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Adrenogenital syndrome : Congenital adrenal hyperplasia (CAH): Genetic lesions in steroidogenesis. Congenital adrenal hyperplasia Autosomal recessive defects Result in diminished synthesis of cortisol In response to adrenal insufficiency POMC – ACTH increase

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Congenital adrenal hyperplasia Autosomal recessive defects

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Congenital adrenal hyperplasia autosomal recessive defects

Adrenogenitalsyndrome: Congenital adrenal hyperplasia (CAH):Geneticlesions in steroidogenesis


Congenital adrenal hyperplasia autosomal recessive defects

Congenital adrenal hyperplasia

  • Autosomal recessive defects

  • Result in diminished synthesis of cortisol

  • In response to adrenal insufficiency

    POMC – ACTH increase

  • ACTH + possibly other peptides derived from the amino-terminal end of POMC stimulate adrenal hypertrophy and hyperplasia (most prominent finding at autopsy).


Congenital adrenal hyperplasia autosomal recessive defects

  • Theory

    CAH is easy to understand: The signs and symptoms of the disease derive from the deficiency of the steroidal end product and the effects of accumulated steroidal precursors proximal to the blocked step.


Congenital adrenal hyperplasia autosomal recessive defects

  • Practice

    Because each steroidogenic enzyme has multiple activities and many extra-adrenal tissues contain enzymes that have similar activity, the complete elimination of a specific adrenal enzyme may not result in the complete elimination of its steroidal products from the circulation  CAH can be confusing.


Congenital adrenal hyperplasia autosomal recessive defects

Example:

  • 3ß – HSD deficiency

  • Affected infants should have low 17 OHP.

  • Due to extraadrenal 3ß – HSD-I have very high 17-OHP.


Congenital adrenal hyperplasia autosomal recessive defects

Congenital lipoid adrenal hyperplasia:

  • Most severe genetic disorder of steroid hormone synthesis.

  • Absence of significant concentrations of all steroids

  • High basal ACTH and plasma renin activity


Congenital adrenal hyperplasia autosomal recessive defects

Congenital lipoid adrenal hyperplasia:

  • Cholesterol transport to the mitochondria is affected (steroidogenic regulatory protein: StAR).

  • Only disorder in steroid hormone biosynthesis that is not caused by a disrupted steroidogenic enzyme.

  • Salt-wasting crisis, 46XYDSD


Congenital adrenal hyperplasia autosomal recessive defects

3ß hydroxysteroid dehydrogenase deficiency

Classic form:

Genetic females have cliteromegaly + mild virilization because the fetal adrenal overproduces large amounts of DHEA, a small portion of which is converted to testosterone by extra-adrenal 3ß HSD Type 1

Genetic males: small phallus+ severe hypospadias


Congenital adrenal hyperplasia autosomal recessive defects

3ß hydroxysteroid dehydrogenase deficiency:

Mild-partial defects: Young girls with premature adrenarche or young women with a history of premature adrenarche + complaints of hirsutism, virilism and oligomenorrhoea.


Congenital adrenal hyperplasia autosomal recessive defects

17 α hydroxylase – 17,20 lyase deficiency:

P450c17 has both 17αhydroxylase and 17-20 lyase activities

Deficient 17 α hydroxylase activity different clinical manifestations of Deficient 17-20 lyase activitydifferent lesions in the same gene


Congenital adrenal hyperplasia autosomal recessive defects

17 α hydroxylase – 17,20 lyase deficiency:

  • Overproduction of corticosterone (glucocorticoid activity)

  • Overproduction of DOC (sodium retention, hypertension and hypokalaemia, suppressed renin activity and aldosterone secretion)


Congenital adrenal hyperplasia autosomal recessive defects

17α hydroxylase – 17,20 lyase deficiency:

Affected females: phenotypically normal but fail to undergo adrenarche and puberty.

