Version October 2024
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]). (See 'CYP17A1 deficiencies' below.)
●3-beta-hydroxysteroid dehydrogenase type 2 deficiency. (See '3-beta-hydroxysteroid dehydrogenase type 2 deficiency' below.)
●CYP11B1 deficiency (11-hydroxylase deficiency [11OHD]). (See '11-beta-hydroxylase deficiency' below.)
●Cytochrome P450-oxidoreductase (POR) deficiency (ORD). (See 'P450 oxidoreductase deficiency (apparent combined CYP17A1 and CYP21A2 deficiency)' below.)
●Hexose-6-phosphate-dehydrogenase deficiency (apparent cortisone reductase deficiency [ACRD]). (See 'Hexose-6-phosphate-dehydrogenase deficiency (apparent cortisone reductase deficiency)' below.)
●Phosphoadenosine phosphosulfate synthase type 2 (PAPSS2) deficiency (apparent dehydroepiandrosterone [DHEA] sulfotransferase deficiency). (See 'PAPSS2 deficiency (apparent DHEA sulfotransferase deficiency)' below.)
●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 atypia 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 [3,9,10,17]:
●Hypertension
●Primary amenorrhea
●Absence of secondary sexual characteristics
●Minimal body hair
●Blind vaginal pouch similar to androgen insensitivity syndrome (46,XY only)
●Small uterus and ovaries that may develop large cysts in adolescence due to high gonadotropins and progesterone (46,XX only)
The hypertension, which is typically detected in early adulthood [18], may be present much earlier [19] and can be severe [20] but may be normalized with treatment [21]. (See 'Treatment' below.)
In partial forms of 17OHD, 46,XY patients are often identified in infancy due to atypical genitalia with intraabdominal or inguinal testes. 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 hydroxylation defect may be observed without clinical manifestations of hypertension or hypokalemia [22].
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 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 [23], 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-beta-hydroxylase deficiency (11OHD) is distinguished by the presence of high androgens as opposed to low androgens in 17OHD. (See '11-beta-hydroxylase deficiency' below.)
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) [24] can be difficult to distinguish from 17OHD and ILD [25] 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 [26,27] 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 [28-30].
Approximately 100 different mutations in the CYP17A1 gene, which is located on chromosome 10q24.3 [31], 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 [7,25,32-45]. 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 [46-49], 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 [11,39,50,51]. 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 preferentially preserved 17-hydroxylase activity [52].
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 can be achieved by mineralocorticoid blockade and physiologic replacement doses of cortisol and sex steroids, rather than by supraphysiologic suppressive doses of glucocorticoid as have been used in the past.
●Glucocorticoid replacement – Patients with glucocorticoid deficiency require physiologic cortisol replacement therapy. Cortisol replacement regimens for children and adults are reviewed in detail separately. (See "Treatment of adrenal insufficiency in children", section on 'Glucocorticoids' and "Treatment of adrenal insufficiency in adults", section on 'Glucocorticoid replacement for all patients'.)
●Mineralocorticoid blockade – 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, corticosterone, and electrolytes; renin suppression can persist for years, despite adequate therapy, in some cases [12,53].
●Sex steroid replacement and fertility – Sex steroid treatment regimens vary with physiologic stage and goals of therapy.
•Puberty induction – 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 "Approach to the patient with delayed puberty", section on 'Estradiol therapy'.)
•Fertility – A few cases of in vitro fertilization and a live birth in a 46,XX patient with incomplete 17OHD have been described [54]. The approach included ovulation induction with gonadotropin stimulation, egg retrieval, and freezing of embryos. During the ovarian stimulation with gonadotropin-releasing hormone (GnRH) agonist and recombinant follicle-stimulating hormone (rFSH) administration, adrenal-derived progesterone secretion was suppressed with dexamethasone. Estradiol valerate was then given to prepare the endometrium, and the frozen-thawed embryo transfer was performed.
•Treatment of atypical genitalia – Treatment for 46,XY patients with a difference 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 genital appearance (difference 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 [55]. Paradoxically, both male and female infants are born with atypical genitalia for reasons explained below. Mutations throughout the HSD3B2 gene have been identified, with a few founder mutations in isolated populations [56-68].
Pathophysiology — 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) [55]. 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).
