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Congenital Adrenal Hyperplasia: Congenital Adrenal Hyperplasia:

Congenital Adrenal Hyperplasia: - PowerPoint Presentation

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Congenital Adrenal Hyperplasia: - PPT Presentation

Shedding Light on an Ambiguous Subject Grand Rounds September 25 2015 Stephanie Gibson MD Lisa Knight MD PGY3 Assistant Professor of Clinical Pediatrics USC Pediatric Endocrinology The most common form of Congenital Adrenal Hyperplasia CAH results from a deficiency of which of th ID: 246023

adrenal cah deficiency hydroxylase cah adrenal hydroxylase deficiency hyperplasia congenital acth male classic female height genitalia normal adult crh genetic salt females

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Slide1

Congenital Adrenal Hyperplasia:

Shedding Light on an Ambiguous Subject

Grand Rounds: September 25, 2015

Stephanie Gibson, MD Lisa Knight, MD

PGY-3 Assistant Professor of Clinical Pediatrics USC Pediatric EndocrinologySlide2

The most common form of Congenital Adrenal Hyperplasia (CAH) results from a deficiency of which of the following?

11-

β

-

hydroxylase

17-OH progesterone

17-

α

-

hydroxylase

21-hydroxylaseSlide3

If both parents have classical CAH, the risk of having a female baby who also has CAH is:

12.5% (1 in 8)

25% (1 in 4)

50% (1 in 2)

None of the aboveSlide4

In the most common form of CAH:

A genetic male may develop ovaries.

Benign tumors may develop in the testes and obliterate testicular function.

A genetic male is born with both fallopian tubes and a prostate and seminal vesicles.

A genetic male is likely to be identified as female at birth.Slide5

Females with CAH have a higher incidence of which of the following when compared to the general population?

Adult height that is 1-2 SD below expected mid-parental target height.

Infertility

Homosexuality

Decreased sexual satisfaction

Only A and B.

All of the AboveSlide6

Dexamethasone

is ______ times more potent than hydrocortisone.

2

5

10

15

20Slide7

Disclosures

Neither myself nor Dr. Knight have any financial relationships to disclose.Slide8

Goals

Review normal genitourinary embryology

Discuss normal adrenal gland physiology and how it is altered in various forms of CAH

Evaluate newborn screens, clinical and laboratory findings consistent with CAHDiscuss prenatal, acute and chronic management of patients with CAHSlide9

Patient Case: Presentation

A.S. is a 1 day old born at term from an uncomplicated pregnancy

Prenatal ultrasound diagnosed her as female

After delivery, however, the external genitalia appeared to be

virilized

A

ssociated scrotal structure

No palpable testes

Mild

rugation

Phallic structure measured

2.5 cm

Urethral opening could not

be visualized on the phallic

structure or on the perineumSlide10

Normal

Gonadal

/Adrenal Development and PhysiologySlide11

Sex Differentiation

Presence of Y chromosome induces differentiation of

bipotential

gonads to testes at 6-8 wks gestation.Remaining internal and external genitalia are also

bipotential

.

Hormonal regulation

Dihydrotestosterone

(DHT)

Testosterone

Anti-M

ϋ

llerian

hormone (AMH) Slide12

Development of Internal GenitaliaSlide13

Development of External GenitaliaSlide14

Adrenal Histology and PhysiologySlide15

Steroidogenic

acute regulatory protein (

StAR

)Slide16

Pathophysiology

of Congenital Adrenal HyperplasiaSlide17

Congenital Adrenal Hyperplasia (CAH)

Family of

autosomal

recessive disorders affecting adrenal steroidogenesis

21-Hydroxylase deficiency

11

β

-

Hydroxylase

deficiency

17

α

-

Hydroxylase

deficiency

3

β

-

Hydroxysteroid

dehydrogenase

deficiency

Lipoid/

StAR

CAH

U.S. Occurrences – 1:15,500 Caucasian births, 1:42,000 African American birthsSlide18

Hypothalamic–Pituitary-Adrenal (HPA) Axis

Normal HPA Feedback

Abnormal HPA Feedback (CAH)