Affected males: absent or incomplete development of the external genitalia


Congenital adrenal hyperplasia autosomal recessive defects

17α hydroxylase – 17,20 lyase deficiency:

Classic presentation: teenage girl with sexual infantilism and hypertension


Congenital adrenal hyperplasia autosomal recessive defects

21 hydroxylase deficiency:

Due to mutations in the gene encoding adrenal P450c21

One of the most common inborn errors of metabolism and accounts for about 95% of CAH


Congenital adrenal hyperplasia autosomal recessive defects

21 hydroxylase deficiency:

Progesterone DOC: aldosterone Ø

-severe hyponatremia

-hyperkalemia hypotension

-acidosis shock

cardiovascular collapse

death


Congenital adrenal hyperplasia autosomal recessive defects

21 hydroxylase deficiency:

17OHP II deoxycortisol: cortisol Ø

  • impairs postnatal carbohydrate metabolism

  • Exacerbates cardiovascular collapse (because a permissive action of cortisol is required for full pressor action of catecholamines)


Congenital adrenal hyperplasia autosomal recessive defects

21 hydroxylase deficiency:

Cortisol ACTH

  • Adrenal hyperplasia

    stimulation of the transcription of the genes for all steroidogenic enzymes  accumulation

    of non 21 hydroxylated steroids especially 17 OHP  these steroids are converted to testosterone.


Congenital adrenal hyperplasia autosomal recessive defects

21 hydroxylase deficiency:

  • In the male fetus additional testosterone from the adrenals has little phenotypic effect

  • In the female fetus ovaries are quiescent-testosterone from the adrenals cause varying degrees of virilization of the external genitalia  mild cliteromegaly ± posterior fusion of the labioscrotal folds  complete labioscoral fusion + a urethra traversing the enlarged clitoris (I-V staging system of PRADER)

  • Ambiguous external genitalia + normal ovaries, Fallopian tubes and uterus or they appear to be male.


Congenital adrenal hyperplasia autosomal recessive defects

21 hydroxylase deficiency:

  • Diagnosis suggested by genital ambiguity in females, a salt-losing episode in the either sex, rapid growth in either sex, virilization in males

  • Plasma 17 OHP markedly elevated and hyperresponsive to stimulation with ACTH.

    Measurements: II-deoxycortisol

    DHEA, androstenedion


Congenital adrenal hyperplasia autosomal recessive defects

17OHP

17OHP assessments should not be made in the first 24h of life.

Premature infants and term infants under severe stress may have elevated 17-OHP.

3ß HSD – P450cII deficiences


Congenital adrenal hyperplasia autosomal recessive defects

21 hydroxylase deficiency:

Clinical forms of 21OHD:

Classical

Salt-wasting 21OHD: Due to complete deficiency of P450c21 activity

(inappropriately large doses result in growth loss. Female survivors may have sexual dysfunction, marry with a low frequency and have decreased fertility.)


Congenital adrenal hyperplasia autosomal recessive defects

Simple virilizing 21 OHD:

Males:

  • often escape diagnosis until age 3-7 years

  • testes remain of pre-pubertal size in CAH.

  • growth rapid-tall for age- bone age advances  final height compromised

  • untreated or poorly treated children may fail to undergo puberty

  • azospermia – small testes


Congenital adrenal hyperplasia autosomal recessive defects

Treatment begun at several years of age:

Suppression of adrenal testosterone secretion may remove tonic inhibition of the hypothalamus  true central precocious puberty.

Poorly treated boys  enlargement of adrenal rests in the testes – (enlarged nodular testes.)


Congenital adrenal hyperplasia autosomal recessive defects

Non-classic 21OHD 

variant of normal?

  • premature development

    of pubic and axillary hair

    (premature pubarche)

    late onset CAH

  • Mild to moderate hirsutism

  • Virilism

  • Menstrual irregularities

  • Decreased fertility


Congenital adrenal hyperplasia autosomal recessive defects

No phenotypic manifestations but i.v. ACTH adm. results in an increased response of plasma 17 OHP.

Cryptic CAH

+ mild impairment in mineralocorticoid secretion


Congenital adrenal hyperplasia autosomal recessive defects

21 hydroxylase deficiency:

Incidence:

Classic CAH : 1/14 000

Non-classic CAH: 1/100


Congenital adrenal hyperplasia autosomal recessive defects

21 hydroxylase deficiency:

21 hydroxylase genes: two 21hydroxylase loci

CYP21A2 functional gene(microsomal cytochrome P450)

CYP21AIP pseudogene


Congenital adrenal hyperplasia autosomal recessive defects

CYP21A2 gene lesions causing 21-OHD (>100)

-Gene conversions (%85)

-Most patients with 21 OHD are compound heterozygotes carrying a different mutation in the alleles inherited from each parent.


