Adolescent Health Care: A Practical Guide

Chapter 8

Abnormal Growth and Development

Joan M. Mansfield

Lawrence S. Neinstein

Chapter 1 described the varied presentation of the normal physical changes of adolescence. The current chapter focuses on the adolescent whose growth and/or development falls outside the range of normal. These issues are usually of enormous concern to adolescents and their family, and the health care provider must have a clear understanding of how to evaluate and manage these problems.

Review of Normal Growth

Chapter 1 covers normal growth and development in detail. Briefly, there are three general phases of growth during childhood and adolescence. In infancy, there is a period of rapid growth. This phase is followed by a relatively steady period of growth during midchildhood, averaging 5 to 6 cm/year with a gradual decrease seen over time. A growth rate of <5 cm/year during this middle childhood phase is considered abnormal. Growth hormone (GH) and thyroid hormone are the primary hormonal determinants of growth during midchildhood. This phase is followed by the adolescent growth spurt, which is caused primarily by the hormones of puberty (estrogen and androgens). GH secretion increases significantly during the pubertal growth spurt under the influence of sex steroids. Thyroid hormone continues to be required for growth. During peak pubertal growth, growth rates increase to the range of 9 cm/year in girls and 10 cm/year in boys. As puberty progresses, estrogen results in the gradual fusion of the epiphyses with eventual termination of growth in height. In evaluating growth during adolescence, it is necessary to assess whether a teen has reached puberty, whether puberty is proceeding normally, and whether the bony epiphyses are still open to permit further growth.

Short Stature without Delayed Puberty

Adolescents who are progressing normally through puberty may present with concerns about short stature. Most of these teens have genetic or familial short stature with other major categories including chronic disease, constitutional delay of growth and development, and endocrine diseases. Girls who are short may seek medical attention for this complaint when they have just reached menarche and worry that future growth in height will be limited. Boys may present as their pubertal growth spurt slows and they are still shorter than they had hoped. Most hormonal deficiencies, chronic diseases, and malabsorptive states which slow growth will also cause at least some delay in puberty or failure to progress normally through puberty, so that these are less likely causes for the short stature in teens who have normal puberty.

Definition of Short Stature

Adult height is strongly dictated by genetic factors; therefore, evaluation of short stature must be assessed considering the heights of family members. Generally, the 3rd percentile on a cross-sectional growth chart is used as the lower limit of normal.

Criteria for Evaluation

An adolescent should be considered for an evaluation of short stature if:

  1. Linear growth rate is<4 to 5 cm/year during the years prior to the normal age for peak linear growth velocity
  2. No evidence of a peak linear growth velocity by age 16 years in boys and 14 years in girls.
  3. Deceleration below an individual's established growth velocity occurs.
  4. The adolescent's height is more than 2 standard deviations (SDs) below the calculated midparental height (see Chapter 1)
  5. The adolescent's height is more than 3 SDs below the mean. Consideration should be given to carrying out a full evaluation if an adolescent's height is between 2 to 3 SDs below the mean; at a minimum, a careful history and physical examination, screening laboratory tests and observation of growth for 6 months is warranted.

Differential Diagnosis

  1. Familial short stature
  2. Chronic illness—can include diseases such as cystic fibrosis, human immunodeficiency virus (HIV) infection, severe asthma, congestive heart failure, renal failure, inflammatory bowel disease, sprue among others
  3. Constitutional delay of puberty

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  1. Endocrine—can include hypothyroidism, isolated GH deficiency, hypercortisolism states and poorly controlled diabetes
  2. Congenital syndromes including Down syndrome (trisomy 21), Ullrich-Turner syndrome (45X), Noonan, Hurler, Silver-Russell syndrome, Laron syndrome (GH receptor gene mutations); deletions of the portion of the X chromosome containing genes for stature can present with short stature but normal puberty
  3. Intrauterine growth retardation
  4. Skeletal disorders—chondrodysplasias (often have abnormally short extremities)

Evaluation

History

  1. Maternal pregnancy history—medical illnesses and medication use
  2. Birth weight and length, and estimate of gestational age—important because premature infants with appropriate small weight tend to have a normal growth potential, whereas infants with intrauterine growth retardation who are inappropriately small for gestational age may not have catch-up growth
  3. Complete review of systems:
  4. Renal—polyuria and polydipsia for hypothalamic and/or pituitary disorders
  5. Cardiac—peripheral edema, murmurs, and cyanosis
  6. Gastrointestinal—diarrhea, flatulence (malabsorption), vomiting, and/or abdominal pain
  7. Pulmonary—sleep apnea, asthma, or symptoms suggestive of cystic fibrosis
  8. Neurological—visual field defects suggesting pituitary neoplasms
  9. Growth history—close review of symptoms (Figs. 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, growth charts for various disease states)
  10. Family history—adult height and growth and pubertal patterns of all first- and second-degree relatives
  11. Dietary history
  12. Review of the growth chart

Physical Examination

A complete physical examination is the next step in the evaluation and should include:

  1. Height and weight
  2. Arm span and upper-to-lower (U/L) body-segment ratio
  3. Sexual maturity ratings (SMRs)
  4. A general physical examination, with special attention to the thyroid gland, ophthalmological examination, neurological examination, and stigmata of congenital syndromes

Laboratory Evaluation

The laboratory evaluation of short stature should include the following:

  1. Routine Laboratory Screening: Includes complete blood cell (CBC) count, sedimentation rate, urinalysis, chemistry profile including serum creatinine and liver enzymes, and also thyroid-stimulating hormone (TSH) and adjusted T4. If celiac disease is suspected, then antiendomysial antibodies, immunoglobulin A, and anti-transglutaminase immunoglobulin G (IgG), transglutaminase antibodies, and anti-gliadin IgG titers may be useful.
  2. Bone Age: X-ray of the left hand and wrist for bone age (since the bone age can determine if there is more potential for growth and be used to estimate predicted final height).
  3. Midparental Height Calculation: It is also useful to obtain the parents' heights and calculate a midparental height (formula provided in Chapter 1). Although there are many genes involved in stature, and an offspring's height frequently varies considerably from midparental height, the midparental or target height can still give a good clue that the short stature is genetic.
  4. Karyotype: A karyotype is sometimes useful in evaluating the extremely short child who presents with normal puberty.
  5. Other Tests: Other tests may be indicated depending on the history and physical examination and may include:
  6. Central imaging studies
  7. Gastrointestinal studies
  8. Endocrine studies:
  9. Serum levels of insulin-like growth factor I (IGF-I) formerly named somatomedin C, and also insulin-like growth factor-binding protein 3 (IGFBP-3).
  10. GH stimulation testing is usually done by a pediatric endocrinologist using one of several protocols (insulin, glucagon, arginine, L-dopa, or clonidine). Two tests are usually carried out together and the patient is considered GH deficient if the GH response is <7 to 10 ng/mL on both tests.

Suggestions for Diagnosis

  1. Constitutional Delay of Puberty: Most short stature in adolescents is the result of either constitutional delay of puberty or familial short stature. Guidelines for diagnosis are outlined later in this chapter.
  2. Genetic or Familial Short Stature: Genetic or familial short stature is suggested by the following:
  3. Normal history and physical examination findings
  4. Birth weight and length that are often below the 3rd percentile for gestational age
  5. Family history of short stature
  6. Growth curve that generally parallels the 3rd percentile
  7. Bone age that is appropriate for chronological age
  8. Chronic Illness: Chronic renal disease and Crohn disease are frequent causes of short stature at tertiary care hospitals. These diseases are usually diagnosed by an abnormal history, physical examination findings, or results of tests including screening CBC, sedimentation rate, urinalysis, and chemistry studies. Renal tubular acidosis can easily be overlooked as a cause of short stature. This process may be suggested by family history, urine pH level, or serum bicarbonate values.
  9. Endocrine Causes: Endocrine causes of short stature, such as hypothyroidism, GH deficiency, and adrenocortical excess, are uncommon. Hypothyroidism and adrenocortical excess can usually be detected by the patient's history, physical examination, or screening laboratory tests. Adolescents with classic GH deficiency can be difficult to differentiate from those with constitutional delay of puberty. This is particularly difficult during the

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time of expected peak linear growth velocity, when the growth of an adolescent with constitutional delay of puberty may seem to differ from the normal growth curve as other adolescents accelerate their growth velocities. Individuals with classic GH deficiency have normal body proportions and often a high-pitched voice, a tendency toward hypoglycemia, a microphallus in boys, a childlike face, soft and finely wrinkled skin, and a large prominent forehead.