Hypothalamus

Anterior Pituitary

Adrenal Cortex

Cortisol

CRH

ACTH

Hypothalamus

Anterior Pituitary

Adrenal Cortex

Cortisol

CRH

ACTHSlide19

21-Hydroxylase DeficiencySlide20

21-Hydroxylase Deficiency

21-Hydroxylase

CRH, ACTHSlide21

21-Hydroxylase Deficiency

>90% of CAH cases

CYP21 gene on chromosome 6

Classic Phenotype

Non-classic Phenotype

Severe form

Mild/late-onset

form

1:15,000

live births

1:1,000 live births

Salt-losing

(67%) or Simple

virilizing

(33%)Slide22

Classic 21-Hydroxylase Deficiency Exam Findings

Females

Males

Enlarged clitoris

Partly-fused,

rugose

labia

majora

Common

urogenital

sinus in place of urethra and vagina

Salt-losing present soon after birth, given

ambigious

genitalia

Normal internal female organs

Subtle

hyperpigmentation

Possible penile enlargement

Salt-losing presents DOL 7-14 with emesis, weight loss, lethargy, dehydration, shock,

hyponatremia

,

hyperkalemia

Non-salt-losing present with early

virilization

at 2-4yrs

Normal male internal organs, but can have small testes if untreated.Slide23

Salt-Wasting 21-Hydroxylase Deficiency

67% patients with classic 21-hydroxylase deficiency

Secondary to

aldosterone deficiency

Associated lab abnormalities:

hyponatremia

,

hyperkalemia

Early signs: frequent feedings

Present with salt-wasting and acute adrenal crisis within weeks after birthSlide24

Signs of Acute Adrenal Crisis

Initial Laboratory Work-up

Decreased activity/fatigue

Altered mental status/ unresponsiveness

Poor feeding/weak suck

Dry mucous membranes

Hyperpigmentation

Abdominal pain

Vomiting

Hyponatremia

Hyperkalemia

Hypoglycemia

Metabolic acidosis

Hypothermia

Hypotension

Dehydration

Lack of weight gain

POC Glucose

CMP (need non-

hemolyzed

sample)

ABG

Cortisol

level

ACTH

17-hydroxyprogesterone level

Pelvic/scrotal ultrasound

KaryotypeSlide25

Non-Classic 21-Hydroxylase Deficiency Exam Findings

Present in late childhood or early adulthood

Hyperandrogenism

manifestations

Premature

adrenarche

Advanced bone age, short adult stature

Female

hirsutism

(60%) or male-pattern baldness

Oligomenorrhea

/Amenorrhea (54%)

Polycystic ovaries

Insulin resistance

Acne (33%)

5-10% children with premature

adrenarche

have an underlying diagnosis of non-classic CAHSlide26

Other Forms of CAHSlide27

11-

β

Hydroxylase Deficiency

11-

Hydroxylase

CRH, ACTHSlide28

17-

α

Hydroxylase/ 17,20 Lyase Deficiency

17-

Hydroxylase

CRH, ACTH

17,20

LyaseSlide29

3-

β

Hydroxysteroid Dehydrogenase Deficiency

3-

Hydroxysteroid

Dehydrogenase

CRH, ACTHSlide30

StAR

(Congenital Lipoid Hyperplasia)

StAR

CRH, ACTHSlide31

Diagnosing CAHSlide32

Prenatal Diagnosis/Treatment

Dexamethasone

<7-8 wks gestation

70% of treated female fetuses are born with normal or only minimally

virilized

genitalia

Still experimental treatment

Chromosome analysis

Chorionic villous sampling (CVS) at 10-12wks

Amniocentesis at 14-18wks

If male, discontinue steroids.

If female, pursue additional molecular testing.

If affected, continue

dexamethasone

to term.

