RECOGNIZING AND MANAGING DISORDERS OF PRECOCIOUS PUBERTY Mike

RECOGNIZING AND MANAGING DISORDERS OF PRECOCIOUS PUBERTY Mike T. Swinyard, MD, FAAP Board Certified Pediatric Endocrinology/Diabetes Mountain Vista Medicine, PC South Jordan, Utah mike@mtnvistamedicine. com (801)-838 -9090

AT THE CONCLUSION OF THIS PRESENTATION, PARTICIPANTS WILL BE ABLE TO: l Be able to explain puberty to families, so they can understand the basis for any necessary laboratory testing to evaluate abnormal early puberty l Compare and contrast premature adrenarche with normal puberty l Compare and contrast premature thelarche with normal puberty

GROWTH AND PUBERTY ASSESSMENT l Detailed Medical History l Detailed Physical Exam l Bone Age Assessment (the single most important test to order) l Focused and Precise Laboratory Testing

MEDICAL HISTORY Onset and progression of signs of puberty l Patient’s stage of puberty, as estimated by family l Mother’s height and age of menarche l Father’s height and age of pubertal growth spurt l Family’s concerns (assess their anxiety & agenda, as preparation for your opportunity to teach them) l Current and previous illnesses/trauma/surgery l Exposure to cosmetics/topical hormones l

PHYSICAL EXAM l An accurate determination of height is crucial, using a reliable stadiometer in those age two years and over l For those patients under two years old, care should be taken to measure an accurate length—Infantometer more reliable than making two marks on exam table paper

PHYSICAL EXAM l Accurately recording height is crucial l Plot both parents’ heights on growth chart l Determine if projected adult height is consistent with parental heights

PHYSICAL EXAM l In assessing growth, the pattern of growth over time is more useful than a single measurement of height l Determine interval growth and annual growth velocity from previous height measurements l Plot growth velocity on growth velocity chart

CALCULATING GROWTH VELOCITY Example: 10/02/07 HT: 112. 0 cm 04/12/08 HT: 114. 4 cm Interval growth in 6 months: 114. 2 -112. 0 = 2. 4 Annual growth rate determined by projecting interval growth for 12 months: A x 12/B = growth velocity (A=Interval Growth, B=Months between measurements) 2. 4 x 12/6 = 4. 8 cm/year

PHYSICAL EXAM l Females—Staging breast development (contour, not size) l Males—Staging l Skin of testicular size (length) exam (café-au-lait spots)

TANNER STAGES FOR GIRLS (BREAST DEVELOPMENT) Tanner Stage 1 No breast tissue. Beware of lipomastia as an imitator. (“Donut sign”) Tanner Stage 2 Areolar enlargement with breast bud Tanner Stage 3 mound Enlargement of breast and areola as single Tanner Stage 4 mound Projection of areola above breast as double Tanner Stage 5 Adult. Papilla (nipple) projects out of areola. Stage 4 and Stage 5 may be difficult to distinguish.

TANNER STAGES FOR BOYS (TESTICULAR LENGTH) Tanner Stage 1 Prepubertal. Length is less than 2. 5 cm (less than one inch). Gently stretch scrotum over testis. Tanner Stage 2 Testicular length is 2. 5 cm (one inch) Tanner Stage 3 Testicular length is 3 cm Tanner Stage 4 Testicular length is 3. 5 cm Tanner Stage 5 Testicular length is 4 cm or greater

TANNER STAGES FOR PUBIC HAIR l Tanner Stage 1 Velus hair similar to abdominal wall or no hair at all l Tanner Stage 2 Dark, sparse hair at base of penis or along inner labia majora l Tanner Stage 3 Dark, curled hair spreading over junction of pubes l Tanner Stage 4 Adult type of hair, but no spread to medial thigh l Tanner Stage 5 Spread to medial thigh and growth of escutcheon

AVERAGE TIMING OF PUBERTAL EVENTS IN GIRLS Onset of Breast Development Age 10 Tanner Stage 2 to Menarche 2 Years (growth rate tapers after menarche) Age At Menarche Start to Finish (End of Growth) 12 Years 3 Years

AVERAGE TIMING OF PUBERTAL EVENTS IN BOYS Onset of Testicular Enlargement 11 ½ Years Time from onset of puberty to Tanner Stage 4 (beginning of growth spurt) 2 Years Start to Finish (End of Growth) 4 Years