 

FIGURE 8.1 Constitutional delay of puberty in girls 2 to 20 years of age (National Center for Health Statistics percentiles). (Adapted from National Center for Health Statistics.NCHS growth charts. www.cdc.gov/growthcharts. 2000.)

Treatment of Short Stature with Growth Hormone

Growth Hormone Deficiency

Patients with classic GH deficiency have marked benefit in statural outcome as the result of GH treatment. In addition, those with complete GH deficiency benefit from treatment (from the metabolic effects of GH) with regard to improving bone density, decreasing fat mass, and improving muscle

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strength, even if epiphyseal fusion has been achieved. It appears these subjects should continue GH treatment at a markedly reduced dose, compared with that used for growth augmentation, throughout life.

Bioengineered human GH has been available since the 1980s and indications for treatment continue to expand. Patients with classical GH deficiency usually present with extreme short stature and slow growth (<4 cm/year) well before adolescence, although acquired GH deficiency, sometimes due to head trauma, may present in adolescence with slow growth and relatively delayed puberty.

 

FIGURE 8.2 Catch-up growth in girls 2 to 20 years of age, with prematurity or deprivation states (National Center for Health Statistics percentiles). (Adapted from National Center for Health Statistics. NCHS growth charts. www.cdc.gov/growthcharts. 2000.)

Other Conditions

Turner Syndrome

GH has been used to increase height velocity and increase final adult height in patients who do not have GH deficiency by GH stimulation tests. GH is approved for use in patients with short stature due to Turner syndrome using

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a higher dose than is recommended for GH deficiency (0.05 mg/kg/day subcutaneously or 0.35 mg/kg/week for Turner syndrome). IGF-I, thyroid screens, and bone ages by x-ray are monitored during therapy. Patients with Turner syndrome should have baseline renal ultrasonography and periodic echocardiograms to screen for aortic root enlargement. Aortic dissection is a rare but potentially fatal cause of severe chest pain in patients with Turner syndrome. GH treatment should ideally be initiated early in childhood when growth rate begins to fall off. Estrogen replacement is usually delayed to age 12 to 14 or sometimes later to maximize height gain in patients with Turner syndrome. GH has also been used in Noonan syndrome.

 

FIGURE 8.3 Low height and low weight in girls 2 to 20 years of age with familial short stature, primordial short stature, with familial short stature or primordial short stature (National Center for Health Statistics percentiles). (Adapted from National Center for Health Statistics. NCHS growth charts. www.cdc.gov/growthcharts. 2000.)

Intrauterine Growth Retardation

GH is also approved by the U.S. Food and Drug Administration for use in patients with short stature due to intrauterine growth retardation, Prader-Willi syndrome, and chronic

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renal failure before transplantation. GH has also been approved for treatment of children and adolescents with idiopathic short stature who are more than 2.25 SD below the mean in height and who are unlikely to catch up in height. Patients who qualify for a trial of treatment with human GH for idiopathic short stature must have open epiphyses permitting further height gain. Patients with severe short stature who desire treatment with GH should be referred to a pediatric endocrinologist.

 

FIGURE 8.4 Decreased height and markedly decreased weight in girls 2 to 20 years of age with chronic illness states (National Center for Health Statistics percentiles). (Adapted from National Center for Health Statistics. NCHS growth charts. www.cdc.gov/growthcharts. 2000.)

Delayed Puberty

Review of Normal Development

The appearance of secondary sex characteristics is a response to rising levels of sex steroid hormones. As outlined in Chapter 1, in the normal sequence of events, the rise of adrenal androgens known as adrenarche occurs by age 8 years and is followed several years later

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by an increase of hypothalamic gonadotropin-releasing hormone (GnRH) pulsations that trigger the synthesis and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary. LH and FSH stimulate gonadal production of sex steroid hormones and development of the germ cells. The absence of puberty may be the result of failure at any point along the hypothalamic-pituitary-gonadal axis. The challenge of evaluating an adolescent with delayed puberty is to differentiate between constitutional delay of puberty, a normal variation in the tempo of development, and organic diseases such as chronic illness, nutritional insufficiency, tumor, or primary endocrinopathy associated with delayed development.

 

FIGURE 8.5 Markedly decreased height and decreased weight in girls 2 to 20 years of age with hypopituitary states, metabolic disorders such as rickets, or hypothyroidism (National Center for Health Statistics percentiles). (Adapted from National Center for Health Statistics. NCHS growth charts. www.cdc.gov/growthcharts. 2000.)

The pattern of normal puberty is discussed in detail in Chapter 1. Readers are reminded that secondary sexual characteristics usually begin to develop between ages 8 and 13 in girls, and 9 and 14 years in boys.

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FIGURE 8.6 Decreased height and increased weight in girls 2 to 20 years of age with Cushing syndrome and hypothyroidism (National Center for Health Statistics percentiles). (Adapted from National Center for Health Statistics. NCHS growth charts. www.cdc.gov/growthcharts. 2000.)

Females

  • Breast budding is the first sign of development in 85% of girls, followed by the appearance of sexual hair. Some normal girls show sexual hair as the first sign of pubertal development.
  • Growth acceleration begins early during female puberty, followed by menarche occurring at an average age of 12.5 years, after peak height velocity has passed.
  • Girls reach menarche an average of 2.3 ± 1(SD) years after the onset of breast budding.

Males

  • The first sign of development in boys is usually enlargement of the testes to >2.4 cm in length (4 mL volume) at an average age of 11.5 years.
  • Enlargement of the testes is followed by phallic enlargement, and the appearance of pubic and axillary hair as androgens are secreted, and ultimately an increase in growth rate with peak height velocity being reached approximately 2.5 years after the onset of testicular development.
  • Boys usually complete testicular development in 3 ± 2 (SD) years.

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FIGURE 8.7 Markedly decreased weight in girls 2 to 20 years of age with anorexia nervosa (National Center for Health Statistics percentiles). (Adapted from National Center for Health Statistics. NCHS growth charts. www.cdc.gov/growthcharts. 2000.)

Definition

In general, two SDs above and below the mean are used to define the range of normal variability. Chapter 1 is helpful in determining guidelines for evaluation, and further guidelines are discussed subsequently.

Delayed development is defined by the absence of breast budding by age 13 in girls or the lack of testicular enlargement by age 14 in boys, both 2.5 SD beyond the average age at onset of these changes. Alterations in the chronological relationship of pubertal events are also common causes for evaluation. These include phallic enlargement in the absence of testicular enlargement in boys or the absence of menarche by age 16, or 4 years after the onset of breast development, in girls. If puberty is interrupted, there is a regression or failure to progress

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in the development of secondary sexual characteristics, accompanied by a slowing in growth rate.

