The Smallest Kid in School: Evaluating Delayed Puberty

Peter A. Lee, MD, PhD; Christopher P. Houk, MD


August 13, 2012

Suspected Delayed Puberty: Making the Diagnosis

A child presenting with suspected delayed puberty requires a thorough history, including family history; a detailed physical examination, with particular attention to breast development in girls and testicular volume in boys; and selected laboratory evaluation.

Although the basic approach to pubertal delay is similar in boys and girls, key details differ.[2,7]


Key components of the history include:

  • Birth and developmental history;

  • General health;

  • Growth, noting any recent changes in height and weight;

  • Intense or excessive exercise;

  • Review of systems, including anosmia, general endocrine and gastrointestinal illnesses, and any therapy (including radiation or chemotherapy);

  • History of any psychiatric disease, including anorexia or alcohol or illicit drug use; and

  • Family history of pubertal timing, menarche, and infertility.

History: Clinical Pearls

  • Development of pubic/sexual hair does not necessarily mean the onset of puberty and may be due to adrenal androgen secretion.

  • In addition to pubertal delay, an unusually slow pace of pubertal development warrants evaluation to exclude abnormalities.

Physical Examination

Key components of the physical examination include:

  • Accurate measurements, including:

    • Height;

    • Weight;

    • Weight for height (body mass index);

    • Upper/lower segment ratio (or total minus sitting height ratio): a ratio less than 1 indicated prepuberty, 1 is consistent with puberty, and greater than 1 suggests hypogonadism; and

    • Arm span: an arm span exceeding height by more than 5 cm suggests delayed epiphyseal closure resulting from delay of sex-steroid exposure.

  • Growth rates before presentation may also be instructive (Figure 1); slowing of the rate of height growth often precedes the onset of puberty. Such slowing is often accentuated before the onset of puberty in boys with constitutional delay.

Figure 1.

Growth charts for female and male children. Left. The female chart shows the typical pattern of height and weight gain for a girl presenting with inflammatory bowel disease (dark blue arrow) and one with Turner syndrome (light blue arrow). Right. The growth pattern of the boy with hypogonadotropic hypogonadism discussed in the article, showing no deceleration of growth rate as puberty is approached (dark blue arrow), and the second growth curve of a typical patient with constitutional delay of puberty, showing growth deceleration (light blue arrow).

  • General examination should identify:

    • Midline facial defects,

    • Syndactyly;

    • Assessment of subcutaneous fat; and

    • Size of the thyroid gland.

  • Neurologic examination should include:

    • Funduscopic examination,

    • Visual acuity, and

    • Sense of smell.

  • Genital examination:

    • Boys: testicular volume or long-axis length, symmetry, and consistency should be noted.

    • Girls: inspection for color of the vaginal mucosa; pinkish mucosa suggests an estrogen effect, whereas a reddish appearance is consistent with prepuberty.

    • Both sexes: Pubertal staging of genital or breast development, genital inspection, and pubic hair should be noted.

Physical Examination: Clinical Pearls

    Initial Diagnostic Testing

    • Serum LH and FSH levels need to be obtained to document or exclude a hypergonadotropic state; and

    • Radiography of the left hand and wrist is done to determine skeletal maturity (bone age) and document biological age; a significant delay suggest a deficit of factors producing normal growth and maturity.

    • A suggested algorithm for the evaluation of the child with pubertal delay is presented in Figure 2.

    On the basis of these results, second-tier testing (discussed later in this article) should then be done to determine a specific diagnosis.

    Figure 2. Algorithm for the evaluation of pubertal delay.

    What Is Causing Pubertal Delay?

    Circulating LH and FSH levels increase at the onset of puberty. Excessive increases occur in the presence of gonadal failure owing to lack of feedback.[8] Accordingly, excessively elevated gonadotropin levels indicate defective gonadal function, a condition that is always pathologic.

    Low gonadotropin levels suggest a delay of endogenous pubertal onset and may or may not indicate a permanent defect. Hypothalamic or, less commonly, pituitary dysfunction results in the inability to secrete LH and FSH. Thus, low gonadotropin levels alone may be inadequate to differentiate a temporary pubertal delay from a permanent one.

