The Turkish Journal of Pediatrics
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Association between genotype, clinical presentation, and severity of congenital adrenal hyperplasia: a review
Abdulmoein E. Al-Agha1, Ali H. Ocheltree2, Masha’el D. Al-Tamimi1
1Department of Pediatrics, King Abdul-Aziz University Hospital, Faculty of Medicine, Jeddah and 2 Department of Internal
Medicine, North West Armed Forces Hospital, Tabuk, Kingdom of Saudi Arabia. E-mail: firstname.lastname@example.org
|Congenital adrenal hyperplasia (CAH) applies to a family of inherited disorders
of steroidogenesis caused by an abnormality in one of the five enzymatic steps
necessary in the conversion of cholesterol to cortisol. The enzyme defects are
transmitted as an autosomal recessive trait. Patients with a “classical” form
of CAH usually present during the neonatal and early infancy period with
adrenal insufficiency, which could be associated with a salt- losing pathology.
Females usually have genital ambiguity. Approximately 67% of classical CAH
patients are classified as “salt-losing”, while 33% have “non-salt-losing” or
the “simple-virilizing” form, reflecting the degree of aldosterone deficiency.
Non-classic 21-hydroxylase deficiency (NC 21-OHD) refers to the condition
in which partial deficiencies of 21-hydroxylation produce less extreme
hyperandrogenemia and milder symptoms. Females do not demonstrate genital
ambiguity at birth. The gene for adrenal 21-hydroxylase, CYP21, is located on
chromosome 6p in the area of human leukocyte antigen (HLA) genes. Specific
mutations may be associated with a certain degree of enzymatic compromise
and the clinical form of 21-hydroxylase deficiency (21-OHD). NC 21-OHD
patients are predicted to have mild mutations on both alleles and one severe
or one mild mutation of the 21-OH locus (compound heterozygote). This
review aims to describe the association between the genotype and clinical
presentations and severity of CAH.|
congenital adrenal hyperplasia, adrenal insufficiency, genital ambiguity,
|Congenital adrenal hyperplasia (CAH) refers
to a group of autosomal recessive disorders
with defects in the biosynthesis of the cortisol
hormone. The synthesis of other steroids, such
as mineralocorticoids and adrenal/gonadal sex
steroids, may also be affected (Fig. 1). The
low level of cortisol stimulates the pituitary
gland to release adrenocorticotropic hormone
(ACTH). This chronic elevation in ACTH
causes hyperplasia of the adrenal cortex, giving
the characteristic enlargement of the gland.
The clinical presentation of the various forms
of CAH depends on the following: 1) the
affected enzyme, 2) the residual enzymatic
activity, 3) consequences of deficiencies of the
end products, and 4) hormonal effects of the
elevated precursors. The defective conversion
of 17-hydroxyprogesterone to 11-deoxycortisol
accounts for more than 90% of cases of CAH.
This conversion is mediated by 21-hydroxylase,
which is also referred to as CYP21A2.
Patients with the “classical” form present during
the neonatal period and early infancy with
adrenal insufficiency with or without salt-losing
or as toddlers with virilization. The “classical”
form is the most severe form of CAH due
to CYP21A2 deficiency in particular. Females
usually have genital ambiguity. Approximately
67% of classical CAH patients are classified as
“salt-losing”, while 33% are classified as “nonsalt-
losing” or “simple-virilizing”, reflecting the
degree of aldosterone deficiency.
“Non-classical” or late-onset CYP21A2
deficiency presents later in life with signs of
androgen excess and without neonatal genital
ambiguity. Clinical features in childhood may
include premature pubarche and accelerated bone age; adolescent and adult females may be
presented with hirsutism, menstrual irregularity,
infertility, and acne. Some patients with nonclassic
CAH remain asymptomatic-.
| ||Figure 1. A scheme of the pathways of steroidogenesis, including an elaboration of the biological process by which
steroids are generated from cholesterol and transformed into other steroids.|
Humans have two CYP21A genes, a nonfunctional
pseudo-gene (CYP21A1 or CYP21P)
and the active gene (CYP21A2 or CYP21), and
both are located on the 35-kilobase region
of chromosome 6p21.3 within the major
histocompatibility locus. The pseudo-gene
produces a truncated enzyme with no activity
because it lacks eight bases from codons 110
to 112, resulting in a stop codon-.