General Guidelines for Evaluating Puberty

In Males:

A male adolescent may be considered to have delayed puberty if:

  1. Genital stage 1 (G1) persists beyond the age of 13.7 years, or pubic hair stage 1 (PH1) persists beyond the age of 15.1 years.
  2. More than 5 years have elapsed from initiation to completion of genital growth.
  3. The following SMRs persist past the listed guidelines:

G2 >2.2 years

PH2 >1.0 year

G3 >1.6 years

PH3 >0.5 year

G4 >1.9 years

PH4 >1.5 years

In Females:

A female adolescent may be considered to have delayed maturation if:

  1. Breast stage 1 (B1) persists beyond the age of 13.4 years, PH1 persists beyond the age of 14.1 years, or there is failure to menstruate beyond the age of 16 years.
  2. More than 5 years have elapsed between initiation of breast growth and menarche.
  3. The following SMRs persist past the listed guidelines:

B2 >1.0 year

PH2 >1.3 years

B3 >2.2 years

PH3 >0.9 year

B4 >6.8 years

PH4 >2.4 years

These general guidelines must be considered in the context of the teen's family history as to growth and pubertal development, his or her previous growth pattern, and with regard to the review of systems and physical examination.

Differential Diagnosis

Delayed development occurs more commonly in boys than girls. Most patients who present for an evaluation of slow growth and delayed development are high school–aged boys who are concerned about their short stature, as well as their lack of muscular and secondary sexual development which puts them at a disadvantage among their peers. Most of these boys have constitutionally delayed development; however, the clinical presentation of the patient with constitutional delay may be indistinguishable from that of the patient whose pubertal delay is the result of an organic lesion.

Constitutional Delay of Puberty

Adolescents with constitutional delay of puberty have often been slow growers throughout childhood. In the absence of sex steroids of puberty, growth may slow even further to <5 cm/year as these children reach an age when puberty would normally occur. Growth velocity increases into the normal range when these teens finally enter puberty. Adolescents with constitutional delay of puberty often have a family history of delayed growth and development in relatives. Teens with constitutional delay of puberty eventually enter puberty on their own. Although they have a longer time to grow before their epiphyses close, they tend to have a less exuberant growth spurt than earlier developers so that their final height is often shorter than average.

Functional Causes of Delayed Puberty

GnRH secretion, can be inhibited centrally by

  1. Inadequate nutrition, including eating disorders
  2. Chronic disease including chronic heart disease, severe asthma, inflammatory bowel disease, celiac disease, juvenile rheumatoid arthritis, chronic renal failure, renal tubular acidosis, sickle cell anemia, diabetes mellitus, systemic lupus erythematosus, cystic fibrosis, and infection with HIV
  3. Severe environmental stress
  4. Intensive athletic training
  5. Hypothyroidism and excess cortisol states
  6. Drugs such as opiates and stimulants

Eating disorders associated with self-imposed restriction of caloric intake can delay or interrupt the progression of puberty. Anorexia nervosa most often develops in girls in early to middle adolescence, who have already entered puberty. Young adolescent boys or girls who are dieting because of fear of obesity may present with the complaint of delayed development. Crohn disease or celiac disease may also present with delayed development and poor growth as the major symptoms. Since adolescence is normally a period of rapid growth and weight gain, failure to gain or small amounts of weight loss may be manifestations of significant nutritional insufficiency. Poor growth and delayed puberty are common in cystic fibrosis, thalassemia major, renal tubular acidosis, renal failure, cyanotic congenital heart disease, sickle cell anemia, systemic lupus erythematosus, acquired immune deficiency syndrome, or very poorly controlled asthma or type 1 diabetes. Patients who are on stimulants such as methylphenidate (Ritalin) for treatment of attention deficit disorder may have decreased appetite because of the medication and slower growth rates as a result of nutritional insufficiency.

Hypothyroidism may present in an adolescent with slowing of height velocity (height dropping percentiles on the growth chart) whose weight is well preserved for height or who is mildly overweight, sometimes with delayed or interrupted pubertal development. The classic signs include dull dry skin, perhaps with scalp hair loss, decrease in pulse rate and blood pressure, constipation, and cold intolerance. A goiter is not always present. Autoimmune thyroiditis is the most common cause of hypothyroidism in teens. There may be a family history of hypothyroidism or autoimmune issues.

Cushing syndrome (endogenous glucocorticoid overproduction) or chronic exposure to high doses of glucocorticoids for medical treatment causes excessive weight gain, slowing of height velocity, and may interrupt or delay puberty or, if endogenous sex steroid production is also increased, may present with precocious puberty without a growth spurt.

Hypothalamic Causes of Delayed Puberty

The ability of the hypothalamus to secrete GnRH may be damaged by:

  1. Local tumors (germinomas, craniopharyngiomas, astrocytomas, or gliomas)

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  1. Infiltrative lesions such as central nervous system (CNS) leukemia or histiocytosis X
  2. CNS irradiation
  3. Traumatic gliosis
  4. Mass lesions such as brain abscesses or granulomas due to sarcoidosis or tuberculosis
  5. Congenital defects in the ability to secrete GnRH (idiopathic hypogonadotropic hypogonadism may be associated with midline craniofacial defects or olfactory defects [Kallmann syndrome] and may be familial). Other congenital brain malformations associated with inability to secrete GnRH include septooptic dysplasia.

Pituitary Causes of Delayed Puberty

Puberty may not begin or may fail to proceed if the pituitary cannot respond to GnRH stimulation with LH and FSH production. This may be due to:

  1. Pituitary tumor
  2. Selective impairment of gonadotrope function by hemochromatosis
  3. Congenital hypopituitarism, which is usually diagnosed either in the neonatal period or with poor growth during childhood; causes include genetic defects that interfere with pituitary formation and empty sella syndrome
  4. Acquired hypopituitarism
  5. Prolactinoma—excessive prolactin production by a pituitary adenoma (prolactinoma) or other tumor may interrupt or prevent puberty by interfering with gonadotropin production. Patients with prolactinomas most often present with secondary amenorrhea often with galactorrhea, but may present with stalled puberty. Headaches are sometimes present. Prolactinomas are more common in girls than boys, but can occur in both. Psychotropic drugs such as antipsychotics are a frequent cause of hyperprolactinemia.

Gonadal Failure

If the gonads are unable to respond to LH and FSH, puberty will not proceed.

The causes of gonadal failure with abnormal karyotype include:

  1. Gonadal Dysgenesis: The most common cause of gonadal failure is gonadal dysgenesis, which occurs in association with abnormalities of sex chromosomes. The gonads fail to develop and become rudimentary streaks. These patients are phenotypic females with normal immature female genitalia. The most common phenotype is Turner syndrome which is caused by absence of part or all of a second sex chromosome. These patients are typically short with a final untreated height averaging 143 cm. Other identifying features of Turner syndrome are low set ears, a webbed neck, widely spaced nipples, a trident hairline, an increased carrying angle of the lower arms, and short forth and fifth fingers and toes. Renal abnormalities such as duplications and horseshoe kidney, and left-sided cardiovascular abnormalities such as bicuspid aortic valve, dilatation of the aortic root and coarctation of the aorta are also associated with Turner syndrome. Half of these patients have 45,X karyotypes whereas the rest are mosaics or have various X chromosome abnormalities or deletions.
  2. Klinefelter Syndrome: Males with Klinefelter syndrome (47,XXY) may present with poorly progressing puberty caused by partial gonadal failure. Although they lack sperm production, their testes can make some testosterone when driven by high levels of gonadotropins (LH and FSH). In the 47,XXY patient with pubertal development, the testes become small and firm because they become fibrotic. Gynecomastia and eunuchoid body habitus are often seen.

