Case Files Pediatrics, (LANGE Case Files) 4th Ed.

CASE 30

Parents bring their 5-year-old daughter to your clinic because she has developed breast and pubic hair over the past 3 months. Physical examination reveals a girl whose height and weight are above the 95th percentile, Tanner stage II breast and pubic hair development, oily skin, and facial acne.

Image What is the most likely diagnosis?

Image What is the best next step in the evaluation?

ANSWERS TO CASE 30: Precocious Puberty

Summary: A 5-year-old girl has breast and pubic hair development, tall stature, and facial acne.

• Most likely diagnosis: Idiopathic central precocious puberty.

• Next step in the evaluation: Inquire about birth history, illnesses, hospitalizations, medications, siblings’ health status, and family history of early puberty and diseases. Serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels and bone age radiographs are helpful.

ANALYSIS

Objectives

1. Understand the underlying causes of precocious puberty.

2. Describe laboratory and radiologic tests that are helpful in determining the etiology of precocious puberty.

3. Establish the treatment and follow-up necessary for a child with precocious puberty.

Considerations

This 5-year-old girl has precocious puberty signs (breast and pubic hair development and tall stature). She may have true (central) precocious puberty or precocious (non-central) pseudopuberty. A central nervous system (CNS) cause of true precocious puberty must be ruled out because she is younger than 6 to 8 years, and a CNS cause must be ruled out in boys at any age below ~9 years.

APPROACH TO:

Precocious Puberty

DEFINITIONS

DELAYED PUBERTY: No signs of puberty in girls by the age of 13 years or in boys by the age of 14 years. May be caused by gonadal failure, chromosomal abnormalities (Turner syndrome, Klinefelter syndrome), hypopituitarism, chronic disease, or malnutrition.

PRECOCIOUS PUBERTY: Secondary sexual characteristic onset before age 6 to 8 years in girls and 9 years in boys. Children in different ethnic groups undergo puberty differently; African-American girls often do so earlier than Caucasian girls.

TRUE (CENTRAL) PRECOCIOUS PUBERTY: Gonadotropin-dependent. Hypothalamic-pituitary-gonadal activation leading to secondary sex characteristics.

PRECOCIOUS (NONCENTRAL) PSEUDOPUBERTY: Gonadotropin-independent. No hypothalamic-pituitary-gonadal activation. Hormones usually are either exogenous (birth control pills, estrogen creams) or from adrenal/ovarian tumors.

PREMATURE ADRENARCHE: Early activation of adrenal androgens (typically in girls ages 6 to 8 years), with gradually increasing pubic/axillary hair development and body odor.

PREMATURE THELARCHE: Early breast development (typically in girls ages 1 to 4 years), without pubic/axillary hair development or linear growth acceleration.

CLINICAL APPROACH

More common in girls, true precocious puberty stems from secretion of hypothalamic GnRH with normal-appearing, but early, progression of pubertal events. Sexual precocity is idiopathic in more than 90% of girls, whereas a structural CNS abnormality is present in 25% to 75% of boys.

Girls with gonadotropin-independent, precocious pseudopuberty have an independent source of estrogens causing their pubertal changes. An exogenous source of estrogen (birth control pills, hormone replacement) or an estrogen-producing tumor of the ovary or adrenal gland must be considered. CNS lesions causing precocious puberty without neurologic symptoms are rarely malignant and seldom require neurosurgical intervention.

A detailed history offers important clues regarding the onset of puberty. Three main patterns of precocious pubertal progression can be identified, particularly in girls. Most girls who are younger than 6 years at onset have rapidly progressing sexual precocity, characterized by early physical and osseous maturation with a loss of ultimate height potential. Girls older than 6 years typically have a slowly progressing variant with parallel advancement of osseous maturation and linear growth and preserved height potential. In a small percentage of girls, there is spontaneous regression or unsustained central precocious puberty at a young age, with normal pubertal development at an expected age.

A neurologic history may identify past hydrocephalus, head trauma, meningoencephalitis, or the presence of headaches, visual problems, or behavioral changes. The type, sequence, and age at which pubertal changes were first noticed (breast and pubic/axillary hair development, external genitalia maturation, menarche) give valuable information regarding the etiology of the problem. Important questions include the following:

• Has the child been rapidly outgrowing shoes and clothes (evidence of linear growth acceleration)?

