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

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

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

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.

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

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

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

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

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 2.5 cm Urethral opening could not be visualized on the phallic structure or on the perineum

Normal Gonadal/Adrenal Development and Physiology

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)

Development of Internal Genitalia

Development of External Genitalia

Adrenal Histology and Physiology

Steroidogenic acute regulatory protein (StAR)

Pathophysiology of Congenital Adrenal Hyperplasia

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 Abnormal HPA Feedback (CAH) Hypothalamus Anterior Pituitary Adrenal Cortex Cortisol CRH ACTH Hypothalamus CRH Anterior Pituitary ACTH Adrenal Cortex Cortisol

21-Hydroxylase Deficiency

21-Hydroxylase Deficiency CRH, ACTH 21-Hydroxylase

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%)

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.

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

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

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

Other Forms of CAH

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

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

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

StAR (Congenital Lipoid Hyperplasia) CRH, ACTH StAR

Diagnosing CAH

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.

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

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

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

Medical Management

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 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

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

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

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

Long-term Sequelae

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.

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.

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

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

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

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.

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

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

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.

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

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

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.

Questions?