Nonclassic congenital adrenal hyperplasia

Nonclassic congenital adrenal hyperplasia

  • Congenital adrenal hyperplasia represents a group of autosomal recessive disorders of the adrenal cortex caused by mutations in various genes encoding for enzymes of steroidogenesis 
    • Nonclassic congenital adrenal hyperplasia refers to mild forms that are typically identified in late childhood, adolescence, or early adulthood
    • Classic congenital adrenal hyperplasia is usually identified in neonates via newborn screening
      • Girls with congenital adrenal hyperplasia come to medical attention because atypical genitalia is noted at birth
  • Clinical presentation differs by type of enzyme deficiency, resulting in different forms of the condition
    • 21-hydroxylase deficiency is the most common (95% of cases), but various forms of nonclassic disease have been described and include 11β-hydroxylase deficiency, 3β-hydroxysteroid dehydrogenase deficiency, and lipoid congenital adrenal hyperplasia 
    • Nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency is most apparent in adolescent or young adult females; typical presentation is hirsutism and irregular menses 
      • Children present with premature adrenarche and advanced bone age
      • Men are almost always asymptomatic
  • Primary diagnostic tool is measurement of 17-hydroxyprogesterone, using corticotropin stimulation 
    • Clinically, nonclassic disease is difficult to distinguish from polycystic ovary syndrome and measuring corticotropin-stimulated 17-hydroxyprogesterone level is the first diagnostic step 
    • Genetic testing may be necessary to confirm diagnosis in case of unequivocal results 
  • Treatment is only used for symptomatic cases, and is directed to the area of concern
    • Oral contraceptives—with or without an antiandrogen—are first choice options to control hyperandrogenic symptoms (eg, hirsutism, acne) and to regulate menses 
    • Glucocorticoids are used sparingly and minimized in duration to accomplish specific goals, largely for infertility or for children with premature adrenarche and advanced bone age 
  • Infertility and higher rate of miscarriage are the main reproductive concerns 
  • Other complications predominantly result from overtreatment with glucocorticoids (eg, reduced bone mineral density, type 2 diabetes, obesity) 

Pitfalls

  • Diagnosis of congenital adrenal hyperplasia is challenging for all forms of the disease and often requires a detailed clinical and hormonal evaluation 
    • Indeterminate results or false-positive results are possible during the diagnostic phase, especially in less common forms of congenital adrenal hyperplasia 
      • Morning basal 17-hydroxyprogesterone levels may not be sufficiently elevated to sensitively identify the disease in cases of mild defects and relying only on basal levels will miss the diagnosis in approximately 10% of cases 
  • When glucocorticoids are deemed necessary, complete suppression of adrenal steroid secretion is inadvisable as it signals overtreatment and is accompanied by attendant adverse cushingoid effects 

Congenital adrenal hyperplasia refers to a group of autosomal recessive disorders caused by single gene defects in the various enzymes required for cortisol biosynthesis 

Broadly, congenital adrenal hyperplasia is categorized as classic or nonclassic based on severity and timing of symptom onset

Nonclassic congenital adrenal hyperplasia refers to mild forms that are typically identified in late childhood (after 60 months), adolescence, or early adulthood 

Classic congenital adrenal hyperplasia is usually identified in neonates via newborn screening, and presents with adrenal insufficiency, salt wasting, and atypical genitalia 

Manifestations vary according to the particular gene mutation and the specific type of enzyme deficiency 

Vast majority of cases (including nonclassic forms) are caused by mutations in CYP21A2, resulting in 21-hydroxylase deficiency 

In nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, the main biochemical abnormality is adrenal androgen excess

Cortisol production may be partially impaired but does not require routine replacement 

Other very rare forms of nonclassic disease exist, such as defects of 11β-hydroxylase activity, encoded by CYP11B1, and defects of 3β-hydroxysteroid dehydrogenase (3β-HSD) activity, encoded by HSD3B2 

Clinical manifestations vary by life stage and sex 

Late childhood girls and boys: premature adrenarche and accelerated bone age

Adolescent and young adult females: hirsutism, oligomenorrhea, acne 

Most men are asymptomatic 

Classification

  • By defective enzyme 
    • 21-hydroxylase deficiency 
      • Most common type of congenital adrenal hyperplasia (more than 95% of all cases) 
        • Postnatal presentation (nonclassic form) during childhood, adolescence, or adulthood occurs in 1:1000 people 
          • Characterized by mild to moderate hyperandrogenemia; cortisol production is normal to mildly impaired 
          • Salt wasting does not occur and females do not have atypical external genitalia
        • Presentation at birth or during early infancy (classic form) occurs in 1:16,000 births worldwide 
          • Complete or nearly complete cortisol and aldosterone deficiency, female atypical genitalia, or virilization in the first few months of life
    • 11β-hydroxylase deficiency 
      • Second most common type of congenital adrenal hyperplasia 
        • Postnatal presentation (nonclassic form) is rare compared with incidence of nonclassic 21-hydroxylase deficiency
        • Presentation at birth (classic form) occurs in 1:100,000 to 1:200,000 live births in populations without consanguineous marriages
      • Results in reduced cortisol secretion, accumulation of precursor 11-deoxycortisol, and excess of the mineralocorticoid precursor 11-deoxycorticosterone (DOC) 
    • 3β-hydroxysteroid dehydrogenase deficiency 
      • Uncommon type accounting for less than 5% of cases of congenital adrenal hyperplasia 
        • Late-onset presentation and mild forms (nonclassic) have been described 
        • Presentation at birth (classic form) is rare but fatal if not diagnosed in a timely manner 
      • Characterized by an impaired biosynthesis of all classes of adrenal corticosteroids and gonadal hormones 
    • Lipoid congenital adrenal hyperplasia (defects in StAR [steroidogenic acute regulatory protein] and cholesterol side-chain cleavage) 
      • True incidence in the general population is unknown, but likely very rare 
        • Postnatal presentation (nonclassic form) is recently recognized, albeit very rare 
        • Presentation at birth (classic form) is the more common form 
      • Generally considered the most severe type of congenital adrenal hyperplasia because synthesis of all adrenal and gonadal steroid hormones is impaired; associated with defects in cholesterol transport, leading to accumulation of cholesterol esters 
      • In classic form, patients present with cortisol deficiency, deficiency of adrenal sex steroids, and atypical genitalia or complete sex reversal in patients with a 46,XY karyotype

