This document provides information on congenital adrenal hyperplasia caused by various enzyme deficiencies in the cortisol biosynthesis pathway. It begins by introducing congenital adrenal hyperplasia as autosomal recessive disorders of cortisol biosynthesis. It then discusses the common causes of congenital adrenal hyperplasia, focusing on 21-hydroxylase deficiency as the most common cause, accounting for over 90% of cases. The document provides details on the etiology, epidemiology, clinical manifestations, diagnosis, and treatment of 21-hydroxylase deficiency. It also briefly summarizes information about other causes of congenital adrenal hyperplasia including 11β-hydroxylase deficiency and 3β-hydroxysteroid dehydrogenase deficiency.

1. BY DR SHIVANANDA POLISETTY
MD PEDIATRICS
AVMCH & R, PUDUCHERRY
Ref: NELSON TEXT BOOK OF PEDIATRICS
CONGENITAL ADRENAL
HYPERPLASIA

2. INTRODUCTION
 Autosomal recessive disorders of cortisol biosynthesis
 Cortisol deficiency corticotropin [ACTH] Adrenocortical hyperplasia
& overproduction of intermediate metabolites.
 Depending on the enzymatic step that is deficient, there may be signs,
symptoms, and laboratory findings are present.
 Mineralocorticoid deficiency
Incomplete virilization or precocious puberty in affected males
Virilization or sexual infantilism in affected females

5. COMMON CAUSES OF CAH
 21-Hydroxylase deficiency (Most common)
 11β-Hydroxylase deficiency
 3β-Hydroxysteroid Dehydrogenase deficiency
 17α-Hydroxylase/17,20-lyase deficiency
 Congenital lipoid Adrenal hyperplasia
 P450 Oxidoreductase deficiency

6. Caused by 21-Hydroxylase Deficiency
ETIOLOGY
 > 90% of CAH cases are caused by 21-hydroxylase deficiency.
 Hydroxylates progesterone and 17-hydroxyprogesterone to yield
11-deoxycorticosterone and 11-deoxycortisol, respectively
 These conversions are required for synthesis of aldosterone and
cortisol, respectively.
 Both hormones are deficient in the -“salt-wasting” form
 “simple virilizing disease”- synthesize adequate amounts of
aldosterone but have elevated levels of androgens of adrenal origin
 These 2 forms are collectively termed classic 21-hydroxylase
deficiency.
 Nonclassic disease have relatively mildly elevated levels of
androgens and may be asymptomatic

7. Cont..
Accounts for 90% of all cases.
 Classic type
1) Salt wasting form
2) Simple virilizing form
 Non-classic type

8. EPIDEMIOLOGY
 Classic 21-hydroxylase deficiency occurs in approximately 1 in
15,000-20,000 births in most populations.
 Approximately 70% - have the salt-losing form,
30% - have the simple virilising form
 Nonclassic disease has a prevalence of approximately 1 in
1,000 in the general population
 There are 2 steroid 21-hydroxylase genes present on
chromosome 6p21.3

10. Cont..
Aldosterone Cortisol Androgens
•Salt wasting
•Hypovolemia
•Shock
•Metabolic syndrome •Virilization
•Precocious puberty

11. 21-Hydroxylase Deficiency
Classic
1) SW form :
 Most Lethal form of 21 hydroxylase
deficiency
 Manifests as Salt water crisis at 2 to 6
weeks of life.
Features :
 Vomiting
 Pigmentation
 Abnormal genital appearance
 Lethargy
 FTT
 Shock with ↓ed Urine output.
Biochemical
Findings :
 Hyponatremia
 Hyperkalemia
 Hypoglycemia
 Metabolic acidosis
 Hemoconcentration

12. Simple virilizing form
 These have milder defect with mineralocorticoid secretion sufficient to
prevent SW.
Features :
 Girls present with genital ambiguity , sometimes virilised to the extent of
being reared as boys and manifests with cyclical Haematuria during
adolescence.
 Boys have peripheral precocious puberty, usually diagnosed very late
with significant bone age advancement and compromised final height.

