Download 21 hydroxylase deficiency

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
• ACTH + possibly other peptides derived
from the amino-terminal end of POMC
stimulate adrenal hypertrophy and
hyperplasia (most prominent finding at
autopsy).
• 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.
• Practice
Because each steroidogenic enzyme
has multiple activities and many extraadrenal 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.
Example:
• 3ß – HSD deficiency
• Affected infants should have
low 17 OHP.
• Due to extraadrenal 3ß –
HSD-I have very high 17-OHP.
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 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
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
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.
17 α hydroxylase – 17,20 lyase deficiency:
P450c17 has both 17α hydroxylase and 17-20 lyase
activities
Deficient 17 α hydroxylase activity
Deficient 17-20 lyase activity
different clinical manifestations of
different lesions in the same gene
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)
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
17α hydroxylase – 17,20 lyase deficiency:
Classic presentation: teenage girl with
sexual infantilism and hypertension
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
21 hydroxylase deficiency:
Progesterone
-severe hyponatremia
-hyperkalemia
-acidosis
DOC: aldosterone Ø
hypotension
shock
cardiovascular collapse
death
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)
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.
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.
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
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
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.)
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
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.)
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
No phenotypic manifestations but i.v. ACTH
adm. results in an increased response of
plasma 17 OHP.
Cryptic CAH
+ mild impairment in mineralocorticoid
secretion
21 hydroxylase deficiency:
Incidence:
Classic CAH : 1/14 000
Non-classic CAH: 1/100
21 hydroxylase deficiency:
21 hydroxylase genes: two 21hydroxylase loci
CYP21A2 functional gene(microsomal cytochrome
P450)
CYP21AIP pseudogene
CYP21A2 gene lesions causing 21OHD (>100)
-Gene conversions (%85)
-Most patients with 21 OHD are compound
heterozygotes carrying a different mutation in
the alleles inherited from each parent.
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.
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
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.
Prenatal diagnosis and treatment of 21 OHD
Dexamethasone 20 µg/kg of maternal body
weight. Said to be controversial and
experimental.
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.
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
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
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.
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.
11 ß hydroxylase deficiency:
Non-classic 11 ß hyd. deficiency: premature
pubarche, hirsutism, virilism, menstrual
irregularities
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)