    Classifying Pubertal Delay

    Pubertal delay may be classified on the basis of gonadotropin levels:

    Temporary hypogonadotropism. Low gonadotropin levels, with temporary delay resulting from physiologic or constitutional delay (Table 1).

    Table 1. Conditions Associated With Temporary Hypogonadotropism

    Significant underweight
    Chronic disease: inflammatory disease, hypercortisolism, malnutrition/eating disorder, excessive exercise (eg, gymnastics); psychogenic or stress-related; hypothyroidism, prolactinoma, brain tumor (eg, craniopharyngioma); alcohol use/abuse
    Testicular volume greater than prepubertal
    Growth acceleration and breast budding in girls
    Recent history of weight gain, consistent with hyperprolactinemia rather than hypothyroidism
    Previous onset of puberty followed by cessation of progression
    Family history of delayed adolescent growth and puberty

    Constitutional delay is the most common cause of pubertal delay in both boys and girls. Approximately 40% of these children have a family history of delayed puberty. Constitutional delay is much more common in males, accounting for about 80% of cases.[9] In girls, that percentage decreases to only 30%.[10] Significant delay is associated with skeletal age delay.

    Unless there is early evidence of the onset of puberty, such as early growth acceleration among girls or early testicular growth among boys, it can be very difficult initially to distinguish constitutional delay from permanent hypothalamic hypogonadism. Systemic diseases and other chronic conditions may also result in delayed puberty, because nutritional delay and other deficits result in immature or impaired GnRH release.

    Permanent hypogonadotropism. Low gonadotropins because of a permanent defect (hypogonadotropic hypogonadism) (Table 2).

    Table 2. Conditions Associated With Permanent Hypogonadotropism

    Midline facial developmental defect
    Known pituitary hormone deficiencies or isolated defect in gonadotropin production
    Among males: cryptorchidism or diminished penis size
    History of radiation therapy or chemotherapy involving the central nervous system
    Genetic defects

    Approximately 33% of cases of idiopathic hypogonadotropic hypogonadism have a genetic cause and are familial; the remainder are sporadic. Isolated defects in gonadotropin production may result from defects in the synthesis or function of GnRH receptors or GnRH posttranslational processing, both of which lead to decreased release of gonadotropins.

    Kallmann syndrome is the most common cause of permanent hypogonadotropism, occurring in approximately 1 in 10,000 males and 1 in 50,000 females. Mutations in the KAL1 (Xp22.3) and KzAL2 (8p12) genes result in autosomal dominant forms.

    Kallmann syndrome results from failure of differentiation or migration of the GnRH-releasing neurons and may be associated with facial midline defects and a tendency to mirror-image movements (synkinesia). It may also be associated with inability (anosmia) or reduced ability (hyposmia) to smell.

    Many hypothalamic (GnRH) and pituitary (LH and FSH) synthesis and secretory defects result in hypogonadotropic hypogonadism. Damage to the hypothalamus, pituitary, or surrounding areas from hemochromatosis may lead to the condition. Hypogonadotropic hypogonadism may result from HIV infection; craniopharyngioma; prolactinomas (with or without galactorrhea); other central nervous system tumors; head trauma, surgery, infections, infiltrative diseases; midline central nervous system defects, including septo-optic dysplasia; and autoimmune pituitary hypophysitis.

    The condition may coexist with other anterior pituitary hormone deficiencies (growth hormone, thyroid-stimulating hormone, and adrenocorticotropic hormone) or may represent an isolated pituitary deficiency. When hypogonadotropic hypogonadism is verified, other pituitary functions should be assessed.

    Other conditions associated with permanent hypogonadotropism include:

    • PROP-1 gene abnormalities: a transcription factor involved in pituitary development, this abnormality is most frequently associated with other pituitary hormone insufficiencies;

    • DAX-1 gene (Xp21) mutation: impairs a nuclear receptor protein involved in steroidogenesis and reproductive development leading to congenital X-linked adrenal hypoplasia;

    • Leptin deficiency: associated with early-onset obesity and delayed puberty;

    • FSH (FSH-beta or beta subunit) gene mutation: characterized by undetectable FSH and elevated LH level; and

    • Kisspeptin receptor/GPR54 mutation: involved in stimulation of GnRH secretion and GnRH receptor mutations (4p13.1).

