CAH is caused by a deficiency in enzymes involved in cortisol or aldosterone synthesis. The most common type (90-95% of cases) is due to 21-hydroxylase deficiency which results in decreased cortisol and aldosterone. Symptoms vary in severity from virilization in females to salt-wasting crisis in infants. Treatment involves glucocorticoid and mineralocorticoid replacement tailored to the individual. Long-term monitoring is needed to ensure appropriate development and prevent health complications.

2. DEFINITION
 CAH is a group of autosomal recessive disorders
involving a partial or complete defect in cortisol
synthesis, aldosterone synthesis, or both, resulting in
varying degrees of deficiency in one or both hormones

3. INHERITENCE
 Is a case of AR.
 Symptomatic patient received only if we have both
allele affected means both parents are carrier.

4. INCIDINCE
 Classic CAH :1/10,000-15,000
 Non-classic: 1/500-1000.

5. Classification
 On basis of severity of enzyme severity: classic vs non-
classic
 On type of enzyme deficiency
 21-hydroxylase deficiency
11 beta-hydroxylase deficiency
17 beta-hydroxylase deficiency
3 beta htdroxysteroid dehydrogenase deficiency
 lipoid CAH

9. 21-hydroxylase deficiency
 90% - 95% cases of CAH are due 21-hydroxylase
deficiency.
 Gene responsible is located on short arm of
chromosome 6 near HLA region
 21-hydroxylase deficiency leads to diminished
conversion of 17-OHP to deoxycortisol.
 Which in turn leads to decreased cortisol synthesis
and stimulation of ACTH leading to adrenal
hyperplasia

10.  21-hydroxylase is also needed in conversion of
progesterone to deoxycorticosterone leading to
diminished aldosterone synthesis which is there in
75% patients of CAH
 Precursors of cortisol/aldosterone accumulates
converted to androgen synthesis in adrenals leading to
their excess

11. Classification
 FOUR TYPES
SIMPLE VIRILIZING
SALT WASTING FORM
NON-CLASSIC FORM
HETROZYGOTE 21-HYDROXYLASE DEFICIENCY

12. SIMPLE VIRILIZING FORM
 THERE IN DECREASED 21-HYDROXYLASE
DEFICIENCY(1-5%)
 ALDOSTERONE LEVELS ARE NORMAL, SO NO
SALT WASTING
 ANDROGENS IN EXCESS
 CORTISOL DECREASED
 17-OHP LEVELS2500-5000

13. SVF PRESENTATION
 FEMALES: GENITAL AMBIGUITY……SO
DIAGNOSED EARLIER THAN MALES
 MALES DUE TO EARLY DEVELOPMENT OF ANY
SECONDARY SEX. CHARACTER..MAY HAVE EARLY
PUBIC HAIRS/SEXUAL PRECOSIOSITY/GROWTH
ACCERATION(MAY HAVE LOW HEIGHT IF
UNDIAGNOSED/NOT TREATED).

14. SALT WASTING FORM
 USUALLY HAVE O % 21 -HYDROXYLASE ACTIVITY
 75% HAVE ALDOSTERONE DEFICIENCY
 FEMALE PATIENT PRESENT LIKE SVF PLUS SALT
WASTING/ADRENAL CRISES
 MALE PRESENT WITH NORMAL GENITALS WITH
ADRENAL CRISIS
 FATAL IF NOT DIAGNOSED OR UNTREATED
 P/W POOR FEEDING/WEIGHT
LOSS/VOMITING/LEHARGY/SEPSIS LIKE
FEATURES

15. NON-CLASSIC OR LATE ONSET CAH
 21-HYDROXYLASE ACTIVITY 25-50%
 PRESENT LATE IN CHILDHOOD/ADULT
 FEMALE PRESENTS LIKE FEATURES OF
PCOS/VIRILIZATION
 MALES ARE USUALLY NORMAL
 17-OPH LEVEL IS BETWEEN500-2500(USUALLY
NEEDS ACTH STIMULATION TEST)
 UPTO 12 % OF PCOS CAUSE IS NON-CLASSIC CAH