History

  • Clinical presentation varies widely according to the adrenal steroids that are deficient or in excess 
  • Classic congenital adrenal hyperplasia manifests in newborns and infants with adrenal insufficiency and atypical genitalia
  • Nonclassic congenital adrenal hyperplasia usually presents and is recognized later in life (end of childhood, adolescence, or early adulthood) 
    • 21-hydroxylase deficiency
      • Symptoms of androgen excess are not evident at birth (as in the classic form) but manifest later at various ages 
        • Late childhood (younger than 10 years)
          • May present with premature adrenarche, noted by early development of pubic hair, axillary hair, oily skin, acne, and/or adult apocrine odor 
          • Puberty onset occurs 2.3 years early, on average 
          • Rapid linear growth is common (crossing of at least 1 linear growth percentile channel on growth chart)
        • Adolescence through adulthood
          • Disease is most clinically apparent in females and typical presentation reflects androgen excess 
            • Hirsutism (78% of adult females) 
              • Excessive growth of coarse terminal hairs in androgen-dependent areas 
            • Oligomenorrhea (55% of females) 
            • Acne (33% of females) 
              • Severe cystic acne refractory to oral antibiotics and retinoic acid is common 
            • Androgenic alopecia (8%) that becomes more severe over time 
            • Subfertility (12%); fertility rate among untreated women is reported to be 50% 
            • Primary amenorrhea (9%) 
          • Males are generally asymptomatic and are most often identified through genetic testing after a female family member is diagnosed 
            • Alternatively, some may be identified during evaluation of severe acne and/or subfertility 
      • Symptoms or signs of glucocorticoid insufficiency are absent, but there may be biochemical evidence of inadequate response to corticotropin stimulation testing
      • Some patients are asymptomatic and disease is never detected 
    • 11β-hydroxylase deficiency
      • Nonclassic form has highly variable clinical manifestations and can be difficult to distinguish from nonclassic 21-hydroxylase deficiency
        • Late childhood
          • Premature adrenarche, mild virilization, and hirsutism are relatively common 
        • Adolescence through adulthood
          • Women report hirsutism and irregular menses 
    • 3β-hydroxysteroid dehydrogenase deficiency
      • Nonclassic form is also difficult to distinguish from nonclassic 21-hydroxylase deficiency and 11β-hydroxylase deficiency 
        • Late childhood
          • Premature adrenarche, acne, and rapid growth 
        • Adolescence through adulthood
          • Women report hirsutism, treatment-resistant acne, and irregular menses (eg, oligomenorrhea) 
    • Lipoid congenital adrenal hyperplasia
      • Nonclassic form presents with mild clinical findings and a later (postinfancy) onset of adrenal insufficiency 
        • Childhood
          • Mild adrenal insufficiency develops in boys and girls, beginning as early as age 2 to 4 years 
            • Symptoms of adrenal insufficiency (eg, weakness, dizziness, nausea, vomiting) usually manifest by age 9 years 
        • Adolescence through adulthood
          • There is no information on adolescents or young adults presenting with nonclassic lipoid congenital adrenal hyperplasia as case reports describe only childhood presentations

Physical examination

  • Examination findings vary according to the defective enzyme(s) and reflect the particular adrenal cortex hormones that are deficient or produced in excess
  • 21-hydroxylase deficiency
    • Late childhood (younger than 10 years)
      • Signs of premature pubarche (development of pubic and axillary hair) before ages 8 and 9 years for girls and boys, respectively 
      • Oily skin (seborrhea) and acne
      • Advanced skeletal maturation and bone age occurs among children with nonclassic form 
        • Accelerated growth and bone advancement is followed by epiphyseal fusion, which may lead to compromised height, in both boys and girls 
      • Genital virilization is not present at birth, as in the classic form 
    • Adolescence through adulthood
      • Signs of hyperandrogenemia in females, including hirsutism, acne, and occasionally mild clitoromegaly
      • Reduced adult stature might occur as a result of premature epiphyseal fusion (patients are tall as children but become short adults) 
      • Androgenic alopecia sometimes appears in adulthood; when present, usually worsens over time 
      • Rarely, male adolescents might display gynecomastia or increased penile length 
      • Signs of virilization, other than mild clitoromegaly, are not present in nonclassic forms in women 
        • While hirsutism refers to the presence of excessive terminal (coarse) hair in androgen-sensitive areas of the female body, virilization is more extensive and has additional features of masculinization, such as deepened voice and male muscle bulk 
  • 11β-hydroxylase deficiency 
    • Late childhood
      • Rapid somatic growth with accelerated bone maturation (both boys and girls) 
      • Hypertension (which is a distinctive clinical feature in classic 11β-hydroxylase deficiency) is often absent in young patients with the nonclassic form 
    • Adolescence through adulthood
      • Hirsutism
      • Short final stature (according to midparental target height) 
      • Hypertension may develop over time 
  • 3β-hydroxysteroid dehydrogenase deficiency
    • Late childhood
      • Premature acne
      • Premature pubarche 
      • Rapid growth acceleration 
    • Adolescence through adulthood
      • Hirsutism
      • Possible short final stature (height below 5th percentile) 
      • Irregular menses (ie, oligomenorrhea, unpredictable menses) 
  • Lipoid congenital adrenal hyperplasia 
    • Childhood
      • Hyperpigmented skin and lips can be a presenting sign 
      • Mild adrenal insufficiency usually becomes clinically apparent in childhood when prompted by the stress of a concomitant illness, noted by the presence of hypotension, hypoglycemia, and/or hyponatremia 

