Congenital Adrenal Hyperplasia and Androgen Insensitivity Syndrome

Question 1

Congenital Adrenal Hyperplasia (CAH)

Answer 1

• A group of autosomal recessive disorders that involve a deficiency of an enzyme involved in the synthesis of cortisol, aldosterone, or both
  
  • Mutation or deletion of CYP21A resulting in a deficiency of 21-hydroxylase is the msot common cause of CAH (90%). However, a mutation or deletion of any of the genes that code for enzymes involved in production of cortisol or aldosterone can result in CAH.

Question 2

Pathophysiology of CAH

Answer 2

• The severity of the clinical manifestation depends on the degree of the cortisol and/or aldosterone deficiency.
• Manifestations are due to the accumulation of precursor adrenocortical hormones. When these hormones are found in excess they result in excess androgen prodction, resulting in virillization or (due to mineralocorticoid properties) cause soidum retention and hypertension. (The lack of cortisol results in a feedback loop that stimulates the pituitary (ACTH) to produce more cortisol, this futher enhances the buildup of precursors, resulting in more androgen production).

Question 3

Types of CAH

Answer 3

• Two copies of the abnormal gene are needed for the disease to occur and phenotypes can vary from a mild form that is only expressed in adolescence or adulthood (noncalssic adrenal hyperplasia) to a severe form that results in adrenal insufficiency in infancy with or without virilization and salt wasting (classic adrenal hyperplasia).
• Classic can futher be divided into salt wasting and simple virilizing.

Question 4

General Presentation of CAH classical

Answer 4

• This is a severe form of CAH. Patients with classical CAH present in the neonatal period and early infancy with adrenal insufficiency with or without salt-losing, or as toddlers with virilization.
• Females (both salt-losing and non-salt-losing) will present with genital ambiguity.
• Males with salt-losing who are not identified by neonatals screening may experience failure to thrive, dehydration, hyponatremia, and hyperkalemia at 7-14 days.
• Males with non-salt-losing present at 2-4 years with early virilization (pubic hair, growth spurt, adult body odor).

Question 5

Presentation of CAH classical

1. Genitalia
2. Growth
3. Sexual Behaviour
4. Reproduction

• Female
• Male

Answer 5

1. Females will have atypical genitalia - clitoral enlargement, labial fusion, and formation of the urogenital sinus.
2. Children are at risk for early pubery and adult short staute (high levels of sex hormones can cause early puberty and premature epiphyseal closure).
3. In female patients the excess androgen exposure can influence the brain - more male-typical play, more cross-gender role behaviour, fewer sexual experiences with men, etc.
4. • Female - fertility rates tend to be low
   • Male - reproduction may be impaired. May have testicular masses made up of adrenal tissue (testicular adrenal rest tumors - may obstruct the seminiferous tubules leading to gonadal dysfunction and infertility).

Question 6

Presentation CAH nonclassical

Answer 6

• Children may present after neonatal period with hyperandrogenism - premature pubarche, medication resistant cystic acne, accelerated growth, and tall stature as children.
• Females - acne, hirsutism, menstral irregularity, reduced fertility (not as low as in classic), and higher rates of spontaneous abortion.
• Males - short stature, may have testicular rests and infertility (not as common as in classic).

Question 7

CAH goals of therapy

Answer 7

• Target of therapy is to provide sufficienct glucocorticoids to reduce excess secretion of CRH and ACTH and resultant hyperandrogenemia so that growth, sexual maturation, and reproduction are normal.
• If patient has salt-losing form, a mineralcortcoid is given to restore serum electrolyte concentration and extracellular fluid volume.

Question 8

Treatment CAH neonates

Answer 8

• Hydrocortisone (glucocorticoid replacement) and fludrocortisone (mineralcorticoid replacement).
• Adrenal crisis - occurs less frequently due to mandatomy newborn screening for CAH. But, if it occurs treat the hypotension and dehydration; reveral of electrolyte and glucose abnormalitie , and correction of cortisol deficiency (IV saline + glucose and insulin if hyperkalemic + hydrocortisone).

Question 9

Treatment of CAH children

Answer 9

• Glucocorticoid - can switch from hydrocortisone to dexametasone or prednisone (needs fewer doses, but can’t be given at young age due to potential of restricting growth).
• Mineralocorticoid and sodium chloride - mineralcorticoid replacement is recommended treatment for classic CAH (whether or not it is salt losing)
  
  • Flodrocortisone - give in dose sufficient to restore normal serum sodium and potassium
  • Salt-tablets/solutions - can be stopped once child eats table food. Child may need excess salt in hot weather or with intense exercise.

Question 10

Diagnosis of CAH

Answer 10

• Atypical genitalia
  
  • 46XX females are borne with clitoral enlargment, labial fusion, and formation of urogential sinus.
  • 46XY males may appear normal at birth or have subtle findings of hyperpigmentation of scrotum or an enlarged phallus.
• 210HD CAH - can be diagnosed based on high serum concentrations of 27-hydroxyprogesterone (17OHP). Most countries do neonata screening for this.

