Congenitaladrenalhyperplasia

CONGENITALCONGENITAL
ADRENALADRENAL
HYPERPLASIAHYPERPLASIA
Soumya Ranjan ParidaSoumya Ranjan Parida
Basic B.Sc. Nursing 4Basic B.Sc. Nursing 4thth
yearyear
Sum Nursing CollegeSum Nursing College

What is CAH?What is CAH?
 It is a familial disorder of adrenal steroid biosynthesis withIt is a familial disorder of adrenal steroid biosynthesis with
autosomal recessive mode of inheritance.autosomal recessive mode of inheritance.
 The defect is expressed as adrenal enzyme deficiency.The defect is expressed as adrenal enzyme deficiency.
 Cortisol deficiency increases secretion of ACTH, which inCortisol deficiency increases secretion of ACTH, which in
turn leads to adrenocortical hyperplasia and overproductionturn leads to adrenocortical hyperplasia and overproduction
of intermediate metabolites.of intermediate metabolites.
 Depending on the enzymatic step that is deficient, thereDepending on the enzymatic step that is deficient, there
may be signs, symptoms and lab findings ofmay be signs, symptoms and lab findings of
mineralocorticoid deficiency or excess; incompletemineralocorticoid deficiency or excess; incomplete
virilization or premature puberty in affected males; andvirilization or premature puberty in affected males; and
virilization or sexual infantilism in affected females.virilization or sexual infantilism in affected females.
 Incidence 1 in 10000 to 15000.Incidence 1 in 10000 to 15000.

BasicsBasics
 EmbryologyEmbryology
 HistologyHistology
 PhysiologyPhysiology

AdrenalAdrenal
 Medulla: Neuroendocrinal cells:Medulla: Neuroendocrinal cells:
CatecholaminesCatecholamines
 Cortex:Cortex:
Zona Glomerulosa: AldosteroneZona Glomerulosa: Aldosterone
Zona Fasciculata: Largest zone, 3/4Zona Fasciculata: Largest zone, 3/4thth
Cortex:Cortex:
CortisolCortisol
Zona Reticularis: AndrogensZona Reticularis: Androgens

ACTHACTH
CholesterolCholesterol
3-B-H 21-H 11-B H (CYP11B1-B2) 18-H3-B-H 21-H 11-B H (CYP11B1-B2) 18-H
Pregnenol Progest DOC Corticosterone AldosteronePregnenol Progest DOC Corticosterone Aldosterone
17-OH 17 OH17-OH 17 OH 21-H 11-BH (CYP11B1)21-H 11-BH (CYP11B1)
Pregnenol Progesterone 11-Deoxicortisol CortisolPregnenol Progesterone 11-Deoxicortisol Cortisol
DHEA Androstenedione EstroneDHEA Androstenedione Estrone
Testosterone EstradiolTestosterone Estradiol
3-B-H3-B-H
3-B-H3-B-H
1717αα
hydroxyhydroxy
1717αα
hydroxyhydroxy
StARStAR
AromataseAromatase
AromataseAromatase
Cholesterol desmolaseCholesterol desmolase

Sexual DifferentiationSexual Differentiation
 Y chromosome is essential for sexualY chromosome is essential for sexual
differentiation.differentiation.
 Y Chromosome: SRY Sex DeterminingY Chromosome: SRY Sex Determining
Region of Y chromosome.Region of Y chromosome.

Normal Sexual DifferentiationNormal Sexual Differentiation
Genital
Ridge
Bipotential
Gonad
SF-1
SF-1
Ovary
Follicular Cells
Theca Cells
Follicles
Mullerian
Duct
Female
Genitalia
Leydig Cells
Sertoli Cells
SF-1
SF-1
Testosterone
AMH
Testis
Mullerian Duct
Regression
Wolffian
Duct
Genital
Tubercle
Urogenital
Sinus
Male
Internal
Genitalia
Penis
Prostate
DHT

CAH occurs due toCAH occurs due to
 21 Hydroxylase Deficiency21 Hydroxylase Deficiency
 1111 ββ Hydroxylase DeficiencyHydroxylase Deficiency
 33 ββ Hydroxylase DeficiencyHydroxylase Deficiency
 17 Hydroxylase Deficiency17 Hydroxylase Deficiency
 Mutation in StAR proteinMutation in StAR protein
 Deficiency of P450 Oxidoreductase.Deficiency of P450 Oxidoreductase.

