et al. 17α-HYDROXYLASE/17, 20-LYASE DEFICIENCY: CLINICAL AND MOLECULAR
CHARACTERIZATION OF EIGHT CHINESE PATIENTS. Endocr Pract 2017; 23:576.
49. Imai T, Globerman H, Gertner JM, et al. Expression and purification of functional human 17 alpha-
hydroxylase/17,20-lyase (P450c17) in Escherichia coli. Use of this system for study of a novel form of combined 17
alpha-hydroxylase/17,20-lyase deficiency. J Biol Chem 1993; 268:19681.
50. Gupta MK, Geller DH, Auchus RJ. Pitfalls in characterizing P450c17 mutations associated with isolated 17,20-lyase
deficiency. J Clin Endocrinol Metab 2001; 86:4416.
51. Geller DH, Auchus RJ, Miller WL. P450c17 mutations R347H and R358Q selectively disrupt 17,20-lyase activity by
disrupting interactions with P450 oxidoreductase and cytochrome b5. Mol Endocrinol 1999; 13:167.
52. Rovner DR, Conn JW, Cohen EL, et al. 17 alpha-Hydroxylase deficiency. A combination of hydroxylation defect and
reversible blockade in aldosterone biosynthesis. Acta Endocrinol (Copenh) 1979; 90:490.
53. Bianchi PH, Gouveia GR, Costa EM, et al. Successful Live Birth in a Woman With 17α-Hydroxylase Deficiency
Through IVF Frozen-Thawed Embryo Transfer. J Clin Endocrinol Metab 2016; 101:345.
54. BONGIOVANNI AM. The adrenogenital syndrome with deficiency of 3 beta-hydroxysteroid dehydrogenase. J Clin
Invest 1962; 41:2086.
55. Moisan AM, Ricketts ML, Tardy V, et al. New insight into the molecular basis of 3beta-hydroxysteroid
dehydrogenase deficiency: identification of eight mutations in the HSD3B2 gene eleven patients from seven new
families and comparison of the functional properties of twenty-five mutant enzymes. J Clin Endocrinol Metab 1999;
84:4410.
56. Lachance Y, Luu-The V, Labrie C, et al. Characterization of human 3 beta-hydroxysteroid dehydrogenase/delta 5-
delta 4-isomerase gene and its expression in mammalian cells. J Biol Chem 1990; 265:20469.
57. Lutfallah C, Wang W, Mason JI, et al. Newly proposed hormonal criteria via genotypic proof for type II 3beta-
hydroxysteroid dehydrogenase deficiency. J Clin Endocrinol Metab 2002; 87:2611.
58. Mermejo LM, Elias LL, Marui S, et al. Refining hormonal diagnosis of type II 3beta-hydroxysteroid dehydrogenase
deficiency in patients with premature pubarche and hirsutism based on HSD3B2 genotyping. J Clin Endocrinol
Metab 2005; 90:1287.
59. Simard J, Rheaume E, Mebarki F, et al. Molecular basis of human 3 beta-hydroxysteroid dehydrogenase deficiency.
J Steroid Biochem Mol Biol 1995; 53:127.
60. Rhéaume E, Lachance Y, Zhao HF, et al. Structure and expression of a new complementary DNA encoding the
almost exclusive 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase in human adrenals and gonads.
Mol Endocrinol 1991; 5:1147.
61. Rhéaume E, Simard J, Morel Y, et al. Congenital adrenal hyperplasia due to point mutations in the type II 3 beta-
hydroxysteroid dehydrogenase gene. Nat Genet 1992; 1:239.
62. Simard J, Rhéaume E, Leblanc JF, et al. Congenital adrenal hyperplasia caused by a novel homozygous frameshift
mutation 273 delta AA in type II 3 beta-hydroxysteroid dehydrogenase gene (HSD3B2) in three male patients of
Afghan/Pakistani origin. Hum Mol Genet 1994; 3:327.
63. Rhéaume E, Sanchez R, Mébarki F, et al. Identification and characterization of the G15D mutation found in a male
patient with 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency: alteration of the putative NAD-binding
domain of type II 3 beta-HSD. Biochemistry 1995; 34:2893.
64. Simard J, Rhéaume E, Sanchez R, et al. Molecular basis of congenital adrenal hyperplasia due to 3 beta-
hydroxysteroid dehydrogenase deficiency. Mol Endocrinol 1993; 7:716.
65. Rhéaume E, Sanchez R, Simard J, et al. Molecular basis of congenital adrenal hyperplasia in two siblings with
