Congenital Adrenal Hyperplasia

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Congenital Adrenal Hyperplasia

• Presented by
• Dr. Deena Abdel-Hadi

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Pathogenesis

• Autosomal recessive disorders of adrenal
  steroidogenesis leading to deficiency of
  cortisol.
• Low cortisol level leads to increase secretion of
  corticotropin , leading to adrenocortical
  hyperplasia .

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Pathogenesis

• Sever mild forms of these disorders caused
  by variations in the severity of the genetic
  mutations have been reported depending on the
  enzymatic step that is deficient , there maybe
  signs , symptoms lab. Findings of
  mineralocorticoid deficiency or excess.

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Etiologic Classification of Adrenocortical
Hyperplasia

• Please see the table

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Deficiency of 21-hydroxylase

• Accounts for 90 of affected patients.
• This P450 enzyme hydroxylate progesterone
  17-hydroxyprogesterone to yield 11-deoxycortisone
  11-deoxycortisol.
• Newborn screening programs using capillary heel
  blood on filter paper disks to detect 21-(OH)lase
  deficiency.
• About 75 of affected infants have the salt
  wasting virilizing 25 have the simple
  virilizing form of the disorder.

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Deficiency of 11B-hydroxylase

• Accounts for 5-8 of cases of adrenal
  hyperplasia.
• This P450 enzyme mediate the 11-hydroxylation of
  11-deoxycortisol to cortisol.
• Hypertension is a distinctive clinical feature of
  the disorder but is absent in the 1st few years
  of life.

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• The serum characteristically contain large
  amounts of both 11-deoxycortisol
  11-deoxycorticosterone ,which are causing
  hypertension prevent symptoms of salt loss
• Prenatal diagnosis is possible by measuring level
  of 11-deoxycortisol in amniotic fluid or in
  maternal urine during pregnancy by DNA probes
  in chorionic villus cells or amniocytes.

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Deficiency of 3B-hydroxysteroid dehydrogenase

• Occurs in lesser than 5 of patients with adrenal
  hyperplasia .
• This enzyme is required for conversion of
  pregnenolone , 17-(OH)pregnenolone
  dehydro-epi-androsterone to progesterone ,
  17(OH)progesterone androstenedione.
• Deficiency of the enzyme result in decrease
  synthesis of cortisol , aldosterone
  androstenedione but increase secretion of
  dehydro-epi-androsterone.

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• In classic form of the disease there are often a
  salt wasting crisis in the new born , boys are
  incompletely virilized have hypospadius
  girls are mildly virilized.
• In non-classic , milder form , salt wasting
  ambiguity of the genitals dont occur ,
  affected individuals may present with precious
  pubarche or with hirshutism , menstrual disorder
  , infertility polycystis ovaries.

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Lipoid adrenal hyperplasia

• It is a rare disorder due to mutation in the gene
  for steroidogenic acute regulatory protein , a
  mitochondrial protein that promotes the movement
  of cholesterol from the outer to the inner
  mitochondrial membrane its the only form of
  CAH that is not caused by a defective
  steroidogenic enzyme.

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• There is a marked accumulation of cortisole
  lipids in the adrenal cortex gonads leading to
  sever impairment of steroidogenesis as well as
  cortisol , aldosterone sex hormone deficiencies
  resulting in
• Genetic males are phenotypically females
  females exhibit no genital abnormality
• Salt losing manifestations are usual.

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17-hydroxylase deficiency

• It consists of 2 distinct reactions
• 17-hydroxylation of pregnenolone progesterone.
• 17 , 20- layse reaction mediating conversion of
  17-(OH)pregnenolone 17-(OH)progesterone to
  dehydro-epi-androsterone androstenedione
  (steroid precursors) of testosterone estrogen.

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• The deficiency results in over production of
• 11-deoxycorticosterone leading to HTN ,
  hypokalemia suppression of renin aldosterone.
  In addition there is inability to synthesize
  normal amounts of sex hormones.
• Affected males are incompletely virilized
  present as phenotypic females or with sexual
  ambiguity (male pseudohermaphroditism)
• Affected females with failure of sexual
  development at the expected time of puberty.

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Clinical Manifestations

• The clinical manifestations in CAH depend on
  which hormones are deficient which are over
  produced.
• They are divided in to
• Non-salt-losing CAH
• Salt-losing CAH
• Non-classic 21-hydroxylase Deficiency

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Non-salt-losing CAH

• Male infant with 21-(OH)lase deficiency appears
  normal at birth ,but signs may appear within the
  1st 6 mo. Of life or develop more gradually
  ,becoming evident at 4-5 yrs. Of age or later.
• Enlargement of the penis ,scrotum
  ,prostate.Appearance of pubic hair,acne,deep
  voice,muscles ,advanced bone age premature
  epiphyseal closure being tall in early
  childhood.
• Testes are prepubertal in size so that they
  appear relatively small in contrast to the
  enlarged penis.
• See the picture please.