16. HETROZYGOGOTE 21-
HYDROXYLASE DEFICIENCY
 USUALY NORMAL GROWTH
 SYMTOMATIC ONLY IF COMPOND HETROZYGOUS
MUTATIONS

18. WORKUP
 Low Na ,high K, high renin usually found in salt
wasting form of CAH.
 Hypoglycemia, usually in stress /crises
 USG in females with CAH shows normal internal
genital organs as androgens don't have any effect on
their development
 Classic CAH patient usually have high 17-OHP levels
usually more than 20,000ng/dl
 Non-classic CAH, levels are low and usually needs
ACTH stimulation test.

19. WORKUP
 ACTH STIMULATION TEST(SYNECTHIN
STIMULATION TEST/SST)
 250 microgram i/m ACTH is given and basal(at 0 time)
and after 60 minutes levels of 17-OHP measured
 IN non-classic CAH value raises from 20-1000 To 1000-
10,000 ng/dl while in non-CAH it will be below 1000
ng/dl

20. Treatment
 Goals
 Goals differs with age group
 In children, goal is to replace cortisol/aldosterone to
avoid salt wasting crises and normalize adrenal
androgens to allow normal growth/skeletal maturation.
under dosing will not obtain optimal results and
overdosing will suppress growth.
 Monitoring by using growth velocity/bone age plus
biochemical markers(17-OHP, androstendione,
testosterone) in bllo/urine/sliva.

21. TREATMENT
 Biochemical investigation are used for monitoring as
they indicate earlier change in dose need
 Short acting steroid like hydrocortisone is used in
childhood and long acting better in adolescence/after
puberty,
 10-15 mg/meter square of hydrocortisone in childhood
usually needed
 fludrocortisone only in salt wasters. 150 ug/meter
square in first year of life and then 100 ug/square
meter in rest of life.

22. Antenatal workup/management
 Chorionic villous sampling for genotyping/17 OHP
levels in amniotic fluid can be used for antenatal
diagnosis of CAH
 Antenatallly, dexamethasone is used….. As
hydrocortisone is inactivated in placenta.
 Only female fetus need Rx,
 To be safe start dexa as soon as pregnancy confirmed
to delivery/fetus is screened

23.  All forms of CAH are inherited as autosomal recessive
traits

25. CYP17A1 DEFICIENCIES
 Most defects in CYP17A1 impair both enzymatic
activities and cause combined 17-hydroxylase/17,20-
lyase deficiency (17OHD), which can be complete or
partial .
 The prevalence appears to be highest in Brazil
 CYP17A1 is expressed both in the human adrenal and
gonads ,and thus, these deficiencies are forms of CAH
that impair both adrenal and gonadal function
 CYP17A1 deficiencies (combined 17-hydroxylase/17,20-
lyase deficiency [17OHD] and isolated 17,20-lyase
deficiency [ILD])

26. Pathophysiology
 The hallmarks of 17OHD, first described in 1966 ,
include hypertension and hypokalemia due to the
accumulation of cortisol precursors with
mineralocorticoid activity upstream of the block, plus
sexual infantilism due to inability to synthesize
androgens and estrogens.
 Unlike most other forms of CAH, mineralocorticoid
excess and high corticosterone production mitigate
the clinical consequences of cortisol deficiency, and
symptomatic adrenal insufficiency is rare

27.  The classic presentation of severe 17OHD in phenotypic females (who can have
46,XX or 46,XY karyotype) includes [3,9,10,17]:
 Hypertension
 Primary amenorrhea
 Absence of secondary sexual characteristics
 Minimal body hair
 The hypertension, which is typically detected in early adulthood , may be
present much earlier and can be severe but may be normalized with treatment

28.  DOC binds with high affinity to the mineralocorticoid
receptor
 DOC excess causes volume expansion, hypertension,
and kaluresis despite suppressed renin and
aldosterone production.