classical nonsalt-losing 3 beta-hydroxysteroid dehydrogenase deficiency. J Clin Endocrinol Metab 1994; 79:1012.
66. Sanchez R, Rhéaume E, Laflamme N, et al. Detection and functional characterization of the novel missense
mutation Y254D in type II 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) gene of a female patient with nonsalt-
losing 3 beta HSD deficiency. J Clin Endocrinol Metab 1994; 78:561.
67. Cara JF, Moshang T Jr, Bongiovanni AM, Marx BS. Elevated 17-hydroxyprogesterone and testosterone in a
newborn with 3-beta-hydroxysteroid dehydrogenase deficiency. N Engl J Med 1985; 313:618.
68. BONGIOVANNI AM, ROOT AW. The adrenogenital syndrome. N Engl J Med 1963; 268:1283.
69. Pang SY, Lerner AJ, Stoner E, et al. Late-onset adrenal steroid 3 beta-hydroxysteroid dehydrogenase deficiency. I.
A cause of hirsutism in pubertal and postpubertal women. J Clin Endocrinol Metab 1985; 60:428.
70. Azziz R, Bradley EL Jr, Potter HD, Boots LR. 3 beta-hydroxysteroid dehydrogenase deficiency in
hyperandrogenism. Am J Obstet Gynecol 1993; 168:889.
71. Pang S, Carbunaru G, Haider A, et al. Carriers for type II 3beta-hydroxysteroid dehydrogenase (HSD3B2)
deficiency can only be identified by HSD3B2 genotype study and not by hormone test. Clin Endocrinol (Oxf) 2003;
58:323.
72. Codner E, Okuma C, Iñiguez G, et al. Molecular study of the 3 beta-hydroxysteroid dehydrogenase gene type II in
patients with hypospadias. J Clin Endocrinol Metab 2004; 89:957.
73. Pang S, Levine LS, Stoner E, et al. Nonsalt-losing congenital adrenal hyperplasia due to 3 beta-hydroxysteroid
dehydrogenase deficiency with normal glomerulosa function. J Clin Endocrinol Metab 1983; 56:808.
74. Rosenfield RL, Rich BH, Wolfsdorf JI, et al. Pubertal presentation of congenital delta 5-3 beta-hydroxysteroid
dehydrogenase deficiency. J Clin Endocrinol Metab 1980; 51:345.
75. Marui S, Castro M, Latronico AC, et al. Mutations in the type II 3beta-hydroxysteroid dehydrogenase (HSD3B2)
gene can cause premature pubarche in girls. Clin Endocrinol (Oxf) 2000; 52:67.
76. White PC, Curnow KM, Pascoe L. Disorders of steroid 11 beta-hydroxylase isozymes. Endocr Rev 1994; 15:421.
77. Rösler A, Leiberman E, Cohen T. High frequency of congenital adrenal hyperplasia (classic 11 beta-hydroxylase
deficiency) among Jews from Morocco. Am J Med Genet 1992; 42:827.
78. White PC, Dupont J, New MI, et al. A mutation in CYP11B1 (Arg-448----His) associated with steroid 11 beta-
hydroxylase deficiency in Jews of Moroccan origin. J Clin Invest 1991; 87:1664.
79. Zachmann M, Tassinari D, Prader A. Clinical and biochemical variability of congenital adrenal hyperplasia due to 11
beta-hydroxylase deficiency. A study of 25 patients. J Clin Endocrinol Metab 1983; 56:222.
80. de Simone G, Tommaselli AP, Rossi R, et al. Partial deficiency of adrenal 11-hydroxylase. A possible cause of
primary hypertension. Hypertension 1985; 7:204.
81. Rösler A, Leiberman E, Sack J, et al. Clinical variability of congenital adrenal hyperplasia due to 11 beta-
hydroxylase deficiency. Horm Res 1982; 16:133.
82. Zhu YS, Cordero JJ, Can S, et al. Mutations in CYP11B1 gene: phenotype-genotype correlations. Am J Med Genet
A 2003; 122A:193.
83. Hochberg Z, Benderly A, Kahana L, Zadik Z. Requirement of mineralocorticoid in congenital adrenal hyperplasia
due to 11 beta-hydroxylase deficiency. J Clin Endocrinol Metab 1986; 63:36.
84. Zadik Z, Kahana L, Kaufman H, et al. Salt loss in hypertensive form of congenital adrenal hyperplasia (11-beta-
hydroxylase deficiency). J Clin Endocrinol Metab 1984; 58:384.
85. Holcombe JH, Keenan BS, Nichols BL, et al. Neonatal salt loss in the hypertensive form of congenital adrenal
