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
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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 SequelaeSlide42Slide43
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?