Congenital Adrenal Hyperplasia

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Congenital Adrenal Hyperplasia

• Dr. Abdelaziz Elamin. MD, PhD, FRCPCH
• Professor of Child Health
• Sultan Qaboos University, Muscat, Oman

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What is CAH?

• It is a familial disorder of adrenal steroid
  biosynthesis with autosomal recessive mode of
  inheritance.
• The defect is expressed as adrenal enzyme
  deficiency.
• 5 major Enzymes deficiency are clinically
  important
• 21-Hydroxylase
• 11-b-Hydroxylase
• 17-a-Hydroxylase
• 3-b-Hsteroid hydrogenese
• 20,22 Desmolase deficiency

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CAH

• The enzyme deficiency causes reduction in
  end-products, accumulation of hormone precursors
  increased ACTH production.
• The clinical picture reflects the effects of
  inadequate production of cortisol aldosterone
  and the increased production of androgens
  steroid metabolites.

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21-Hydroxylase Deficiency

• Most common type, accounts for gt80 of cases.
• Incidence is 15000 to 115000 live birth.
• Gene is located on the short arm of chromosome 6
  near the C4 locus in close association with HLA
  genes.
• Heterozygous carriers can be detected by ACTH
  stimulation test.

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21-Hydroxylase deficiency/2

• It is characterized by reduced production of
  cortisol and aldosterone and increased production
  of progesterone
  17-OH-progesterone, and sex steroids.
• The urinary steroid metabolites
  (17-ketosteroids and pregnanetriol) are
  elevated above normal levels.

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21-Hydroxylase deficiency/3

• Decreased secretion of aldosterone results in
  salt loss with hyponatremia and hyperkalemia
  plasma renin activity is therefore elevated.
• In partial enzyme deficiencies, the aldosterone
  deficiency is not expressed, and patients remain
  normonatremic and normokalemic.
• The excess androgens causes virilization of girls
  ambiguous genitalia dark scrotum in boys.

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21-Hydroxylase Deficiency/4

• 2 forms, classic early virilization type with or
  without salt-losing crisis and non-classic type
  with late-onset virilization.
• Male babies with non salt-losing non-classic type
  remains asymptomatic till late childhood when
  they may show signs of sexual precocity.

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21-Hydroxylase Deficiency/5

• Because members of the same family may have
  classic, non-classic asymptomatic forms, the
  disorder may be due to allelic variations of the
  same enzyme.
• Mass neonatal screening using filter paper blood
  sample for 17-OH-Progesterone is used in the USA.

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11-b-Hydroxylase Deficiency

• Accounts for 5-10 of cases of CAH.
• Gene is located on the long arm of chromosome 8.
• It is characterized by low plasma renin activity
  elevation of serum 11-Deoxycortisol and
  11-deoxycorticosterone.
• Because of the strong mineralocorticoid activity
  of deoxycorticosterone, the condition is
  characterized by salt retention, hypertension
  hypokalemic alkalosis.
• The elevated plasma androgens may cause
  virilization of the female fetus.

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17-a-Hydroxylase deficiency

• Genetic defect is on chromosome 10.
• Presents with similar features of those of
  11-Hydroxylase deficiency except that Androgens
  are low, so no virilization in girls genitalia
  is ambiguous in boys.

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3-b-hydroxysteroid dehydrogenase deficiency

• This is a very rare disorder that results in
  accumulation of DHEA, which is converted to
  testosterone in peripheral tissues.
• It can cause virilization of female fetus and
  leads to ambiguous genitalia in the newborn.

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Pathophysiology

• Anatomically, the adrenal gland can be divided
  into 3 zones
• Zona glomerulosa, which produces predominately
  mineralocorticoid
• Zona fasciculata, which produces predominately
  glucocorticoid
• Zona reticularis, which produces predominately
  androgens

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Enzyme pathway

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ESSENTAILS OF DIAGNOSIS

• Increased linear growth with advanced bone age
  and eventual short stature
• Pseudohermaphorditism in girls due to androgen
  virilizing effect
• Isosexual precocity in boys with small infantile
  testes.

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ESSENTAILS OF DIAGNOSIS/2

• Adrenal crisis with salt-loss metabolic
  acidosis or Hypertension hypokalemic alkalosis.
• Low cortisol with high androgens, ACTH and
  steroid precursors e.g. 17-OH-Progest. or
  11-Deoxycortisol.