hyperplasia. Pediatrics 1980; 65:777.
86. Storr HL, Barwick TD, Snodgrass GA, et al. Hyperplasia of adrenal rest tissue causing a retroperitoneal mass in a
child with 11 beta-hydroxylase deficiency. Horm Res 2003; 60:99.
87. Ghazi AA, Hadayegh F, Khakpour G, et al. Bilateral testicular enlargement due to adrenal remnant in a patient with
C11 hydroxylase deficiency congenital adrenal hyperplasia. J Endocrinol Invest 2003; 26:84.
88. Cathelineau G, Brerault JL, Fiet J, et al. Adrenocortical 11 beta-hydroxylation defect in adult women with
postmenarchial onset of symptoms. J Clin Endocrinol Metab 1980; 51:287.
89. Lucky AW, Rosenfield RL, McGuire J, et al. Adrenal androgen hyperresponsiveness to adrenocorticotropin in
women with acne and/or hirsutism: adrenal enzyme defects and exaggerated adrenarche. J Clin Endocrinol Metab
1986; 62:840.
90. Joehrer K, Geley S, Strasser-Wozak EM, et al. CYP11B1 mutations causing non-classic adrenal hyperplasia due to
11 beta-hydroxylase deficiency. Hum Mol Genet 1997; 6:1829.
91. Reisch N, Högler W, Parajes S, et al. A diagnosis not to be missed: nonclassic steroid 11β-hydroxylase deficiency
presenting with premature adrenarche and hirsutism. J Clin Endocrinol Metab 2013; 98:E1620.
92. GREEN OC, MIGEON CJ, WILKINS L. Urinary steroids in the hypertensive form of congenital adrenal hyperplasia.
J Clin Endocrinol Metab 1960; 20:929.
93. Lashansky G, Saenger P, Dimartino-Nardi J, et al. Normative data for the steroidogenic response of
mineralocorticoids and their precursors to adrenocorticotropin in a healthy pediatric population. J Clin Endocrinol
Metab 1992; 75:1491.
94. Lashansky G, Saenger P, Fishman K, et al. Normative data for adrenal steroidogenesis in a healthy pediatric
population: age- and sex-related changes after adrenocorticotropin stimulation. J Clin Endocrinol Metab 1991;
73:674.
95. DYRENFURTH I, SYBULSKI S, NOTCHEV V, et al. Urinary corticosteroid excretion patterns in patients with
adrenocortical dysfunction. J Clin Endocrinol Metab 1958; 18:391.
96. GABRILOVE JL, SHARMA DC, DORFMAN RI. ADRENOCORTICAL 11-BETA-HYDROXYLASE DEFICIENCY AND
VIRILISM FIRST MANIFEST IN THE ADULT WOMEN. N Engl J Med 1965; 272:1189.
97. Auchus RJ. The classic and nonclassic concenital adrenal hyperplasias. Endocr Pract 2015; 21:383.
98. Pang S, Levine LS, Lorenzen F, et al. Hormonal studies in obligate heterozygotes and siblings of patients with 11
beta-hydroxylase deficiency congenital adrenal hyperplasia. J Clin Endocrinol Metab 1980; 50:586.
99. Curnow KM, Slutsker L, Vitek J, et al. Mutations in the CYP11B1 gene causing congenital adrenal hyperplasia and
hypertension cluster in exons 6, 7, and 8. Proc Natl Acad Sci U S A 1993; 90:4552.
100. Grigorescu Sido A, Weber MM, Grigorescu Sido P, et al. 21-Hydroxylase and 11beta-hydroxylase mutations in
Romanian patients with classic congenital adrenal hyperplasia. J Clin Endocrinol Metab 2005; 90:5769.
101. Krone N, Riepe FG, Götze D, et al. Congenital adrenal hyperplasia due to 11-hydroxylase deficiency: functional
characterization of two novel point mutations and a three-base pair deletion in the CYP11B1 gene. J Clin Endocrinol
Metab 2005; 90:3724.
102. Helmberg A, Ausserer B, Kofler R. Frame shift by insertion of 2 basepairs in codon 394 of CYP11B1 causes
congenital adrenal hyperplasia due to steroid 11 beta-hydroxylase deficiency. J Clin Endocrinol Metab 1992;
75:1278.
103. Naiki Y, Kawamoto T, Mitsuuchi Y, et al. A nonsense mutation (TGG [Trp116]-->TAG [Stop]) in CYP11B1 causes
steroid 11 beta-hydroxylase deficiency. J Clin Endocrinol Metab 1993; 77:1677.
104. Kuribayashi I, Massa G, van den Tooren-de Groot HK, et al. A novel nonsense mutation in the Cyp11B1 gene from
