Shedding Light on an Ambiguous Subject
Grand Rounds: September 25, 2015
Stephanie Gibson, MD
PGY-3
Lisa Knight, MD
Assistant Professor of Clinical Pediatrics
USC Pediatric Endocrinology

The most common form of Congenital
Adrenal Hyperplasia (CAH) results from a deficiency of which of the following?
25% 25% 25% 25%
1.
11-β-hydroxylase
2.
17-OH progesterone
3.
17-α- hydroxylase
4.
21-hydroxylase
1 2 3 4

If both parents have classical CAH, the risk of having a female baby who also has CAH is:
25% 25% 25% 25%
1.
12.5% (1 in 8)
2.
25% (1 in 4)
3.
50% (1 in 2)
4.
None of the above
1 2 3 4

1.
A genetic male may develop ovaries.
2.
Benign tumors may develop in the testes and obliterate testicular function.
3.
A genetic male is born with both fallopian tubes and a prostate and seminal vesicles.
4.
A genetic male is likely to be identified as female at birth.
25%
1
25%
2
25%
3
25%
4

Females with CAH have a higher incidence of which of the following when compared to the general population?
1.
Adult height that is 1-2 SD below expected mid-parental target height.
2.
Infertility
3.
Homosexuality
4.
Decreased sexual satisfaction
5.
Only A and B.
6.
All of the Above
17% 17% 17% 17% 17% 17%
1 2 3 4 5 6

Dexamethasone is ______ times more potent than hydrocortisone.
1.
2
2.
5
3.
10
4.
15
5.
20
20% 20% 20% 20% 20%
1 2 3 4 5

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

• 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 CAH
• Discuss prenatal, acute and chronic management of patients with CAH

• 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
▫ Associated 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 perineum

• 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-Mϋllerian hormone (AMH)

Steroidogenic acute regulatory protein (StAR)

Congenital Adrenal Hyperplasia (CAH)
• Family of autosomal recessive disorders affecting adrenal steroidogenesis
▫ 21-Hydroxylase deficiency
▫ 11β-Hydroxylase deficiency
▫ 17α-Hydroxylase deficiency
▫ 3β-Hydroxysteroid dehydrogenase deficiency
▫ Lipoid/StAR CAH
• U.S. Occurrences – 1:15,500 Caucasian births,
1:42,000 African American births

Hypothalamic–Pituitary-Adrenal (HPA) Axis
Normal HPA Feedback
Hypothalamus
CRH
Anterior Pituitary
ACTH
Adrenal Cortex
Cortisol
Abnormal HPA Feedback (CAH)
Hypothalamus
CRH
Anterior Pituitary
ACTH
Adrenal Cortex
Cortisol

21-Hydroxylase
21-Hydroxylase Deficiency
CRH, ACTH

• >90% of CAH cases
• CYP21 gene on chromosome 6
Classic Phenotype
Severe form
1:15,000 live births
Salt-losing (67%) or Simple virilizing (33%)
Non-classic Phenotype
Mild/late-onset form
1:1,000 live births

Classic 21-Hydroxylase Deficiency Exam Findings
Females
• 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
Males
• 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.

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 birth

Signs of Acute Adrenal Crisis
• 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
Initial Laboratory Work-up
• POC Glucose
• CMP (need non-hemolyzed sample)
• ABG
• Cortisol level
• ACTH
• 17-hydroxyprogesterone level
• Pelvic/scrotal ultrasound
• Karyotype

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 CAH

11 Hydroxylase
11-β Hydroxylase Deficiency
CRH, ACTH

17-α Hydroxylase/ 17,20 Lyase Deficiency
17 Hydroxylase
CRH, ACTH
17,20 Lyase

3-β Hydroxysteroid Dehydrogenase Deficiency
CRH, ACTH
3
Hydroxysteroid
Dehydrogenase

StAR (Congenital Lipoid Hyperplasia)
StAR
CRH, ACTH

• 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.