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ESSENTIALS OF DIAGNOSIS/3

• Diagnosis is confirmed by measurement of ACTH,
  Cortisol, Aldosterone,
  17-OH-progesterone, Testosterone urinary
  17-ketosteroids.
• Needs alertness for the possibility in all babies
  with Diarrhea Vomiting, hypoglycemia or ? BP.

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CLINICAL COURSE

• The clinical phenotype depends upon the nature
  and severity of the enzyme deficiency.
• Approximately 50 of patients with classic
  congenital adrenal hyperplasia due to
  21-hydroxylase (CYP21) deficiency have salt
  wasting due to inadequate aldosterone synthesis.
• Girls are usually recognized at birth because of
  ambiguous genitalia.

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CLINICAL COURSE/2

• Non salt losing CAH present late in childhood
  with precocious pubic hair and/or clitoromegaly,
  often accompanied by accelerated growth and
  advanced bone age.
• Those individuals with mild deficiencies of the
  enzyme present in adolescence or adulthood with
  varying virilizing symptoms ranging from
  oligomenorrhea to hirsutism and infertility.

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GIRLS WITH CAH

• Have ambiguous genitalia at birth
• complete fusion of the labioscrotal folds and a
  phallic urethra. clitoromegaly and partial fusion
  of the labioscrotal folds
• In less severe forms, genitalia is normal at
  birth. Precocious pubic hair clitoromegaly and
  excess facial or body hair appear later in
  childhood, often accompanied by tall stature.

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BOYS WITH CAH

• Are unrecognized at birth because their genitalia
  are normal.
• They are not diagnosed until later, often with a
  salt wasting crisis resulting in dehydration,
  hypotension, hyponatremia and hyperkalemia or
  later in childhood with early pubic hair
  phallic enlargement accompanied by accelerated
  linear growth and advancement of skeletal
  maturation.
• High blood pressure hypokalemia may occur in
  those with 11-b-hydroxylase deficiency and
  17-a-hydroxylase deficiency due to the
  accumulation of the mineralocorticoid
  desoxycorticosterone

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Laboratory Findings

• Demonstration of inadequate production of
  cortisol and/or aldosterone in the presence of
  accumulation of excess concentrations of
  precursor hormones is diagnostic.
• In 21-hydroxylase deficiency, very high serum
  17-hydroxyprogesterone is characteristic together
  with very high urinary pregnanetriol (metabolite
  of 17-hydroxyprogesterone).

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Laboratory Findings/2

• 11-b-hydroxylase deficiency is characterized by
  high serum 11-deoxycorticosterone and
  11-deoxycortisol concentrations with elevation of
  its urinary metabolites (tetrahydrocompound-S).
• Both are accompanied by elevated 24-hour urinary
  17-ketosteroids, the urinary metabolites of
  adrenal androgens.

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Laboratory Findings/3

• Salt wasting forms of adrenal hyperplasia are
  accompanied by low serum aldosterone,
  hyponatremia, hyperkalemia and elevated plasma
  renin activity indicating hypovolemia.
• In contrast hypertensive forms of adrenal
  hyperplasia (11-b-hydroxylase deficiency and
  17-a-hydroxylase deficiency) are associated with
  suppressed plasma renin activity and hypokalemia.

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Other Tests

• A karyotype
• is essential in the evaluation of the infant
  with ambiguous genitalia in order to establish
  the chromosomal sex.
• Prenatal diagnosis of adrenal hyperplasia is
  possible through biochemical and genetic tests.

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Imaging studies

• A pelvic ultrasound in the infant with ambiguous
  genitalia to demonstrate the presence or absence
  of a uterus or associated renal anomalies
• A urogenitogram is often helpful to define the
  anatomy of the internal genitalia.
• A CT scan of the adrenal gland to R/O bilateral
  adrenal hemorrhage in the patient with signs of
  acute adrenal failure
• A bone age study is useful in the evaluation of
  the child who develops precocious pubic hair,
  clitoromegaly, or accelerated linear growth.

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TREATMENT PRINCIPLES

• Treatment is life-long
• Treatment goals are
• to maintain growth velocity skeletal
  maturation.
• to normalize electrolytes hormone levels using
  the smallest dose of glucocorticoids that will
  suppress the ?ACTH to normal. Mineralocorticoid
  replacement may be needed to sustain normal
  electrolyte homeostasis.