a subject with the steroid 11beta-hydroxylase form of congenital adrenal hyperplasia. Endocr Res 2003; 29:377.
105. Portrat S, Mulatero P, Curnow KM, et al. Deletion hybrid genes, due to unequal crossing over between CYP11B1
(11beta-hydroxylase) and CYP11B2(aldosterone synthase) cause steroid 11beta-hydroxylase deficiency and
congenital adrenal hyperplasia. J Clin Endocrinol Metab 2001; 86:3197.
106. Hampf M, Dao NT, Hoan NT, Bernhardt R. Unequal crossing-over between aldosterone synthase and 11beta-
hydroxylase genes causes congenital adrenal hyperplasia. J Clin Endocrinol Metab 2001; 86:4445.
107. Simm PJ, Zacharin MR. Successful pregnancy in a patient with severe 11-beta-hydroxylase deficiency and novel
mutations in CYP11B1 gene. Horm Res 2007; 68:294.
108. Rösler A, Leiberman E, Rosenmann A, et al. Prenatal diagnosis of 11beta-hydroxylase deficiency congenital
adrenal hyperplasia. J Clin Endocrinol Metab 1979; 49:546.
109. Cerame BI, Newfield RS, Pascoe L, et al. Prenatal diagnosis and treatment of 11beta-hydroxylase deficiency
congenital adrenal hyperplasia resulting in normal female genitalia. J Clin Endocrinol Metab 1999; 84:3129.
110. Peterson RE, Imperato-McGinley J, Gautier T, Shackleton C. Male pseudohermaphroditism due to multiple defects
in steroid-biosynthetic microsomal mixed-function oxidases. A new variant of congenital adrenal hyperplasia. N Engl
J Med 1985; 313:1182.
111. Shackleton C, Marcos J, Malunowicz EM, et al. Biochemical diagnosis of Antley-Bixler syndrome by steroid
analysis. Am J Med Genet A 2004; 128A:223.
112. Adachi M, Asakura Y, Tachibana K, Shackleton C. Abnormal steroidogenesis in three patients with Antley-Bixler
syndrome: apparent decreased activity of 17alpha-hydroxylase, 17,20-lyase and 21-hydroxylase. Pediatr Int 2004;
46:583.
113. Fukami M, Nishimura G, Homma K, et al. Cytochrome P450 oxidoreductase deficiency: identification and
characterization of biallelic mutations and genotype-phenotype correlations in 35 Japanese patients. J Clin
Endocrinol Metab 2009; 94:1723.
114. Huang N, Pandey AV, Agrawal V, et al. Diversity and function of mutations in p450 oxidoreductase in patients with
Antley-Bixler syndrome and disordered steroidogenesis. Am J Hum Genet 2005; 76:729.
115. Williamson L, Arlt W, Shackleton C, et al. Linking Antley-Bixler syndrome and congenital adrenal hyperplasia: a
novel case of P450 oxidoreductase deficiency. Am J Med Genet A 2006; 140A:1797.
116. Wudy SA, Hartmann MF, Draper N, et al. A male twin infant with skull deformity and elevated neonatal 17-
hydroxyprogesterone: a prismatic case of P450 oxidoreductase deficiency. Endocr Res 2004; 30:957.
117. Fukami M, Hasegawa T, Horikawa R, et al. Cytochrome P450 oxidoreductase deficiency in three patients initially
regarded as having 21-hydroxylase deficiency and/or aromatase deficiency: diagnostic value of urine steroid
hormone analysis. Pediatr Res 2006; 59:276.
118. Antley R, Bixler D. Trapezoidocephaly, midfacial hypoplasia and cartilage abnormalities with multiple synostoses
and skeletal fractures. Birth Defects Orig Artic Ser 1975; 11:397.
119. Dhir V, Ivison HE, Krone N, et al. Differential inhibition of CYP17A1 and CYP21A2 activities by the P450
oxidoreductase mutant A287P. Mol Endocrinol 2007; 21:1958.
120. Pandey AV, Kempná P, Hofer G, et al. Modulation of human CYP19A1 activity by mutant NADPH P450
oxidoreductase. Mol Endocrinol 2007; 21:2579.
121. Fukami M, Horikawa R, Nagai T, et al. Cytochrome P450 oxidoreductase gene mutations and Antley-Bixler
syndrome with abnormal genitalia and/or impaired steroidogenesis: molecular and clinical studies in 10 patients. J