29. Diagnosis
 In general, the diagnosis is established by showing
elevated DOC (>100 ng/dL [>3 nmol/L])
 and corticosterone (>4000 ng/dL [>116 nmol/L])
 with low cortisol (<5 mcg/dL [<138 nmol/L]),
androgens, and estrogens.
 Progesterone is also elevated , while aldosterone and
renin are suppressed .
 Gonadotropins and corticotropin (ACTH) are elevated
even in children

31. Treatment
 The goals of treatment in classic 17OHD are to mitigate the
effects of mineralocorticoid excess, prevent glucocorticoid
deficiency, and restore desired secondary sexual
characteristics with attendant benefits such as improved bone
mineral density (BMD). T
 This is achieved by mineralocorticoid blockade and
physiologic replacement of cortisol and sex steroids, rather
than by supraphysiologic suppressive doses of glucocorticoid.
 For patients reared as female, spironolactone is the drug of
choice to block the mineralocorticoid receptor.
 Medications are titrated based on monitoring blood pressure,
DOC, and electrolytes; renin suppression can persist for years,
despite adequate therapy

32.  Puberty is induced with low-dose estrogen at the
expected time of pubarche.
 Cyclical withdrawal bleeding is only required for
46,XX females with an intact uterus.

33. 3-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 2 DEFICIENCY

34.  3-beta-hydroxysteroid dehydrogenase type 2 (HSD3B2)
deficiency is a rare form of congenital adrenal
hyperplasia (CAH) in which synthesis of all active
steroid hormones is impaired.
 This very rare disorder, like combined 17-
hydroxylase/17,20-lyase deficiency (17OHD), impairs
both adrenal and gonadal steroid production .
 Paradoxically, both male and female infants are born
with genital ambiguity

35.  all are deficient, and since androgens are precursors to
estrogens, estrogen biosynthesis is also impaired .
 The resulting corticotropin (ACTH) excess drives the
production of the 3-beta-hydroxy-delta-5-steroids
pregnenolone, 17-hydroxypregnenolone, and
dehydroepiandrosterone (DHEA), as well as their
sulfates .
 Unlike 17OHD, the accumulating precursor steroids do
not compensate for cortisol deficiency, and newborns
suffer from hypotension and hyperkalemia as in 21-
hydroxylase deficiency (21OHD)

36.  Testosterone deficiency results in genital ambiguity in
46,XY newborns and persists throughout adulthood.
In contrast, girls are born with mild-to-moderate
clitoromegaly but little labioscrotal fusion
 Undiagnosed girls proceed to develop androgen
excess, including precocious pubarche, acne, and
hirsutism with menstrual disturbances.

37.  The formation of active androgens in girls occurs
because a second enzyme, HSD3B1, is abundant in
liver and skin , and this enzyme converts circulating
DHEA to androstenedione.
 The markedly elevated output of precursor steroids
leads to relatively high amounts of testosterone in girls
but fails to compensate fully for the defect in testicular
testosterone synthesis in boys
 Newborn females often have mild virilization and
clitoromegaly due to peripheral conversion of adrenal-
derived DHEA to testosterone by the type 1 enzyme

38.  Clinical and biochemical phenotype — Much like
21OHD, most patients present as neonates or in early
infancy with clinical manifestations of both cortisol
and aldosterone deficiency, with feeding difficulties,
vomiting, volume depletion, hyponatremia, and
hyperkalemia

39.  The primary biochemical abnormalities are greatly
increased ratios of delta-5 to delta-4 steroids in serum
(best obtained after cosyntropin stimulation) or in
urine, such as a high ratio of 17-hydroxypregnenolone
(delta-5) to 17-hydroxyprogesterone (17OHP, delta-4)
in serum or a high ratio of pregnanetriol to
pregnanediol in urine
 The markedly increased delta-5 steroids distinguish
this condition from the other diseases in the
differential diagnosis, which include 11-beta-
hydroxylase deficiency (11OHD), 21OHD,