13. Cont..
A. A 6-yr-old girl with congenital virilizing
adrenal hyperplasia. The height age was 8.5 yr,
and the bone age was 13 yr.
B. Notice the clitoral enlargement and
labial fusion.
C. Her 5 yr old brother was not considered to be
abnormal by the parents. The height age was of
8 yr,and the bone age was 12.5yr

14. Non-classic type
 Produce normal amounts of cortisol and aldosterone at the expense of mild-to-
moderate overproduction of sex hormoneprecursors.
At presentation
 Hirsutism(most common) symptom in approximately 60 percent of symptomatic
women,
 Oligomenorrhea (54 %)
 Acne (33 %).
 Decreased fertility is an indication for glucocorticoid treatment in both men and
women

15. DIAGNOSIS- Lab Investigations
 Glucose/dextrose stick at bedside
 Sr. Electrolytes
 LFT
 Arterial blood gas/serum pH
 Cortisol
 ACTH
 17-OHP
 Pelvic ultrasonography
 Karyotype

16. Prenatal diagnosis
 Prenatal diagnosis
In the 1st trimester by chorionic villus sampling or
in the 2nd trimester by amniocentesis.
 This is usually done if the parents already have an affected child.
 Most often, the CYP21 gene is analyzed for frequently occurring mutations;
more rare mutations may be detected by DNA sequencing.

17. Newborn screening
 By analyzing 17-hydroxyprogesterone levels in dried blood
obtained by heelstick and absorbed on filter paper cards;
 Potentially affected infants are typically quickly recalled for additional
testing (electrolytes and repeat 17-hydroxyprogesterone
determination) at approximately 2 wk of age.
 Infants with salt-wasting disease often have abnormal electrolytes by
this age but are usually not severely ill.
 The nonclassic form of not reliably detected by newborn screening
 Positive predictive value can be improved by using cutoff levels
based on gestational age, and by second-tier screening methods
such as liquid chromatography followed by tandem mass
spectrometry.

18. Treatement
 Glucocorticoid Replacement
 Mineralocorticoid Replacement
 Surgical management of ambiguous genitalia
 Prenatal screening

19. Glucocorticoids
 Treatment also suppresses excessive production of androgens and
thus minimizes problems such as excessive growth and skeletal
maturation and virilization.
 Dose - 15-20 mg/m2/24 hr of hydrocortisone daily administered
orally in 3 divided doses.
 Double or triple doses are indicated during periods of stress, such
as infection or surgery.
 Indications - classic 21-hydroxylase deficiency & nonclassic
disease with signs of androgen excess
 Overtreatment is also suggested by excessive weight gain.
 Pubertal development & skeletal maturation should be evaluate
regularly
 Hormone levels, particularly 17-hydroxyprogesterone and
androstenedione, should be measured early in the morning, before

20. Cont..
 Menarche occurs at the appropriate age in most girls with adequate
treatement
 In some children, especially if the bone age is 12 yr or more, spontaneous
central (i.e., gonadotropin-dependent) puberty may occur when treatment
is started, because hydrocortisone suppresses production of adrenal
androgens and thus stimulates release of pituitary gonadotropins
 Males with 21-hydroxylase deficiency who have had inadequate
corticosteroid therapy may develop testicular adrenal rest tumors, which
usually regress with increased steroid dosage.
 Testicular MRI, ultrasonography, and color flow Doppler examination help
define the character and extent of disease.

21. Mineralocorticoid Replacement
 Patients with salt-wasting disease (i.e.,aldosterone deficiency) require
mineralocorticoid replacement with fludrocortisone.
 Infants may have very high mineralocorticoid requirements in the 1st few
mo of life, usually 0.1-0.3 mg/day in 2 divided doses & occasionally up to
0.4 mg/day, and sodium supplementation (sodium chloride, 8 mmol/kg) in
addition to the mineralocorticoid.
 Older infants and children are 0.05-0.1 mg/day of fludrocortisone.
 In Simple virilizing disease low dose of fludrocortisone in addition to
hydrocortisone (these patients have normal aldosterone levels)
 Tachycardia and hypertension are signs of overtreatment

22. Cont..
 Serum electro lytes should be measured frequently in early infancy as
therapy is adjusted.
 Plasma renin activity is a useful way to determine adequacy of therapy;
 Additional approaches to improve outcome include an antiandrogen such
as flutamide , and/or an aromatase inhibitor such as anastrozole, and
thus retards skeletal maturation
 Aromatase inhibitors should not be used in pubertal girls, they will retard
normal puberty and expose the ovaries to excessive levels of
gonadotropins.