Post-partum Diagnosis of 21-OH CAH
17-OHP Screen Obtained
Normal Elevated 17-OHP
Borderline
Repeat 17-OHP
Compare to normals for birth weight and EGA
Elevated
Physical exam
ACTH stim test
Endocrine referral
DNA analysis

• Newborn screens
▫ High 17-hydroxyprogesterone (17-OHP) level >242 nmol/L on day of life 3
▫ Increased 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 ultrasound

• 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 region

• 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 age

Glucocorticoid
Hydrocortisone (Cortef, Solu-cortef)
Prednisone
Prednisolone (Orapred, Prelone)
Methylprednisone (Solu-Medrol)
Dexamethasone (Decadron)
Potency
1
4
4
5
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 mg

Patient Case (cont.): Diagnosis and
Treatment
• Presumed dx was classical CAH
• Medication management:
▫ Hydrocortisone 1mg PO q8hrs (~ 15mg/m 2 /day)
▫ Fludrocortisone 0.1 mg qday

Lab Test
17-OH Progesterone
ACTH
Karyotype
FISH for SRY
Result
12,400 ng/dL
587 pg/mL
46, XX
Negative
Reference Range
7-77 ng/dL
6-48 pg/mL
-
-

• 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.

• Decision of genital surgery needs to involve multidisciplinary 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.

• 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 infertility

• Small testicular size
• Gonadal function less impaired in males
▫ Oligospermia
• Testicular adrenal rests

• 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 reported

• Overall, IQ is similar among patients with CAH and their matched controls.
• Some data show that poorly controlled saltwasting children with CAH are prone to learning disabilities.

The most common form of Congenital
Adrenal Hyperplasia (CAH) results from a deficiency of which of the following?
25% 25% 25% 25%
1.
11-β-hydroxylase
2.
17-OH progesterone
3.
17-α- hydroxylase
4.
21-hydroxylase
1 2 3 4

If both parents have classical CAH, the risk of having a female baby who also has CAH is:
25% 25% 25% 25%
1.
12.5% (1 in 8)
2.
25% (1 in 4)
3.
50% (1 in 2)
4.
None of the above
1 2 3 4

1.
A genetic male may develop ovaries.
2.
Benign tumors may develop in the testes and obliterate testicular function.
3.
A genetic male is born with both fallopian tubes and a prostate and seminal vesicles.
4.
A genetic male is likely to be identified as female at birth.
25%
1
25%
2
25%
3
25%
4

Females with CAH have a higher incidence of which of the following when compared to the general population?
1.
Adult height that is 1-2 SD below expected mid-parental target height.
2.
Infertility
3.
Homosexuality
4.
Decreased sexual satisfaction
5.
Only A and B.
6.
All of the Above
17% 17% 17% 17% 17% 17%
1 2 3 4 5 6

Dexamethasone is ______ times more potent than hydrocortisone.
1.
2
2.
5
3.
10
4.
15
5.
20
20% 20% 20% 20% 20%
1 2 3 4 5

1.
Antal, Z, Zhou, P. Congenital Adrenal Hyperplasia: Diagnosis, Evaluation, and
Management. Pediatrics in Review. 2009; 30(7):e49-e56.
2.
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.
3.
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.
4.
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.
5.
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.
6.
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.
7.
Lifshitz, E. (Ed.). (2007). Pediatric Endocrinology, Fifth Edition (Vol 2: Growth, Adrenal,
Sexual, Thyroid, Calcium, and Fluid Balance Disorders.) New York, NY: Informa
Healthcare.
8.
Merke, D, Bornstein, S. Congenital Adrenal Hyperplasia. Lancet. 2005; 365:2125-36.
9.
Michala, L, et al. Practice changes in childhood surgery for ambiguous genitalia? Journal
of Pediatric Urology. 2014; 10: 934-940.
10.
Sarafoglou, K. (Ed.). (2009). Pediatric Endocrinology and Inborn Errors of Metabolism.
New York, NY: McGraw Hill Medical.
11.
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.