CAH due to 21-HDCAH due to 21-HD
 Causes more than 90% of CAH.Causes more than 90% of CAH.
 This is an P450 enzyme (CYP21, P450c21)This is an P450 enzyme (CYP21, P450c21)
 Hydroxylate progesterone and 17 OHP toHydroxylate progesterone and 17 OHP to
yield DOC and 11-deoxycortisol.yield DOC and 11-deoxycortisol.
 These two hormones are deficient in the mostThese two hormones are deficient in the most
severe, “salt wasting” form of the disease.severe, “salt wasting” form of the disease.
 Less severely affected pt can synthesizeLess severely affected pt can synthesize
aldosterone but have elevated levels ofaldosterone but have elevated levels of
androgens: “Simple virilizing disease”.androgens: “Simple virilizing disease”.

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

GENETICSGENETICS
 There are two steroids 21-hydroxylase genes,There are two steroids 21-hydroxylase genes,
CYP21P and CYP21 on chromosome 6p21.3.CYP21P and CYP21 on chromosome 6p21.3.
 CYP21 is the active gene.CYP21 is the active gene.
 CYP21P is 98% identical in DNA sequence to CYP21CYP21P is 98% identical in DNA sequence to CYP21
but is a pseudogene due to nine different mutations.but is a pseudogene due to nine different mutations.
 More than 90% of mutations causing 21-HD areMore than 90% of mutations causing 21-HD are
recombinations between these two genes.recombinations between these two genes.
 The deleterious mutations in CYP21P have varyingThe deleterious mutations in CYP21P have varying
effects on enzymatic activity when transferred toeffects on enzymatic activity when transferred to
CYP21.CYP21.
 Disease severity correlates well with the mutationsDisease severity correlates well with the mutations
carried by an affected individual.carried by an affected individual.

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

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

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

LABORATORY FINDINGSLABORATORY FINDINGS
 Pt with salt-losing disease have hyponatremia,Pt with salt-losing disease have hyponatremia,
hyperkalemia, acidosis and often hypoglycemiahyperkalemia, acidosis and often hypoglycemia
usually 1-2 wk or longer after birth.usually 1-2 wk or longer after birth.
 17-OH progesterone is high. Measurement is best17-OH progesterone is high. Measurement is best
30 min after an IV bolus of cosyntropin30 min after an IV bolus of cosyntropin (ACTH 1-24).(ACTH 1-24).
 Cortisol level is low.Cortisol level is low.
 Androstenedione and testosterone are elevated inAndrostenedione and testosterone are elevated in
affected females.affected females.
 ACTH is high but have no diagnostic utility.ACTH is high but have no diagnostic utility.
 High Renine levels with low levels of aldosterone.High Renine levels with low levels of aldosterone.

ADITIONAL STUDIESADITIONAL STUDIES
 Evaluation of ambiguous genitalia requiresEvaluation of ambiguous genitalia requires
physical exam to define anatomy, locate thephysical exam to define anatomy, locate the
meatus, palpate the scrotum or labia andmeatus, palpate the scrotum or labia and
inguinal regions for testes.inguinal regions for testes.
 Ultrasonography is useful to evaluate internalUltrasonography is useful to evaluate internal
organs.organs.
 Rapid karyotype can quickly determine theRapid karyotype can quickly determine the
genetic sex of the infant.genetic sex of the infant.