The causes of gonadal failure with normal karyotype include:

  1. Acquired Gonadal Disorders
  2. Infection—viral or tubercular orchitis or oopheritis
  3. Trauma—bilateral testicular torsion resulting in anorchia is another cause of gonadal failure in males
  4. Postsurgical removal
  5. Radiation, chemotherapy with agents such as cyclophosphamide
  6. Autoimmune oophoritis or orchitis (sometimes with multiple autoimmune endocrine abnormalities)
  7. The resistant ovary syndrome
  8. Sarcoidosis
  9. Fragile X may present as secondary amenorrhea in females with ovarian failure
  10. Cryptorchidism—in males who are cryptorchid, the testes may fail to function, particularly if they remain intraabdominal beyond infancy
  11. Congenital Gonadal Disorders
  12. Anorchism: In the “vanishing testis syndrome”, the testes are absent in a phenotypic male, presumably as a result of destruction in utero.
  13. Pure gonadal dysgenesis: This presents as absent puberty in patients with a normal karyotype (46,XX or 46,XY), normal stature, and a female phenotype.
  14. Enzyme defects in androgen and estrogen production: Enzymatic defects, such as 17α-hydroxylase or 20,22-desmolase deficiency, which render the gonad unable to produce estrogens or androgens, are other rare causes of primary gonadal failure. No specific cause for gonadal failure can be found in many cases.
  15. Gonadal failure is associated with other diseases such as congenital galactosemia in girls and ataxia telangiectasia.
  16. Androgen-Receptor Defects
  17. Complete androgen insensitivity (previously referred to as “testicular feminization”) presents as a patient who is a phenotypic female with tall stature, absence of sexual hair, normal breast development and timing of puberty, but absence of menarche. The vagina is a short pouch and there is no uterus. The karyotype is 46,XY, and testosterone levels are elevated.
  18. Incomplete (previously referred to as a variety of syndromes, including Reifenstein syndrome)

Syndromes Associated with Pubertal Delay

There are several syndromes that are characterized by extreme obesity, short stature, and delayed puberty. These include the following:

  1. Prader-Willi (extreme obesity, developmental delay, small hands and feet, and chromosome 15 deletion)
  2. Lawrence-Moon-Bardet-Biedel (obesity, polydactaly, retinitis pigmentosa, genital hypoplasia, developmental delay)
  3. Borjeson-Forseeman-Lehman (obesity, severe mental deficiency, microcephaly, epilepsy and skeletal anomalies)

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Another congenital syndrome is congenital absence of the uterus and upper vagina (Mayer-Rokintansky-Kuster-Hauser syndrome). This is associated with normal puberty, but absent menses.

Work-Up of Delayed Puberty

Most adolescents with delayed maturation have constitutional delay of puberty. However, this diagnosis is made by excluding other causes. Following is a discussion of the evaluation of the adolescent with delayed puberty, including criteria for a provisional diagnosis of constitutional delay of puberty. A detailed history and physical examination will help focus and minimize the laboratory testing needed to evaluate an adolescent with delayed development.

History

  1. Neonatal History: The neonatal history should include birth weight, history of previous maternal miscarriages and congenital lymphedema (Turner syndrome). The past medical history should focus on any history of chronic disease, congenital anomalies, previous surgery, radiation exposure, chemotherapy, or drug use.
  2. Growth Records: Past growth measurements that are plotted on appropriate developmental charts for height, weight, and body mass index are important in evaluating the adolescent with delayed puberty. The overall pattern of growth and changes in that pattern often lead to a diagnosis. Examples of growth charts in various disease states are provided in Figures 8.1 through 8.7. The child whose delayed puberty is associated with a nutritional deficiency due to an eating disorder, inflammatory bowel disease, celiac disease, or other chronic disease will show a greater decline in weight gain than in height and be underweight for height (Fig. 8.4). In contrast, the child who has delayed puberty on the basis of an endocrinopathy such as acquired hypothyroidism or gonadal dysgenesis will have a greater slowing in height gain than in weight gain, and have weight well preserved for height, often being mildly overweight (Fig. 8.6).
  3. Review of Systems: Special attention should be paid to weight changes, dieting, environmental stress, exercise and athletics, gastrointestinal symptoms, headache, neurological symptoms (including abnormal peripheral vision and anosmia), and symptoms suggestive of thyroid disease.
  4. Nutritional History and Eating Habits: This helps to discount a problem of chronic malnutrition.
  5. Family History: The family history should include the heights, and timing of secondary sexual development and fertility of family members, a history of anosmia, and a history of endocrine disorders.

Physical Examination

A complete physical examination is indicated for the adolescent with delayed puberty, but the following areas are of particular importance:

  1. Overall nutritional status and measurements of height, weight and vital signs
  2. Body measurements including:
  3. Arm span
  4. Upper to lower segment ratio: This can be measure by measuring symphysis pubis to floor for lower, subtracting lower from total height for upper. This measurement can be useful for patients who have either short extremities (short bone syndromes, congenital short stature syndromes) or long extremities (eunuchoid appearance). The normal U/L ratio is 1.7 at birth, 1.0 at age 10 years, and 0.9 to 1.0 in adulthood in Caucasians, and 0.85 to 0.9 in African-Americans. Hypothyroidism will cause a U/L ratio to remain greater than 1.0, which would be the case in most patients with chondrodysplasia. Hypogonadism will usually have a U/L ratio close to 0.9 or less. A normal ratio is often found in those with GH deficiency, constitutional delay of puberty, and chronic disease states.
  5. Congenital anomalies, including midline facial defects
  6. Staging of sexual maturity: The patient should be examined for a delay in pubertal development as assessed by staging of breast and pubic hair in girls, and genitalia and pubic hair in boys. Pubic hair may be present, although the genitalia are prepubertal in a boy who had normal adrenarche, but lacks gonadal activation. Any evidence of heterosexual development, such as clitoromegaly or hirsutism in girls or gynecomastia in boys should be noted.
  7. Thyroid: Check for evidence of goiter. Absence of goiter can be seen with hypothyroidism.
  8. Chest: Check for evidence of chronic pulmonary disease.
  9. Cardiac: Check for evidence of congenital heart disease.
  10. Abdomen: Check for abdominal distension as a sign of a malabsorptive disease and check for evidence of liver or spleen enlargement as a sign of a chronic systemic disorder.
  11. Genital examination: The examination of the external genitalia in girls should focus on obvious congenital anomalies and an assessment of estrogen effect. A pale pink vaginal mucosa with white secretion indicates the current presence of estrogen. A pelvic examination is not necessary as a part of the initial evaluation of a girl with delayed secondary sexual development, but should be done if possible to rule out gynecological congenital anomalies in a girl who has normal pubertal development but delayed menarche. The pelvic examination should be carried out by a practitioner who is familiar with the techniques used for examining nonsexually active teen girls such as assessing the depth of the vagina with a saline-moistened cotton-tipped applicator, and using a one finger bimanual vaginal–abdominal examination if the vaginal introitus comfortably permits. If amenorrhea is a problem, then either a complete pelvic examination is indicated or pelvic ultrasonography can be performed if needed to determine the presence of müllerian structures (uterus and tubes) and to visualize ovaries.
  12. Neurological examination: This will help eliminate from consideration any intracranial pathology. Ophthalmoscopic and visual-fields examination is done to rule out abnormalities of the optic nerves and to look for evidence of intracranial hypertension.

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Laboratory Tests

Laboratory evaluation should be focused according to the clinical impression (see clue to diagnosis). In the patient who is underweight for height, studies would include screening tests for chronic disease or malabsorptive states such as celiac disease.

Bone Age

The most useful initial examination in delayed puberty and slow growth is often an x-ray of the left hand and wrist for a bone age assessment. This information can be used to assess how much height growth potential remains in the patient with short stature and delayed development. A predicted adult height can be obtained using the Bayley-Pinneau tables in the Atlas of Skeletal Maturation by Gruelich and Pyle (or see Table 1.5).

  1. Constitutional Delay of Puberty: The patient with constitutional delay of puberty will usually have an equal delay of height age and bone age. Caution should be used in height predictions in patients with constitutional delay of puberty since boys with constitutional delay and short stature frequently reach a final height short of the final adult height predicted by the tables.
  2. Delayed Bone Age: Patients with GH deficiency, hypothyroidism, and chronic disease usually have bone ages that are delayed several years behind their chronological age.
  3. Normal or Delayed Bone Age: Often seen with Turner syndrome.

Bone age may also be used in conjunction with height age and chronological age to give clues about a diagnosis as indicated below. Height age is determined by locating the corresponding age at which the patient's height would be equal to the 50th percentile. See Table 8.1.