40.  In 46,XY children raised as males, replacement doses
of glucocorticoid (hydrocortisone) and
mineralocorticoid (fludrocortisone acetate) are often
sufficient to attenuate adrenal-derived androgen
production enough to normalize growth and to
prevent bone age advancement.
 At the time of expected puberty, gender-appropriate
replacement of androgens or estrogens with progestins
should be started and advanced slowly to adult
regimens. In undervirilized 46,XY males, testosterone
therapy may be used during childhood to augment
penile size prior to initiation of puberty

41. 11-BETA-HYDROXYLASE DEFICIENCY

42. Pathogenesis
 Deficiency of 11-beta-hydroxylase activity in the zona
fasciculata blocks the conversions of 11-
deoxycorticosterone (DOC) and 11-deoxycortisol to
corticosterone and cortisol, respectively. The resulting
increase in corticotropin (ACTH) secretion causes the
accumulation of 11-deoxysteroid precursors and
adrenocortical hyperplasia

43.  The clinical manifestations of the disorder result from
high adrenal production of the mineralocorticoid
DOC and the androgen precursor
dehydroepiandrosterone sulfate (DHEAS), which are
metabolized to androstenedione and active androgens
in the adrenal and/or peripheral organs
 Consequently, the two characteristic clinical features
are hypertension with hypokalemia, as found in any
other form of mineralocorticoid excess, and androgen
excess

44.  Classically, female newborns are identified with
ambiguous genitalia, including clitoral enlargement
and labioscrotal fusion as in 21OHD
 Boys may have increased penile size, but unless born
into a kindred known to carry 11OHD, they are often
not diagnosed at birth or by newborn screening of 17-
hydroxyprogesterone (17OHP), which is not as high in
this disorder as it is in 21OHD.

45.  In children who are not diagnosed at birth, 11OHD
presents as premature adrenarche, with body odor and
axillary and pubic hair development. Somatic growth
and bone age generally advance faster than in
idiopathic premature adrenarche, suggesting the
diagnosis of 11OHD.
 The hypertension and hypokalemia distinguish 11OHD
from 21OHD and HSD3B2 deficiency, and the
androgen excess distinguishes 11OHD from 17OHD.

46. Biochemical features
 Patients with classic CYP11B1 deficiency have a
characteristic set of hormonal findings, often with
hypokalemia:
 High serum concentrations of 11-deoxycortisol, DOC,
DHEA and DHEAS, androstenedione, and
testosterone, with low cortisol and corticosterone

47.  Because 17OHP also accumulates above the 11-beta-
hydroxylase block, 17OHP is often moderately elevated
in 11OHD. Consequently, the differential diagnosis for
a young girl with mild virilization, androgen excess,
and moderate 17OHP elevations includes nonclassic
21OHD, 11OHD, and 3HSD3B2 deficiency. These
diagnoses can only be distinguished by measurement
of additional steroids including 11-deoxycortisol, DOC,
and 17-hydroxypregnenolone, to pinpoint the
enzymatic defect

49. Treatment approach
 The goals of therapy in children with 11OHD are to
reduce mineralocorticoid and adrenal androgen
precursor synthesis sufficiently to ameliorate the
hypertension, hypokalemia, and androgen excess
 Children are generally treated with glucocorticoids
only, typically hydrocortisone (10 to 25 mg/m2), which
is preferred over prednisolone (approximately 0.1
mg/kg) or dexamethasone (up to 0.01 mg/kg), to
lower ACTH secretion.

50.  spironolactone is sometimes added to antagonize both
androgens and mineralocorticoids, allowing reduced
glucocorticoid dosing, particularly in adults. Given the
phenotypic variability in this disease, treatment must
be tailored to minimize the dose of glucocorticoid so as
to prevent iatrogenic Cushing's syndrome
 In adolescent girls, facial hair growth and acne should
be examined. Genital malformations in affected
females may require surgical correction with one or
more surgeries and vaginal dilation

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