Congenital Adrenal Hyperplasia Due to Steroid - PowerPoint Presentation

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Congenital Adrenal Hyperplasia Due to Steroid21-Hydroxylase Deficiency

Slide2

References

Pediatric Practice ENDOCRINOLOGY

(Michael S.

Kappy,MD,PhD

)

An Endocrine Society Clinical Practice Guideline

WILLIAMS Textbook of Endocrinology

The

new

england

journal

of

medicine

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Salt-Wasting form of CYP21 deficiency

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Clinical manifestations

Increased

androgen

production

starts

early in fetal life, between

6 and 10

weeks of

gestation.

In

the female fetus, this results in

variable degrees

of posterior fusion of the labia, and

hypertrophy of

the clitoris

.

The

degree of

masculinization

of the external genitalia

of the

female fetuses is usually classified as described

by

Prader

.

Despite

the

virilized

appearance

of the

external genitalia,

the uterus and fallopian tubes

are normal

.

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Later in life,

hypersecretion

of androgens in either sex causes early appearance of

pubic hair

, usually between

6 months and 2 years of age.

This is followed by early appearance of

axillary

hair

between

2 and 4 years of age

, and

facial hair

between

8 and 14 years of age.

Acne

and

deepening of the voice

will also occur.

The anabolic effect of elevated adrenal androgens in infancy and early childhood causes rapid skeletal maturation.

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Simple

virilizing

form of CYP21 deficiency

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CYP21 deficiency

is not complete.

Decreased in

cortisol

secretion

A decrease in

cortisol

secretion reduces negative feedback at the hypothalamic-pituitary level, which leads to

increased secretion of CRH and ACTH.

The increased ACTH activity is capable of

restoring

cortisol

secretion to an

approximately normal rate.

Increased secretion of

cortisol

precursors

The increased ACTH concentration required to normalize

cortisol

secretion markedly elevates production of

cortisol

precursors. The immediate precursor, which reaches the highest plasma concentration, is

17-

hydroxyprogesterone

.

There is also increased secretion of

progesterone

and

17-hydroxypregnenolone.

High concentrations of plasma ACTH cause the

adrenocortical

hyperplasia characteristic of the syndrome.

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Nonclassical

form of CYP21 deficiency

(late-onset)

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This form of CAH has the mildest degree of CYP21 deficiency.

Patients with

nonclassic

21-hydroxylase deficiency produce normal amounts of

cortisol

and

aldosterone

at the expense of mild-to-moderate overproduction of sex hormone precursors.

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In females there is no abnormality of the external genitalia at birth.

There are little or no signs of androgen effects during childhood.

Hirsutism

is the single most common symptom

at presentation in approximately 60 percent of

symptomatic women, followed by

oligomenorrhea

(54 percent) and acne (33percent). Infertility appears to be a presenting symptom in only 13 percent of women.

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Heterozygote 21-Hydroxylase Deficiency

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Salt-wasting, simple

virilizing

, and late-onset 21-hydroxylase deficiency are all caused by homozygous or compound heterozygote mutations in the human 21-hydroxylase gene (

CYP21A2).

In the carrier or heterozygote state, only

one allele is mutated.

The clinical significance of the heterozygote state is uncertain; it does not appear to disadvantage

reproductive capability but may cause signs of

hyperandrogenism

in adult women.

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Diagnosis

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Approximately 10 percent of severely affected term newborns have low initial base-line 17-

hydroxyprogesterone

levels.

False negative results occur when infants are discharged early from the

hospital and thus have been screened before they are two to three days old, a time for which there are no established normative data.

Conversely, most sick or premature infants have elevated 17-hydroxyprogesterone levels without having inborn errors in steroid biosynthesis, especially those with gestational ages of less than 31 weeks.

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The gold standard for differentiating 21-hydroxylase

deficiency from other

steroidogenic

enzyme defects

is the

corticotropin

(

cosyntropin

) stimulation

test, performed by injecting a 0.125-mg or 0.25-mg

bolus of

cosyntropin

and measuring base-line and

stimulated levels of 17-hydroxyprogesterone

.