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• Females with 21-(OH)lase deficiency presents as
  female peudohermaphrodism (see the picture
  please), with evidence of masculinization,clitoris
  enlargement,labial fusion,urogenital
  sinus,presence of pubic axillary hair,acne deep
  voice,thought their internal genital organs are
  normal.
• Virilized female pseudohermaphrodites whose
  condition undiagnosed until later childhood or
  adult life have been reared as MALES.

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• With 11-(OH)lase defect, salt losing
  manifestations dont occur .
• Most pt.s are hypertensive,with gynecomastia.
• Virilization occurs as sever or more sever than
  that occurring with the 21-(OH)lase defect.
• Salt wasting also doesnt occur in 17-(OH)lase /
  17,20 lyase deficiency, HTN hypokalemia present
  2ry to excessive 11-deoxycorticostrone secretion.
• As a result of gonadal steroid deficiency males
  have degrees of sexual ambiguity females have
  sexual infantilism.

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Salt-losing CAH

• Symptoms appear shortly after birth with failure
  to regain birth weight ,progressive wt. Loss
  ,dehydration ,vomiting ,anorexia , disturbances
  in H.R. rhythm ,cyanosis , dyspnea.
• Without treatment collapse death may occur with
  in a few weeks .

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• In female infants virilization of external
  genitals diagnose most cases . Hirsutism
  ,irregular menses polycystic ovaries, occur
  during adolescence adulthood.
• In males genitals appear normal clinical
  picture are likely to confuse with those of
  pyloric stenosis,intestinal obstruction,heart
  disease ,cows milk intolerance , or other cause
  of F.T.T.

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• Males manifest variable degrees of hypogonadism,
  although appropriate male 2ry sexual development
  may occur.
• Patients with lipoid adrenal hyperplasia are
  salt losers.

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Nonclassic 21-(OH)lase deficiency

• Affected females have normal genitals at birth.
• Males females may present with precious
  pubarche ,early development of pubic axillary
  hair , hirsutism ,acne ,menses disorders
  infertility later in life. some are completely a
  symptomatic.
• Nonclassic 3B-HSD deficiency 11-(OH) deficiency
  are having similar presentation.

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Laboratory Findings Diagnosis

• Please see the table

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Differential Diagnosis

• A virilizing adrenocortical tumor (administration
  of hydrocortisone quickly reduces urinary
  17-ketosteroid excretion plasma levels of
  dehydro-epi-androsterone sulfate level to normal
  in CAH pt.s but not in virilizing tumors).
• Adrenal tumor (u/s scan ,CT scan MRA).

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Prenatal Diagnosis Treatment

• 1st trimester
• DNA analysis HLA genotyping og chorionic
  villus cells.
• 2nd trimester
• measuring 17-(OH) progesterone
  androstenedione in amniotic fluid as well as by
  HLA typing DNA analysis of amniotic fluid cells.

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• Prenatal treatment by maternal Dexamethasone
  administration .
• Maternal side effects have included edema
  ,excessive weight gain ,HTN ,glucose intolerance
  ,cushingoid facial features sever striae with
  permanent scarring.
• DNA analysis of chorionic villus cells can be
  used for the prenatal diagnosis of all forms of
  CAH.

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Treatment

• Administration of glucocorticoids inhibits
  excessive production of androgens and prevents
  progressive virilization.
• Infants usually require 2.5-5 mg Q8-12 hrs daily
  children 5-10 mg Q 8-12 hrs daily.
• Patients with salt-losing dse. elevated plasma
  Renin activity require a mineralocorticoid
  sodium supplement in addition to the
  glucocorticoid.

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• Maintenance therapy with 9-alpha-fluro-hydrocortis
  oneFlorinef (mineralocoid) (0.05-0.3 mg daily)
  NaCl,1-3g , is usually sufficient to normalize
  plasma Renin activity.
• Increased doses are indicated during periods of
  stress such as infection or surgery for patients
  with salt-losing non-salt-losing CAH.

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• Prolonged ,inadequate adrenal suppression may
  also result in adenomatous changes in the
  adrenal gland.
• Those disorders(lipoid CAH , 17-OHP/ 17,20-lyase
  deficiency , 3B HSB deficiency) associated with
  gonadal sex hormone deficiency require sex
  hormone replacement to induce sustain puberty
  with the sex rearing.

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• Surgical correction of ambiguous external
  genitalia begins by 1 year of life to permit
  normal development of gender identity.

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