The two CYP21A genes are more than 90%
homologous. This high degree of homology
facilitates recombination events during meiosis,
with consequent exchanges of segments of
DNA between the two genes.
· Unequal crossover exchanges leading to
deletions of large segments of the CYP21P
gene or a non-functioning CYP21P/CYP21
fusion gene (macro-conversion) account for
about 20% of CYP21A2 mutations described
· Other hybrid CYP21A1/CYP21A2 gene
products have decreased, not halted, enzyme
activity. A patient who is heterozygous for
this and with a typical large gene deletion
may have non-classic CYP21A2 deficiency.
· Altered regions of the CYP21A1 gene can
be transferred to the CYP21A2 gene through
non-reciprocal gene conversion. This is a
process by which a segment of genetic
material is transferred to a closely related
gene, altering its sequence,.
· These micro-conversion events represent
acquisition of smaller segments of the
CYP21A1 sequence by the CYP21A2 gene
and result in deleterious point mutations
that reduce enzyme activity. They are present
in about 70% of patients with defined
· Eighteen gene conversion mutations account
for nearly all affected alleles in various
ethnic groups3,13-15. The remaining 5% of
patients with defined abnormalities have one
or more of the 60 point mutations,-.
Among 130 Brazilian patients, 20% did not
have a known mutation, suggesting that
other mutations occur. A novel missense
mutation was subsequently identified in
three patients with suggestion of a founder
effect. No mutation was detected in the
entire coding region of the gene and up to 1
kb of the 5'-flanking promoter region of the
gene in a Mexican and three Japanese patients,
suggesting that more distant mutations may
occur,. It is not always possible to predict
the phenotype of these patients from the
specific mutation(s) of the CYP21A2 gene,
but there are general correlations between
genotype and phenotype,-. Patients with
CYP21A2 mutations can be divided into
groups according to the predicted effect of the
mutation on 21-hydroxylase enzymatic activity,
as determined by site-directed mutagenesis and
expression and in vitro analysis of enzymatic
The salt-losing form of the disorder is most
often associated with large deletions or intron
2 mutations that affect splicing and result in
no enzyme activity, while patients with the
simple virilizing form have low but detectable
enzyme activity (i.e., 1-2%) that supports
sufficient aldosterone and glucocorticoid
production. This most commonly results from
point mutations leading to non-conservative
amino-acid substitutions such as Ile172Asp.
Women with the non-classic form may be
either compound heterozygotes (with a classic
mutation and a variant allele) or heterozygotes
with two variant alleles, allowing for 20-60%
of normal enzymatic activity (e.g., with point
mutations leading to conservative amino acid
substitutions such as Val281Leu). Patients who
are compound heterozygotes for two different
CYP21A2 mutations usually have the phenotype
associated with the less severe of the two
genetic defects. Heterozygotes may have mild
biochemical abnormalities, but no clinically
important endocrine disorder,. Despite these
general correlations, the CYP21A2 deficiency
phenotype does not always correlate precisely
with the genotype,, suggesting that other
genes influence the clinical manifestations. In
general, there appears to be high concordance
rates between genotype and phenotype in
patients with the most severe and the mildest
forms of the disease, but less genotypephenotype
correlation in moderately affected
Genetics Deficiencies of Uncommon Causes
1). Deficiency of 17-alpha-hydroxylase
Deficiency of 17-alpha-hydroxylase activity is
a rare form of CAH. Approximately 120 cases
have been reported,. However, prevalence
may be higher, particularly in Brazil, where the
founder effects account for over 80% of mutant
alleles caused by only two mutations,.