Causes

  • All types are caused by autosomal-recessive mutations affecting the genes encoding for enzymes involved in adrenal cortex steroidogenesis 
    • Most genetic defects are compound heterozygous with different mutations in 2 alleles for a particular gene 
    • In each form, accumulation of precursors immediately proximal to the impaired hydroxylation step in the cortisol synthesis pathway leads to shunting into the androgen pathway 
  • 21-hydroxylase deficiency (OMIM #201910)
    • Caused by mutations in CYP21A2 gene 
      • Mutations causing residual 21-hydroxylase activity of about 20% to 50% are associated with nonclassic form, as compared to 0 to 2% for classic forms 
      • Genotype-phenotype correlations for nonclassic types are approximately 70%; typically, the milder of the 2 affected alleles determines phenotype
    • Most mutations result from nonallelic homologous recombination between the active gene, CYP21A2, and its highly homologous nonfunctional pseudogene, CYP21A2P;results in gene conversion events in which the functional gene acquires deleterious CYP21A1P sequences 
    • Mutations located in noncoding genomic regions are possible but uncommon 
  • 11β-hydroxylase deficiency (OMIM #202010)
    • Caused by mutations in CYP11B1 gene 
    • May occur as homozygous, heterozygous, or compound heterozygous mutations 
    • Most mutations associated with nonclassic disease cause a partial impairment of 11β-hydroxylase activity between 23% and 40% 
  • 3β-hydroxysteroid dehydrogenase deficiency (OMIM #201810)
    • Caused by mutations in HSD3B2 gene 
      • Nonclassic (late-onset) form is not an allelic variant of the classic form 
  • Lipoid congenital adrenal hyperplasia (OMIM #201710)
    • Caused by mutations in 1 of 2 genes: the STAR gene encoding for steroidogenic acute regulatory protein or CYP11A1 gene encoding for cholesterol side-chain cleavage 
      • Most patients with nonclassic form carry R188C mutation in STAR gene 
        • Mutations result in STAR proteins that retain about 20% to 25% of normal activity 

Risk factors and/or associations

Age
  • Nonclassic congenital adrenal hyperplasia manifests signs and symptoms starting in late childhood through young adulthood 
    • For nonclassic 21-hydroxylase deficiency, the condition becomes apparent before age 10 years in 11% of patients and between the ages of 10 to 40 years in 80% of patients 
Genetics
  • All forms of congenital adrenal hyperplasia are inherited in a monogenic autosomal recessive pattern
    • Family history of congenital adrenal hyperplasia increases risk of inheriting genetic defects
Ethnicity/race
  • Nonclassic 21-hydroxylase deficiency occurs in white populations at a rate of about 1 in 1000 
    • More frequent in populations of specific ethnicities, including:
      • Ashkenazi Jewish populations 
      • Hispanic populations 
      • Yugoslavic populations 
      • Italian populations 
  • 11β-hydroxylase deficiency
    • Nonclassic presentation has been reported among different ethnicities, including British/Caucasian, Pakistani, Turkish, and Italian
  • 3β-hydroxysteroid dehydrogenase deficiency
    • Reported patients with nonclassic disease come from unrelated pedigrees and diverse ethnic origins 
  • Nonclassic lipoid congenital adrenal hyperplasia has been described in patients from Thailand, Canada, Jordan, India, and Pakistan

How is Nonclassic congenital adrenal hyperplasia diagnosed?