Clin Endocrinol Metab 2005; 90:414.
122. Kelley RI, Kratz LE, Glaser RL, et al. Abnormal sterol metabolism in a patient with Antley-Bixler syndrome and
ambiguous genitalia. Am J Med Genet 2002; 110:95.
123. Mann RK, Beachy PA. Novel lipid modifications of secreted protein signals. Annu Rev Biochem 2004; 73:891.
124. Aleck KA, Bartley DL. Multiple malformation syndrome following fluconazole use in pregnancy: report of an
additional patient. Am J Med Genet 1997; 72:253.
125. Pursley TJ, Blomquist IK, Abraham J, et al. Fluconazole-induced congenital anomalies in three infants. Clin Infect
Dis 1996; 22:336.
126. Aguilar A, Wu S, De Luca F. P450 oxidoreductase expressed in rat chondrocytes modulates chondrogenesis via
cholesterol- and Indian Hedgehog-dependent mechanisms. Endocrinology 2009; 150:2732.
127. Agrawal V, Huang N, Miller WL. Pharmacogenetics of P450 oxidoreductase: effect of sequence variants on activities
of CYP1A2 and CYP2C19. Pharmacogenet Genomics 2008; 18:569.
128. Hart SN, Li Y, Nakamoto K, et al. Novel SNPs in cytochrome P450 oxidoreductase. Drug Metab Pharmacokinet
2007; 22:322.
129. Hart SN, Zhong XB. P450 oxidoreductase: genetic polymorphisms and implications for drug metabolism and toxicity.
Expert Opin Drug Metab Toxicol 2008; 4:439.
130. Hart SN, Wang S, Nakamoto K, et al. Genetic polymorphisms in cytochrome P450 oxidoreductase influence
microsomal P450-catalyzed drug metabolism. Pharmacogenet Genomics 2008; 18:11.
131. Huang N, Agrawal V, Giacomini KM, Miller WL. Genetics of P450 oxidoreductase: sequence variation in 842
individuals of four ethnicities and activities of 15 missense mutations. Proc Natl Acad Sci U S A 2008; 105:1733.
132. Kranendonk M, Marohnic CC, Panda SP, et al. Impairment of human CYP1A2-mediated xenobiotic metabolism by
Antley-Bixler syndrome variants of cytochrome P450 oxidoreductase. Arch Biochem Biophys 2008; 475:93.
133. Cragun DL, Trumpy SK, Shackleton CH, et al. Undetectable maternal serum uE3 and postnatal abnormal sterol and
steroid metabolism in Antley-Bixler syndrome. Am J Med Genet A 2004; 129A:1.
134. Shackleton C, Marcos J, Arlt W, Hauffa BP. Prenatal diagnosis of P450 oxidoreductase deficiency (ORD): a disorder
causing low pregnancy estriol, maternal and fetal virilization, and the Antley-Bixler syndrome phenotype. Am J Med
Genet A 2004; 129A:105.
135. Chun K, Siegel-Bartelt J, Chitayat D, et al. FGFR2 mutation associated with clinical manifestations consistent with
Antley-Bixler syndrome. Am J Med Genet 1998; 77:219.
136. Reardon W, Smith A, Honour JW, et al. Evidence for digenic inheritance in some cases of Antley-Bixler syndrome?
J Med Genet 2000; 37:26.
137. Tsai FJ, Wu JY, Yang CF, Tsai CH. Further evidence that fibroblast growth factor receptor 2 mutations cause Antley-
Bixler syndrome. Acta Paediatr 2001; 90:595.
138. Adachi M, Asakura Y, Matsuo M, et al. POR R457H is a global founder mutation causing Antley-Bixler syndrome
with autosomal recessive trait. Am J Med Genet A 2006; 140:633.
139. Shackleton C, Malunowicz E. Apparent pregnene hydroxylation deficiency (APHD): seeking the parentage of an
orphan metabolome. Steroids 2003; 68:707.
140. Tomlinson JW, Walker EA, Bujalska IJ, et al. 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific
regulator of glucocorticoid response. Endocr Rev 2004; 25:831.
141. Biason-Lauber A, Suter SL, Shackleton CH, Zachmann M. Apparent cortisone reductase deficiency: a rare cause of
hyperandrogenemia and hypercortisolism. Horm Res 2000; 53:260.
142. Draper N, Walker EA, Bujalska IJ, et al. Mutations in the genes encoding 11beta-hydroxysteroid dehydrogenase
type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency. Nat Genet 2003;