The formation of active androgens in girls occurs because a second enzyme, HSD3B1, is abundant in liver and skin [57], 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 [69]. In contrast to 21OHD, 11-oxygenated androgens are relatively low, especially 11-ketotestosterone [70].
A "nonclassic" form of HSD3B2 deficiency that causes hirsutism, menstrual irregularity, or both in adolescent or young adult women was previously suggested [71], 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 [58,59,72,73]. 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) [56,58].
Clinical and biochemical features — 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 [55,60].
●Clinical features – Testosterone deficiency results in atypical genitalia in 46,XY newborns and persists throughout adulthood. 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 [74].
Newborn females often have mild virilization due to peripheral conversion of adrenal-derived DHEA to testosterone by the type 1 enzyme. Females are born with mild-to-moderate clitoromegaly but little labioscrotal fusion (Prader scores II to III) (figure 5), suggesting androgen excess late in gestation [56]. Undiagnosed girls proceed to develop androgen excess, including precocious pubarche, acne, and hirsutism with menstrual disturbances. Unlike 21OHD, this disease is not specifically targeted in neonatal screening programs, and rare girls may have severe deficiency but few symptoms and escape diagnosis until they are evaluated for delayed puberty [75,76]. Premature pubarche with exaggerated serum 17-hydroxypregnenolone responses to ACTH has been described in three girls with missense mutations of the gene [77].
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]).
●Biochemical features – 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 17-hydroxypregnenolone (delta-5) to 17-hydroxyprogesterone (17OHP, delta-4) in serum (figure 4). As described above, serum delta-5 steroid concentrations are extremely elevated, whereas the corresponding delta-4 steroids are also elevated but not to the same degree, still yielding a high ratio. An important corollary to this pattern is that 17OHP is elevated in all androgen-excess forms of classic or nonclassic CAH (21OHD, 11-hydroxylase deficiency [11OHD], and HSD3B2 deficiency), and the latter two diagnoses should only be considered in children and women when the 17OHP is elevated and 21OHD has been excluded, including false-positive 17OHP elevation in newborn screening for 21OHD.
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 "Clinical manifestations 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 noncarriers based on steroid measurements, even after cosyntropin stimulation [73].
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 [58]. 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 [59], such that only stimulated delta-5-17-hydroxypregnenolone values >5000 ng/dL (150 nmol/L) or more should be considered consistent with the diagnosis.
Treatment — Similar to treatment of 17OHD, therapy must include replacement of both adrenal and gonadal steroid deficiencies. (See 'CYP17A1 deficiencies' above.)
●In 46,XY children reared as males, replacement doses of glucocorticoid (hydrocortisone) and mineralocorticoid (fludrocortisone acetate) are often sufficient to attenuate adrenal-derived androgen production enough to normalize growth and to prevent bone age advancement. Suppression of ACTH and DHEA is generally not necessary to maintain active androgens in the prepubertal range.
●In children reared as females, somewhat higher doses may be needed to prevent excess production of androgens derived from adrenal precursors, particularly during adolescence.
●At the time of expected puberty, puberty is induced with low-dose androgens or estrogens. In undervirilized 46,XY males, testosterone therapy may be used during childhood to augment penile size prior to initiation of puberty. (See "Approach to the patient with delayed puberty", section on 'Therapy'.)
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 [78]. In Jews of Moroccan ancestry, 11OHD prevalence is as high as 1 in 5000 due to the R448H founder mutation [79,80]. 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.
Pathophysiology — 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 presentation — The clinical manifestations of the disorder result from high adrenal production of the mineralocorticoid DOC and androgen precursors, which are metabolized to active androgens in the adrenal and/or peripheral organs (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.
Clinical findings — Classically, female newborns are identified with atypical genitalia, including clitoral enlargement and labioscrotal fusion as in 21OHD (see "Evaluation of the infant with atypical genital appearance (difference 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 "Clinical manifestations and 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 atypia or signs of hyperandrogenism [81]. 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 [78,82]. Although it is ascribed to DOC excess, the correlations between blood pressure and serum DOC concentrations [81,83] or severity of the deficiency based on genotype [84] are poor. A few patients with 11OHD have salt-wasting or hypotensive crises [81,85-87], 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 [88,89].
