CONGENITAL ADRENAL HYPERPLASIA

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CONGENITAL ADRENAL HYPERPLASIA

• Oscar Ingaramo. MD

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INTRODUCTION

• Is a family of AR disorders of cortisol
  biosynthesis.
• Cortisol deficiency increases secretion of ACTH,
  which in turn leads to adrenocortical hyperplasia
  and overproduction of intermediate metabolites.

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INTRODUCTION (cont.)

• Depending on the enzymatic step that is
  deficient, there may be signs, symptoms and lab
  findings of mineralocorticoid deficiency or
  excess incomplete virilization or premature
  puberty in affected males and virilization or
  sexual infantilism in affected females.

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• ACTH
• Cholesterol
• 3-B-H 21-H
  11-B H (CYP11B1-B2) 18-H
• Pregnenol Progest DOC Corticosterone
  Aldosterone
• 17-OH 17 OH 21-H
  11-BH (CYP11B1)
• Pregnenol Progesterone
  11-Deoxicortisol Cortisol
• DHEA Androstenedione
  Estrone
• Testosterone
  Estradiol

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CAH due to 21-HD

• Causes more than 90 of CAH.
• This is an P450 enzyme (CYP21, P450c21)
• Hydroxylate progesterone and 17 OHP to yield DOC
  and 11-deoxycortisol.
• These two hormones are deficient in the most
  severe, salt wasting form of the disease.
• Less severely affected pt can synthesize
  aldosterone but have elevated levels of
  androgens Simple virilizing disease.

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INCIDENCE

• Classic 21-HD occurs in about 1 in 15,000-20,000
  birth.
• Approximately 75 fo affected infants have the
  salt-losing form, whereas 25 have the simple
  virilizing form of the disorder.

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GENETICS

• There are two steroids 21-hydroxylase genes,
  CYP21P and CYP21 on chromosome 6p21.3.
• CYP21 is the active gene.
• CYP21P is 98 identical in DNA sequence to CYP21
  but is a pseudogene due to nine different
  mutations.
• More than 90 of mutations causing 21-HD are
  recombinations between these two genes.
• The deleterious mutations in CYP21P have varying
  effects on enzymatic activity when transferred to
  CYP21.
• Disease severity correlates well with the
  mutations carried by an affected individual.

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CLINICAL MANIFESTATIONS

• 1) ALDOSTERONE AND CORTISOL DEFICIENCY
• - Both hormones are deficient in the most
  severe, salt wasting form of the disease.
• - Include progressive weight loss, anorexia,
  dehydration, weakness, hypotension, hypoglycemia,
  hypoNa, and hyperkalemia.
• - These problems typically first develop in
  affected infants at 2wk of age.
• - ACTH levels are high as well as 17-OH
  progest and progesterone.

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CLINICAL MANIFESTATIONS

• 2) PRENATAL ANDROGEN EXCESS
• - 17-OH progest is shunted into the pathway
  for androgen biosynthesis, leading to high levels
  of testosterone.
• - This problem begins by 8-10 wk of
  gestation leading to abnormal genital development
  in females.
• - Clitoris resembles a penis and, because
  the urethra opens below this organ, pt may be
  mistakenly presumed to be males with hypospadias
  and cryptorchidism.
• - Testosterone has no effect on development
  of female internal reproductive structures from
  mullerian ducts.
• - Male infants appear normal at birth.

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CLINICAL MANIFESTATIONS

• 3) POSTNATAL ANDROGEN EXCESS
• - Untreated children of both sexes develop
  additional signs of androgen excess after birth.
• - Rapid somatic growth and accelerated
  skeletal maturation with premature closure of
  epiphysis.
• - Pubic and axillary hair, acne and deep
  voice may develop. In girls, breast development
  and menstruation do not occur unless the
  excessive production of androgens is suppressed
  by tx.

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• ACTH
• Cholesterol
• 3-B-H 21-H
  11-B H (CYP11B1-B2) 18-H
• Pregnenol Progest DOC Corticosterone
  Aldosterone
• 17-OH 17 OH 21-H
  11-BH (CYP11B1)
• Pregnenol Progesterone
  11-Deoxicortisol Cortisol
• DHEA Androstenedione
  Estrone
• Testosterone
  Estradiol

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LABORATORY FINDINGS

• Pt with salt-losing disease have hyponatremia,
  hyperkalemia, acidosis and often hypoglycemia
  usually 1-2 wk or longer after birth.
• 17-OH progesterone is high. Measurement is best
  30 min after an IV bolus of cosyntropin (ACTH
  1-24).
• Cortisol level is low.
• Androstenedione and testosterone are elevated in
  affected females.
• ACTH is high but have no dx utility.
• High Renine levels with low levels of aldosterone.