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MODES OF TREATMENT

• Steroid replacement
• Supportive therapy when needed
• Treatment is life-long
• Plastic surgery for ambiguous genitalia at early
  age
• Genetic counseling
• Psychological support

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Acute Medical Management

• Fluid therapy in babies with salt losing crisis
  0.9 sodium chloride 20 ml/kg as IV bolus,
  followed by a continuous IV infusion of 0.9 or
  0.45 saline 3200 ml/m2/day.
• If the patient is hypoglycemic, 2-4 ml of 10
  dextrose will correct the hypoglycemia.
• Patients with 11-b-hydroxylase and
  17-alpha-hydroxylase deficiency, may be
  hypokalemic and require potassium.

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Long Term Therapy

• Glucocorticoids Replacement
• Hydrocortisone 10-15 mg/m2/day divided in 3
  oral doses. Dose should doubled during crisis
  stressful conditions. The goals of therapy are
• To replace the body's requirement under normal
  conditions and during stress.
• To suppress ACTH secretion, which drives the
  adrenal gland to overproduce adrenal androgens in
  virilizing forms of congenital adrenal
  hyperplasia.

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Long Term Therapy/2

• Mineralocorticoids Treatment
• Fludrocortisone acetate 0.05-0.2 mg once daily
  orally is indicated for patients who have
  salt-wasting forms of CAH to replace the
  aldosterone that is insufficiently produced by
  the adrenal cortex. It will restore the sodium-
  potassium balance.

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New Trends of treatment

• A New approach therapy is the combined use of
  4 drugs
• glucocorticoid (to suppress ACTH and adrenal
  androgen production),
• mineralocorticoid (to reduce angiotensin II
  concentrations),
• aromatase inhibitor (to slow skeletal
  maturation),
• flutamide (an androgen blocker to reduce
  virilization)

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Surgical Management

• Infants with CAH may require surgical evaluation
  and, if needed, corrective surgery.
• Traditional approach is clitroplasty early in
  life, followed by vaginoplasty after puberty.
  
• Some female infants with adrenal hyperplasia are
  only mildly virilized and may not require
  corrective surgery if they receive adequate
  medical therapy to prevent further virilization.
  

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Further Outpatient Care

• Monitor patients adequacy of dosing of
  glucocorticoid and/or mineralocorticoid.
• Too little glucocorticoid results in symptoms of
  adrenal insufficiency (e.g., anorexia, nausea,
  vomiting, abdominal pain, asthenia) and will
  result in progressive virilization and
  advancement of skeletal maturation in virilizing
  forms of CAH.
• Too much glucocorticoid results in excess weight
  gain, cushingoid features, hypertension,
  hyperglycemia, cataracts, and growth failure.

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Patient Education

• Educate the caretakers and patients about the
  nature of the disease.
• Patients parents must understand the need for
  additional glucocorticoids in times of illness
  and stress in order to avoid an adrenal crisis
  which may be life-threatening.

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Neonatal Screening

• Is done by measuring 17-hydroxyprogesterone from
  heel blood samples collected on filter paper.
• Mass neonatal screening program is adopted in the
  USA.
• This approach has permitted early identification
  of newborns with CAH and prevented salt wasting
  crisis in boys who are unrecognized at birth.
• It also identifies the completely virilized girls
  with ambiguous genitalia who may be mistaken for
  boys with cryptorchidism

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Prenatal diagnosis

• Done by chorionic villus sampling at 8-12 wk
  amniocentesis at 18-20 wk.
• HLA typing in combination with measurement of
  17-OH-progesterone androstenedion in amniotic
  fluid is used for antenatal diagnosis.

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Prenatal Treatment

• Prenatal treatment of 21-hydroxylase deficiency
  prevents intrauterine virilization of female
  fetuses.
• According to the protocol proposed by Carlson et
  al, the mother is treated with dexamethasone (20
  m/kg/d in 3 divided doses) as soon as the
  pregnancy is recognized to suppress fetal ACTH
  secretion prevent the fetal adrenal gland from
  overproducing adrenal androgens.

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PROGNOSIS

• Is good and complications like short stature,
  sexual precocity metabolic effects are not seen
  with early adequate therapy.
• However, children with CAH are at ? risk of
  developing mesodermal tumours e.g. osteogenic
  sarcoma, pulmonary liposarcoma, uterine
  leiomyomata and brain tumours.

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PROGNOSIS /2

• Late diagnosis inadequate therapy may cause
  
• Death of newborns with salt-losing types if
  patients are not provided with stress doses of
  glucocorticoid in times of illness, trauma, or
  surgery.
• Psychological problems in girls with ambiguous
  genitalia.
• Short stature and infertility.