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Congenital adrenal hyperplasia (CAH)

Congenital adrenal disease causing defective steroidogenesis (glucocorticoids, mineralocorticoids, or sex steroids).

Congenital adrenal disease causing defective steroidogenesis (glucocorticoids, mineralocorticoids, or sex steroids).

  • Autosomal recessive inheritance
  • M/C cause of adrenal insufficiency in the pediatric age group
  • M/C inborn error in adrenal function

History:

In 1865, Luigi de Crecchio, a Neapolitan anatomist, reported the earliest documented description of a patient presumed to have 21-hydroxylase deficiency. At autopsy, the cadaver was described as having labioscrotal fusion, a 10 cm curved phallus with hypospadias, bilateral undescended testes, a vagina, a uterus, fallopian tubes, ovaries, and markedly enlarged adrenal glands. This individual had ambiguous genitalia at birth, reportedly presented as a male throughout his adult life, and presumably died of adrenal insufficiency in his 40s during an episode of vomiting, diarrhea, and prostration. Just over 100 years later in 1957, the nonclassic or mild form of 21-hydroxylase deficiency was described by Jacques Decourt, Max-Fernand Jayle, and Ettiene Baulieu.

El-Maouche, D., Arlt, W., & Merke, D. P. (2017). Congenital adrenal hyperplasia. Lancet (London, England), 390(10108), 2194–2210. https://doi.org/10.1016/S0140-6736(17)31431-9

Physiology

Adrenal gland endocrinology:

Three classes of steroid hormone are produced by the adrenal cortex after uptake of precursor cholesterol from the plasma: mineralocorticoids, glucocorticoids and sex steroids
  • Zona glomerulosa | Mineralocorticoids (aldosterone and deoxycorticosterone): Aldosterone secretion is principally under the control of the renin–angiotensin–aldosterone system and its action leads to enhanced uptake of sodium in the distal renal tubule following binding to the mineralocorticoid receptor.
  • Zona fasciculata | Glucocorticoids (cortisol and corticosterone): Secreted in response to stimulation by adrenocorticotrophic hormone (ACTH) and have wide-ranging effects mediated by the glucocorticoid receptors.
  • Zona reticularis | Androgens (sex steroids)

Steroidogenic pathway:

The glucocorticoid (cortisol), mineralocorticoid (aldosterone), and adrenal androgen synthetic pathways are the focus of the pathophysiology of CAH. ACTH binds to its receptor, the MC2R, which is a G-protein coupled receptor that increases adenylyl cyclase activity and cytoplasmic cAMP concentration (see Fig. 1). Increased cAMP then leads to an activation of StAR protein and an increase in cholesterol transport into the mitochondria.
The normal human steroidogenic pathway: Under normal conditions, the human adrenal cortex produces only small amounts of estrone, estradiol, testosterone, and adrenostenediol. The main adrenal secretory products are aldosterone (produced in the zona glomerulosa), and cortisol, dehydroepiandrosterone (DHEA), and androstenedione (produced in the zonae fasciculata and reticularis). | StAR, steroidogenic acute regulatory protein; P450scc, side-chain cleavage, HSD, hydroxysteroid dehydrogenase | Xu, S., Hu, S., Yu, X., Zhang, M., & Yang, Y. (2017). 17α‑hydroxylase/17,20‑lyase deficiency in congenital adrenal hyperplasia: A case report. Molecular Medicine Reports, 15, 339-344. https://doi.org/10.3892/mmr.2016.6029

Pathophysiology

Congenital adrenal hyperplasia (CAH:

Inadequate cortisol production in the fetus provides subnormal negative feedback inhibition of the fetal hypothalamus and pituitary. This leads to an increase in fetal plasma ACTH in an attempt to normalize fetal cortisol. The increase in fetal plasma ACTH increases StAR-mediated cholesterol transport into the mitochondria to acutely increase steroidogenesis in the fetal adrenal gland. In the long term, the increased ACTH leads to hyperplasia of the fetal adrenal cortex with a dramatic increase in size of the fetal adrenal gland. A consequence of this increased activity in the early steroidogenic pathway is an increase in the production of precursors for adrenal androgens (e.g., 17-α-OH-progesterone) upstream from the enzyme deficiency. This will lead to steroid precursor “spill-over” into the androgen pathway resulting in enormous increases in, for example, DHEA. Whereas DHEA is a relatively weak androgen under usual circumstances, the enormous increase in DHEA in an XX fetus can lead to virilization of the highly steroid sensitive genitalia during fetal development. As a result, an XX-fetus can be born with ambiguous genitalia
Mechanism of virilization in female fetuses with congenital adrenal hyperplasia. An enzyme defect (usually partial; in this case to P450c21) in the steroidogenic pathway leads to decreased production of cortisol and a shift of precursors into the adrenal androgen pathway. Because cortisol negative feedback is decreased, ACTH release from the fetal pituitary gland increases. Although cortisol can eventually be normalized, it is at the expense of ACTH-stimulated adrenal hypertrophy and excess fetal adrenal androgen production. | Widmaier EP, Raff H, Strang KT. Vander’s Human Physiology: The Mechanisms of Body Function. 13. McGraw-Hill; Boston: 2014. p. 609. figure 17.5.