As with 21OHD, a milder or nonclassic form featuring androgen excess without hypertension has been described [78,90-93] (see 'Clinical and biochemical features' 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 "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children".)
Biochemical findings — Patients with classic CYP11B1 deficiency have a characteristic set of hormonal findings, often with hypokalemia:
●High serum concentrations of 11-deoxycortisol, DOC, androstenedione, and testosterone, with low cortisol and corticosterone (figure 6 and table 1). Unlike in 21OHD, 11-oxygenated androgens are not produced, because of the 11-hydroxylase deficiency [94]. (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children".)
●Increased urinary excretion of 11-deoxysteroid metabolites, most prominently tetrahydro metabolites of 11-deoxycortisol and DOC, which are normally present in trace quantities [95]. 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) [78,96,97]. To diagnose mild or nonclassic 11OHD in adolescents and young adults, basal serum 11-deoxycortisol values may be normal, and cosyntropin stimulation testing is often required to establish the diagnosis [98,99], using the criteria of 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 forms of 21OHD, 11OHD, and 3HSD3B2 deficiency. These diagnoses can only be distinguished by measurement of additional steroids including 11-deoxycortisol, DOC, and 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 extremely rare for HSD3B2 deficiency [100]. Heterozygous carriers of 11OHD have no detectable biochemical abnormalities [101]. (See "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)
Genetics — 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 [80,102-104], frameshifts [105], and nonsense mutations [106,107] 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 [80]. In two patients, the disorder occurred as a result of unequal recombination between the CYP11B1 and CYP11B2 genes [108,109], which is reminiscent of the genetic event leading to glucocorticoid-remediable aldosteronism (GRA). (See "Familial hyperaldosteronism", section on 'Glucocorticoid-remediable aldosteronism'.)
Treatment — 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 can 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 syndrome. (See "Epidemiology and clinical manifestations of Cushing 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 sex-specific normal range. In postpubertal boys and men, a serum androstenedione concentration higher than testosterone indicates that the androgens are adrenal derived and that 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 and dose adjustment'.)
●In adolescent girls, facial hair growth and acne should be examined. Vaginal inadequacy in affected females may require reconstruction with one or more surgeries and vaginal dilation. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children".)
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. The use of spironolactone to treat hyperandrogenism in premenopausal women is reviewed separately. (See "Management of hirsutism in premenopausal women", section on 'Antiandrogens'.)
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 [110]. Pregnancy in 11OHD is not as well studied as in 21OHD, but in both disorders, a goal of treatment for women attempting pregnancy is to suppress adrenal-derived progesterone production in the follicular phase.
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 [111] or by sequencing the CYP11B1 gene amplified from DNA in chorionic villus biopsy samples [112]. 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 [112]. (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 [113], while its genetic cause, cytochrome P450 oxidoreductase (POR) mutations, was not identified until 2004 [24,26]. The POR enzyme serves as an electron donor flavoprotein 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 [113], 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) [26,114].
Approximately 100 cases of ORD have been reported [24-26,115-119]; a significant number of reported patients had been previously misdiagnosed with CYP17A1, CYP19A1, and CYP21A2 deficiency, respectively [24,25,120]. 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 characteristic 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 [121] 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 [122]. Mineralocorticoid-related hypertension is not a feature of ORD, although two young adults with ORD and coincident arterial hypertension have been described [24].
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 differences of sex development (DSD). 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 increased flux of precursor steroids through an alternative pathway to dihydrotestosterone during fetal life, which declines shortly after birth [26]. In addition, some POR mutants may also affect aromatase activity [123], in particular R457H, the most frequently found mutation in the Japanese population, which is invariably associated with 46,XX DSD in homozygous neonates [116,124].
Pubertal development in ORD is not well studied but appears to be dominated by the consequences of sex steroid deficiency [116]. 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 17OHD and 21OHD).
Malformations reported in patients affected by ORD constitute one type of ABS [121]; 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. Retinoic acid toxicity due to impaired activity of the CYP26 family enzymes, which also use POR and degrade retinoic acid, might also contribute. The loss of cholesterol synthesis during embryogenesis impairs signaling molecules important for body patterning and development [116,117,125-129]. 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 [130-135].