PRENATAL DX AND TXPRENATAL DX AND TX
 Prenatal dx is possible late in the first trimesterPrenatal dx is possible late in the first trimester
by analysis of DNA obtained by chorionic villusby analysis of DNA obtained by chorionic villus
sampling or during amniocentesis during thesampling or during amniocentesis during the
second trimester.second trimester.
 Dexamethasone daily crosses the placenta andDexamethasone daily crosses the placenta and
suppresses the secretion of steroids by thesuppresses the secretion of steroids by the
fetal adrenal. This ameliorate the virilization offetal adrenal. This ameliorate the virilization of
the external genitalia in affected females.the external genitalia in affected females.
 There is insufficient information to determineThere is insufficient information to determine
whether there are any long-term risks.whether there are any long-term risks.

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

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

TREATMENT (cont.)TREATMENT (cont.)
 2) MINERALOCORTICOID2) MINERALOCORTICOID
REPLACEMENT:REPLACEMENT:
- Pt with salt wasting disease require tx with- Pt with salt wasting disease require tx with
fludrocortisone.fludrocortisone.
- Some pt require sodium supplementation- Some pt require sodium supplementation
in addition to the mineralocorticoid.in addition to the mineralocorticoid.
- Serum electrolytes should be measured- Serum electrolytes should be measured
frequently.frequently.
- Plasma renine level is a useful may to- Plasma renine level is a useful may to
monitor tx.monitor tx.

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

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

ACTHACTH
CholesterolCholesterol
3-B-H 21-H 11-B H (CYP11B1-B2) 18-H3-B-H 21-H 11-B H (CYP11B1-B2) 18-H
Pregnenol Progest DOC Corticosterone AldosteronePregnenol Progest DOC Corticosterone Aldosterone
17-OH 17 OH17-OH 17 OH 21-H 11-BH (CYP11B1)21-H 11-BH (CYP11B1)
Pregnenol Progesterone 11-Deoxicortisol CortisolPregnenol Progesterone 11-Deoxicortisol Cortisol
DHEA Androstenedione EstroneDHEA Androstenedione Estrone
Testosterone EstradiolTestosterone Estradiol
3-B-H3-B-H
3-B-H3-B-H
1717αα
hydroxyhydroxy
1717αα
hydroxyhydroxy
StARStAR
AromataseAromatase
AromataseAromatase

 Aldosterone synthetic capacity is normal so it isAldosterone synthetic capacity is normal so it is
unusual to see signs of adrenal insufficiency,unusual to see signs of adrenal insufficiency,
such as hypotension, hypoglycemia,such as hypotension, hypoglycemia,
hyponatremia and hyperkalemia.hyponatremia and hyperkalemia.
 Approximately two thirds of patients becomeApproximately two thirds of patients become
hypertensive because of deoxycorticosteronehypertensive because of deoxycorticosterone
which has mineralocorticid activity.which has mineralocorticid activity.
 All signs and symptoms of androgen excessAll signs and symptoms of androgen excess
found in 21-OHD may occur 11-OHD.found in 21-OHD may occur 11-OHD.
 Female pseudohermaphroditism occurs.Female pseudohermaphroditism occurs.

LABORATORY FINDINGSLABORATORY FINDINGS
 Plasma levels of 11-Desoxicortisol andPlasma levels of 11-Desoxicortisol and
DOC are elevated.DOC are elevated.
 Plasma renin levels are suppressed.Plasma renin levels are suppressed.
 Aldosterone levels are low even thoughAldosterone levels are low even though
the ability of synthesis is intact.the ability of synthesis is intact.
 Hypokalemic alkalosis may occur.Hypokalemic alkalosis may occur.

TREATMENTTREATMENT
 Hydrocortisone is used in doses similar toHydrocortisone is used in doses similar to
those used for 21-OHD.those used for 21-OHD.
 Hypertension usually resolves withHypertension usually resolves with
glucocorticoid tx.glucocorticoid tx.