  • Diagnosis starts with clinical suspicion, typically when an adolescent or young adult female presents with symptoms and signs of androgen excess or when a child presents with premature adrenarche 
    • However, in asymptomatic males, diagnosis is most often made through genetic testing after a diagnosis is made in a female family member
    • Distinction between classic and nonclassic forms is determined by the absence of atypical genitalia in female newborns and milder symptoms postnatally in cases of nonclassic forms 
  • Consider testing for nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in the following situations:
    • Child (boy or girl) with premature adrenarche and advanced bone age
    • Adolescent or young adult female with oligomenorrhea and hyperandrogenemia (apparent polycystic ovary syndrome), especially in women of Mediterranean or Ashkenazi Jewish descent
    • Family history of congenital adrenal hyperplasia
  • A logical approach to diagnostic testing in most cases is to begin evaluation for nonclassic 21-hydroxylase deficiency 
    • If evaluation for nonclassic 21-hydroxylase deficiency yields normal findings, ensure that other entities in the differential diagnosis have been considered (eg, Cushing syndrome, polycystic ovary syndrome, androgen-secreting tumors, hyperprolactinemia of various sources)
    • When clinical suspicion persists for a less common type (eg, nonclassic 11β-hydroxylase deficiency or 3β-hydroxysteroid dehydrogenase deficiency), refer to a center with expertise in evaluating rare forms of congenital adrenal hyperplasia
      • Owing to their rarity, a diagnosis of nonclassic 11β-hydroxylase deficiency or 3β-hydroxysteroid dehydrogenase deficiency should be pursued in patients with androgen excess during childhood only after more common causes (eg, idiopathic premature adrenarche, 21-hydroxylase deficiency) and reasonable differential diagnoses have been excluded 
      • Diagnosis of nonclassic lipoid congenital adrenal hyperplasia would only be considered and further pursued in a patient presenting with postinfancy adrenal insufficiency
  • Diagnosis of nonclassic 21-hydroxylase deficiency is based on laboratory measurement of 17-hydroxyprogesterone concentrations
    • Initial test is measuring basal 17-hydroxyprogesterone levels in plasma or serum 
      • 17-hydroxyprogesterone level is the primary diagnostic means of detecting 21-hydroxylase deficiency, as this is the steroid intermediate that is just before the blocked enzymatic step in cortisol synthesis 
      • Obtain early-morning blood sample (before 8 AM) 
        • For women, laboratory testing should occur in follicular phase of menstrual cycle
        • If patient is amenorrheic or oligomenorrheic, sample may be drawn on a random day 
    • Basal 17-hydroxyprogesterone results
      • Level greater than 1000 ng/dL is diagnostic for congenital adrenal hyperplasia 
      • Level less than 200 ng/dL usually excludes congenital adrenal hyperplasia
      • If level falls between 200 and 1000 ng/dL, perform additional testing with corticotropin-stimulated measurements of 17-hydroxyprogesterone 
        • Retesting after corticotropin stimulation is necessary in case of indeterminate results
  • Additional testing should be included as part of the initial assessment
    • In children presenting with growth acceleration, determine bone age with radiograph of left hand and wrist
    • In women presenting with hirsutism, document extent of body hair as defined by the modified Ferriman-Gallwey scoring system 
      • Useful method to assess magnitude of hair growth and monitor subsequent responses to treatment
    • Ancillary hormone testing for anyone with suspected diagnosis of congenital adrenal hyperplasia
      • Total testosterone and sex hormone–binding globulin (or free testosterone by equilibrium dialysis) 
      • Androstenedione 
      • Serum DHEA-S (dehydroepiandrostenedione-sulfate) 
  • Genetic testing is informative in select situations 
    • Molecular genetic analysis of the CYP21A2 gene can be used to confirm diagnosis in cases that remain equivocal after hormonal testing and corticotropin stimulation 
    • After biochemical diagnosis of nonclassic type, CYP21A2 genotyping can be offered to patients to detect compound heterozygosity for severe alleles that may result in classic congenital adrenal hyperplasia—the more severe form of the disease—in their progeny 
  • Measure additional hormones in the adrenal steroid biosynthesis pathway when atypical forms of nonclassic disease are under consideration 
    • Biochemical hormonal evaluation of nonclassic 11β-hydroxylase deficiency 
      • Baseline and corticotropin-stimulated measurements of 11-deoxycortisol, deoxycorticosterone, and cortisol
    • Biochemical hormonal evaluation of nonclassic 3β-hydroxysteroid dehydrogenase deficiency 
      • Baseline and corticotropin-stimulated measurements of 17-hydroxypregnenolone and cortisol
    • Biochemical hormonal evaluation of lipoid congenital adrenal hyperplasia 
      • Measurements of cortisol, aldosterone, plasma renin activity, and gonadal steroids
  • Other than to estimate bone age, imaging is not a standard part of the diagnostic work-up for nonclassic disease (advised against by the Endocrine Society), but various imaging studies might be used to investigate other conditions that fall within differential diagnosis 

Laboratory

  • 17-hydroxyprogesterone
    • Preferred method is liquid chromatography or tandem mass spectrometry 
    • Basal 17-hydroxyprogesterone level less than 200 ng/dL usually excludes diagnosis while basal level greater than 1000 ng/dL strongly suggests diagnosis of nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 
      • Exercise caution against automatically relying on baseline 17-hydroxyprogesterone level to exclude nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, because mild defects may have only minimally elevated levels, especially in the afternoon, leading to false-negative results and diagnoses 
        • Relying only on basal levels will miss diagnosis in approximately 10% of cases 
    • Level between 200 to 1000 ng/dL requires further testing with corticotropin stimulation 
      • Post–corticotropin stimulation levels of 17-hydroxyprogesterone over 1000 to 1500 ng/dL confirm diagnosis of nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 
        • In classic disease, post–corticotropin stimulation level of 17-hydroxyprogesterone most often exceeds 10,000 ng/dL 
    • If basal level is greater than 1000 ng/dL, corticotropin stimulation is unnecessary
  • Serum cortisol
    • Obtain to ensure adequacy of glucocorticoid reserves
    • Measure baseline cortisol level and corticotropin-stimulated cortisol level
    • Serum cortisol levels are within reference range (at least 18 mcg/dL) after corticotropin stimulation in most patients with nonclassic disease. Exceptions include:
      • Patients with nonclassic lipoid congenital adrenal hyperplasia, who develop adrenal insufficiency after infancy
      • Some patients with 21-hydroxylase deficiency have slightly reduced glucocorticoid reserve, defined as a cortisol response to corticotropin that is slightly impaired (14-18 mcg/dL)
      • It is uncommon for a patient with nonclassic 21-hydroxylase deficiency to have a subnormal cortisol level after corticotropin stimulation
        • Rarely, there may be some patients that straddle the classic/nonclassic boundary and might benefit from chronic low-dose glucocorticoid therapy 
  • 11-deoxycortisol and deoxycorticosterone
    • Elevated serum 11-deoxycortisol and deoxycorticosterone concentrations after corticotropin stimulation are diagnostic of 11-hydroxylase deficiency
      • Obtain baseline cortisol level and corticotropin-stimulated cortisol level 
        • Cortisol level should be at least 18 mcg/dL after corticotropin stimulation
      • Nonclassic 11β-hydroxylase deficiency is suggested when 11-deoxycortisol level is greater than 1800 ng/dL and cortisol level is at least 18 mcg/dL 
  • 17-hydroxypregnenolone
    • Nonclassic 3β-hydroxysteroid dehydrogenase deficiency is suggested when post–corticotropin stimulation levels of 17-hydroxypregnenolone are greater than 3000 ng/dL 
    • Obtain baseline cortisol level and corticotropin-stimulated cortisol level
      • Cortisol level should be at least 18 mcg/dL after corticotropin stimulation 
  • Serum testosterone
    • Testosterone is the most useful, clinically sensitive marker of androgen excess in women
    • Assess testosterone concentration using total testosterone level with sex hormone–binding globulin level or by using testosterone that is measured by equilibrium dialysis 
      • Bioavailable testosterone can be calculated from total testosterone and sex hormone–binding globulin 
    • Utility of serum testosterone depends on use of an accurate, specific assay with well-defined reference intervals 
      • The most accurate and specific assays use mass spectrometry 
        • Reference range values are standardized for early morning, when levels are the highest; in women, they are standardized for the follicular phase of the menstrual cycle (days 4-10)
      • Automated immunometric assays used in most hospital laboratories do not accurately measure testosterone at the low levels found in women 
  • Serum androstenedione
    • Levels are elevated in nonclassic form of disease 
      • In normal females, androstenedione is secreted from both the adrenal cortex and the ovaries, but in 21-hydroxylase deficiency most androstenedione is of adrenal origin 
    • Levels are also increased in any condition of adrenal androgen excess; therefore, elevation is nonspecific
  • Serum DHEA-S
    • Levels are generally elevated in nonclassic form of disease 
  • Serum aldosterone 
    • Order for suspected nonclassic lipoid congenital adrenal hyperplasia; low levels may be diagnostic
  • Plasma renin activity 
    • Order for suspected nonclassic lipoid congenital adrenal hyperplasia; elevated plasma renin activity may be diagnostic
  • Molecular genetic analysis
    • Analysis of the CYP21A2 gene, which encodes 21-hydroxylase, may be used to confirm diagnosis of nonclassic congenital adrenal hyperplasia 
      • When post–corticotropin-stimulated 17-hydroxyprogesterone levels fall near but less than the cutoff range of 1000 ng/dL (equivocal range), genetic testing is indicated to verify diagnosis
    • Some experts also propose that genetic analysis (along with genetic counseling) should be offered to all patients with biochemically confirmed nonclassic disease, because these patients frequently carry alleles that may result in classic disease (more severe form) in their progeny 
    • Genetic analysis can be a useful adjunct to newborn screening for family studies, and to accurately distinguish between heterozygous mutation carriers and affected patients
    • Commercial sequencing is available for the major genes involved in nonclassical disease, but it is mostly used for 21-hydroxylase deficiency 
      • Mutational analysis of CYP21A2 detects 90% to 95% of mutant alleles for 21-hydroxylase deficiency 
    • Sequencing of other genes is also commercially available
      • CYP11B1 (11β-hydroxylase deficiency)
      • HSD3B2 (3β-hydroxysteroid dehydrogenase deficiency)
      • STAR, encoding steroidogenic regulatory protein (lipoid congenital adrenal hyperplasia)