The CYP17 gene encodes an enzyme that
has both 17-hydroxylase and 17, 20-lyase
(desmolase, or side-chain cleavage) activities.
The hydroxylation of C17 of progesterone is
required for cortisol production as well as for
synthesis of androgens and estrogens. Lyase
activity is required for synthesis of androgens
and their derivatives, the estrogenic C18
steroids. Although CYP17 has both activities in
vitro, human CYP17 deficiency syndromes have
been observed in which patients apparently
lack only 17-hydroxylase deficiency or only 17,
20-lyase deficiency,. Most patients, however,
have a combined defect.
2). 17-hydroxylase defect:
Reduction of cortisol production by the
17-hydroxylase defect results in an increased
ACTH secretion. Therefore, there is an
increased production of 11-deoxysteroids
including corticosterone, mineralocorticoids,
11-deoxycorticosterone, and 18-hydroxydeoxycorticosterone,.
Thus, one consequence
of 17-alpha-hydroxylase deficiency is
mineralocorticoid excess. The ensuing volume
expansion inhibits rennin release and therefore
the synthesis of aldosterone.
3). 17, 20 lyase defect:
Reduction of androgen production by
impairment of 17, 20 lyase activity leads to
combined androgen and estrogen deficiency
because only androgens can be aromatized
to form estrogens. 17-alpha-hydroxylase
activity (CYP17) is also expressed in the
gonads so that gonadal steroidogenesis is also
decreased in patients with this disorder. CYP17
deficiency like other forms of CAH appears to
be inherited as an autosomal recessive trait.
Several cases were reported, and they were
the product of consanguineous marriages and obligate heterozygotes with mild defects
in CYP17 activity that can be revealed by
ACTH stimulation,,. Nearly 40 different
mutations in the CYP17 gene, which is located
on chromosome 10, have been defined at the
molecular level. These include small insertions
that disrupt the normal reading frame of the
gene and lead to premature termination,,
deletions of single codons, deletions of several
codons, large deletions with insertions of
foreign DNA, and a variety of nonsense or
missense mutations of CYP17 that produce
stop codons, impair CYP17 enzyme activity,
or alter splice sites-. Two mutations have
been described in splice receptor sites. There
may be factors other than the CYP17 genotype
that determine the phenotype of individuals
with CYP17 deficiency. In a study of 24
patients from 19 families in Brazil, the majority
(20/24) had one of two mutations, both of
which were completely inactive in vitro].
However, for patients with the same mutation,
the phenotype was sometimes variable. As
an example, of three male (XY karyotyping)
patients with an R362C mutation, the first
presented at birth with ambiguous genitalia,
the second had female external genitalia and
normokalemia, and the third had the classical
presentation (hypertension, hypokalemia, and
pubertal delay). A rare variant, with combined
CYP21A2 and CYP17 deficiency, has been
described in both boys and girls and appears
to be due to mutations in the gene encoding
oxidoreductase, not the CYP17 and CYP21A2
4). 3-beta-hydroxysteroid dehydrogenase
3-beta-hydroxysteroid dehydrogenase deficiency
is a rare form of CAH, in which synthesis of
all steroid hormones is impaired as 3-betahydroxysteroid
catalyzes the rearrangement of the double bonds
in the ring (A) of steroids and conversion of a
hydroxyl group at the 3 position to a keto group.
