1. 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 Endocrinology

2. 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-hydroxylase

3. If both parents have classical CAH, the risk of having a female baby who also has CAH is:
None of the above

4. 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.

5. 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 Above

6. Dexamethasone is ______ times more potent than hydrocortisone.2 5 10 15 20

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

8. 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 CAH
Discuss prenatal, acute and chronic management of patients with CAH

9. 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
Associated scrotal structure
No palpable testes
Mild rugation
Phallic structure measured cm
Urethral opening could not be visualized on the phallic structure or on the perineum

10. Normal Gonadal/Adrenal Development and Physiology

11. 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-Mϋllerian hormone (AMH)

12. Development of Internal Genitalia

13. Development of External Genitalia

14. Adrenal Histology and Physiology

15. Steroidogenic acute regulatory protein (StAR)

16. Pathophysiology of Congenital Adrenal Hyperplasia

17. 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

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

19. 21-Hydroxylase Deficiency

20. 21-Hydroxylase Deficiency
CRH, ACTH
21-Hydroxylase

21. 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%)

22. 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 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.

23. 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

24. Decreased activity/fatigue Altered mental status/ unresponsiveness
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

25. 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

26. Other Forms of CAH

27. 11-β Hydroxylase Deficiency
CRH, ACTH
11- Hydroxylase

28. 17-α Hydroxylase/ 17,20 Lyase Deficiency
CRH, ACTH
17,20 Lyase
17- Hydroxylase

29. 3-β Hydroxysteroid Dehydrogenase Deficiency
CRH, ACTH
3- Hydroxysteroid Dehydrogenase

30. StAR (Congenital Lipoid Hyperplasia)
CRH, ACTH
StAR

31. Diagnosing CAH

32. 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.

33. 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 analysis

34. Corticotropin stimulation test
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

35. 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 region

36. Medical Management

37. Medicinal and Laboratory Management
Supplemental glucocorticoids
Hydrocortisone 12-20mg/m2 per day divided TID
Dexamethasone Qday
Continuous subcutaneous therapy?
Stress-dose when ill or undergoing surgery
Supplemental mineralocorticoids
Fludrocortisone mg, 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

38. Hydrocortisone (Cortef, Solu-cortef) 1 Prednisone 4
Glucocorticoid
Potency
Hydrocortisone (Cortef, Solu-cortef) 1
Prednisone 4
Prednisolone (Orapred, Prelone)
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 mg

39. Patient Case (cont.): Diagnosis and Treatment
Presumed dx was classical CAH
Medication management:
Hydrocortisone 1mg PO q8hrs (~ 15mg/m2/day)
Fludrocortisone 0.1 mg qday

40. 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

41. Long-term Sequelae

43. 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.

44. 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.

45. 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 infertility

46. Reproductive Function in Males
Small testicular size
Gonadal function less impaired in males
Oligospermia
Testicular adrenal rests

47. 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 reported

48. 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.

49. 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-hydroxylase

50. If both parents have classical CAH, the risk of having a female baby who also has CAH is:
None of the above

51. 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.

52. 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 Above

53. Dexamethasone is ______ times more potent than hydrocortisone.2 5 10 15 20

54. 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):
Creighton, S, et al. Objective costmetic and anatomical outcomes at adolescence of feminising surgery for ambiguous genitalia done in childhood. The Lancet. 2001; 358:
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):
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:
Hindmarsh, P. The child with difficulty to control Congenital Adrenal Hyperplasia: is there a place for continuous subcutaneous hydrocortisone therapy. Clinical Endocrinology. 2014; 81:
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:
Michala, L, et al. Practice changes in childhood surgery for ambiguous genitalia? Journal of Pediatric Urology. 2014; 10:
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):

55. Questions?