Question 11

Embryologic development of sexual characteristics

Answer 11

• During embryonic development there is as stage where the embryo is sexually indifferent and has the ability to develop either male of female strucutre.
• There are 2 primitive ducts that can develop into either male or female reproductive tracts
  
  1. Wolffian duct - develops into epididymis, vas deferences, seminal vesciles, and ejaculatory duct
  2. Mulleriuan duct - develops into fallopian tubes, uterus, and upper part of the vagina
• Sexual differentiation starts with sexual determination, depending upon the chromosome of the fetus

Question 12

Sexual differentiation

Answer 12

• Sexual differentiation involved specification of the gonads as either testes or ovaries. Starts at 5 weeks.
• XY - SRY gene (sex determinaing region of Y) will be present. Proteins produced by SRY activates a gene network that will result in development of testes. Once the testes start to develop, the support cells in the testes differentiate and direct sexual differentiation.
• XX - no SRY gene. Gonades will develop as ovaries. Ovarian development occurs in the absence of SRY gene, but does not occur by default. Several genes are necessary to initiate ovarian development and to suppress the gene network responsible for testis development.

Question 13

External Genitalia Development

Answer 13

• Starts at 5 weeks at the sexually indifferent stage. At this point the embryo has primitive structres that will develop into either male or female external genitalia.
  
  • Genital tubercle = clitoris or glands penis
  • Labioscrotal swelling = labia major or scrotum
  • Urogential folds = labial minor and urethra
• Typically male - By 10 weeks, if androgens are present (specifically DHT) the urethral folds will meet up and seal. The labioscrotal swellings “swell” towrds each other and the tip of the genital tubercle becomes the glans penis. At this point you still don’t have a proper urethra, just a urogenital sinus. Next, the labioscrotal swellings continue to swell and become the scrotum with the formation of the midline raphe. The urethral folds seal off and now empty into the glands penis. (Testicles will not fully move down into the scrotum until the 3rd trimester).
• Typically female - a lack of DHT makes it so the labioscrotal swellings don’t fuse and it becomes the labia majora. The urogential folds do not meet and become the vestibule and labia minoria. Finally, the genital tubercle becomes the cliteroris.

Question 14

Androgen Insensitivity Syndrome (AIS)

Answer 14

• AIS is an X-linked recessive condition that results in a lack of normal masculinization of external genitalia in XY individuals.
  
  • Can either be complete androgen insensitivity syndrome (CAIS) or partial androgen insensitivity syndrome (PAIS) depending on the amount of residual receptor function.
• In AIS, patients ave normal tests, normal testosterone production, and normal conversion to DHT (dihydrotestosterone). The tests produce the normal amount of mullerian-inibiting substance and thus patients have no mullerian and no wolffian structures (they have testes because this is not part of woliffian, but part of SRY).

Question 15

Complete AIS

Answer 15

• Patients with CAIS have 46XY karyotypes and present with female external genitalia (normal labia, clitoris, and vaginal introitus).

Question 16

Partial AIS

Answer 16

• The phenotypes of patients with PAIS may vary from midly virilized female external genitalia (ex. clitoromegaly) to midly undervirilized male external genitalia (ex. hypospadias and/or diminshed penile size).

Question 17

Pathophysiology of AIS

Answer 17

• Due to a loss of function mutation in the androgen receptor (AR) gene.
  
  • AR gene is located in the long arm of the X chromosome and many different mutations are possible - complete or partial gene deletions, point mutations, small insertions, etc.
• Depending on the mutation, you can have a variety of different defects from a complete loss of the androgen receptor to changes in the receptor binding affinity.
• Loss of androgen receptor function means that despite normal levels of androgen synthesis they cannot act on the tissues.

Question 18

Clinical features CAIS

Answer 18

• Infancy - may present with inguinal masses or hernias containing testes in an otherwise healthy female child; may be diagnosed after karyotyping reveals 46XY geneotype.
• Adolescence - may present in adolescence for primary amenorrhea and little to no axillary or pubic hair. Growth tends to follow that of a typical girl.
• Most report female gender identity.

Question 19

Clinical features PAIS

Answer 19

Can range from women with mild degrees of virilization to fertile but undervirilized men.

• Female phenotype with mild virilization
• Predominantly male phenotype
• Infertile male syndrome - slight undervirilization, gynecomastia and infertility.
• Undervirilized fertile male syndrome

Question 20

Investigations AIS

Answer 20

• Karyotype - may be necessary to differentiate an undermasculinized male from a masculinized female.
• Serum testosterone - in CAIS you would expect these women to have serum testosterone in the normal male range or above
• Capacity for testosterone synthesis - can administer hCG- most people with CAIS and PAIS should have normal serum testosterone response after hCG administration.
• Ratio of testosterone to DHT in serum - can be used to differentiate AIS from 5-alpha reducatsae deficiency (ratio is normal in AIS).
• Serum anti-mullerian hormone - would be in normal male range
• Pelvic ultrasound - can look for mullerian strucutres (would be absent in AIS).

Question 21

Management AIS

Answer 21

• Orchiopexy - removal of cryptochid testes. Can be delayed in CAIS females until after puberty safely. In PAIS female patients, testes should be removed before puberty to prevent virilization.
• Hormone replacement - for females with AIS, hormone therapy is indicated once testes are removed, or at the time of puberty if testes were removed before.
  
  • Females should be given low doses of estrogen to promote feminization and be gradually increased to full adult dose.
• Surgery of urogenital tract - in females, vaginal depth can be shallow. Patients can do dilator therapy, followed by vaginoplasty if they don’t get the desired result.