• Has the child’s appetite increased?

• Has the child developed body odor?

• Was the child possibly exposed to an exogenous source of sex steroids (oral contraceptives, hormone replacement, anabolic steroids)?

• At what ages did parents and siblings undergo puberty?

• Is there a known or suspected family history of congenital adrenal hyperplasia?

Physical examination offers further important information (Figures 30-1 and 30-2). Serial height measurements are critical for determining the child’s growth velocity.

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Figure 30-1. Female Tanner staging.

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Figure 30-2. Male Tanner staging.

The skin should be examined for café-au-lait spots (neurofibromatosis, McCune-Albright disease), oiliness, and acne. The presence of axillary hair and body odor, the amount of breast tissue, and whether the nipples and areolae are enlarging and thinning are documented. The amount, location, and character of pubic hair should be noted. The abdomen is palpated for masses. Boys are examined for enlargement of the penis and testes (>2.5 cm in precocious puberty) and thinning of the scrotum (prepubertal scrotum is thick and nonvascular). If the testes are different in size and consistency, a unilateral mass is considered. Testicular transillumination may be helpful. In girls, the clitoris, labia, and vaginal orifice are examined to identify vaginal secretions, maturation of the labia minora, and vaginal mucosa estrogenization (dull, gray-pink, and rugaed rather than shiny, smooth, and red). A neurologic examination also is performed.

In precocious puberty, serum sex hormone concentrations usually are appropriate for the observed stage of puberty, but inappropriate for the child’s chronologic age. Serum estradiol concentration is elevated in girls, and serum testosterone level is elevated in boys with precocious puberty. Because LH and FSH levels fluctuate, single samples often are inadequate. An immunometric assay for LH is more sensitive than the radioimmunoassay when using random blood samples; with this test, serum LH is undetectable in prepubertal children, but is detectable in 50% to 70% of girls (and an even higher percentage of boys) with central precocious puberty. A gonadotropin-releasing hormone (GnRH) stimulation test, measuring response time and peak values of LH and FSH after intravenous administration of GnRH, is a helpful diagnostic tool.

Bone age radiographs are advanced beyond chronologic age in precocious puberty. Organic CNS causes of central sexual precocity are ruled out by computed tomography (CT) or magnetic resonance imaging (MRI), particularly in girls younger than 6 years and in all boys. Pelvic ultrasonography is indicated if gonadotropin-independent causes of precocious puberty (ovarian tumors/cysts, adrenal tumors) are suspected based on examination.

The goal of treating precocious puberty is to prevent premature closure of the epiphyses, allowing the child to reach full adult growth potential. Gonadotropin-releasing hormone agonists are used for treatment of central precocious puberty. These analogues desensitize the gonadotropic cells of the pituitary to the stimulatory effect of GnRH produced by the hypothalamus. Nearly all boys and most girls with rapidly progressive precocious puberty are candidates for treatment. Girls with slowly progressive puberty do not seem to benefit from GnRH agonist therapy in adult height prognosis. A pediatric endocrinologist should evaluate children considered for GnRH agonist treatment.

COMPREHENSION QUESTIONS

30.1 A 5-year-old girl has bilateral breast development that was first noticed 6 months ago. She takes no medications, and no source of exogenous estrogen is present in the home. Family history is unremarkable. Physical examination reveals a girl who is at the 50th percentile for height and weight, with normal blood pressure, normal skin without oiliness, Tanner stage II breasts, soft abdomen without palpable masses, no body odor, no pubic/axillary hair, and mild estrogenization of the vagina. Which of the following is the most likely explanation for the child’s breast development?