Routine Laboratory Tests

Initial laboratory studies to be considered in the adolescent with delayed puberty include a CBC count, erythrocyte sedimentation rate (useful as a screening test for chronic illness such as inflammatory bowel disease) electrolytes, blood urea nitrogen, creatinine, glucose, calcium, phosphorus, albumin, liver enzymes and urinalysis.

Evaluation for Celiac Disease

Evaluation for celiac disease (antitissue transglutaminase and total IgA, or celiac panel) should be considered. More extensive testing for inflammatory bowel disease includes an upper gastrointestinal tract series with small bowel follow through and barium enema.

Central Imaging Studies

If there is a suspicion of a CNS tumor, cranial magnetic imaging with contrast is the best way to evaluate the hypothalamus and pituitary. A computed tomography (CT) scan is a less sensitive alternative.

Hormonal Tests

Hormonal tests to be considered include thyroid function tests (adjusted T4, TSH), prolactin, LH and FSH, dehydroepiandrosterone sulfate, testosterone or estradiol, and IGF-I and IGFBP-3.

In the early stages (Tanner stage 2) of puberty, breast budding and vaginal maturation in girls and penile and testicular enlargement in boys are more sensitive indicators of pubertal neuroendocrine-gonadal function than a single daytime measurement of gonadotropin (LH and FSH) levels, estradiol or testosterone. LH, FSH, and testosterone or estradiol may be in the prepubertal range on a daytime sample even though these hormones are actively being secreted at night. Testosterone or estradiol levels may be valuable in following the patient whose puberty is not progressing normally by clinical assessment of growth and secondary sexual development.

GH is secreted primarily during sleep, so daytime levels are expected to be low. IGF-I and IGFBP-3 are used to assess GH sufficiency. IGF-I levels should be compared with normals for bone age rather than chronological age since the levels increase during puberty. IGF-I levels are low in patients with nutritional insufficiency. Patients with delayed puberty and slow growth often have temporarily decreased GH secretion simply due to pubertal delay which increases to normal as puberty begins. If GH deficiency is suspected, the patient should be referred to a pediatric endocrinologist for GH stimulation testing. Patients with constitutional delay of puberty who are prepubertal may appear GH deficient on GH stimulation testing unless primed with estrogen before the test.

TABLE 8.1
Typical Relationships between Bone Age, Height Age, and Chronological Age for Causes of Delayed Puberty or Short Stature

Cause of Delayed Puberty or Short Stature

Relationship between Bone Age (BA), Chronological Age (CA), and Height Age (HA)

Genetic

HA <BA = CA

Skeletal dysplasia

HA ≤ BA < CA or BA < HA < CA

Constitutional

HA = BA<CA

Hypopituitarism

HA ≤ BA <CA

Hypothyroidism

BA < HA <CA

Hypogonadism

BA ≤ HA <CA

Systemic illness

BA = HA <CA

LH and FSH determinations are only useful if they are elevated since these hormones are secreted primarily during sleep in the early phases of puberty. Early to midpubertal levels (Tanner breast stage 2) are indistinguishable from prepubertal levels, usually with a very low LH and FSH higher than LH. Elevated LH and FSH levels are suggestive

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of primary gonadal failure. If LH and FSH levels are elevated, further laboratory evaluation would include blood karyotyping in search of a chromosomal abnormality such as 45,X. Patients with gonadal dysgenesis who have Y chromosomal material present should have their gonads removed surgically because of an increased risk for gonadoblastoma. If the chromosomes are normal in the patient with gonadal failure, antiovarian antibodies may be obtained to look for autoimmune gonadal damage. Pelvic ultrasonography may be used to visualize the uterus and ovaries, but should be interpreted with caution since the prepubertal uterus is small and may be missed on ultrasonography. A vaginal ultrasonography is usually postponed until adulthood.

TABLE 8.2
Criteria for Provisional Diagnosis of Constitutional Delay of Puberty

U/L, upper-to-lower; CBC, complete blood cell; LH, luteinizing hormone; FSH, follicle-stimulating hormone.
From Barnes HV. Recognizing normal and abnormal growth and development during puberty. In: Moss AV, ed. Pediatrics update: reviews for physicians. New York: Elsevier–North Holland Publishing, 1979:103, with permission.

Required features

 Detailed negative review of systems

 Evidence of appropriate nutrition

 Linear growth of at least 3.7 cm/yr

 Normal findings on physical examination, including genital anatomy, sense of smell, and U/L body-segment ratio

 Normal CBC, sedimentation rate, urinalysis results, adjusted T4 concentration, and noncastrate levels of serum LH and FSH

 Bone age delayed 1.5–4.0 yr compared with chronological age

Supportive features

 Family history of constitutional delay of puberty

 Height between 3rd and 25th percentiles for chronological age

If the initial prolactin level is elevated, it should be repeated without a breast examination on the day of the testing, and ideally in a fasting state. Patients with significantly elevated prolactin levels should have a cranial magnetic resonance imaging (MRI) with contrast.

Neuroendocrine Pharmacological Testing

If there is a question of multiple pituitary hormone defects, the patient may be referred to an endocrinologist for pharmacological and physiological tests of neuroendocrine function. A GnRH stimulation test with gonadorelin (Factrel), 2.5 µg/kg intravenously, maximum 100 µg, has been used in the past to assess pituitary LH and FSH response in the evaluation of delayed puberty. If the patient has central puberty, there will be a large increase in LH during the 2 hours after GnRH is given (sample can be drawn at 45 minutes). Since GnRH is currently not commercially available, GnRH analog stimulation tests are substituted (leuprolide acetate 500 µg).

Constitutional Delay of Puberty

The chief diagnostic challenge in the patient with pubertal delay is to distinguish between constitutional delay and true GnRH deficiency. About 90% to 95% of delayed puberty is constitutional delay of puberty. No single test reliably separates patients with constitutional delay from those with idiopathic hypogonadotropic hypogonadism.

This diagnosis is made by excluding the other causes, as discussed. However, using the guidelines in Table 8.2, one can confidently make a provisional diagnosis.

Clues to Other Diagnoses

  1. Gonadotropin deficiency
  2. Low serum FSH and LH levels, particularly if bone age is more than 13 years
  3. Low response to GnRH
  4. Abnormal central imaging study results
  5. History of neurological symptoms, CNS infections, radiation, or disease
  6. Possible absence of sense of smell (Kallmann syndrome)

The presence of midline facial defects, anosmia, cryptorchidism, or microphallus strongly suggests idiopathic hypogonadotropic hypogonadism; however the diagnosis cannot be firmly established until the patient reaches the age of 18 years and is still prepubertal. Genes for hypothalamic hypogonadism have been identified, as have some genes for familial pubertal delay.

  1. Gonadal disorder
  2. History of genital radiation, surgery, infection, or trauma
  3. Castrate levels of FSH and LH
  4. Abnormal karyotype, such as 46,XY in a phenotypic girl
  5. Low U/L body-segment ratio
  6. Arm span may exceed height by >2 inches
  7. Gynecomastia in a boy
  8. Small testes in boys with genetic hypogonadal disorders: Testes rarely exceed 6 cm3in volume
  9. Turner syndrome: Excluding constitutional delay of puberty, one of the more common causes of maturation delay is Turner syndrome. The patient may have a 45,X karyotype or a mosaic karyotype such as 45,X/46,XX or ring or isochromosomes. Patients with

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Turner syndrome usually have some of the following characteristics:

  • Short stature
  • Streak gonads
  • Absent pubertal growth spurt
  • Poor development of secondary sexual characteristics, with less breast development than pubic hair development
  • Lymphedema
  • Nail dysplasia
  • High arched palate
  • Strabismus
  • Hearing deficit due to chronic otitis
  • Cubitus valgus
  • Webbing of the neck
  • Low hairline
  • Shield-shaped chest
  • Coarctation of the aorta
  • Horseshoe kidneys
  • Short fourth metacarpal
  • Multiple pigmented nevi
  • Normal vagina, cervix, and uterus
  • Poor space-form perception with normal overall intelligence

Savendahl and Davenport (2000) recommend a karyotype in all girls with unexplained short stature, delayed puberty, webbed neck, lymphedema, or coarctation of the aorta. Karyotype should also be considered for girls with a height below the 5th percentile and two or more features of Turner syndrome, such as high palate, nail dysplasia, short fourth metacarpal, and strabismus.