Deficiency of this enzyme results in decreased
synthesis of cortisol, aldosterone, androgens, and
estrogens. Cortisol deficiency leads to increased
ACTH secretion and therefore accumulation
of excessive amounts of steroid precursors
with the delta-5, 3-hydroxy configuration
(e.g., delta-5-pregnenolone, 17-alphahydroxypregnenolone,
(DHEA), and dehydroepiandrosterone-sulfate
(DHEAS). The decreased enzyme activity
in this disorder is caused by mutations in
the 3-beta-hydroxysteroid dehydrogenase II
gene. In patients with the severe, salt-wasting
form, nonsense mutations introducing codons,
insertion and deletion mutations causing frame
shifts-, and point mutations that alter enzyme
function have all been described. On the other
hand, all patients without salt-wasting have had
missense mutations causing single amino acid
substitutions that reduced the affinity of the
enzyme for substrates or cofactors. The 3-betahydroxysteroid
dehydrogenase type 1 gene,
which is normally expressed in the placenta and
peripheral tissues, is intact in these patients,
providing an explanation for the near normal or
even elevated serum concentrations of delta-4
steroids (such as 17-alpha-hydroxyprogesterone
and androstenedione) in many patients. The
substrates for the peripheral enzyme (delta-5-
and DHEAS) are increased because of the
defect in the type II enzyme in steroidogenic
Most patients present as neonates or in early
infancy with clinical manifestations of both
cortisol and aldosterone deficiencies with
feeding difficulties, vomiting, volume depletion,
hyponatremia, and hyperkalemia. Females may
have mild virilization of their external genitalia,
presumably due to excess DHEA, a little of
which is converted peripherally to testosterone.
Males have varying degrees of failure to
normal genital development ranging from
hypospadias to male pseudohermaphroditism
[46 XY disorder of sex development (DSD),
as new nomenclature] with near normal
female external genitalia. However, 3-betahydroxysteroid
dehydrogenase deficiency is
not a common finding in patients who present
with apparent idiopathic hypospadias. In one
study, only 2 out of 90 boys with hypospadias
had evidence of subtle molecular abnormalities
in the 3-beta-hydroxysteroid dehydrogenase
gene. Rarely, patients with severe 3-betahydroxysteroid
dehydrogenase deficiency have
few symptoms and may not be diagnosed
until they seek care for delayed puberty.
Premature pubarche with exaggerated serum
17-alpha-hydroxypregnenolone responses to
ACTH has been described in three girls with
missense mutation of the gene. A late-onset or the non-classic form of 3-beta-hydroxysteroid
dehydrogenase deficiency that causes hirsutism
and menstrual irregularity in adolescent and/or
young adult women has also been described.
The basis for the diagnosis was exaggerated
with serum delta-5-pregnenolone responses to
ACTH, but the validity of these results has
5). Congenital lipoid adrenal hyperplasia:
Congenital lipoid adrenal hyperplasia is the
rarest and usually the most severe form of
adrenal steroidogenesis defect. Congenital lipoid
adrenal hyperplasia is characterized by deficiency
of all adrenal and gonadal steroid hormones,
increased ACTH secretion, and marked adrenal
hyperplasia with progressive accumulation
of cholesterol esters. It is transmitted as an
autosomal recessive trait. It has been thought
that the defect in this disorder would reside
in the CYP11A1 (side chain cleavage) gene.
However, CYP11A1 is required for biosynthesis
of progesterone, and placental progesterone
synthesis is required to maintain pregnancy.
Therefore, complete CYP11A1 deficiency was
thought to be lethal and no homozygous
mutation has been identified in any patient
with congenital lipoid adrenal hyperplasia,.
Subsequently, two patients with congenital
lipoid adrenal hyperplasia have been shown to
have heterozygous mutations of CYP11A1,.
One had apparent haploinsufficiency of
CYP11A1 and the other was a compound
heterozygote with partial inactivation of the
gene. The defect in the majority of patients
within congenital lipoid adrenal hyperplasia
resides in a gene on chromosome 8 that
codes for a protein called the steroidogenic
acute regulatory protein (StAR). StAR is a
mitochondrial phosphoprotein that mediates
the acute response to steroidogenic stimuli
by increasing cholesterol transport from the
outer to the inner mitochondrial membrane-.