23. Surgical Management of Ambiguous
Genitals
 Significantly virilized females usually undergo surgery between 2-6 mo of
age.
 Severe clitoromegaly, the clitoris is reduced in size, with partial excision of
the corporal bodies and preservation of the neurovascular bundle
 Vaginoplasty and correction of the urogenital sinus usually are performed
at the time of clitoral surgery
 In adolescent and adult females with poorly controlled 21-hydroxylase
deficiency (hirsutism, obesity, amenorrhea), bilateral laparoscopic
adrenalectomy (with hormone replacement)
 But they may exhibit signs of elevated ACTH levels such as abnormal
pigmentation.

24. Prenatal Treatment
 Besides genetic counseling, the main goal of prenatal diagnosis is to
facilitate appropriate prenatal treatment of affected females.
 Mothers with pregnancies at risk are given dexamethasone, in an amount
of 20 μg/kg prepregnancy maternal weight /day in 2 or 3 divided doses.
 This suppresses secretion of steroids by the fetal adrenal, including
secretion of adrenal androgens.
 Children exposed to this therapy have slightly lower birthweights.
 Effects on personality or cognition, such as increased shyness may
present
 Maternal side effects included edema, excessive weight gain,
hypertension, glucose intolerance, cushingoid facial features, and severe

25. Congenital Adrenal Hyperplasia Caused by
11β-Hydroxylase Deficiency
ETIOLOGY
 Deficiency of 11β-hydroxylase is caused by a mutation in the
CYP11B1 gene located on chromosome 8q24.
 It mediates 11-hydroxylation of 11-deoxycortisol to cortisol.
 Because 11-deoxycortisol is not converted to cortisol, levels of
corticotropin are high.
 In consequence, precursors particularly 11-deoxycortisol and
deoxycorticosterone accumulate and are shunted into androgen
biosynthesis in the same manner as occurs in 21-hydroxylase
deficiency.
 The adjacent CYP11B2 gene encoding aldosterone synthase is
generally unaffected in this disorder, so patients are able to

26. EPIDEMIOLOGY
 11β-Hydroxylase deficiency accounts for approximately 5% of cases of
adrenal hyperplasia; its incidence in the general population has been
estimated as 1 in 250,000 to 1 in 100,000.
 The disorder occurs relatively frequently in Israeli Jews of North African
origin (1 in 15,000-17,000 live births).
 This disorder presents in a classic, severe form and very rarely in a
nonclassic, milder form.

27. CLINICAL MANIFESTATIONS
 Cortisol is not synthesized, aldosterone synthetic capacity is normal, and
some corticosterone is synthesized by the intact aldosterone synthase
enzyme.
 Approximately 65% of patients become hypertensive due to elevated
levels of deoxycorticosterone
 Infants transiently develop signs of mineralocorticoid deficiency after
treatment with hydrocortisone , Due sudden suppression of
deoxycorticosterone secretion
 All signs and symptoms of androgen excess that are found in 21-
hydroxylase deficiency may also occur in 11β-hydroxylase deficiency.

28.  Plasma levels of 11-deoxycortisol and deoxycorticosterone are elevated.
 As deoxycorticosterone and metabolites have mineralocor ticoid activity,
plasma renin activity is suppressed.
 Consequently, aldosterone levels are low even though the ability to
synthesize aldosterone is intact.
 Hypokalemic alkalosis occasionally occurs.
LABORATORY FINDINGS

29. TREATMENT
 Patients are treated with hydrocortisone in doses similar to those used for
21-hydroxylase deficiency.
 Mineralocorticoid replacement is rarely.
 Hypertension often resolves with glucocorticoid treatment
 If it is of long standing CCB’s may be beneficial under these
circumstances.