Imaging

  • Radiograph of left hand and wrist 
    • Indicated to estimate bone age in children presenting with growth acceleration 
    • Most commonly used methods of scoring skeletal maturity are the Tanner-Whitehouse and Greulich-Pyle methods
      • Greulich-Pyle method is most commonly used by pediatric radiologists and endocrinologists in the United States while the Tanner-Whitehouse method is favored among European endocrinologists; accuracy of the 2 are comparable 
      • Advanced bone age is defined as 2 standard deviations above the mean for chronologic age
      • Pediatric endocrinologists often prefer to evaluate bone age radiographs directly; readings performed by radiologists less experienced with bone age estimation may differ from readings by clinicians with expertise in interpretation of bone age radiographs 
    • Nonclassic congenital adrenal hyperplasia may be associated with advanced bone age and is a presenting sign of various forms in late childhood 
    • Rapidly advancing bone age can also represent a normal variant or be caused by any condition that accelerates the onset of puberty, including obesity and idiopathic premature adrenarche, although the bone age is typically not as advanced as in nonclassic congenital adrenal hyperplasia

Functional testing

  • Corticotropin (cosyntropin) stimulation test 
    • Standard diagnostic procedure for all forms of congenital adrenal hyperplasia
    • Perform test in the morning before 8 AM; in menstruating females, this must be done during follicular phase of menstrual cycle
    • At start of test (time = 0), draw baseline levels of cortisol and 17-hydroxyprogesterone
      • When testing for 11β-hydroxylase deficiency, also measure baseline 11-deoxycortisol and deoxycorticosterone levels
      • When testing for 3β-hydroxysteroid dehydrogenase deficiency, also measure baseline levels 17-hydroxypregnenolone
    • At start of test (time = 0), administer 250 mcg IV bolus of synthetic corticotropin
    • 1 hour after bolus (time = 60 minutes), draw blood samples to measure adrenal cortex hormone concentrations
      • Measure corticotropin-stimulated cortisol level for all considerations
      • For 21-hydroxylase deficiency, measure corticotropin-stimulated levels of 17-hydroxyprogesterone
      • For 11β-hydroxylase deficiency, measure corticotropin-stimulated levels of 11-deoxycortisol and deoxycorticosterone
      • For 3β-hydroxysteroid dehydrogenase deficiency, measure corticotropin-stimulated levels of 17-hydroxypregnenolone
    • Test interpretation
      • Diagnostic 17-hydroxyprogesterone level for nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency is 1000 ng/dL (approximately 3 times upper reference limit of 17-hydroxyprogesterone concentrations observed in unaffected women) 
      • Level of 17-hydroxypregnenolone level for nonclassic congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiency is typically greater than 3000 ng/dL 
      • Cortisol level should be at least 18 mcg/dL after corticotropin stimulation test; subnormal response is uncommon in all forms except for lipoid congenital adrenal hyperplasia
        • Late-onset adrenal insufficiency is standard for lipoid congenital adrenal hyperplasia
        • Corticotropin-stimulated cortisol level less than 18 mcg/dL indicates at least partial adrenal insufficiency 