Diagnosis and differential diagnosis — Comprehensive urine GC-MS analysis 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) [114]. 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 marker test; subsequent analysis of maternal urine reveals a characteristic steroid precursor pattern facilitating prenatal diagnosis [114,136]. Maternal virilization, associated with a high excretion of specific androgen metabolites and manifesting around mid-gestation, is frequently but not invariably observed during these pregnancies [26,114,137].
Individual plasma steroid measurements 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 [120]. As a result of 21-hydroxylase inhibition, serum 17OHP may be elevated but to a lesser degree than in 21OHD. Consequently, only some of the patients are picked up at neonatal CAH screening [116,124]. 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 [138-140]. However, the FGFR2 gene in patients with ORD is normal [24,26,125], and patients with proven FGFR2 mutations do not present with disordered steroidogenesis or disordered sex development [139]. Genetic analysis of a cohort of patients with ABS phenotype revealed clear segregation of FGFR2 and POR mutations [117]. 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 other or 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 White individuals [117]. R457H is predominantly found in Japanese populations [115,116,124] and represents a global founder mutation [141].
Genotype-phenotype correlations are not fully established, yet certain patterns are emerging between specific mutations and phenotypic expression of ABS [116].
Treatment — The goals of treatment in ORD are to replace glucocorticoid deficiency when present and to restore desired secondary sexual characteristics at time of puberty. (See "Treatment of adrenal insufficiency in adults" and "Approach to the patient with 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 [124,139]. (See "Diagnosis of adrenal insufficiency in adults", section on 'ACTH stimulation tests'.)
Some patients may have a normal cortisol response to corticotropin (ACTH) and do not require glucocorticoid replacement [26]. Most ORD patients have normal baseline secretion but fail to achieve a completely normal cortisol response [114,116,142]. If the response is a borderline fail, stress dose cover for intercurrent illness and surgery might be advised. However, if the test is clearly failed, permanent hydrocortisone replacement is recommended. As there is no accumulation of androgens, ACTH suppression is unnecessary, and hydrocortisone replacement should be administered in the lowest dose possible. (See "Treatment of adrenal insufficiency in adults", section on 'Glucocorticoid replacement for all patients' and "Treatment of adrenal insufficiency in children", section on 'Glucocorticoids'.)
Mineralocorticoid replacement is not required, and blood pressure requires careful monitoring. If mineralocorticoid precursor accumulation causes hypertension as in 17OHD, spironolactone can be used to control mineralocorticoid-mediated hypertension [24].
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 "Approach to the patient with delayed puberty", section on 'Therapy'.)
ABS malformations require supportive treatment, including orthopedic and surgical management, which may include ventriculoperitoneal shunts and tracheostomy. The most severely affected patients may have decreased survival due to malformation-related complications [136]. 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 [143]. 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 [143].
Clinical presentation — ACRD clinically presents with hyperandrogenism, manifesting as premature pubarche or with oligomenorrhea, acne, and hirsutism (similar to 21OHD). Genetically confirmed ACRD has been described in approximately 10 patients [144-150]. 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.
Hormonal criteria for diagnosis — 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 [147,151]. Some patients with ACRD also have polymorphic HSD11B1 sequence variants that are not disease-causing mutations [145,152,153].
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. Clinical and laboratory assessments are used to titrate therapy, similar to 21OHD. (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 [154]. Subsequently, a patient of Turkish origin [155] 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 [156].
Pathophysiology — 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 androgens.
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) [157]. 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 (as well as chondrocytes), while PAPSS1 is ubiquitously expressed [155]. 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 [157].
Clinical presentation and genetics — 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 nonclassic 21OHD, including oligomenorrhea, acne, hirsutism, and eventually secondary amenorrhea at the age of 13 years [155]. 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 [155].
A family with two postpubertal brothers who are compound heterozygotes for a null frame-shift allele and mutation G270D has also been described [156,158]. 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.
Treatment — 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. Boys might not require treatment upon reaching adulthood, whereas women will likely require chronic therapy. Additional options for the treatment of hyperandrogenism in premenopausal women are reviewed separately. (See 'P450 oxidoreductase deficiency (apparent combined CYP17A1 and CYP21A2 deficiency)' above and "Management of hirsutism in premenopausal women", section on 'Management'.)