34:434.
143. Jamieson A, Wallace AM, Andrew R, et al. Apparent cortisone reductase deficiency: a functional defect in 11beta-
hydroxysteroid dehydrogenase type 1. J Clin Endocrinol Metab 1999; 84:3570.
144. Lavery GG, Walker EA, Tiganescu A, et al. Steroid biomarkers and genetic studies reveal inactivating mutations in
hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency. J Clin Endocrinol Metab 2008;
93:3827.
145. Małunowicz EM, Romer TE, Urban M, Bossowski A. 11beta-hydroxysteroid dehydrogenase type 1 deficiency
('apparent cortisone reductase deficiency') in a 6-year-old boy. Horm Res 2003; 59:205.
146. Nikkilä H, Tannin GM, New MI, et al. Defects in the HSD11 gene encoding 11 beta-hydroxysteroid dehydrogenase
are not found in patients with apparent mineralocorticoid excess or 11-oxoreductase deficiency. J Clin Endocrinol
Metab 1993; 77:687.
147. Phillipov G, Palermo M, Shackleton CH. Apparent cortisone reductase deficiency: a unique form of hypercortisolism.
J Clin Endocrinol Metab 1996; 81:3855.
148. Mason PJ, Stevens D, Diez A, et al. Human hexose-6-phosphate dehydrogenase (glucose 1-dehydrogenase)
encoded at 1p36: coding sequence and expression. Blood Cells Mol Dis 1999; 25:30.
149. Draper N, Powell BL, Franks S, et al. Variants implicated in cortisone reductase deficiency do not contribute to
susceptibility to common forms of polycystic ovary syndrome. Clin Endocrinol (Oxf) 2006; 65:64.
150. Smit P, Dekker MJ, de Jong FJ, et al. Lack of Association of the 11beta-hydroxysteroid dehydrogenase type 1 gene
83,557insA and hexose-6-phosphate dehydrogenase gene R453Q polymorphisms with body composition, adrenal
androgen production, blood pressure, glucose metabolism, and dementia. J Clin Endocrinol Metab 2007; 92:359.
151. Faiyaz ul Haque M, King LM, Krakow D, et al. Mutations in orthologous genes in human spondyloepimetaphyseal
dysplasia and the brachymorphic mouse. Nat Genet 1998; 20:157.
152. Noordam C, Dhir V, McNelis JC, et al. Inactivating PAPSS2 mutations in a patient with premature pubarche. N Engl
J Med 2009; 360:2310.
153. Oostdijk W, Idkowiak J, Mueller JW, et al. PAPSS2 deficiency causes androgen excess via impaired DHEA
sulfation--in vitro and in vivo studies in a family harboring two novel PAPSS2 mutations. J Clin Endocrinol Metab
2015; 100:E672.
154. Strott CA. Sulfonation and molecular action. Endocr Rev 2002; 23:703.
155. Ahmad M, Faiyaz Ul Haque M, Ahmad W, et al. Distinct, autosomal recessive form of spondyloepimetaphyseal
dysplasia segregating in an inbred Pakistani kindred. Am J Med Genet 1998; 78:468.
156. Sugawara T, Holt JA, Driscoll D, et al. Human steroidogenic acute regulatory protein: functional activity in COS-1
cells, tissue-specific expression, and mapping of the structural gene to 8p11.2 and a pseudogene to chromosome
13. Proc Natl Acad Sci U S A 1995; 92:4778.
157. Lin D, Sugawara T, Strauss JF 3rd, et al. Role of steroidogenic acute regulatory protein in adrenal and gonadal
steroidogenesis. Science 1995; 267:1828.
158. Clark BJ, Wells J, King SR, Stocco DM. The purification, cloning, and expression of a novel luteinizing hormone-
induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute
regulatory protein (StAR). J Biol Chem 1994; 269:28314.
159. Stocco DM, Ascoli M. The use of genetic manipulation of MA-10 Leydig tumor cells to demonstrate the role of
mitochondrial proteins in the acute regulation of steroidogenesis. Endocrinology 1993; 132:959.
160. Stocco DM, Sodeman TC. The 30-kDa mitochondrial proteins induced by hormone stimulation in MA-10 mouse
Leydig tumor cells are processed from larger precursors. J Biol Chem 1991; 266:19731.