30. Congenital Adrenal Hyperplasia
Caused by 3β-Hydroxysteroid Dehydrogenase
Deficiency
ETIOLOGY
 Deficiency of 3β-hydroxysteroid dehydrogenase (3β-HSD) occurs in fewer
than 2% of patients with adrenal hyperplasia.
 This enzyme is required for conversion of Δ5 steroids (pregnenolone, 17-
hydroxypregnenolone, dehydroepiandrosterone [DHEA]) to Δ4 steroids
(progesterone, 17-hydroxyprogesterone, and androstenedione).
 Thus, deficiency of the enzyme results in synthesis of cortisol,
aldosterone, and androstenedione but increased secretion of DHEA.
 The 3β-HSD isozyme expressed in the adrenal cortex and gonad is
encoded by the HSD3B2 gene located on chromosome 1p13.1.

31. CLINICAL MANIFESTATIONS
 Cortisol ,Aldosterone,Androstenedione and testosterone are not
synthesized
 Boys are incompletely virilized.with varying degrees of hypospadias , with
or without bifid scrotum or cryptorchidism.
 DHEA levels are elevated and this hormone is a weak androgen, girls are
mildly virilized, with clitoral enlargement.
 Postnatally, DHEA secretion cause precocious adrenarche.
 During adolescence and adulthood, hirsutism, irregular menses, and
polycystic ovarian disease occur in females
 Males manifest variable degrees of hypogonadism

32. LABORATORY FINDINGS
 The hallmark of this disorder is the marked elevation of the Δ5
steroids (such as 17-hydroxypregnenolone and DHEA) preceding the
enzymatic block
 Patients may also have elevated levels of 17- hydroxyprogesterone
because of the extraadrenal 3β-HSD activity that occurs in peripheral
tissues
 The ratio of 17- hydroxypregnenolone:17-hydroxyprogesterone is
markedly elevated in 3β-HSD deficiency, in contrast to the decreased
ratio in 21-hydroxylase deficiency.
 Plasma renin activity is elevated in the salt-wasting form.

33. TREATMENT
 Patients require glucocorticoid and mineralocorticoid replacement with
hydrocortisone and fludrocortisone, respectively, as in 21- hydroxylase
deficiency.
 Incompletely virilized genetic males a depot form of testosterone 25 mg
every 4 wk early in infancy to increase the size of the phallus.
 They may also require testosterone replacement at puberty

34. Congenital Adrenal Hyperplasia Caused by 17-Hydroxylase
Deficiency
ETIOLOGY
 Less than 1% of CAH cases are caused by 17-hydroxylase
deficiency
 Catalyzes 2 distinct reactions:17-hydroxylation of pregnenolone
and progesterone to 17-hydroxypregnenolone and 17-
hydroxyprogesterone, respectively, and the 17,20-lyase reaction
mediating conversion of 17-hydroxypregnenolone to DHEA and, to
a lesser extent, 17-hydroxyprogesterone to Δ4-androstenedione.
 DHEA and androstenedione are steroid precursors of testosterone
and estrogen .
 The enzyme is expressed in both the adrenal cortex and the

35. CLINICAL MANIFESTATIONS
 Cannot synthesize cortisol & sex hormones
 Because corticosterone is an active glucocorticoid, patients do not
develop adrenal insufficiency.
 Deoxycorticosterone is synthesized in excess.
 This can cause hypertension, hypokalemia, and suppression of renin
and aldosterone secretion
 Males are incompletely virilized and present as phenotypic females
(but gonads are usually palpable in the inguinal region or the labia) or
with sexual ambiguity.
 Females present with failure of sexual development at the expected
time of puberty.

36. TREATMENT
 Require cortisol replacement to suppress secretion of
deoxycorticosterone and thus control hypertension.
 Additional antihypertensive medication may be required.
 Females require estrogen replacement at puberty.
 Genetic males may require either estrogen or androgen
supplementation depending on the sex of rearing.
 Because of the possibility of malignant transformation of abdominal
testes with androgen insensitivity syndrome, genetic males with severe
17-hydroxylase deficiency being reared as females require
gonadectomy at or before adolescence

37. Lipoid Adrenal Hyperplasia
ETIOLOGY
 Lipoid adrenal hyperplasia is a rare disorder,
 Accumulation of cholesterol and lipids in the adrenal cortex and gonads,
associated with severe impairment of all steroidogenesis.
 Caused by mutations in the gene for StAR protein , a mitochondrial protein that
promotes the movement of cholesterol from the outer to inner mitochondrial
membrane
 Some cholesterol is able to enter mitochondria even in the absence of StAR, so
not completely impair steroid biosynthesis.
 The accumulation of cholesterol in the cytoplasm is cytotoxic, eventually leading
to death of all steroidogenic cells
 This occurs prenatally in the adrenals and testes.
 The ovaries do not normally synthesize steroids until puberty, so cholesterol
does not accumulate and the ovaries can retain the capacity to synthesize
estrogens until adolescence