Other diagnostic tools

  • Ferriman-Gallwey score
    • Modified Ferriman-Gallwey score is the gold standard method for evaluating hirsutism 
      • Scale evaluates magnitude of hair growth in 9 androgen-dependent areas: upper lip, chin, upper chest, upper arms, upper and lower abdomen, tights, upper and lower back 
      • These body areas are assigned a score from 0 (absence of terminal hairs) to 4 (extensive terminal hair growth), and these separate scores are totaled to provide a hormonal hirsutism score 
      • Variation among different ethnic groups should be taken into consideration 
    • Ferriman-Gallwey total scores that define hirsutism in women of reproductive age are as follows: 
      • United States and United Kingdom black or white women: 8 or higher
      • Mediterranean, Hispanic, and Middle Eastern women: 9 to 10
      • South American women: 6 or higher
      • Asian women:
        • 2 or higher for Han Chinese women
        • 7 or higher for southern Chinese women
    • Ferriman-Gallwey scores range widely from 11 to 40 in patients with nonclassic 21-hydroxylase deficiency 

Differential Diagnosis

Most common

Treatment Goals

  • Children
    • Slow skeletal maturation and achieve normal height
  • Adolescents
    • Eliminate or lessen severity of acne and reduce signs of hirsutism
  • Adults
    • Mitigate hirsutism and acne
    • Restore fertility
      • When using glucocorticoids, avoid excessive dosing that could result in iatrogenic Cushing syndrome and its complications (eg, reduced bone mineral density) 

Recommendations for specialist referral

  • Endocrinologist
    • For all patients, refer to guide diagnostic testing, interpret results, and manage therapy for symptomatic conditions 
    • For patients experiencing infertility, refer to reproductive endocrinologist 
    • For pregnant patients, refer to endocrinologist familiar with managing congenital adrenal hyperplasia 
  • For patients who plan to conceive, refer to genetic counselor to determine risk that progeny will inherit a severe mutation 

Treatment Options

Treatment of nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency is based on the specific health concern and age range

  • Adult nonpregnant women
    • Treat individually according to symptoms; do not treat asymptomatic nonpregnant patients 
    • Consider treating in cases of patient-important hyperandrogenism (impacting quality of life) or infertility 
      • Major issues related to hyperandrogenemia are menstrual irregularity, hirsutism, and acne
      • Patient-important concept refers to acne, or unwanted sexual hair growth of any degree that causes sufficient distress for women to seek treatment 
      • Base decision to treat on discussion of benefits and harms, and in accordance with patient wishes 
    • Do not prescribe routine glucocorticoid or mineralocorticoid replacement to women with nonclassic congenital adrenal hyperplasia
      • Those with nonclassic 21-hydroxylase deficiency do not require adrenal corticosteroid replacement for normal health 
    • Infertility
      • Glucocorticoids are considered first line therapy to induce ovulation 
        • Prescribe a glucocorticoid that does not traverse the placenta (hydrocortisone)
        • Minimize duration of glucocorticoid therapy to accomplish the goal for the requisite period of time (eg, restoring fertility) 
      • Using clomiphene to induce ovulation is reserved for cases where glucocorticoid therapy fails
    • Hirsutism and acne
      • Treatment regimens may need to incorporate pharmacologic therapies, cosmetic procedures, and psychological support
      • Oral contraceptives with or without an androgen antagonist (eg, antiandrogens such as spironolactone) are first line therapy to treat hirsutism 
        • A reasonable approach is to start with an oral contraceptive, then add an antiandrogen after 6 months if response is suboptimal 
        • Women must use adequate contraception if antiandrogen monotherapy is used
        • All formulations of oral contraceptives are essentially equally effective for hirsutism 
          • For women with hirsutism and high risk for venous thromboembolism (eg, those who are obese or older than 39 years), prescribe an oral contraceptive containing the lowest effective dose of ethinyl estradiol (20 mcg) and a low-risk progestin (ie, levonorgestrel or norgestimate) 
        • All androgen antagonists appear to be similarly effective; however, flutamide is not recommended owing to risk of hepatotoxicity 
      • Remission of hirsutism is difficult with glucocorticoid monotherapy 
        • Oral contraceptives and androgen antagonists are often more effective for treating hirsutism in women with nonclassic congenital adrenal hyperplasia 
      • For all pharmacologic methods, a trial of 6 months is necessary to fully evaluate efficacy 
      • Consider adding topical (eg, eflornithine cream) or direct hair removal methods for women who desire additional cosmetic benefit 
    • Irregular menses or oligomenorrhea
      • Oral contraceptives are a treatment option, instead of glucocorticoid therapy, to restore regular cycles since they provide contraception and do not lead to cushingoid effects 
  • Late childhood and adolescent females
    • Prescribe glucocorticoid treatment for the subset of patients in whom nonclassic congenital adrenal hyperplasia is diagnosed starting in late childhood, in the following situations: 
      • Inappropriately early onset and rapid progression of adrenarche
        • Consider treating early onset of body hair and body odor only when bone maturation is sufficiently accelerated to adversely affect future height
        • Option to withhold treatment with careful monitoring if there is premature pubarche without advanced bone age
      • Evidence of accelerated bone age
      • Adolescents with overt virilization
      • Adolescent females with irregular menses and acne
        • Glucocorticoid treatment for 3 months is often effective in regulating menses and reducing acne
        • Hirsutism does not respond well to glucocorticoid monotherapy, and if this is the main concern, an oral contraceptive with or without an antiandrogen medication is a better option
    • Guidelines suggest that children who are treated for nonclassic congenital adrenal hyperplasia should be given the option of tapering or discontinuing therapy once near-adult height is attained 
  • Adolescent or adult males
    • Do not routinely treat with daily glucocorticoid therapy 
    • Exceptions include cases complicated by infertility or testicular adrenal rest tumors 
      • Testicular adrenal rest tumors are not typically seen in patients with nonclassical congenital adrenal hyperplasia
  • General supportive care of 21-hydroxylase deficiency
    • Offer genetic counseling to patients considering conception 
    • Implement efforts to educate patients during transition from pediatric care to adult care
    • Offer psychological counseling to promote a healthy self-image and help patients cope with psychosocial issues that can affect adherence to medical therapy 