Steroid 21-hydroxylase deficiency (M/C, 90% cases):

Function of 21-hydroxylating cytochrome P450 is deficient, creating a block in P450 cortisol production pathway. This leads to an accumulation of 17-hydroxyprogesterone (17-OHP), a precursor adjacent of the 21-hydroxylation step. Excess 17-OHP is then shunted into the intact androgen pathway, where the 17,20-lyase enzyme converts the 17-OHP to Δ4-androstenedione, the major adrenal androgen.
  • Classical form: Complete 23 hydroxylase deficiency
    • Salt wasting type: Severe form in which both coritsol and aldosterone deficient with excess androgens
    • Simple virilizing type: Impaired synthesis of cortisol and adequate amounts of aldosterone. Clinical features manifest solely due to excess androgens.
  • Non-classical form: Characterized by partial 21-hydrocylase deficiency in which normal levels of cortisol and aldosterone are present with excess androgen production
Clinical forms of CAH | Dessinioti, C., & Katsambas, A. (2009). Congenital adrenal hyperplasia. Dermato-endocrinology, 1(2), 87–91. https://doi.org/10.4161/derm.1.2.7818

Other enzyme deficiencies:

  • 11β-hydroxylase deficiency (#2 M/C): M/C enzyme deficiency leading to childhood hypertension
  • 17α-hydroxylase deficiency
  • 3β-HSD (hydroxysteroid dehydrogenase) deficiency
Types of congenital adrenal hyperplasia | Genetics of Congenital Adrenal Hyperplasia – Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Types-of-congenital-adrenal-hyperplasia_tbl1_314161316 [accessed 29 Jan, 2021]

Clinical features

Virilization of female genitalia:

Adrenocortical function begins at the 7th week of gestation; thus, a female fetus with classical CAH is exposed to adrenal androgens at the critical time of sexual differentiation (9-12 weeks gestational age). Androgens masculinize external female genitalia causing genital ambiguity

Seen in classical 21OHD and 11β-hydroxylase deficiency CAH

  • Clitoral enlargement
  • Fusion & scrotalization of labial folds
  • Phallus in the male position (d/t rostral migration of the urethral/vaginal perineal orifice)
Different degrees of virilization according to the scale developed by Prader [15]. Stage I: clitoromegaly without labial fusion Stage II: clitoromegaly and posterior labial fusion Stage III: greater degree of clitoromegaly, single perineal urogenital orifice, and almost complete labial fusion Stage IV: increasingly phallic clitoris, urethra-like urogenital sinus at base of clitoris, and complete labial fusion Stage V: penile clitoris, urethral meatus at tip of phallus, and scrotum-like labia (appear like males without palpable gonads) | New M, Yau M, Lekarev O, et al. Congenital Adrenal Hyperplasia. [Updated 2017 Mar 15]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK278953/
A, A 6-yr-old girl with congenital virilizing adrenal hyperplasia. The height age was 8.5 yr, and the bone age was 13 yr. B, Notice the clitoral enlargement and labial fusion. C, Her 5-yr-old brother was not considered to be abnormal by the parents. The height age was 8 yr, and the bone age was 12.5 yr. | (2021) Congenital Adrenal Hyperplasia and Related Disorders | Obgyn Key. Retrieved January 29, 2021, from https://obgynkey.com/congenital-adrenal-hyperplasia-and-related-disorders/
Three virilized females with untreated congenital adrenal hyperplasia. All were erroneously assigned male sex at birth, and each had a normal female sex-chromosome complement. Infants A and B had the salt-wasting form and received the diagnosis early in infancy. Infant C was referred at 1 yr of age because of bilateral cryptorchidism. Notice the completely penile urethra; such complete masculinization in females with adrenal hyperplasia is rare; most of these infants have the salt-wasting form. | (2021) Congenital Adrenal Hyperplasia and Related Disorders | Obgyn Key. Retrieved January 29, 2021, from https://obgynkey.com/congenital-adrenal-hyperplasia-and-related-disorders/

Normal internal female genitalia:

Females with CAH do not have testis and therefore do not produce anti-Müllerian hormone (AMH), which is produced by the testicular Sertoli cells. Internal female structures are Müllerian derivatives and are not androgen responsive.