161. Bose HS, Sugawara T, Strauss JF 3rd, et al. The pathophysiology and genetics of congenital lipoid adrenal
hyperplasia. N Engl J Med 1996; 335:1870.
162. Katsumata N, Kawada Y, Yamamoto Y, et al. A novel compound heterozygous mutation in the steroidogenic acute
regulatory protein gene in a patient with congenital lipoid adrenal hyperplasia. J Clin Endocrinol Metab 1999;
84:3983.
163. González AA, Reyes ML, Carvajal CA, et al. Congenital lipoid adrenal hyperplasia caused by a novel splicing
mutation in the gene for the steroidogenic acute regulatory protein. J Clin Endocrinol Metab 2004; 89:946.
164. Fujieda K, Okuhara K, Abe S, et al. Molecular pathogenesis of lipoid adrenal hyperplasia and adrenal hypoplasia
congenita. J Steroid Biochem Mol Biol 2003; 85:483.
165. Miller WL. Disorders in the initial steps of steroid hormone synthesis. J Steroid Biochem Mol Biol 2017; 165:18.
166. Bose HS, Pescovitz OH, Miller WL. Spontaneous feminization in a 46,XX female patient with congenital lipoid
adrenal hyperplasia due to a homozygous frameshift mutation in the steroidogenic acute regulatory protein. J Clin
Endocrinol Metab 1997; 82:1511.
167. Baker BY, Lin L, Kim CJ, et al. Nonclassic congenital lipoid adrenal hyperplasia: a new disorder of the steroidogenic
acute regulatory protein with very late presentation and normal male genitalia. J Clin Endocrinol Metab 2006;
91:4781.
168. Sahakitrungruang T, Soccio RE, Lang-Muritano M, et al. Clinical, genetic, and functional characterization of four
patients carrying partial loss-of-function mutations in the steroidogenic acute regulatory protein (StAR). J Clin
Endocrinol Metab 2010; 95:3352.
169. Gassner HL, Toppari J, Quinteiro González S, Miller WL. Near-miss apparent SIDS from adrenal crisis. J Pediatr
2004; 145:178.
170. Fujieda K, Tajima T, Nakae J, et al. Spontaneous puberty in 46,XX subjects with congenital lipoid adrenal
hyperplasia. Ovarian steroidogenesis is spared to some extent despite inactivating mutations in the steroidogenic
acute regulatory protein (StAR) gene. J Clin Invest 1997; 99:1265.
171. Tajima T, Fujieda K, Kouda N, et al. Heterozygous mutation in the cholesterol side chain cleavage enzyme
(p450scc) gene in a patient with 46,XY sex reversal and adrenal insufficiency. J Clin Endocrinol Metab 2001;
86:3820.
172. Achermann JC, Ito M, Ito M, et al. A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal
and adrenal failure in humans. Nat Genet 1999; 22:125.
173. Hauffa BP, Miller WL, Grumbach MM, et al. Congenital adrenal hyperplasia due to deficient cholesterol side-chain
cleavage activity (20, 22-desmolase) in a patient treated for 18 years. Clin Endocrinol (Oxf) 1985; 23:481.
174. Nakae J, Tajima T, Sugawara T, et al. Analysis of the steroidogenic acute regulatory protein (StAR) gene in
Japanese patients with congenital lipoid adrenal hyperplasia. Hum Mol Genet 1997; 6:571.
175. Khoury K, Barbar E, Ainmelk Y, et al. Gonadal function, first cases of pregnancy, and child delivery in a woman with
lipoid congenital adrenal hyperplasia. J Clin Endocrinol Metab 2009; 94:1333.
176. Hiort O, Holterhus PM, Werner R, et al. Homozygous disruption of P450 side-chain cleavage (CYP11A1) is
associated with prematurity, complete 46,XY sex reversal, and severe adrenal failure. J Clin Endocrinol Metab 2005;
90:538.
177. Guran T, Buonocore F, Saka N, et al. Rare Causes of Primary Adrenal Insufficiency: Genetic and Clinical
Characterization of a Large Nationwide Cohort. J Clin Endocrinol Metab 2016; 101:284.
178. Katsumata N, Ohtake M, Hojo T, et al. Compound heterozygous mutations in the cholesterol side-chain cleavage
enzyme gene (CYP11A) cause congenital adrenal insufficiency in humans. J Clin Endocrinol Metab 2002; 87:3808.