  1. Chronic illness

 .    Abnormal findings on review of systems or physical examination

  1. Falling off height and weight curves at onset of disease
  2. Abnormal CBC count, sedimentation rate, urinalysis results, or chemistry panel results

Management of Delayed Puberty

Before age 14 years in girls and age 16 years in boys, if there is no evidence of an underlying disease or neurological abnormality and the initial evaluation reveals normal prepubertal hormone levels, the adolescent can be seen at 6-month intervals for measurements of growth, assessment of pubertal status by physical examination, and reassurance if progression of secondary sexual development is evident. After the first signs of testicular or beast enlargement are observed, follow-up at regular intervals is desirable to reassure the patient and parents that puberty is progressing. Since the testes begin to enlarge in males before increased testosterone production and increased growth velocity occur, support and guidance in dealing with the frustrations of delayed puberty are important, even after there is evidence that secondary sexual development has begun.

If the evaluation reveals primary gonadal failure, cyclic estrogen and progestin therapy in girls or testosterone therapy in boys will be necessary. Adolescents with hypogonadotropic hypogonadism or hypopituitarism will also need estrogen or testosterone replacement, often with replacement of other hormones as well. Short courses of estrogen or testosterone can also to be used to initiate development in constitutional delay of puberty if there is no sign of development by age 14 in girls or 15 in boys.

Treatment for Girls

In girls, there are several regimens for replacing estrogen and progesterone. If growth is desired, estrogen is begun at a low dose, since height velocity is greater at low estrogen doses, and higher doses cause more rapid epiphyseal closure. The three phases of estrogen replacement are:

  1. Induction of breast development and increase in height velocity in the patient with no secondary sexual development
  2. Establishment of normal menses and increase in bone mineralization
  3. Long-term maintenance of a normal estrogen state

Induction of Breast Development

In the first phase, a number of low dose estrogen preparations have been used: estrogen regimens include conjugated estrogens (Premarin) 0.3 mg tablet or less (1/2 tablet) daily by mouth, 0.3 mg estrone sulfate (Estratab), or 0.5 mg micronized estradiol (Estrace) for the first 6 to 12 months of treatment or until linear growth slows. Although lower doses of ethinyl estradiol (10 µg) and transdermal estradiol (5–10 µg) have been used in research studies to induce puberty, the lowest dose estradiol transdermal patch available is 25 µg and the lowest dose of ethinyl estradiol available is 20 µg.

Induction of Menses

In the second phase, the daily dose of estrogen is increased to 0.625 mg conjugated estrogens, 1.0 mg micronized estradiol, 20 µg ethinyl estradiol, or a 50 µg transdermal estradiol patch. After 2 to 3 months, a progestin such as (medroxyprogesterone [Provera] 5–10 mg or norethindrone 0.7–1 mg) or micronized progesterone 200 mg is added initially 5 days each month.

Long-term Estrogen Replacement

In the third phase, 10 mg of medroxyprogesterone or other progestin is given 12 to 14 days a month to decrease the risk of endometrial hyperplasia. Estrogen regimens for long-term replacement include conjugated estrogens 0.625 mg, ethinyl estradiol 20 µg, esterified estrogens 0.625 mg, micronized estradiol 1.0 mg, or transdermal estradiol 50 to 100 µg. Once growth is essentially complete, estrogen can also be replaced as a 20 to 35 µg oral contraceptive pill, or combined estrogen–progestin transdermal patch.

Oral estrogens pass first through the liver which could theoretically increase side effects. Transdermal alternatives include estradiol patches (Vivelle dot, Climera, Alora, and Estraderm) which are changed once or twice a week depending on the preparation. An oral progestin (medroxyprogesterone 10 mg or micronized progesterone 200 mg) is added for 12 to 14 days each month. One transdermal regimen is Vivelle dot (0.05 mg) for 2 weeks each month followed by Combipatch 0.05 mg estradiol/0.14 mg norethindrone acetate for 2 weeks.

Many patients with delayed puberty have decreased bone density for age. The optimal dose of estrogen replacement for increasing bone density in adolescents remains to be established, but it is probably higher than in menopausal women. A bone density by dual-energy x-ray absorptiometry (DXA) of the hip and spine at baseline and every 2 years is commonly carried out in adolescents on estrogen or testosterone replacement. Bone density is compared with age-matched norms. The importance of

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appropriate calcium (1,300 mg/day) intake by diet or supplements and at least 400 IU vitamin D to support bone calcification should be stressed on each visit. The timing of initiation of sex steroid therapy to achieve maximum height depends on the patient's chronological and skeletal age, and current height velocity.

Treatment for Boys

In boys with constitutional delay of puberty, 3 to 6 month courses of testosterone 1% gel 2.5 to 5 gm daily or intramuscular testosterone enanthate 25 to 50 mg every 2 to 4 weeks can be used to initiate secondary sexual development. Intramuscular hCG is used less commonly. Exposure to testosterone or hCG may speed the onset of the patient's own puberty. Since sex steroids cause fusion of epiphyses, care must be taken in the timing and monitoring of these therapies so that final height is not compromised. These patients should therefore be referred to an endocrinologist for treatment. The timing of such an intervention must take into account such complex issues as psychosocial stress, self-image, and school performance which appear to be more affected by pubertal delay than by short stature alone. Males with gonadal failure, hypopituitarism, or hypothalamic hypogonadism are maintained on long-term testosterone replacement using testosterone gel. They should receive dietary adequate calcium and vitamin D and should have DXA scans for spinal and hip bone density measurements since they are at risk for a low bone mass. In both males and females whose delayed puberty is due to abnormalities in hypothalamic GnRH secretion that do not correct with time, fertility can be achieved using a small pump to deliver pulses of GnRH intravenously or subcutaneously for weeks or months. Some GnRH-deficient males will achieve spermatogenesis with hCG alone or in combination with FSH. Ovulation can be induced by FSH and hCG in GnRH-deficient females.

Treatment of Specific Conditions

Hypothyroidism

Treatment is begun with levothyroxine (see Chapter 9 for hypothyroidism). Thyroid function tests are repeated in 6 weeks and the dose is adjusted to maintain the TSH concentration in the midnormal range. The final dose is usually 75 to 100 µg in females and 100 to 125 µg in males. Noncompliance with medication is often the underlying issue in teens whose TSH is elevated despite receiving unusually high doses of thyroid replacement. A 7-day pill package and adult supervision of doses may be helpful. Once the dose is established, thyroid tests are repeated at 6-month intervals. Catch-up growth is expected when thyroid hormone replacement is initiated, but patients who have been untreated for several years will lose some adult height.