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) [159,160]. This mitochondrial phosphoprotein normally mediates the acute response to steroidogenic stimuli by increasing cholesterol transport from the outer to the inner mitochondrial membrane [159,161-163], 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 [62].
The role of StAR has been studied by sequencing the gene in patients with LCAH [160,164-167]. More than 100 patients and 40 different mutations have been described [168]; 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 [169], 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 [170]. These patients typically present in childhood 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 [171]. Sex steroid deficiency might become manifest at the time of expected puberty, particularly in boys.
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 [172] 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 [173].
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 [169].
Boys with nonclassic LCAH may present with adrenal insufficiency but have normal male external genitalia.
Biochemical findings — Patients with LCAH have very low serum cortisol and aldosterone concentrations and very high plasma ACTH concentrations and plasma renin activity [174-176]. 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 [176].
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 the adrenals and, in boys, also the gonads.
Treatment — Classic LCAH has been fatal during infancy in two-thirds of reported patients [176], but some patients survive [169,177]. Glucocorticoid and mineralocorticoid deficiency is managed by replacement therapy as in any form of adrenal insufficiency [176]. These replacement regimens are reviewed in detail separately. (See "Treatment of adrenal insufficiency in children" and "Treatment of adrenal insufficiency in adults".)
Replacement therapy alone is required, as the high ACTH will not cause excess of unwanted steroids [176]. At the time of puberty, low-dose estradiol therapy is provided to complete the development of secondary sexual characteristics, as all patients are phenotypically female. Those with 46,XX karyotype and intact uterus require periodic progesterone withdrawal bleeding as well. 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 [178]. (See "Approach to the patient with delayed puberty", section on 'Estradiol therapy'.)
In nonclassic LCAH, glucocorticoid replacement therapy alone is required, at least during childhood. Pubertal development and fertility in these patients have not been studied adequately.
CHOLESTEROL SIDE-CHAIN CLEAVAGE ENZYME (CYP11A1) 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 (cytochrome P450 11A1, CYP11A1). 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 [165,166].
Subsequently, two patients with LCAH were shown to have heterozygous mutations of CYP11A1 [167,168]. 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 [174,179].
Pathophysiology and genetics — CYP11A1, 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 [180]. Some patients harbor two null alleles [179], which is difficult to reconcile with the presumed requirement of progesterone to maintain pregnancy [168]. Affected patients with apparent haploinsufficiency have been described [174,181]. A CYP11A1 variant E314K is now recognized as a common disease-causing allele in children with congenital cortisol deficiency [182].
Clinical presentation and biochemical features — 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 [168]. 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" and "Approach to the patient with delayed puberty", section on 'Therapy'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Classic and nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)
SUMMARY AND RECOMMENDATIONS
●21-hydroxylase deficiency (21OHD) – The most frequent cause of congenital adrenal hyperplasia (CAH) is 21-hydroxylase deficiency (21OHD). Several less common causes of CAH exist. (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children" and "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)
●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 progestogens, mineralocorticoids, glucocorticoids, and androgens, including the precursors of dihydrotestosterone and estrogens. 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) – 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) combines apparent partial CYP17A1 and CYP21A2 deficiencies. This disorder has two characteristic 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 when present and to restore desired secondary sexual characteristics at the time of normal puberty (figure 3). (See 'P450 oxidoreductase deficiency (apparent combined CYP17A1 and CYP21A2 deficiency)' above.)
●Hexose-6-phosphate-dehydrogenase deficiency (apparent cortisone reductase deficiency [ACRD]) – 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) – 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.)
●Cholesterol side-chain cleavage enzyme (CYP11A1) deficiency – CYP11A1, encoded by CYP11A1, catalyzes the conversion of cholesterol to pregnenolone in the mitochondria of steroidogenic cells. All patients described with CYP11A1 deficiency had adrenal insufficiency, and the adrenal glands are not enlarged as in most cases of LCAH. (See 'Cholesterol side-chain cleavage enzyme (CYP11A1) deficiency' above.)
ACKNOWLEDGMENTS — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.
The UpToDate editorial staff acknowledges Wiebke Arlt, MD, DSc, FRCP, FMedSci, who contributed to an earlier version of this topic review.
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