Topic 15686 Version 15.0

GRAPHICS

Normal adrenal steroidogenesis

ACTH: corticotropin.

Graphic 71558 Version 4.0

17α-hydroxylase/17,20 lyase (CYP17A1) deficiency

Graphic 52616 Version 1.0

Differential diagnosis of ACTH-dependent mineralocorticoid excess

Disease Abnormal steroids Clinical features Defective gene

17-hydroxylase deficiency ↑ DOC, corticosterone Sexual ambiguity or infantilism CYP17A1

↓ 17OH-steroids, cortisol Autosomal recessive
↓ aldosterone
↓ androgens and estrogens

11-beta-hydroxylase ↑ DOC, 11-deoxycortisol Androgen excess CYP11B1

deficiency ↓ corticosterone, cortisol Autosomal recessive
↓ aldosterone
↑ androgens

Syndrome of apparent ↑ cortisol/cortisone ratios Mimicked by licorice ingestion HSD11B2

mineralocorticoid excess ↓ aldosterone Autosomal recessive
Normal androgens

Glucocorticoid-remediable ↑ 18OH- & 18-oxo-cortisol Strokes common Chimeric gene

aldosteronism ↑ aldosterone Autosomal dominant CYP11B1/CYP11B2
Normal cortisol
Normal androgens

Glucocorticoid resistance Moderate ↑ DOC, cortisol Compensated adrenal NR3C1 (glucocorticoid

↑ androgens insufficiency receptor)

Variable estrogens Androgen excess Other

Autosomal recessive

Cushing's disease ↑ cortisol & metabolites Cushingoid features Various tumor syndromes
Variable other steroids Variable mineralocorticoid Also sporadic
excess

ACTH: corticotropin; DOC: 11-deoxycorticosterone; 17OH: 17-hydroxy; 18OH: 18-hydroxy.

Graphic 104126 Version 3.0

Apparent combined CYP17A1 and CYP21A2 deficiency (P450 oxidoreductase
deficiency)

Graphic 53155 Version 1.0

3β-hydroxysteroid dehydrogenase type 2 (HSD3B2) deficiency

Graphic 74160 Version 1.0

Virilization (external view)

Normal and abnormal differentiation of the external genitalia. Diagrams of normal female
and male anatomy flank a series of schematic representations of different degrees of
virilization, graded using the scale developed by Prader.

Reproduced with permission from: White PC, Speiser PW. Congenital adrenal hyperplasia due to
21-hydroxylase deficiency. Endocr Rev 2000; 21:245. http://edrv.endojournals.org/. Copyright
© 2000 The Endocrine Society.

Graphic 52525 Version 6.0

11β-hydroxylase (CYP11B1) deficiency

Graphic 64361 Version 1.0

Apparent cortisone reductase deficiency (H6PDH deficiency)

Graphic 62897 Version 3.0

Apparent DHEA sulfotransferase deficiency (PAPSS2 deficiency)

Graphic 74694 Version 1.0

Characteristics of different forms of congenital adrenal hyperplasia

3-beta-
21- 11-beta- Aldosterone 17-alpha-
hydroxysteroid Lipoid
Disease hydroxylase hydroxylase synthase hydroxylase
dehydrogenase hyperplasia
deficiency deficiency deficiency deficiency
deficiency

Defective gene CYP21A2 (P450 CYP11B1 (P450 CYP11B2 (P450 CYP17A1 (P450 HSD3B2 (3-beta-HSD STAR (StAR)
(protein) 21A2) 11B1) 11B2) 17A1) type 2)

Ambiguous + in females + in females No + in males + in males + in males

genitalia
No puberty in Mild in females No puberty in
females females

Addisonian crisis + Rare Salt wasting No + ++

only

Incidence (general 1:11,000 - 1:100,000 Rare Rare Rare Rare

population) 23,000

Hormones

Glucocorticoids ↓ ↓ Normal Corticosterone ↓ ↓

normal

Mineralocorticoids ↓ ↑ ↓ ↑ ↓ ↓

Androgens ↑ ↑ Normal ↓ ↓ in males ↓

↑ in females

Estrogens Relatively ↓ in Relatively ↓ in Normal ↓ ↓ ↓

females females

Physiology

Blood pressure ↓ ↑ ↓ ↑ ↓ ↓

Na balance ↓ ↑ ↓ ↑ ↓ ↓

K balance ↑ ↓ ↑ ↓ ↑ ↑

Acidosis + ± Alkalosis + ± Alkalosis + +

Elevated steroid 17OHP DOC, 11- Corticosterone, DOC DHEA, 17-delta-5- None
metabolites deoxycortisol ±18-hydroxy- corticosterone hydroxypregnenolone
corticosterone

Na: sodium; K: potassium; 17OHP: 17-hydroxyprogesterone; DOC: deoxycorticosterone; DHEA: dehydroepiandrosterone.

Reproduced with permission from: White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev
2000; 21:245. Copyright 2000 The Endocrine Society.

Graphic 76865 Version 4.0

Congenital lipoid adrenal hyperplasia (StAR deficiency & CYP11A1
deficiency)

StAR: steroidogenic acute regulatory protein; ACTH: corticotropin.

Graphic 56021 Version 3.0