Turner Syndrome and Gonadal Dysgenesis

Short stature associated with Turner syndrome can be treated with human growth hormone (hGH). The U.S. Food and Drug Administration and other worldwide regulatory agencies have approved the use of hGH for statural improvement in Turner syndrome. The hGH therapy should be started before the adolescent years and before beginning estrogen therapy for feminization. The dose used is approximately double that used for subjects with classic GH deficiency. Data from the National Cooperative Growth Study from Genentech has shown GH to be effective in improving the final height of girls with Turner syndrome and that GH is safe for these patients (Blethen et al., 1996). Oxandrolone (0.075 to 0.25 mg/kg/day) or fluoxymesterone (2.0 mg/day) can be added to GH therapy to improve the growth response. If this is done, it is usually begun after 2 to 3 years of GH therapy alone, before feminization, for a limited time, and with great caution because androgens have the following disadvantages:

  1. Potential for hepatic toxic effects
  2. Advancement of the bone age
  3. Potential for mild androgenic characteristics, such as clitoral enlargement
  4. Delay of treatment with estrogen and therefore delay of inducement of female secondary sexual characteristics

Anabolic steroids as the sole therapy for this syndrome are no longer recommended. Secondary sexual characteristics in females are achieved through the use of increasing doses of conjugated estrogens as discussed above. Chernausek et al. (2000) evaluated the timing of estrogen replacement in girls with Turner syndrome with regards to final height outcome. Patients in whom estrogen treatment was delayed until the age of 15 years gained an average of 8.4 cm over their projected height. Those who started estrogen at 12 years of age gained only 5.1 cm. They found that growth was stimulated for 2 years after beginning estrogen replacement therapy and that the timing of estrogen therapy is important for final height. This indicates that for some girls, particularly those who are shortest and in whom GH has not been given for more than 2 years, delaying estrogen therapy may be indicated to improve height outcome.

If there is a Y chromosome present on the initial study done to diagnose Turner syndrome, no further chromosomal analysis is required to anticipate that the patient will require gonadectomy. However, Y chromosomal material, rather than a full Y chromosome, may be present in girls who are virilized, either at birth or with puberty not as the result of androgen therapy. They should have fluorescent in situ hybridization (FISH) for the Y chromosome to ensure that no Y chromosomal material has been translocated. The presence of any Y material is an indication for gonadectomy, to prevent potential malignant neoplasias. Surgery should be followed by hormonal replacement therapy during and after puberty.

Chronic Illness

Treatment of pubertal delay caused by chronic illness necessitates treating the underlying disorder. For example, enzyme replacement in cystic fibrosis, gluten-free diet in celiac disease, corrective surgery for congenital heart disease, and hyperalimentation in inflammatory bowel disease usually result in catch-up growth and maturity. Medications such as steroids or antimetabolites can inhibit growth. Catch-up growth can be observed after discontinuation of treatment with these drugs. In some cases, the disease process is irreversible, such as in sickle cell anemia. The pubertal delay in sickle cell anemia is thought to be hypogonadism, possibly caused by a zinc deficiency. Zinc has been used with some early experimental success in alleviating this problem. In patients with chronic renal failure, there may be some growth after improved nutrition and hemodialysis

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or transplantation. However, many patients with chronic renal failure remain short. Recent studies suggest that GH can be administered to subjects with chronic renal failure before transplantation to improve height, without causing deterioration of underlying renal function (Fine et al., 1994). HIV infected children who have poor growth and body wasting may benefit from the anabolic effects of short-term GH administration; however, long-term use of such agents remains under investigation (Mulligan et al., 1993).

Patient Education

Young adolescents are preoccupied with their physical appearance. Any variation from the normal timing of sexual development is a major source of embarrassment to them and evokes feelings of personal inadequacy. A review of a patient's progress on the growth pubertal growth and growth chart can help reassure him or her that growth is proceeding in a pattern that is appropriate. For patients who have a permanent defect in reproductive function, counseling and support from both the primary health provider and medical specialist can be helpful in enabling the patient to establish a positive self-image of himself or herself as a capable adult. Further counseling by a mental health professional may be necessary. Questions about fertility should be answered as they arise, with emphasis on the patient's ability to function normally as a marriage partner and parent of adopted children. With current technology, pregnancies are possible using in vitro fertilization with donor eggs in patients with ovarian failure.

Excessive Growth: Tall Stature

Tall stature is seldom a complaint in males, but is occasionally a source of concern in adolescent females. This is less common than in the past since the role models of athletes and fashion models have made tall stature more socially acceptable in women now than in the past. Most commonly, tall stature is genetic and one or both parents are also tall.

Differential Diagnosis

  1. Constitutional tall stature
  2. Excess GH (e.g., GH-secreting tumors)
  3. Anabolic steroid excess (exogenous, adrenal tumor, gonadal tumor, congenital adrenal hyperplasia—classic or nonclassical, precocious puberty, premature adrenarche)
  4. Hyperthyroidism
  5. Miscellaneous
  6. Marfan syndrome
  7. Neurofibromatosis
  8. Hypogonadism in boys
  9. Androgen-receptor deficiency in boys
  10. Estrogen deficiency in boys
  11. Homocystinuria
  12. Hereditary abnormalities of the skeleton
  13. Soto syndrome

Evaluation

Obese girls tend to be taller than average, perhaps due to higher levels of insulin. Many genetically tall girls who are above the 95th percentile for height in the early adolescent period are experiencing an early pubertal growth spurt, but will have a final adult height in the normal range. Review of the growth chart and a bone age are useful. If growth rate is excessive, evaluation might include thyroid function tests looking for hyperthyroidism, and an IGF-I, IGFBP-3, and random GH to exclude GH excess. If GH is low, acromegaly is unlikely. Elevated GH may be a random pulse and should be repeated. IGF-I is elevated in acromegaly. Marfan syndrome is usually diagnosed clinically. The phenotype is characterized by tall stature, lean body habitus and elongated extremities. A slit lamp examination by an opthamologist may detect lens dislocation in 50% of patients. Echocardiogram may reveal a dilated aortic root. The syndrome is caused by a gene abnormality causing deficient fibrillin production.

Treatment

In the past, high doses of estrogen were used to limit height gain in girls whose predicted height would be more than 6 ft (183) cm. Estrogen affects growth by suppressing IGF-I and accelerating epiphyseal fusion. This is seldom done currently since female tall stature has become more socially acceptable. High-dose estrogen treatment in girls is associated with side effects which include nausea, breast soreness, hypertension, and, rarely, blood clots.

The treatment of boys has been studied less extensively. Theoretically, administration of high-dose testosterone could accelerate epiphyseal fusion, but concerns of this therapy would include edema, acne, weight gain and a decrease in testicular volume. Therefore, tall stature in boys is typically not treated.

Precocious Puberty

Definition

In boys, development before age 9 years or 2.5 SD earlier than average is considered precocious. Early development in boys is rare. There are 10 times as many girls with precocious puberty as boys. There is currently a controversy over the definition of precocious puberty in North American girls. In girls, the cut off has traditionally been 8 years or 2.5 SD below the average of breast development. However, a 1997 study by Herman-Giddens (Herman-Giddens et al., 1997) of 17,000 American girls found a mean age of breast development of just below 10 years in Caucasian girls and 9 years in African-American girls; 15% of African-American girls having the appearance of breast development by 7 to 8 years and 5% of Caucasian girls having breast development by 7 to 8 years. Pubic hair was present in 3% of Caucasian girls and 18% of African-American girls by age 7 to 8 years. This has led to a revision of the definition of precocious puberty by the Lawson Wilkins Pediatric Endocrine Society as the presence of breast or pubic hair before age 7 in Caucasian and before age 6 years in African-American girls. Since then, numerous reports have pointed out that cases of true pathology such as CNS tumors may be missed by excluding 7- to 8-year-old

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girls from evaluation. Girls who have both pubic hair and breast development at ages 7 to 8, should have at least a bone age for height prediction, a review of growth and history, and consideration of further testing. Girls with rapid progression or unusual progression of puberty, a predicted height below 150 cm or -2 SD below target midparental height, those with neurological symptoms, or girls who are having psychological difficulty due to early puberty should be referred for further evaluation and consideration of possible suppression of puberty with GnRH analog therapy. Puberty is normally held back in humans during childhood by inhibitory connections to the hypothalamus which suppress GnRH pulsations. If these inhibitory connections are damaged, GnRH pulse amplitude increases, and central puberty ensues. There is often a family history of early puberty in girls with precocious puberty; some studies suggest an autosomal dominant pattern with variable penetrance.

The vast majority of girls with central precocious puberty have idiopathic precocious puberty. Boys are much more likely to have a specific lesion causing their precocity.