Drug therapy

  • Glucocorticoids
    • Hydrocortisone
      • Note: Dosing is individualized according to severity of symptoms and response to therapy 
      • Children
        • Treat only the subset of patients with nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency if there are signs of precocious puberty and advanced bone age
        • Recommended dosing of glucocorticoids is substantially lower for nonclassic congenital adrenal hyperplasia compared to classic disease 
        • During childhood, the preferred glucocorticoid is hydrocortisone because its short half-life minimizes the adverse effects typical of longer-acting, more potent corticosteroids, especially growth suppression 
          • Hydrocortisone Oral tablet; Adolescents and Children: initially, 6 mg/m²/day PO given in 3 divided doses; individualize doses to minimize symptoms of adrenal insufficiency while avoiding growth retardation and cushingoid symptoms that occur with overdosage. 
      • Adults
        • Recommended dosing of glucocorticoids is substantially lower for nonclassic congenital adrenal hyperplasia compared to classic disease 
          • Hydrocortisone Oral tablet; Adult females: 20 mg/day PO given in 2 divided doses. Individualize and adjust dosing according to severity of symptoms, response to therapy, and stress level. 
    • Prednisone
      • Dosing is individualized according to severity of symptoms and response to therapy 
      • Children
        • Treat only the subset of patients with nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency if there are signs of precocious puberty and advanced bone age
        • Recommended dosing of glucocorticoids is substantially lower for nonclassic congenital adrenal hyperplasia compared to classic disease 
        • During childhood, the preferred glucocorticoid is hydrocortisone because its short half-life minimizes the adverse effects typical of longer-acting, more potent corticosteroids, especially growth suppression 
          • Prednisone Oral solution; Children and Adolescents: Dosing should be individualized and under the guidance of a specialist. NOTE: Hydrocortisone is the preferred glucocorticoid in infants.
      • Adults
        • Treat only the subset of patients with nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency if there is infertility
        • Recommended dosing of glucocorticoids is substantially lower for nonclassic congenital adrenal hyperplasia compared with classic disease 
          • Prednisone Oral tablet; Adults: initially, 1 mg PO daily at bedtime. Dose to be individualized according to severity of symptoms and response to therapy. 
    • Dexamethasone
      • Only used for specific situations in adults 
        • For management of testicular adrenal rest tumors in adult males
          • Dexamethasone Oral tablet; Adult males: 0.25 mg PO twice daily. 
        • For management of women with nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency with very prominent androgen excess, irregular menses, and infertility, using a low dose at night
          • Dexamethasone Oral tablet; Adult females: 0.25 mg PO at bedtime given every other day or 3 days a week. 
  • Antiandrogens
    • Spironolactone 
      • Spironolactone Oral tablet; Adult females: 50 to 200 mg/day PO in 1 or 2 divided doses.
    • Finasteride
      • Finasteride Oral tablet [Alopecia]; Adult, non-pregnant women: 5 mg PO once daily either alone or in combination with oral contraceptives shown to reduce hirsutism in women with mild hirsutism; minimal adverse reactions compared to other antiandrogens.
  • Eflornithine cream
    • For cosmetic management of unwanted facial hair
      • Eflornithine Hydrochloride Topical cream [Cosmetic Use]; Adult, Geriatric, and Adolescent females: Apply a thin layer twice daily, at least 8 hours apart, to affected facial area(s).

Nondrug and supportive care

  • Genetic counseling
    • Recommended for all patients considering conception, owing to elevated risks associated with bearing a child with congenital adrenal hyperplasia (classic or nonclassic) 
      • Children of women with nonclassic 21-hydroxylase deficiency have about 2.5% risk of being born with classic 21-hydroxylase deficiency disease and a 15% risk for having nonclassic disease 
  • Psychological therapy can help patients cope with an impaired body image and issues of sexuality that result from a disordered sex development 
    • Offer psychological support for cosmetic concerns (eg, significant hirsutism and acne), which can be deeply distressing to patients and result in adverse effects on psychological well‐being and quality of life 
  • Cosmetic treatments for hirsutism
    • Methods of direct hair removal include depilation and epilation
      • Shaving is a depilation method that removes hair down to just below the surface of the skin; shaving does not affect the rate or duration of the anagen phase or diameter of hair
      • Chemical depilatory agents, which are commonly used to dissolve the hair, are effective but contain sulfur and have an unpleasant odor
      • Epilation methods (eg, plucking, waxing) are safe and inexpensive, but cause some discomfort
    • Bleaching with products containing hydrogen peroxide and sulfates masks the presence of undesired hair, particularly facial hair
    • Topical products to slow hair growth (ie, eflornithine) are modestly effective, but effects are limited to short term 
    • Long-term methods to remove hair include electrolysis, laser therapy, and intense pulsed-light therapy 