Congenital adrenal hyperplasia autosomal recessive defects

Prenatal diagnosis and treatment of 21 OHD

Fetal adrenal is active in steroidogenesis from early in gestation  a diagnosis can be made by aminocentesis and measurement of amniotic fluid 17 OHP. Concentrations of ∆4 androstenedione are also elevated in the amniotic fluid of fetuses with 21 OHD. Only reliable for identifying fetuses affected with severe salt-losing.


Congenital adrenal hyperplasia autosomal recessive defects

Prenatal diagnosis and treatment of 21 OHD

  • If a fetus is known to be at risk because the parents are known heterozygotes, 21 OHD can be diagnosed by HLA typing of fetal amniocytes or by analysis of fetal amniocyte DNA.

  • If the fetus has the same HLA type as the previously affected child the fetus will be affected

  • A fetus that shares one parent’s HLA type with the index case will be a heterozygote carrier

  • A fetus having both haplotypes differing from the index case will be unaffected


Congenital adrenal hyperplasia autosomal recessive defects

Prenatal diagnosis and treatment of 21 OHD

Female fetuses affected with 21 OHD begin to become virilized at about 6-8 wks gestation. By administering dexamethasome to the mother as soon as pregnancy is diagnosed fetal adrenal steroidogenesis is suppressed. Only 1/8 of the pregnancies of heterozygous parents would harbour an affected female fetus.


Congenital adrenal hyperplasia autosomal recessive defects

Prenatal diagnosis and treatment of 21 OHD

Dexamethasone 20 µg/kg of maternal body weight. Said to be controversial and experimental.


Congenital adrenal hyperplasia autosomal recessive defects

21 hydroxylase deficiency:

Diagnosis:

The measurement of 17 OHP response to i.v.synthetic ACTH. Individual patient responses must be compared with age and sex matched data from normal children. Plasma renin activity and its response to salt restriction constitute an especially useful test.


Congenital adrenal hyperplasia autosomal recessive defects

21 hydroxylase deficiency:

Treatment:

- Overtreatment

- Undertreatment

  • 10-20 mg of hydrocortisone per m² per day in three divided doses (growing children)

    Oral mineralocorticoid fluorocortisone (9 alfa fluorocortisol.)

    Newborns = 100-200 µg/day

    In older children = 50-150 µg

    Additional salt supp in the newborn: 1-2g of NaCl/day


Congenital adrenal hyperplasia autosomal recessive defects

21 hydroxylase deficiency:

Growth should be managed at 3-4 mo intervals along with annual assessment of bone age.

  • Urinary KS

  • Serum ∆4 androstenedion

  • DHEA

  • DHEA sulphate

  • Testosterone


Congenital adrenal hyperplasia autosomal recessive defects

Lesions in isoenzymes of P450c11 = 11ß hydroxylase deficiency, corticosterone methyl oxidase deficiency, glucocorticoid suppressible hypertension:

There are two distinct forms of 11 hydroxylase:

P450c11 ß mediates the 11 ß hydroxylation of 11 deoxycortisol to cortisol - 11 ß hydroxylation of DOC to corticosterone in the zonae fasciculata and reticularis.

P450C11AS: izoenzyme of P450C11ß. Aldosterone synthase is found only in zona glomerulosa and mediates 11 ß hydroxylation, 18 hydroxylation and 18 oxidation, it is the only enzyme required to convert DOC to aldosterone.


Congenital adrenal hyperplasia autosomal recessive defects

11 ß hydroxylase deficiency:

Severe deficiency of P450c11 ß: 5-8% CAH 

Cortisol  virilization of affected females. DOC accumulates  these patients can retain sodium but hypertension occurs, renin activity is normal or suppressed. The genetic lesions causing 11 ß hydroxylase deficiency are in the CYP 11 ß1 gene that encodes P450c11 ß.


Congenital adrenal hyperplasia autosomal recessive defects

11 ß hydroxylase deficiency:

Non-classic 11 ß hyd. deficiency: premature pubarche, hirsutism, virilism, menstrual irregularities


Congenital adrenal hyperplasia autosomal recessive defects

Cytochrome P450 oxidoreductase deficiency

  • Apparent combined

    P450C17 (17-hydroxylase)

    P450C21 (21-hydroxylase)

    deficiency.

  • Affected girls: ambiguous genitalia

    no progression of virilization after birth

  • Affected boys: sometimes undermasculinized

    ± Bone malformations (Antley-Bixler skeletal malformation syndrome)


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