StAR is expressed in the adrenal cortex and
gonads but not in the placenta, and for this
reason, placental synthesis of progesterone,
which requires CYP11A1, is unaffected in
congenital lipoid adrenal hyperplasia. The
role of StAR has been studied by sequencing
the gene in patients with congenital lipoid
adrenal hyperplasia-. More than 35 different
mutations have been described; furthermore,
the mutated StAR proteins were inactive
in functional assays. Most of the mutations
reduce activity of the lipid transfer domain
of the StAR protein. Steroidogenic cells that
lacked StAR were initially capable of low levels
of steroidogenesis; this explains why some
steroid hormones may be secreted after puberty.
Bose et al. concluded that the congenital
lipoid adrenal hyperplasia phenotype is the
result of two separate events: 1) the initial
defect in steroidogenesis due to the StAR
mutation, and 2) a subsequent further defect
in steroidogenesis due to cellular damage from
accumulated cholesterol esters. The “two hit”
hypothesis is supported by data from a girl with
a homozygous StAR mutation who underwent
spontaneous puberty at the age of 13.
In mice, with knocked out StAR and
apolipoprotein A-1 genes, the lipid deposits
were composed mostly of high-density
lipoprotein (HDL)-derived cholesterol esters.
The mitochondrial structure of StAR knockout
mice is less abnormal than that of CYP11A1
knockout mice, perhaps because CYP11A1
plays an important role in determining the
morphology of steroidogenic mitochondria.
A patient with male pseudohermaphroditism
(46,XY DSD) and adrenal insufficiency who was
phenotypically similar to patients with StAR
deficiency had a mutation of the SF-1 gene.
Patients with congenital lipoid hyperplasia
caused by StAR mutations typically have
severe adrenal insufficiency very soon after
birth, although they occasionally present later
in infancy, with vomiting, diarrhea, volume
depletion, hyponatremia, and hyperkalemia.
Male infants usually have female external
genitalia due to lack of testicular androgen
production. In comparison, female infants are
normally developed at birth and occasional
patients undergo spontaneous puberty. A
possible explanation for the relative sparing
of ovarian steroid synthesis may be the
dormancy of the ovary until puberty, thereby
preventing the excess cholesterol accumulation
that damages the adrenal glands and testes.
The same explanation may account for the
detectable, if very low, serum aldosterone
concentrations with high plasma rennin activity
in these patients; the adrenocortical cells
destined to become glomerulosa cells are
minimally stimulated in utero. This condition
should be considered in a neonate with any symptoms or signs of adrenal insufficiency
and in male DSD (46,XY DSD). The diagnosis
is confirmed by the absence of demonstrable
steroid biosynthetic activity by either the
adrenals or the gonads. The two patients with
CYP11A1 deficiency presented with adrenal
insufficiency at a later age and did not have
enlarged adrenal glands. One was incompletely
virilized at birth with an XY karyotype and low
levels of all measured steroids when diagnosed
at the age of 4 years. The other patient had
an XX karyotype and presented with adrenal
insufficiency at the age of 9 months.
6). 11-beta-hydroxysteroid dehydrogenase
type 1 (apparent cortisone reductase)
This rare disorder is not a true CAH (i.e., does
not involve a defect in cortisol biosynthesis
but is associated with adrenal hyperplasia
and changes in the cortisol metabolism).
11-Beta-hydroxysteroid dehydrogenase type
1 (HSD11B1) is expressed in certain tissues
such as the liver, adipose tissue, brain, and
adrenal gland, in which it regulates the local
availability of glucocorticoids. Six women and
one boy have been reported to have deficient
expression of this enzyme-. However, no
mutation in the coding regions of the gene was
found, suggesting either that the defect lies
outside the coding region or that some other
abnormality results in inhibition of the function
of the enzyme. The disorder may result from
either an autosomal recessive or an acquired
defect. Additional studies in four patients
demonstrated a triallelic digenic pattern of
inheritance. Each affected individual was
homozygous or heterozygous for two mutations
in intron 3 of the HSD11B1 gene; the other
introns, exons and 1.5 kb of the promoter
region, were normal. In vitro, transcriptional
activation of constructs containing these
mutations was 2.5 times lower than that of
wild type constructs. However, since 25% of
unaffected individuals were heterozygotic for
these mutations and 3% were homozygous,
this mutation alone does not explain the
cortisone reductase deficiency. Each of the
affected individuals, but none of the unaffected
individuals, also had a mutation in exon 5 of the
hexose-6-phosphate dehydrogenase (H6PDH)
gene. Since HSD11B1 requires NADPH for
activity and H6PDH generates NADPH, it is
likely that the combination of mutations led
to cortisone reductase deficiency .