REMEMBER In both girls and boys… the peak growth rate occurs in the second half of puberty…Tanner Stage 3 and later

DEFINITION OF PRECOCIOUS PUBERTY l Secondary sexual characteristics evident before age 8 years in girls l Secondary sexual characteristics evident before age 9 years in boys

CLASSIFICATION OF PRECOCIOUS PUBERTY Gonadotropin-dependent (central or true precocious puberty). Characteristics match gender of patient (isosexual) Gonadotropin-independent (peripheral precocious puberty). Characteristics may be isosexual or contrasexual, (inappropriate for child’s gender), including virilization (masculinization) of girls or feminization of boys. Incomplete precocious puberty (“normal variants”), including premature thelarche and premature adrenarche

GONADOTROPIN-DEPENDENT PRECOCIOUS PUBERTY l Early maturation of the hypothalamicpituitary-gonadal axis l Idiopathic in more than 80% l Almost all idiopathic cases are in girls)

CAUSES OF GONADOTROPININDEPENDENT PRECOCIOUS PUBERTY Excess (“independent” or unregulated) secretion of sex hormones (androgens or estrogens) from the gonads or adrenals Exposure to exogenous sources of sex steroids (estrogen-containing creams, testosterone gel used to treat adult hypogonadism in men) Ectopic production of h. CG from a germ cell tumor Very rare disorders (Mc. Cune-Albright syndrome)

PREMATURE THELARCHE l Isolated and non-progressive breast development in an infant/toddler girl l No acceleration of height growth l No acceleration of bone development (Less than 2 SDs above the mean for chronological age)

PREMATURE ADRENARCHE Early appearance of adrenal androgen-mediated skin changes in any combination of pubic hair, axillary hair, body odor, oily skin, oily hair, and mild acne…in either boys or girls. l No clitoromegaly in girls (no larger than a pencil eraser or less than 5 mm in diameter) l No acceleration in height growth or advanced bone development (Less than 2 SDs above the mean for chronological age) l

BONE AGE ASSESSMENT Determined by a radiograph of the left hand wrist compared with the standards in the Greulich and Pyle Atlas for males and females l The delay (or advancement) of the bone age is expressed in standard deviations (SDs) below or above the patient’s chronological age l An advanced bone age is 2 or more SDs above the mean for chronological age l Obese children or children with tall stature and tall parents may have a bone age which is 2 -3 SDs above the mean for chronological age l

EVALUATION OF PRECOCIOUS PUBERTY IN THE PRIMARY CARE SETTING The most helpful screening test in the work-up of the patient with precocious puberty is the bone age. l It is non-invasive and provides valuable information, as to whether further testing may even be needed. l Few other tests used in medicine can make that claim. l

LH AND FSH TESTING PROCEED WITH CAUTION l Although readily available at hospital and reference laboratories, measurement of LH and FSH in children is fraught with problems, including… Need for relatively higher sample volumes in children Very poor sensitivity at the levels seen in the earliest stages of puberty

LH AND FSH TESTING l If incomplete forms of early puberty (premature thelarche or premature adrenarche) are not a possibility, then measure LH, FSH and estradiol (in girls) and LH, FSH and total testosterone (in boys) with isosexual precocious puberty l Send out these labs to Esoterix or Quest Diagnostics for high-sensitive assays to save your patients a redraw

REVIEW l Measurement of LH and FSH will guide the evaluation of precocious puberty, if development is isosexual. Also measure total testosterone in boys and estradiol in girls. l Measurement of LH and FSH will not help the evaluation of contrasexual development, since it is “contrary to” the patient’s gender and not consistent with activation of the hypothalamicpituitary-gonadal axis

REVIEW l Central precocious puberty is gonadotropindependent, so LH and FSH levels are detectable l Peripheral precocious puberty is gonadotropin-independent, so LH and FSH levels are very low or undetectable

ADDITIONAL STUDIES Isosexual central precocious puberty in girls with pubic hair and breast growth, or any girl with menstrual periods Pelvic ultrasound to assess uterus/ovaries Pituitary MRI and/or leuprolide stimulation testing after consultation with a pediatric endocrinologist

ADDITIONAL STUDIES l Isosexual central precocious puberty (penile and testicular enlargement) in boys Pituitary MRI and/or leuprolide stimulation testing after consultation with a pediatric endocrinologist