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ADITIONAL STUDIES

• Evaluation of ambiguous genitalia requires
  physical exam to define anatomy, locate the
  meatus, palpate the scrotum or labia and inguinal
  regions for testes.
• Ultrasonography is useful to evaluate internal
  organs.
• Rapid karyotype can quickly determine the genetic
  sex of the infant.

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PRENATAL DX AND TX

• Prenatal dx is possible late in the first
  trimester by analysis of DNA obtained by
  chorionic villus sampling or during amniocentesis
  during the second trimester.
• Dexamethasone daily crosses the placenta and
  suppresses the secretion of steroids by the fetal
  adrenal. This ameliorate the virilization of the
  external genitalia in affected females.
• There is insufficient information to determine
  whether there are any long-term risks.

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NEWBORN SCREEN

• Analyzes 17-OH progesterone levels in dried blood
  obtained by heel-stick.
• Potencially affected infants are recalled for
  additional testing at 2wk of age.
• Seem to be effective in preventing many cases of
  adrenal crisis in affected males.
• The cut-off 17-OH prog levels for recalls are set
  so low that there is high frequency of
  false-positive results (high sensitivity and low
  specificity)

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• ACTH
• Cholesterol
• 3-B-H 21-H
  11-B H (CYP11B1-B2) 18-H
• Pregnenol Progest DOC Corticosterone
  Aldosterone
• 17-OH 17 OH 21-H
  11-BH (CYP11B1)
• Pregnenol Progesterone
  11-Deoxicortisol Cortisol
• DHEA Androstenedione
  Estrone
• Testosterone
  Estradiol

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TREATMENT

• 1) GLUCOCORTICOID REPLACEMENT
• - Cortisol deficiency is treated with
  hydrocortisone daily, 10-20 mg/m2/24hs.
• - Also suppresses excessive production of
  androgens.
• - Double or triple doses are indicated during
  periods of stress.
• - Tx must be continued indefinitely.
• - Linear growth, weight gain, pubertal
  development and skeletal maturation must be
  followed closely.

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TREATMENT (cont.)

• 2) MINERALOCORTICOID REPLACEMENT
• - Pt with salt wasting disease require tx with
  fludrocortisone.
• - Some pt require sodium supplementation in
  addition to the mineralocorticoid.
• - Serum electrolytes should be measured
  frequently.
• - Plasma renine level is a useful may to
  monitor tx.

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TREATMENT (cont.)

• 3) SURGICAL MANAGEMENT OF AG.
• - Virilized females usually undergo surgery
  between 4-12 mo of age.
• - Sex assignment of infants with intersex
  conditions is usually based on expected sexual
  functioning and fertility in adulthood with
  surgical correction of the external genitals to
  conform with the sex assignment.

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• ACTH
• Cholesterol
• 3-B-H 21-H
  11-B H (CYP11B1-B2) 18-H
• Pregnenol Progest DOC Corticosterone
  Aldosterone
• 17-OH 17 OH 21-H
  11-BH (CYP11B1)
• Pregnenol Progesterone
  11-Deoxicortisol Cortisol
• DHEA Androstenedione
  Estrone
• Testosterone
  Estradiol

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CAH due to 11 B-OHD

• It is due to a mutation in the CYP11B1 gene
  located in the chromosome 8q24.
• CYP11B1 mediates 11-hydroxylation of 11-DOCA to
  cortisol.
• Levels of corticotropin are high. In consequence,
  precursors accumulate and are shunted into
  androgen biosynthesis in the same manner as
  occurs in 21 OHD.
• However, CYP11B2 gene encoding aldosterone
  synthesis is unaffected in this disorder.

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CLINICAL MANIFESTATIONS

• Aldosterone synthetic capacity is normal so it is
  unusual to see signs of adrenal insufficiency,
  such as hypotension, hypoglycemia, hyponatremia
  and hyperkalemia.
• Approximately two thirds of patients become
  hypertensive.
• All signs and symptoms of androgen excess found
  in 21-OHD may occur 11-OHD.

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LABORATORY FINDINGS

• Plasma levels of 11-Desoxicortisol and DOC are
  elevated.
• Plasma renin levels are suppressed.
• Aldosterone levels are low even thougn the
  ability of synthesis is intact.
• Hypokalemic alkalosis may occur.

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TREATMENT

• Hydrocortisone is used in doses similar to those
  used for 21-OHD.
• Hypertension usually resolves with glucocorticoid
  tx.

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• THANK YOU.