A. Adrenal tumor

B. Central precocious puberty

C. Congenital adrenal hyperplasia

D. Premature adrenarche

E. Premature thelarche

30.2 A 4-year-old boy has started growing pubic hair and has recently exhibited aggressive “bullying” behavior at his preschool. History reveals the boy to be a term infant without postnatal complications. The child takes no medications. Family history is unremarkable. He has one younger sister who is well. Physical examination reveals height and weight above the 95th percentile, marked muscular development, Tanner stage II pubic hair development, scant axillary hair, prepubertal testicular size, a masculine voice, and oily skin. The abdominal examination is normal. The child’s bone age is 6 years. Which of the following is the most appropriate next step in management?

A. Brain MRI

B. Dexamethasone challenge test

C. Reassure the family that no studies are needed

D. Serum 17α-hydroxyprogesterone level

E. Testicular ultrasound

30.3 A mother brings to your clinic her 13-year-old daughter who is “falling behind” in growth and who has not yet exhibited pubertal changes. Physical examination reveals a height less than the 5th percentile, no signs of secondary sexual characteristics, a small mandible, low posterior hairline, prominent ears, and a broad chest. Which of the following is the most appropriate next step in management?

A. Abdominal ultrasound

B. Bone age radiograph

C. Chromosome analysis

D. Reassure the family and recommend height measurement in 6 months

E. Treat with growth hormone injections

30.4 A father brings his 14-year-old son to your clinic because his teacher has concerns about his poor school performance and maladjusted behavior. He has poor grades in all subjects, is extremely shy, and has always had difficulty in adjusting socially. On examination, he is at the 95th percentile for height and 5th percentile for weight. It is very difficult to engage him in conversation. The testes are prepubertal, he has mild hypospadias, and he has no secondary sexual characteristics. Which of the following is the most likely cause of his pubertal delay?

A. Hypopituitarism

B. Klinefelter syndrome

C. Marfan syndrome

D. Noonan syndrome

E. Testicular tumor

ANSWERS

30.1 E. All of this child’s findings are estrogen related. She has no virilization. Postulated premature thelarche causes include ovarian cysts and transient gonadotropin secretion. No treatment is necessary.

30.2 D. Boys with congenital adrenal hyperplasia have virilization despite prepubertal testicles. This results from a disorder of steroid synthesis, leading to a deficiency of cortisol and an overproduction of androgenic intermediary metabolites such as 17α-hydroxyprogesterone.

30.3 C. This child has Turner syndrome (45, XO). Other features include webbed neck, high arched palate, increased nevi, renal anomalies, increased arm-carrying angle, and edema of the hands and feet. Treatment includes recombinant human growth hormone and estrogen replacement therapy.

30.4 B. Klinefelter syndrome (47,XXY) usually comes to attention because of gynecomastia and small testes. These males usually are clinically normal at birth. Treatment involves replacement therapy with a long-acting testosterone beginning at age 11 to 12 years.


CLINICAL PEARLS

Image True precocious puberty is the onset of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. It stems from secretion of hypothalamic gonadotropin-releasing hormone and is more common in girls.

Image Precocious puberty is idiopathic in more than 90% of girls, and a structural central nervous system abnormality is noted in 25% to 75% of boys.

Image When compared to norms, the serum estradiol level is elevated in girls and the testosterone level is elevated in boys with precocious puberty. Bone age radiographs are advanced beyond chronologic age.

Image The goal of treating precocious puberty is to prevent premature closure of the epiphyses, allowing the child to reach full adult growth potential.


REFERENCES

Garibaldi L, Chemaitilly W. Disorders of pubertal development. In: Kliegman RM, Stanton BF, St. Geme JW, Schor NF, Behrman RE, eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: WB Saunders; 2011:1886-1894.

Plotnick LP, Long DN. Puberty and gonadal disorders. In: McMillan JA, Feigin RD, DeAngelis CD, Jones MD, eds. Oski’s Pediatrics: Principles and Practice. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:2079-2084.

Styne DM, Cuttler L. Normal pubertal development. In: Rudolph CD, Rudolph AM, Lister GE, First R, Gershon AA, eds. Rudolph’s Pediatrics. 22nd ed. New York, NY: McGraw-Hill; 2011:2074-2077.

White PC. Congenital adrenal hyperplasia and related disorders. In: Kliegman RM, Stanton BF, St. Geme JW, Schor NF, Behrman RE, eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: WB Saunders; 2011:1930-1939.