If both parents have classic CAH, the risk of having a daughter with CAH is 1:8.Slide33

Post-partum Diagnosis of 21-OH CAH

17-OHP Screen Obtained

Normal

Elevated 17-OHP

Compare to

normals

for birth weight and EGA

Borderline

Elevated

Repeat 17-OHP

Physical exam

ACTH

stim

test

Endocrine referral

DNA analysisSlide34

Newborn screens

High 17-hydroxyprogesterone (17-OHP) level >242

nmol

/L on day of life 3Increased false-positive risk with premature infants

Need for age-adjusted levels

Prenatal treatment with

glucocorticoids

Corticotropin

stimulation test

17-OHP > 45nmol/L (1400 ng/

dL

) is diagnostic.

Plasma

renin

activity (PRA) to

aldosterone

ratio

Evaluate ambiguous genitalia with

karyotype

and pelvic/abdominal ultrasoundSlide35

Patient Case (cont.): Evaluation

DOL 1 Electrolytes:

Hypoglycemia that responded easily to IV dextrose (GIR between 6-8 mg/kg/min)

Normal Na and K

Pelvic U/S: No testes present in scrotum, inguinal canals or abdomen

Pelvic MRI: Uterus and ovaries present

The following

labwork

was sent:

17-OH progesterone

ACTH

Karyotype

FISH for SRY regionSlide36

Medical ManagementSlide37

Medicinal and Laboratory Management

Supplemental

glucocorticoids

Hydrocortisone 12-20mg/m

2

per day divided TID

Dexamethasone

Qday

Continuous subcutaneous therapy?

Stress-dose when ill or undergoing surgery

Supplemental

mineralocorticoids

Fludrocortisone

0.1-0.2mg, up to 0.4mg, per day

Sodium chloride 1-2g (1g = 17

mEq

sodium)

Regular labs

17-OHP,

Androstenedione

Watch for Cushing’s syndrome

Annual bone ageSlide38

Glucocorticoid

Potency

Hydrocortisone (

Cortef

,

Solu-cortef

)

1

Prednisone

4

Prednisolone (

Orapred

,

Prelone

)

4

Methylprednisone

(

Solu

-Medrol)

5

Dexamethasone (

Decadron

)

20-25

Maintenance Adrenal Gland Production of Cortisol: 6 mg/m2/day

Maintenance Oral Hydrocortisone Dose: 12 mg/m2/day

Emergency Glucocorticoid Dosing

(IM or IV)

Infant

Child

Adult

Methylprednisone

25 mg

50 mg

100 mg

Dexamethasone

1 mg

2 mg

4-5 mgSlide39

Patient Case (cont.): Diagnosis and Treatment

Presumed dx was classical CAH

Medication management:

Hydrocortisone 1mg PO q8hrs (~ 15mg/m

2

/day)

F

ludrocortisone 0.1 mg

qday

Slide40

Patient Case (cont.): Results

Lab Test

Result

Reference Range

17-OH Progesterone

12,400 ng/

dL

7-77

ng

/

dL

ACTH

587

pg

/mL

6-48 pg/

mL

Karyotype

46, XX

-

FISH for SRY

Negative

-Slide41

Long-term SequelaeSlide42
Slide43

Linear Growth

Children with classic CAH have accelerated linear growth, but adult height is 1-2 standard deviations below mean target height.

Recommend use of lowest effective treatment dose to maintain hormone levels, vary with age.

Non-classic CAH adult height consistent with mean parental height if appropriately treated.Slide44

Genitalia Reconstructive Surgery

Decision of genital surgery needs to involve multi-disciplinary approach.

Goal: is to remove redundant erectile tissue, preserve the sexually sensitive

glans

clitoris, and provide a normal vaginal orifice that functions adequately for menstruation, intercourse, and delivery.

Procedures:

Clitoroplasty

with

vaginoplasty

in the neonate less common.

Partial clitoral reduction in infancy with

vaginoplasty

reserved for late adolescence.

In general, procedures have improved, but overall outcome is not optimal.

