Congenital Adrenal Hyperplasia - PowerPoint Presentation

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					Congenital Adrenal Hyperplasia


            Presented by
       Dr. Deena Abdel-Hadi



                              1
           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 .



                                           2
           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.


                                              3
 Etiologic Classification of
Adrenocortical Hyperplasia

      Please see the table




                               4
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.
                                                5
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.

                                             6
            Continue…….
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.


                                                    7
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.
                                                     8
            Continue…….
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 don’t occur , & affected
individuals may present with precious pubarche or
with hirshutism , menstrual disorder , infertility &
polycystis ovaries.

                                                    9
  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 & it’s the only form of CAH that
is not caused by a defective steroidogenic
enzyme.
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              Continue…….
  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.

                                                  11
     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.



                                                      12
             Continue……
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.
                                                 13
    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

                                            14
         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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          Continue………
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.

                                                 16
             Continue………
With 11-(OH)lase defect, salt losing manifestations
don’t 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 doesn’t 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.
                                                   17
         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 .

                                              18
            Continue…….
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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           Continue…..


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


                                            20
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.
                                             21
Laboratory Findings &
     Diagnosis

    Please see the table




                           22
     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).

                                           23
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.

                                            24
             Continue…….
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.
                                              25
             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.
                                             26
             Continue……
Maintenance therapy with 9-alpha-fluro-
hydrocortisone[Florinef (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.
                                             27
            Continue……
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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           Continue……


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




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Thank you

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