ADDITIONAL STUDIES l Contrasexual peripheral precocious puberty in virilized girls (clitoromegaly) with or without pubic hair Total testosterone as an overall indicator of androgen exposure DHEA-Sulfate as a screen for virilizing adrenal tumor 17 -hydroxyprogesterone androstenedione as a screen for congenital adrenal hyperplasia ACTH stimulation testing or adrenal imaging next with

ADDITIONAL STUDIES l Isosexual peripheral precocious puberty in boys with or without pubic hair h. CG measurement for testicular tumor DHEA-Sulfate as a screen for virilizing adrenal tumor 17 -hydroxyprogesterone androstenedione as a screen for congenital adrenal hyperplasia ACTH stimulation testing, adrenal, or testicular imaging next with guidance from pediatric endocrinologist

TREATMENT Incomplete Precocious Puberty (premature thelarche and premature adrenarche)… REASSURANCE AND FOLLOW-UP Central Precocious Puberty (treatment is Gn. RH agonists, e. g. Lupron Peripheral Precocious Puberty (eliminate exposure to exogeneous source of sex steroids; surgery to remove testicular, ovarian or adrenal tumor or ovarian follicular cyst)

TREATMENT (2) Peripheral Precocious Puberty (rare forms)… Congenital Adrenal Hyperplasia is treated with glucocorticoids Mc. Cune-Albright Syndrome and Familial Male. Limited Precocious Puberty are treated with aromatase inhibitors and antiandrogens

REFERENCES Carel JC, Leger J. Clinical practice: Precocious puberty. N Engl J Med 2008; 358: 2366. Muir A. Precocious puberty. Pediatr Rev 2006; 27: 373.

CASE STUDY #1 8 year old boy with several dark pubic hairs at the base of the penis for the past several months. No genital enlargement. He has always been tall, as per parents. They describe him as moody and quick to cry. They have noticed strong body odor and oily hair. l PMH unremarkable. Father 6’ 2’’. Mother 5’ 10’’. l Height and weight are at the 97 th percentile l Tanner stage 3 pubic hair with testicle <2. 5 cm l

CASE STUDY #1 l Bone Age is 9 ½ years which is 18 months (2 SDs) above the mean for chronological age DIAGNOSIS? TREATMENT?

CASE STUDY #2 7 ½ year old African American girl who experienced a menstrual period a few months before. She has pubic hair, body odor, oily skin and mild acne. l Mother is 5’ 6’’with menarche at age 12. Father’s height and onset of puberty are not available. l Child is at the 90 th percentile for both height and weight with no recent acceleration in either parameter. l Child is Tanner Stage 4 for both pubic hair and breast development. No café-au-lait spots. l

CASE STUDY #2 Bone Age is 11 years at a chronological age of 7 7/12 years. This is 3. 4 SDs above the mean for chronological age. LH was 18 (nl for prepubertal girls is <0. 03). FSH was 8. 5 (nl is <4. 2) and estradiol was 39 (nl <15). These results were during leuprolide stimulation testing.

CASE STUDY #2 Pelvic ultrasound was read as abnormal because of a prominent endometrial stripe on the lateral views, which is typically seen in pubertal girls. Ovaries were unremarkable. Pituitary MRI indicated some slight prominence of the gland, given her age, but no overt pathology.

CASE STUDY #2 l Treatment with Lupron has stabilized bone development and she has had no further menstrual periods. l She continues to be at Tanner Stage 4 for pubertal development

CASE STUDY #3 A six year old girl developed a bump in the left breast over the preceding several months. This had progressed to both sides, but most recently the right side regressed, so only left-sided breast growth remains. She has had no vaginal discharge, neither bloody or mucous in nature. No pubic hair growth, body odor or skin changes. No acceleration in height growth.

CASE STUDY #3 l Mother is 5’ 7’’ with onset of menarche at age 12 years. Father is 5’ 11’’ with normal onset of puberty. l Height and weight are at the 50 th percentile l Tanner Stage 2 on the left. Tanner 1 on right l Tanner Stage 1 pubic hair.

CASE STUDY #3 l Bone Age is 1 SD above the mean What Next?

CASE STUDY #3 l LH was 0. 021 (nl is <0. 03) l FSH was 0. 664 (nl is <4. 2) l Estradiol was 2. 0 (nl is <15) Diagnosis? What Next?

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