RECOGNIZING AND MANAGING DISORDERS OF PRECOCIOUS PUBERTY Mike T. Swinyard, MD, FAAP Board Certified Pediatric Endocrinology/Diabetes Mountain Vista Medicine,

RECOGNIZING AND MANAGING RECOGNIZING AND MANAGING DISORDERS OFDISORDERS OF

PRECOCIOUS PUBERTYPRECOCIOUS PUBERTY

Mike T. Swinyard, MD, FAAPBoard Certified Pediatric Endocrinology/Diabetes

Mountain Vista Medicine, PCSouth Jordan, Utah

[email protected](801)-838-9090

AT THE CONCLUSION OF THIS AT THE CONCLUSION OF THIS PRESENTATION, PARTICIPANTS PRESENTATION, PARTICIPANTS

WILL BE ABLE TO:WILL BE ABLE TO:Be able to explain puberty to families, so

they can understand the basis for any necessary laboratory testing to evaluate abnormal early puberty

Compare and contrast premature adrenarche with normal puberty

Compare and contrast premature thelarche with normal puberty

GROWTH AND PUBERTY GROWTH AND PUBERTY ASSESSMENTASSESSMENT

Detailed Medical HistoryDetailed Physical ExamBone Age Assessment (the single most

important test to order)Focused and Precise Laboratory Testing

MEDICAL HISTORYMEDICAL HISTORY

Onset and progression of signs of puberty

Patient’s stage of puberty, as estimated by family

Mother’s height and age of menarche

Father’s height and age of pubertal growth spurt

Family’s concerns (assess their anxiety & agenda, as preparation for your opportunity to teach them)

Current and previous illnesses/trauma/surgery

Exposure to cosmetics/topical hormones

PHYSICAL EXAMPHYSICAL EXAM

An accurate determination of height is crucial, using a reliable stadiometer in those age two years and over

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


Accurately recording height is crucial

Plot both parents’ heights on growth chart

Determine if projected adult height is consistent with parental heights


In assessing growth, the pattern of growth over time is more useful than a single measurement of height

Determine interval growth and annual growth velocity from previous height measurements

Plot growth velocity on growth velocity chart

CALCULATING GROWTH CALCULATING GROWTH VELOCITYVELOCITY

Example:10/02/07 HT: 112.0 cm04/12/08 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


Females—Staging breast development (contour, not size)

Males—Staging of testicular size (length)

Skin exam (café-au-lait spots)

TANNER STAGES FOR GIRLS TANNER STAGES FOR GIRLS (BREAST DEVELOPMENT)(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 Enlargement of breast and areola as single mound

Tanner Stage 4 Projection of areola above breast as double mound

Tanner Stage 5 Adult. Papilla (nipple) projects out of areola. Stage 4 and Stage 5 may be difficult todistinguish.

TANNER STAGES FOR BOYS TANNER STAGES FOR BOYS (TESTICULAR LENGTH)(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 FORTANNER STAGES FORPUBIC HAIRPUBIC HAIR

Tanner Stage 1 Velus hair similar to abdominal wall or no hair at all

Tanner Stage 2 Dark, sparse hair at base of penis or along inner labia majora

Tanner Stage 3 Dark, curled hair spreading over junction of pubes

Tanner Stage 4 Adult type of hair, but no spread to medial thigh

Tanner Stage 5 Spread to medial thigh and growth of escutcheon

AVERAGE TIMING OF AVERAGE TIMING OF PUBERTALPUBERTAL

EVENTS IN GIRLSEVENTS IN GIRLSOnset of Breast Development Age 10

Tanner Stage 2 to Menarche 2 Years

(growth rate tapers after menarche)

Age At Menarche 12 Years

Start to Finish (End of Growth) 3 Years

AVERAGE TIMING OF AVERAGE TIMING OF PUBERTALPUBERTAL

EVENTS IN BOYSEVENTS IN BOYSOnset of Testicular Enlargement 11 ½ Years

Time from onset of puberty to Tanner 2 Years Stage 4 (beginning of growth spurt)

Start to Finish (End of Growth) 4 Years

REMEMBERREMEMBER

In both girls and boys…

the peak growth rate occurs in the second

half of puberty…Tanner Stage 3 and later

DEFINITION OF DEFINITION OF PRECOCIOUS PUBERTYPRECOCIOUS PUBERTY

Secondary sexual characteristics evident before age 8 years in girls

Secondary sexual characteristics evident before age 9 years in boys

CLASSIFICATION OF CLASSIFICATION OF PRECOCIOUS PUBERTYPRECOCIOUS 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 GONADOTROPIN-DEPENDENT PRECOCIOUS PUBERTYPRECOCIOUS PUBERTY

Early maturation of the hypothalamic-pituitary-gonadal axis

Idiopathic in more than 80% Almost all idiopathic cases are in girls)

CAUSES OF GONADOTROPIN-CAUSES OF GONADOTROPIN-INDEPENDENT PRECOCIOUS INDEPENDENT PRECOCIOUS

PUBERTYPUBERTYExcess (“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 hCG from a germ cell tumor

Very rare disorders (McCune-Albright syndrome)

PREMATURE THELARCHEPREMATURE THELARCHE

Isolated and non-progressive breast development in an infant/toddler girl

No acceleration of height growthNo acceleration of bone development

(Less than 2 SDs above the mean for chronological age)

PREMATURE ADRENARCHEPREMATURE 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.