38. CLINICAL MANIFESTATIONS
 Unable to synthesize any adrenal steroids
 Can be confused with adrenal hypoplasia congenita.
 Salt-losing manifestations are typical, and many infants die in
early infancy.
 Genetic males are unable to synthesize androgens and thus are
phenotypically female but with gonads palpable in the labia
majora or inguinal areas.
 Genetic females appear normal at birth and may undergo
feminization at puberty with menstrual bleeding.
 They too, progress to hypergonadotropic hypogonadism when
accumulated cholesterol kills granulosa cells in the ovary.

39. LABORATORY FINDINGS
 Adrenal and gonadal steroid hormone levels are low in lipoid adrenal
hyperplasia, with a decreased or absent response to stimulation (ACTH,
human chorionic gonadotropin).
 Plasma renin levels are increased.
 Imaging studies of the adrenal gland demonstrating massive adrenal
enlargement in the newborn help establish the diagnosis of lipoid adrenal
hyperplasia.

40. TREATMENT
 Patients require glucocorticoid and mineralocorticoid replacement.
 Genetic males are usually assigned a female sex of rearing; thus both
genetic males and females require estrogen replacement at the
expected age of puberty.

41. Deficiency of P450 Oxidoreductase
(Antley-Bixler Syndrome)
 P450 oxidoreductase (POR, gene located on chromosome 7q11.3) is
required for the activity of all microsomal cytochrome P450 enzymes
including the adrenal enzymes CYP17 and CYP21.
 Complete POR deficiency abolishes all microsomal P450 activity.
 This is embryonically lethal
 Have partial deficiencies of 17-hydroxylase and 21-hydroxylase activities
in the adrenals
 Deficiency of 17-hydroxylase leads to incomplete masculinization in
males; 21-hydroxylase deficiency may lead to virilization in females.
 Additionally, aromatase (CYP19) activity in the placenta is decreased,
leading to unopposed action of androgens produced by the fetal adrenal.
 This exacerbates virilization of female fetuses and may virilize the
mother of an affected fetus as well.

42. Antley-Bixler syndrome
 Because many other P450
enzymes are affected, patients
often have other congenital
anomalies collectively referred to
as Antley-Bixler syndrome.
 These include
 Craniosynostosis;
 Brachycephaly;
 Frontal bossing;
 Severe midface hypoplasia with
proptosis & choanal stenosis or
atresia;
 Humeroradial synostosis
 Medial bowing of ulnas;
 Long, slender fingers with
camptodactyly;
 Narrow iliac wings;
 Anterior bowing of femurs;
 Malformations of the heart and
kidneys.

43. LABORATORY FINDINGS
 Serum steroids that are not 17- or 21-hydroxylated are most increased,
including pregnenolone and progesterone.
 17-Hydroxy, 21- deoxysteroids are also increased, including 17-
hydroxypregnenolone, 17-hydroxyprogesterone, and 21-deoxycortisol.
 Urinary steroid metabolites may be determined by quantitative mass
spectrometry.
 Metabolites excreted at increased levels include pregnanediol,
pregnanetriol, pregnanetriolone, and corticosterone metabolites.
 Urinary cortisol metabolites are decreased.
 Genetic analysis demonstrates mutations in the POR gene.

44. DIFFERENTIAL DIAGNOSIS
 This disorder must be distinguished from other forms of CAH,
particularly 21-hydroxylase deficiency in females, which is far more
common and has similar laboratory findings.
 Suspicion for POR deficiency may be raised if the mother is virilized or
if the associated abnormalities of Antley-Bixler syndrome are present.
 Conversely, virilization of both the mother and her daughter can result
from a luteoma of pregnancy
 Antley-Bixler syndrome may also occur without abnormalities of steroid
hormone biosynthesis, resulting from mutations in the fibroblast growth
factor receptor FGFR2.

45. Summery of CAH- Home taking

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