Causes

Central causes of precocious puberty include the following:

  1. CNS tumors (optic gliomas, craniopharyngiomas, dysgerminomas, ependymoma)
  2. CNS malformations (hamartomas, arachnoid and suprasellar cysts, hydrocephalus, septooptic dysplasia)
  3. Infiltrative lesions (histiocytosis, granulomas, abscess)
  4. CNS damage (irradiation, trauma, meningitis, encephalitis)

Gonadotropin-independent causes of precocity in girls include the following:

  1. Ovarian cysts, sometimes with McCune-Albright syndrome
  2. Ovarian or adrenal estrogen secreting tumors
  3. Severe hypothyroidism
  4. Exposure to exogenous estrogen

In boys, in addition to the central causes listed above, precocious puberty can be caused by androgen exposure, congenital adrenal hyperplasia, gonadal and adrenal tumors secreting androgens, and familial activating mutations of the LH receptor.

Incomplete Forms of Precocious Puberty

Premature Thelarche

Premature thelarche occurs often in female infants and toddlers. Self-limited breast budding which is also transient occurs in girls aged 6 and above. There is no sustained growth spurt or bone age advancement in these girls. Breast budding may appear and recede several times before sustained puberty ensues.

Premature Adrenarche

Benign premature adrenarche presents with underarm odor, and pubic and/or axillary hair development usually at ages 6 to 8 years. Bone age is often slightly advanced (1 year) and adrenal androgens are in the pubertal range. Twenty percent of the girls with benign premature adrenarche will go on to have polycystic ovary syndrome as teens. Patients with a history of intrauterine growth retardation followed by excessive weight gain and insulin resistance in childhood may present with premature adrenarche. They are at increased risk for polycystic ovary syndrome and sometimes glucose intolerance as teens. Virilization in girls is rare and can be due to an androgen secreting adrenal or ovarian tumor, topical androgen exposure, or congenital adrenal hyperplasia. Symptoms of virilization include rapid growth and bone age advancement, deepening of the voice, clitoromegaly or muscular development. A thorough evaluation is required.

Evaluation of Precocious Puberty

History

History includes a review of family history of endocrine or pubertal disorders, timing of puberty in family members, use of estrogen or androgen containing gels by family members, and heights of family members. The patient's past history should be reviewed for evidence of predisposing medical conditions. The growth chart should be obtained.

Physical Examination

The physical examination includes careful measurement of height and weight, vital signs, examination of the skin for large irregular café au lait spots suggestive of McCune-Albright syndrome, examination of the fundi, assessment for thyroid enlargement, abdominal examination, Tanner staging (measurement of breast or testicular and phallic dimensions, and pubic hair staging). The vaginal introitus can be examined for signs of estrogen effect on the labia minora and presence of leukorrhea in the frog-leg position. Internal examination is not necessary unless unexplained vaginal bleeding is present in which case an experienced observer can often visualize the vagina and cervix in the knee chest position without instrumentation. In boys, the testicular examination should focus on any testicular asymmetry or masses, or phallic enlargement without testicular enlargement suggesting a source of androgens outside of the testes, such as congenital adrenal hyperplasia.

Laboratory Evaluation

A bone age x-ray of the left hand and wrist is useful. If the bone age is 2 years advanced, more evaluation is usually indicated (Fig. 8.8). A baseline prediction of adult height can be made using the average charts from the Bayley-Pinneau table at the back of the Gruelich and Pyle Atlas of Skeletal maturation (see Chapter 1 for details).

Laboratory evaluation might include an LH, FSH, estradiol, DHEAS, and TSH in girls, and in boys, a testosterone and 8 a.m. 17 OH progesterone and DHEAS, hCG, LH, and FSH. The LH and FSH will be in the prepubertal range (LH less than FSH) in the early stages of central puberty. By the time breast or gonadal development is in Tanner SMR stage 3, LH and FSH are often in the pubertal range. To confirm central puberty, it is sometimes necessary to do a GnRH or GnRH analog stimulation test (GnRH itself has recently been unavailable) using 500 µg leuprolide acetate and obtaining an LH, FSH, and estradiol or testosterone 45 minutes to 2 hours after the injection. If estradiol is markedly elevated (more than 100 pg/mL) and LH and FSH are suppressed, an ovarian cyst or more

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rarely tumor is suspected. A pelvic ultrasonography can be done in girls if an ovarian cyst or tumor is thought to be the cause of the precocity. In boys, a hCG test should be done to rule out a hCG-producing tumor that could be causing testosterone production. A cranial MRI with contrast should be done to rule out CNS lesion in all boys with central precocious puberty, in all girls younger than 6 years, and should be considered in girls between 6 and 8 years of age depending on the clinical history. An adrenocorticotropic hormone (ACTH) stimulation test may be needed if congenital adrenal hyperplasia is suspected as a cause of androgen excess.

 

FIGURE 8.8 Flow sheet for evaluation of isosexual precocious puberty. hCG, human chorionic gonadotropin; CT, computed tomography; MRI, magnetic resonance imaging. (Adapted from Brenner PE. Precocious puberty in the female. In: Mishell DR, Davajan VC, eds. Reproductive endocrinology, infertility, and contraception. Philadelphia: FA Davis Co, 1979.)

Treatment of Precocious Puberty

If the evaluation has not revealed a specific treatable cause of precocious puberty and the child has central precocious puberty, GnRH analog treatment should be considered. Most girls in the 7 to 9 year range do not require treatment for suppression of puberty.

Many girls in this age range have a slow intermittent progression of their puberty and reach a final height which is not short. Early developers take longer on average to reach menarche than later developers. Often parents are most worried about how they will handle menses in a grade school child, and can be reassured that menarche is not imminent in most cases and that menses can be suppressed if necessary using GnRH analog therapy. Untreated girls should be followed up at 6 month to 1 year intervals. If the child has an initial predicted adult height below 62 in. (157 cm), bone age may need to be repeated in 6 months to 1 year because the predicted height can decline with rapid bone age advancement, and therapy may be required to preserve height potential. Depot leuprolide at an initial dose of 0.3 mg/kg can be given q28 days intramuscularly. LH, FSH, and estradiol in girls or testosterone in boys can be obtained 45 minutes to 2 hours after the depot leuprolide to document adequate suppression of puberty on therapy after 2 to 3 months of treatment. Partial suppression of puberty has been achieved in girls with gonadotropin

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independent puberty (McCune-Albright syndrome) with the aromatase inhibitor testolactone. Similar regimens with antiandrogens and testolactone have been used in boys with familial LH-activating mutations.

Web Sites

For Teenagers and Parents

http://www.magicfoundation.org. Magic Foundation with information about growth disorders and brochures about many disorders.

http://www.hgfound.org. Human Growth Foundation Web site with information and support for children and adults with growth disorders.

http://www.keepkidshealthy.com/welcome/conditions/delayed puberty.html. Information from keepkidshealthy on delayed puberty.

http://www.turner-syndrome-us.org/. Information about Turner syndrome.

http://www.humatrope.com. Information from Eli Lilly about synthetic GH.

http://www.novonordisk.com/. Facts from novo on GH deficiency and treatment.

http://www.toosoon.com. Information from Lupron Association on precocious puberty.

For Health Professionals

http://humatrope.com. Information from Lilly on GH.

http://www.aafp.org/afp/990700ap/209.html. Review article from the American Academy of Family Physicians on Evaluation of Growth Disorders.

References and Additional Readings

Adan L, Souberbielle JC, Brauner R. Management of the short stature due to pubertal delay in boys. J Clin Endocrinol Metab 1994;78:478.

Albanese A, Stanhope R. Investigation of delayed puberty. Clin Endocrinol 1995;43:105.

Albanese A, Stanhope R. Predictive factors in the determination of final height in boys with constitutional delay of growth and puberty. J Pediatr 1995;126:545.

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