33ββ Hydroxysteroid DehydrogenaseHydroxysteroid Dehydrogenase
Deficiency:Deficiency:
 HSD3B2 gene located on 1p13.1HSD3B2 gene located on 1p13.1
 Both cortisol and aldosterone not synthesized soBoth cortisol and aldosterone not synthesized so
they are prone for salt wasting crisis.they are prone for salt wasting crisis.
 As Androstenedione and testosterone are notAs Androstenedione and testosterone are not
synthesized boys are incompletely virilized. Butsynthesized boys are incompletely virilized. But
DHEA can cause mild virilization in females.DHEA can cause mild virilization in females.
 DHEA can also cause precocious adrenarche.DHEA can also cause precocious adrenarche.
 Hirsutism, irregular menses, PCOD occur inHirsutism, irregular menses, PCOD occur in
females. Males manifest variable degree offemales. Males manifest variable degree of
hypogonadism.hypogonadism.

Diagnosis and treatment:Diagnosis and treatment:
 Increased 17 Hydroxypreganenolone andIncreased 17 Hydroxypreganenolone and
DHEA.DHEA.
 Treatment: Gluco and mineralocorticoidTreatment: Gluco and mineralocorticoid
replacement with hydrocortisone andreplacement with hydrocortisone and
fludrocortisone.fludrocortisone.

17 Hydroxylase Deficiency17 Hydroxylase Deficiency
 Gene 10q24.3Gene 10q24.3
 Pt with 17 hydroxylase deficiency cannot synthesizePt with 17 hydroxylase deficiency cannot synthesize
cortisol but their ability to synthesize corticosterone iscortisol but their ability to synthesize corticosterone is
intact.intact.
 Corticosterone is an active glucocorticoid so pt do notCorticosterone is an active glucocorticoid so pt do not
develop adrenal insufficiency.develop adrenal insufficiency.
 Deoxycorticosterone causes hypertension andDeoxycorticosterone causes hypertension and
hypokalemia.hypokalemia.
 Males are incompletely virilized and present asMales are incompletely virilized and present as
phenotypic females.phenotypic females.
 Affected females present with failure of sexualAffected females present with failure of sexual
development at expected time of puberty.development at expected time of puberty.

 Increased DOC levels and decreased 17Increased DOC levels and decreased 17
OHP levels.OHP levels.
 Treatment: Cortisol replacement.Treatment: Cortisol replacement.
Estrogen androgen replacement as per sexEstrogen androgen replacement as per sex
of rearingof rearing

Lipoid Adrenal HyperplasiaLipoid Adrenal Hyperplasia
 Mutation in StAR protein.Mutation in StAR protein.
 Pt unable to synthesize any steroid.Pt unable to synthesize any steroid.
 Salt losing manifestations are usual andSalt losing manifestations are usual and
patient die early in infancy.patient die early in infancy.
 Males appear as phenotypic females.Males appear as phenotypic females.
 Females normal at birth but afterwardsFemales normal at birth but afterwards
develop hypergonadotropicdevelop hypergonadotropic
hypogonadism.hypogonadism.

 Low adrenal and gonadal steroids.Low adrenal and gonadal steroids.
 Decresed or no response to ACTH.Decresed or no response to ACTH.
 Tx: Gluco and mineralocorticoidTx: Gluco and mineralocorticoid
replacement. Estrogen therapy.replacement. Estrogen therapy.

Deficiency of P450 OxidoreductaseDeficiency of P450 Oxidoreductase
 P 450 oxidoreductase is required forP 450 oxidoreductase is required for
activity of all microsomal cytochrome P450activity of all microsomal cytochrome P450
enzymes including adrenals.enzymes including adrenals.
 Partial deficiency of 17 or 21 hydroxylase.Partial deficiency of 17 or 21 hydroxylase.
 Male or female pseudohermaphroditism.Male or female pseudohermaphroditism.
 Many other enzymes affected: AntleyMany other enzymes affected: Antley
Bixler syndrome.Bixler syndrome.

Congenitaladrenalhyperplasia

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