    Permanent hypergonadotropism. Elevated gonadotropin levels because of gonadal failure (hypergonadotropic hypogonadism) (Table 3).

    Table 3. Conditions Associated With Permanent Hypergonadotropism

    Radiation therapy or chemotherapy involving the pelvis
    Prior surgery or trauma involving the pelvis or gonads
    Small, firm or nonpalpable testes
    Unusual causes: galactosemia, gonadal dysgenesis (XX or XY), androgen insensitivity (androgen receptor defect in 46,XY), and autoimmune gonadal failure
    Klinefelter syndrome usually does not present with delayed onset of puberty, although completion of puberty may not occur and testicular volume is diminished
    Turner syndrome (indicated by short stature and typical facies, among other features)

    Hypergonadotropic hypogonadism is always pathologic and is generally permanent. It can occur as a result of radiation injury when the total dose exceeds 6 Gy, an absorbed ionizing radiation dose that is associated with permanent ovarian failure. Several chemotherapeutic agents, including cyclophosphamide, busulfan, procarbazine, and etoposide, also may lead to the condition; in this situation, however, some recovery may occur.

    Other causes include:

    • Premature gonadal failure in Klinefelter syndrome, Turner syndrome, or other forms of gonadal dysgenesis;

    • Autoimmune disease;

    • Galactosemia (GALT enzyme gene [9p13]);

    • Mutations in gonadotropin (FSH-beta gene) and gonadotropin receptor genes;

    • Abdominopelvic trauma;

    • Infectious disease (mumps, shigella, malaria, varicella); and

    • Androgen receptor defects in phenotypic females.

    Autoimmune polyglandular syndromes (APS) are constellations of multiple endocrine gland insufficiencies. The components of type 1 APS include autoimmune adrenal insufficiency (Addison disease), hypoparathyroidism, and mucocutaneous candidiasis; more than one half of affected girls will also experience ovarian failure.

    The most common form of APS is type 2, also known as Schmidt syndrome. Features of this syndrome include Addison disease; autoimmune thyroid disease; type 1 diabetes mellitus; and, less commonly, hypogonadism. Approximately 10% of girls with type 2 APS also have ovarian failure.

    Several conditions, including HIV infection, autoimmunity, Präder-Willi syndrome, and Noonan syndrome, may be associated with both hypo- and hypergonadotropic hypogonadism.

    Second-Tier Testing

    Second-tier testing, if indicated, is initiated after gonadotropin status and other results of first-tier testing are known. This stage of the diagnostic evaluation should be based on history and physical findings and LH/FSH levels.

    Elevated gonadotropin levels. A karyotype and iron studies should be considered. In girls, ovarian antibodies and pelvic/abdominal ultrasonography should be considered. In girls with type 1 APS, the presence of side-chain cleavage enzyme autoantibodies is a predictor of future ovarian failure.

    Low gonadotropin levels. Additional tests should include complete blood count, complete metabolic panel, prolactin levels, immunoglobulin F1, TSH, free thyroxine, bone age radiography, and GnRH/GnRH analogue stimulation testing to assess pubertal gonadotropin response. Onset of puberty can be documented by a significant increase gonadotropin levels, generally with LH levels peaking at about 8-10 mIU/mL; lower peaks suggest an immature system or a deficiency. Central nervous system MRI should be obtained if an intracranial mass is suspected.

    In girls with either low or high gonadotropin levels, pelvic/abdominal ultrasonography should be obtained to visualize ovarian and uterine size and symmetry. In addition, determination of endometrial stripe (a measure of the thickness of the endometrial lining) provides an indication of amount of pubertal hormone stimulation.

    Single measurements of estradiol and testosterone are relatively unhelpful for diagnosis, whereas numerous measurements over time may be helpful. The adrenal androgen dehydroepiandrosterone sulfate is a good marker of adrenarche and can be helpful in documenting adrenarche.

    When hyperprolactinemia is identified and hypothyroidism has been eliminated as a secondary cause, pituitary MRI should be performed.