No clitoromegaly in girls (no larger than a pencil eraser or less than 5 mm in diameter)

No acceleration in height growth or advanced bone development (Less than 2 SDs above the mean for chronological age)

BONE AGE ASSESSMENTBONE AGE ASSESSMENT

Determined by a radiograph of the left hand and wrist compared with the standards in the Greulich and Pyle Atlas for males and females

The delay (or advancement) of the bone age is expressed in standard deviations (SDs) below or above the patient’s chronological age

An advanced bone age is 2 or more SDs above the mean for chronological age

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

EVALUATION OF EVALUATION OF PRECOCIOUS PUBERTY IN PRECOCIOUS PUBERTY IN

THE PRIMARY CARE SETTINGTHE PRIMARY CARE SETTING

The most helpful screening test in the work-up of the patient with precocious puberty is the bone age.

It is non-invasive and provides valuable information, as to whether further testing may even be needed.

Few other tests used in medicine can make that claim.

LH AND FSH TESTINGLH AND FSH TESTING PROCEED WITH CAUTIONPROCEED WITH CAUTION

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 TESTINGLH AND FSH TESTING

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

Send out these labs to Esoterix or Quest Diagnostics for high-sensitive assays to save your patients a redraw

REVIEWREVIEW

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.

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 hypothalamic-pituitary-gonadal axis

REVIEWREVIEW

Central precocious puberty is gonadotropin-dependent, so LH and FSH levels are detectable

Peripheral precocious puberty is gonadotropin-independent, so LH and FSH levels are very low or undetectable

ADDITIONAL STUDIESADDITIONAL 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


Isosexual central precocious puberty (penile and testicular enlargement) in boys

Pituitary MRI and/or leuprolide stimulation testing after consultation with a pediatric endocrinologist


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 and androstenedione as a screen for congenital adrenal hyperplasia

ACTH stimulation testing or adrenal imaging next with guidance from pediatric endocrinologist


Isosexual peripheral precocious puberty in boys with or without pubic hair

hCG measurement for testicular tumor DHEA-Sulfate as a screen for virilizing adrenal tumor

17-hydroxyprogesterone and androstenedione as a screen for congenital adrenal hyperplasia

ACTH stimulation testing, adrenal, or testicular imaging next with guidance from pediatric endocrinologist

TREATMENTTREATMENT

Incomplete Precocious Puberty (premature thelarche and premature adrenarche)…

REASSURANCE AND FOLLOW-UP

Central Precocious Puberty (treatment is GnRH 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)TREATMENT (2)

Peripheral Precocious Puberty (rare forms)…

Congenital Adrenal Hyperplasia is treated with glucocorticoids

McCune-Albright Syndrome and Familial Male-Limited Precocious Puberty are treated with aromatase inhibitors and antiandrogens

REFERENCESREFERENCES

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 #1CASE 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.

PMH unremarkable. Father 6’ 2’’. Mother 5’10’’. Height and weight are at the 97th percentile Tanner stage 3 pubic hair with testicle <2.5 cm


Bone Age is 9 ½ years which is 18 months (2 SDs) above the mean for chronological age

DIAGNOSIS?

TREATMENT?


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.

Mother is 5’6’’with menarche at age 12. Father’s height and onset of puberty are not available.

Child is at the 90th percentile for both height and weight with no recent acceleration in either parameter.

Child is Tanner Stage 4 for both pubic hair and breast development. No café-au-lait spots.


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.


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.


Treatment with Lupron has stabilized bone development and she has had no further menstrual periods.

She continues to be at Tanner Stage 4 for pubertal development


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.


Mother is 5’7’’ with onset of menarche at age 12 years. Father is 5’11’’ with normal onset of puberty.

Height and weight are at the 50th percentileTanner Stage 2 on the left. Tanner 1 on

rightTanner Stage 1 pubic hair.


Bone Age is 1 SD above the mean

What Next?


LH was 0.021 (nl is <0.03)FSH was 0.664 (nl is <4.2)Estradiol was 2.0 (nl is <15)

Diagnosis?

What Next?

THANK YOUTHANK YOU

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RECOGNIZING AND MANAGING DISORDERS OF PRECOCIOUS PUBERTY Mike T. Swinyard, MD, FAAP Board Certified Pediatric Endocrinology/Diabetes Mountain Vista Medicine,