Special populations

  • Pregnant women
    • Refer pregnant women with nonclassic congenital adrenal hyperplasia to an endocrinologist
    • Use a glucocorticoid to treat women with nonclassic disease and infertility or history of miscarriage 
      • Hydrocortisone and prednisone are preferred because they are easily metabolized by the placenta
      • Avoid dexamethasone, which crosses the placenta and may have a long-term adverse impact on fetal intellectual development
    • Advise women with congenital adrenal hyperplasia (nonclassic or classic) who are using a glucocorticoid before pregnancy to continue regimen and maintain prepregnancy doses 
      • Retrospective series report high rates of pregnancy loss in women with nonclassic 21-hydroxylase deficiency, but rates are lower in women who were treated with glucocorticoids 
      • If a woman affected with nonclassic congenital adrenal hyperplasia becomes pregnant in the absence of glucocorticoid treatment, she need not be treated during pregnancy 
    • Individualize treatment 
      • Adjust glucocorticoid doses throughout pregnancy, particularly in the second and third trimesters, if symptoms and signs of adrenal insufficiency occur 
        • Glucocorticoid dosage increase of 20% to 40% from 24th week of gestation onward may be beneficial 
      • Prescribe stress doses of glucocorticoids during labor and delivery
      • If glucocorticoids are used, monitor glucose tolerance throughout pregnancy 
  • Patients with major illness
    • Consider stress dosing with glucocorticoids if a patient becomes critically ill under the following circumstances: 
      • There is documentation of inadequate response to corticotropin stimulation testing (this occurs in a minority of nonclassic cases), or
      • Patient has been using daily replacement or supraphysiologic doses of glucocorticoids in other contexts rendering them with iatrogenic adrenal suppression
    • Situations that warrant stress dose of glucocorticoids include febrile illness (greater than 38.5°C), gastroenteritis with dehydration, surgery accompanied by general anesthesia, and major trauma 
    • Instructions for prescribing stress glucocorticoid dosage are as follows:
      • Increase maintenance dose 2- to 3-fold for duration of stress period 
      • For a surgical procedure, a total of 5 to 10 times the daily maintenance dose may be required for the initial 24 to 48 hours 
      • Do not prescribe dexamethasone because of its delayed action 
      • Taper to maintenance doses when patient is stable
    • Do not prescribe glucocorticoid replacement during severe stress in previously untreated adults with nonclassic congenital adrenal hyperplasia, unless there is clear prior documentation that their adrenal function is suboptimal based upon a subnormal cortisol response after corticotropin stimulation 
    • Do not increase glucocorticoid doses for mental and emotional stress, minor illnesses, or for use before physical exercise 

Monitoring

  • Children
    • Monitor growth velocity, body weight, and bone age every 4 to 6 months 
    • For children treated with glucocorticoids, monitor for overreplacement (eg, weight gain, central obesity, striae)
  • Adolescents and adults
    • Regularly monitor severity of excess body hair using the modified Ferriman-Gallwey scoring system 
    • Annually measure levels of 17-hydroxyprogesterone, androstenedione, and testosterone 
      • Maintain androstenedione and testosterone levels within the age-adjusted reference range
      • In females, target ratio of testosterone to sex hormone–binding globulin: less than 0.05
      • If glucocorticoids are used, do not aim to normalize 17-hydroxyprogesterone as this results in overtreatment and risk of cushingoid adverse effects 
    • Monitor bone density periodically in patients treated with glucocorticoids if:
      • Glucocorticoids are used at an equivalent of 0.5 mg dexamethasone daily or higher 
      • Any glucocorticoid preparation is used for a prolonged period of time at higher than average replacement dosing 
      • Patient experiences a nontraumatic fracture 

Complications

  • Optimal therapeutic regimens are difficult to achieve, and often short- and long-term complications related to glucocorticoid and/or androgen excess arise, reflecting over- or undertreatment 
  • Overtreatment with glucocorticoids is common, leading to the development of iatrogenic cushingoid features (hypercortisolism) 
    • These problems include reduced bone mineral density and increased risk for cardiovascular disease, metabolic syndrome, and type 2 diabetes 
      • Osteoporosis may result in increased incidence of bone fractures
    • Gestational diabetes mellitus occurs in over 20% of pregnant women with 21-hydroxylase deficiency 
  • Testicular adrenal rest tumors associated with 21-hydroxylase deficiency can occur in men, albeit rarely 
    • Frequently observed in men with classic form of disease, but these tumors have also been observed in nonclassic form 
  • Infertility
    • Up to 30% of women with nonclassic disease have subfertility or infertility 
      • May be reversed by glucocorticoid therapy 
    • Most men with nonclassic disease are not infertile; however, isolated cases of oligospermia and subfertility have been reported in some men with nonclassic 21-hydroxylase deficiency 
  • Miscarriage
    • Women with nonclassic disease have a higher rate of miscarriage than those who are not affected (greater than 25% versus 10%-15%) 
  • Psychosocial consequences
    • Hyperandrogenic signs can cause anguish in many patients 
      • Severe acne in adolescents is often disabling, causing young patients to withdraw from social function
      • Hirsutism and loss of scalp hair in females and males are embarrassing

Prognosis

  • There is a paucity of natural history studies on nonclassic congenital adrenal hyperplasia
    • Long-term outlook for people with nonclassic 21-hydroxylase deficiency is generally good 
    • Mortality does not appear to be increased in nonclassic disease 
    • However, classic congenital adrenal hyperplasia is associated with increased mortality 
  • Quality of life may be reduced for adults with congenital adrenal hyperplasia, depending on glucocorticoid treatment and other health outcomes 
    • Increased adiposity, development of insulin resistance, and use of glucocorticoids are factors that contribute to impaired quality of life 

Screening

At-risk populations

  • Progeny of patients with nonclassic congenital adrenal hyperplasia
    • Children of women with nonclassic 21-hydroxylase deficiency have about 2.5% risk of being born with classic 21-hydroxylase deficiency disease and a 15% risk for having nonclassic disease 
    • The same increased risk theoretically applies equally to children born to fathers with nonclassic 21-hydroxylase deficiency, but data for male parents are lacking 

Screening tests

  • If an affected prospective parent is known to have nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, preconception genetic testing can help families to understand the risk of affected offspring 
    • To refine risk, CYP21A2 genotyping is recommended for the known affected parent (if not already done) before pregnancy planning
    • Genetic testing of the second parent determines whether the progeny are at risk of inheriting a mutant allele from each parent
  • All newborns in the United States (and in many other developed countries) are screened for congenital adrenal hyperplasia 
    • Screening method uses 17-hydroxyprogesterone measurement, primarily to detect 21-hydroxylase deficiency

Sources

El-Maouche D et al: Congenital adrenal hyperplasia. Lancet. 390(10108):2194-210, 2017 Reference

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