Early surgery has been correlated with a higher risk of sexual

disatisfaction

.Slide45

Reproductive Function in Females

Delayed spontaneous menarche compared to peers, atrophic breast tissue

Poorly controlled females

Hirsutism

Oligomenorrhea

, Amenorrhea

Menorrhagia

Absence of

thelarche

, Precocious

adrenarche

Cystic acne

Cystic ovaries

Fertility and offspring concerns

Some evidence of infertilitySlide46

Reproductive Function in Males

Small testicular size

Gonadal

function less impaired in malesOligospermia

Testicular adrenal restsSlide47

Psychosexual Concerns

Females with CAH (especially salt-wasters)

Male-typical play

Physical aggression

Low-interest in infants/maternal nurturing

Most raised as female express female gender identity, gender role, and heterosexual orientation

Increased rate of homosexuality compared to peers

Males with CAH

No evidence of atypical gender behavior reportedSlide48

Developmental Concerns

Overall, IQ is similar among patients with CAH and their matched controls.

Some data show that poorly controlled salt-wasting children with CAH are prone to learning disabilities.Slide49

The most common form of Congenital Adrenal Hyperplasia (CAH) results from a deficiency of which of the following?

11-

β

-

hydroxylase

17-OH progesterone

17-

α

-

hydroxylase

21-hydroxylaseSlide50

If both parents have classical CAH, the risk of having a female baby who also has CAH is:

12.5% (1 in 8)

25% (1 in 4)

50% (1 in 2)

None of the aboveSlide51

In the most common form of CAH:

A genetic male may develop ovaries.

Benign tumors may develop in the testes and obliterate testicular function.

A genetic male is born with both fallopian tubes and a prostate and seminal vesicles.

A genetic male is likely to be identified as female at birth.Slide52

Females with CAH have a higher incidence of which of the following when compared to the general population?

Adult height that is 1-2 SD below expected mid-parental target height.

Infertility

Homosexuality

Decreased sexual satisfaction

Only A and B.

All of the AboveSlide53

Dexamethasone

is ______ times more potent than hydrocortisone.

2

5

10

15

20Slide54

References

Antal

, Z, Zhou, P. Congenital Adrenal Hyperplasia: Diagnosis, Evaluation, and Management.

Pediatrics in Review.

2009; 30(7):e49-e56.

Bomberg

, E, et al. The Relation of

Peripubertal

and Pubertal Growth to Final Adult Height in Children with Classic Congenital Adrenal Hyperplasia.

The Journal of Pediatrics

. 2015; 166(3):743-749.

Creighton, S, et al. Objective

costmetic

and anatomical outcomes at adolescence of

feminising

surgery for ambiguous genitalia done in childhood.

The Lancet

. 2001; 358: 124-125.

Gatelais

, F, et al. Effect of Single and Multiple Courses of Prenatal Corticosteroids on 17-Hydroxyprogesterone Levels: Implication for Neonatal Screening of Congenital Adrenal Hyperplasia.

Pediatric Research

. 2004; 56(5):701-705.

Heino

, F, et al. Sexual Orientation in Women with Classical or Non-classical Congenital Adrenal Hyperplasia as a Function of Degree of Prenatal Androgen Excess.

Arch. Sex

Behav

.

2008; 37: 85-99.

Hindmarsh

, P. The child with difficulty to control Congenital Adrenal Hyperplasia: is there a place for continuous subcutaneous hydrocortisone therapy.

Clinical Endocrinology

. 2014; 81: 15-18.

Lifshitz

, E. (Ed.). (2007).

Pediatric Endocrinology, Fifth Edition (

Vol

2: Growth, Adrenal, Sexual, Thyroid, Calcium, and Fluid Balance Disorders

.) New York, NY:

Informa

Healthcare.

Merke

, D, Bornstein, S. Congenital Adrenal Hyperplasia.

Lancet

. 2005; 365:2125-36.

Michala

, L, et al. Practice changes in childhood surgery for ambiguous genitalia?

Journal of Pediatric Urology

. 2014; 10: 934-940.

Sarafoglou

, K. (Ed.). (2009).

Pediatric Endocrinology and Inborn Errors of Metabolism

. New York, NY: McGraw Hill Medical.

White

, P,

Speiser

, P. Long-term consequences of childhood-onset congenital adrenal hyperplasia.

Best Practice & Research Clinical Endocrinology and Metabolism

. 2002; 16(2):273-288.Slide55

Questions?