Patients with 11-beta-hydroxysteroid deficiency
present as adolescent or adult women with
truncal obesity, facial plethora, oligomenorrhea,
hirsutism, infertility, and/or acne. One patient
even had a successful pregnancy. Another
six-year-old boy presented with gonadotropinindependent
precocious puberty. The adrenal
glands are diffusely enlarged. Patients with
deficiency in this enzyme have normal serum
cortisol concentrations, high serum adrenal
androgen concentrations, very high urinary
excretion of 5-beta-reduced cortisone metabolites
(tetrahydrocortisone and cortolones), and very
low urinary excretion of cortisol metabolites
(tetrahydrocortisol and cortols), especially the
5-alpha-reduced metabolites. Conversion of
orally administered cortisone to cortisol is
impaired. Adrenal steroidogenesis is suppressed
normally by administration of low-dose
dexamethasone (0.5 mg every 6 hours for 48
Familial Glucocorticoid Resistance:
This is a rare syndrome that is not a true CAH,
but is associated with adrenal hyperplasia and
clinical features similar to those of CYP11B1
(11-beta-hydroxylase) deficiency. Familial
glucocorticoid resistance is inherited as an
autosomal recessive or dominant disorder
characterized by mutations in the glucocorticoid
receptor gene, leading to diminished cortisol
action and secondary stimulation of ACTH
release,. However, some patients with clinical
and biochemical glucocorticoid resistance never
had mutations in the glucocorticoid receptor
gene, indicating the presence of other defects
in the glucocorticoid action.
Glucocorticoid receptor defects include decreased
steroid binding affinity caused by missense
point mutations in the ligand binding domain,
defective nuclear binding caused by a missense
point mutation in the DNA-binding domain
and decreased receptor number caused by a
four-base splice site deletion in exon 6. Mutant
receptors may impair the function of receptors
coded by the normal allele by preventing normal
dimerization or exerting antagonistic effects
on glucocorticoid response elements (GREs),
thereby exerting dominant negative effects that
result in autosomal dominant expression-.
Some of the mutations reduce binding of
the receptor-ligand complex to transcription
factors or co-activators. Patients with familial
glucocorticoid resistance present in childhood to
adulthood with hirsutism, male pattern baldness,
menstrual abnormalities and infertility in
women, isosexual precocious puberty, abnormal
spermatogenesis and infertility in boys, and
with hypertension and hypokalemic alkalosis
in both sexes. The clinical presentation varies
from asymptomatic to severely symptomatic.
Heterozygotes have mild glucocorticoid
resistance but are asymptomatic,,. Plasma
ACTH and serum cortisol concentrations are
increased in this disorder, but maintain their
normal diurnal rhythm-. They are relatively
resistant to suppression with dexamethasone.
Serum concentrations of adrenal androgens
(delta-4-androstenedione, DHEA and its
sulfate [DHEAS]) and of ACTH-dependent
mineralocorticoids (cortisol, corticosterone, and
deoxycorticosterone) are also increased because
of the chronically elevated plasma ACTH
concentration. Serum aldosterone and plasma
rennin activity tend to be decreased. The adrenal
glands appear normal to moderately enlarged.
Symptoms of adrenal insufficiency do not
occur in patients with familial glucocorticoid
resistance because of the compensatory
increases in ACTH and cortisol secretion.
The excess of androgens and mineralocorticoid
can be ameliorated by the administration of
dexamethasone (0.5 to 1.5 mg/day). Thiazide
diuretics administered alone may cause severe
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