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Medical treatment of CAH in growing

patients

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Patients with classic 21-hydroxylase deficiency require long-term

glucocorticoid

treatment.

The goal of therapy is to reduce excessive androgen secretion by replacing the deficient hormones.

Treatment with GCs prevents adrenal crisis and

virilization

,

allowing normal

growth

and development.

Overtreatment may suppress growth, increase blood pressure, and cause iatrogenic Cushing’s syndrome.

Attempts to

completely normalize 17-OHP

levels typically result in overtreatment.

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During childhood, the preferred GC is HC.

In one trial, the estimated growth-suppressive effect of

prednisolone

was about 15-fold more potent than HC ,

dexamethasone

is 70- to 80-fold more potent.

When HC doses exceed 20 mg/m2 . d in infants and 15–17 mg/m2 . d

in adolescents, there is loss of height SD score (SDS) and shorter

adult height SDS.

Therefore, as with younger patients, it is important during puberty to

treat with the lowest possible dose.

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At or near completion of linear growth, long-acting GCs may be used although HC remains a treatment option.

Infants with salt-wasting 21-hydroxylase deficiency require MCs in addition to GC treatment as well as supplemental sodium chloride.

Although the

aldosterone

biosynthetic defect is clinically apparent only in the salt-wasting form, subclinical

aldosterone

deficiency is present in all forms of 21-hydroxylase deficiency and can be best evaluated by the

aldosterone

to PRA ratio.

Consequently, all patients with elevated PRA or

aldosterone

to PRA ratio benefit from

fludrocortisone

therapy and adequate dietary sodium.

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Sensitivity to MCs may vary over time, and recovery from salt wasting has been described in some patients, most probably secondary to

extraadrenal

21-hydroxylation.

Therefore, the need for continuing MCs should be reassessed periodically based on blood pressure, PRA, and the

aldosterone

to PRA ratio. It is particularly important to monitor blood pressure in infants who are often initially treated with high doses of MC due to immature renal tubular capacity to reabsorb sodium.

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Feminizing surgery

Recommendation:

We suggest that for severely

virilized

(

Prader

stage3) females, clitoral and

perineal

reconstruction be considered in infancy and performed by an experienced surgeon in a center with similarly experienced pediatric endocrinologists, mental health professionals, and social work services.

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The adult short stature of many CAH patients may be caused by

hypercortisolism

,

hyperandrogenism

, or both.

In a study of 341 treated patients with classic CAH, 124 were examined at adult height. Males and females were 10 and 8 cm shorter than expected, respectively.

A

metaanalysis

of data from 18 centers worldwide showed that the mean adult height of patients with classic CAH was 1.37 SD (10 cm) below the mean, and patients diagnosed before 1 yr of age had increased adult height outcomes (0.54 SD) .

Patients who were diagnosed late or were exposed to GC doses higher than 15 mg/m2 d had diminished height .

Overtreatment during infancy or treatment with long-acting, high-potency GCs may also reduce height.

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Monitoring therapy in growing children

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Normal growth and growth velocity are important variables in children.

The therapeutic goal is to use the lowest dose of

glucocorticoid

that adequately suppresses adrenal androgens and maintains normal growth and weight gain.

17-OHP,

androstenedione

, and testosterone are the best indicators of the adequacy of GC treatment.

Normal levels of 17-OHP and the other steroids are not a treatment goal but instead indicate overtreatment.

ACTH measurements are not useful for a diagnostic or therapeutic profile in CAH patients.

Acceptably treated CAH patients have mildly elevated steroid levels and

dose adjustments should be made in the overall clinical picture and not solely based on a single 17-OHP measurement.

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GC treatment of adults with CAH or NCCAH

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Recommendation:

We suggest that adult patients with classic CAH be treated with HC or long-acting GCs.

The need for MCs decreases with

age.

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Monitoring treatment of adults with CAH

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Optimal levels for 17-OHPand

androstenedione

have not been defined.

Testosterone levels in men normally reflect

gonadal

rather than adrenal function and therefore are not useful for monitoring therapy.

Men with large testicular adrenal rests may have low morning testosterone indicating poor

Leydig

cell function.