Postnatal effects and growth: Central precocious puberty

Deficient postnatal treatment in boys and girls results in continued exposure to excessive androgens
  • Progressive penile/clitoral enlargement
  • Premature pubic hair (pubarche), axillary hair, acne
  • Rapid growth usually accompanied by premature epiphyseal maturation & closure (patient with CAH is a tall child but a short adult unless appropriate treatment is begun earlier in childhood)
  • Impaired fertility

Signs of hyperandrogenism:

  • Males:
    • Male-pattern alopecia (temporal balding)
    • Acne
  • Females:
    • Hirsutism: Excessive growth of coarse terminal hairs in androgen-dependent areas in women.
  • Menstrual irregularities
    • Polycystic Ovarian Syndrome (PCOS)
Modified Ferriman-Gallwey Scoring System. This semi-objective scoring system is based on observation of nine body areas including upper lip, chin, chest, arm, upper abdomen, lower abdomen, upper back, lower back, and thighs. The areas are scored from 1 (minimal terminal hairs present) to 4 (equivalent to a hairy man). If no terminal hairs are noted in the specific body area being examined the score is zero. Clinically terminal hair hairs can be distinguished from vellus hairs primarily by their length (i.e. greater than 0.5 cm) and the fact that they are usually pigmented | Ricardo Azziz, copyright 1997

Behavioral masculinization:

  • Reduced female gender satisfaction
  • Reduced heterosexual interest in adulthood
  • Gender dysphoria
  • No effect on cognitive abilities

Reduced fertility:

  • In females: D/t anovulation, secondary PCOS, irregular menses, non-suppressible serum progesterone levels, or an inadequate introitus)
  • In males: Reduced sperm counts and low testosterone (as a result of small testes d/t suppression of gonadotropins)

Diagnosis

Diagnosis of CAH must be suspected in infants born with ambiguous genitalia.

Hormonal screening:

  • 17-hydroxyprogesterone (17-OHP) blood levels (IOC for 21-hydroxylase deficiency)
  • 11-deoxycortisol (IOC for 11β-hydroxylase deficiency)
Podgórski, R., Aebisher, D., Stompor, M., Podgórska, D., & Mazur, A. (2018). Congenital adrenal hyperplasia: clinical symptoms and diagnostic methods. Acta biochimica Polonica, 65 1, 25-33 .

ACTH stimulation test:

GOLD STANDARD for hormonal diagnosis: 250 μg cosyntropin IV, measuring levels of 17-OHP and Δ4 androstenedione at baseline and 60 min
Nomogram relating baseline to ACTH-stimulated serum concentrations of 17-hydroxyprogesterone (17-OHP). The scales are logarithmic. A regression line for all data points is shown. Data points cluster as shown into 3 non-overlapping groups: classic and non-classic forms of 21-hydroxylase deficiency are readily distinguished from each other and from those that are heterozygotes and unaffected. Distinguishing unaffected from heterozygotes is difficult. | New MI, Lorenzen F, Lerner AJ, et al. 1983 Genotyping steroid 21-hydroxylase deficiency: hormonal reference data. J Clin Endocrinol Metab 57:320-6.

Management

The primary goal of treating classic CAH is to reduce the excess adrenal androgen production and replace the deficient hormones, namely cortisol and aldosterone. Proper treatment will prevent both adrenal crisis and ongoing virilization

Glucocorticoid (GC) & mineralocorticoid (MC) replacement therapies:

Mainstays of treatment
  • Glucocorticoid replacement: Life-long hydrocortisone (15-20 mg/m2/24hr orally in 3 divided doses)
  • Mineralocorticoid replacement: Fludrocortisone (higher dose in infants)
Algorithm of treatment, diagnosis and decision-making for prenatal treatment of fetuses at risk for 21-hydroxylase deficiency congenital adrenal hyperplasia. | Mercado AB, Wilson RC, Cheng KC, Wei JQ, New MI 1995 Extensive personal experience: Prenatal treatment and diagnosis of congenital adrenal hyperplasia owing to steroid 21-hydroxylase deficiency. J Clin Endocrinol Metab 80:2014-2020. Permission obtained.

Surgical management:

Indicated in significantly virilized females by the age of 2-6 months

Prenatal steroid therapy:

Indicated in pregnancies at risk (previously affected child). Steroid therapy is started as soon as pregnancy is diagnosed
  • Dexamethasone (20 μg/kg): Suppress secretion of steroids by fetal adrenals and prevent virilization of external genitalia of affected females.
    • Later chorionic villous biopsy is preformed to determine sex and genotype and therapy is continued only if fetus is female

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