July 2009
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What the Adult Endocrinologist Needs to Know About Pediatric Endocrinology
Constitutional growth delay is the most common cause of short stature in adolescents.
Reviewed By Katrina L. Parker, MD
To attain normal growth, children must have adequate nutrition, no debilitating disease, a normal emotional and home environment, and adequate hormone production (including insulin, thyroxine, parathyroid hormone, testosterone/estrogen, and growth hormone).1
To monitor childhood growth, it is critical that the physician obtains accurate measurements at regular intervals, records the data properly, uses the proper equipment, and also pays equal attention to both sexes.2 Short stature is defined as height standard deviation score (SDS) ≤2.25 for age and gender—approximately 3% of children fall into this category. The normal stages of growth and development are the intrauterine period, neonatal period, infancy, childhood, adolescence, and late adolescence. Expected growth rates at various ages are displayed in Table 1.
CONSTITUTIONAL GROWTH DELAY
Kaplan3 described constitutional growth delay (CGD) in a comparison of normal growth and growth disorders patterns. About 20% of normal infants will cross two major length-for-age percentiles by 2 years of age.4
Nonendocrine causes of short stature include familiar/genetic short stature, CGD, target tissue defects, chromosomal disorders, dysmorphic syndromes, systemic disorders, and psychosocial dwarfism. Familiar/genetic short stature and CGD are considered normal variants. The features of familiar short stature are normal annual growth rate (≥5 cm/yr), height at or below the 5th percentile with no systemic or endocrine disease present, pubertal development and growth spurt at normal age, skeletal age equal to chronological age, and relatively short ancestors.
Midparental height for boys can be calculated by adding the father's height plus 13 cm to the mother's height and dividing by 2; for girls, the formula is the same but subtract 13 cm from the father's height. Target height is then the midparental height ±2 standard deviations (1 SD ~ 2 in).
CGD is the most common cause of short stature and sexual infantilism in adolescents. These children may be referred to as "slow growers" or "late bloomers," and will have a period of growth deceleration. During the first 2 years of life, height and weight is ≤5th percentile and down-crosses percentiles until age 2 to 3 years. Growth parallels below the curve, and these children will grow at a normal rate until adolescence.
Children with CGD will present with a normal history and physical examination but with delayed pubertal development; delayed skeletal age; normal, genetically appropriate, predicted adult height; and a positive family history of delayed development.
Target tissue defects such as bone and cartilage disorders and intrauterine growth retardation can also cause short stature. Physicians should measure relative body growth, which is a ratio of the upper segment to the lower segment of the body.
Pathologically disproportionate short stature can be caused by familial hypophosphatemic rickets. This is an X-linked dominant inheritance associated with disproportionate short stature, which includes bowing of the legs, late dentition, and low serum phosphate levels. Achondroplasia is associated with minimum or no qualitative abnormality in endocardial ossification. These individuals reach an average adult height of 125 cm for women and 135 cm for men. It is a familial autosomal dominant mutation of the fibroblast growth receptor 3 (FIGF R3) gene.
Intrauterine growth retardation is when infants have birth weights and length >2 SDs below the mean for gestational age (corrected for race and sex). These children will either have catch-up growth after birth to genetic potential or have permanent short stature (22%).6
SMALL FOR GESTATION AGE
Chromosomal disorders can cause small for gestational age (SGA), such as Turner's syndrome (monosomy of chromosome X or 45,XO). The 45,XO karyotype is found in about 15% of spontaneous abortions, and parents of affected children complain of short stature or pubertal delay. A karyotype is needed to confirm the diagnosis.
Other dysmorphic syndromes include Russell-Silver, Prader-Willi, Noonan, and Albright's hereditary osteodystrophy. Features of Russell-Silver syndrome are short stature, born SGA, clinodactyly, skeletal asymmetry, and small triangular facies with downturning of the corners of the mouth. Prader-Willi syndrome is caused by the absence of paternal contribution of chromosome 15. These children have moderate intrauterine and postnatal growth retardation, marked hypotonia, round facies, obesity, mental retardation, and hypogonadism. Noonan's syndrome is an autosomal dominant mutation of protein-tyrosine phosphatase, nonreceptor-type 11; its incidence is about one in 1,000 to 2,500 live births. These children can have short stature, hypertelorism, congenital heart defects, webbed neck, undescended testes, poor muscle tone, feeding difficulties, and a concave or sunken chest.
DIAGNOSIS OF GROWTH DISORDERS
Nonendocrine systemic disorders can affect growth (Table 2) as can socioeconomic factors. Malnutrition is the most common cause of growth retardation worldwide, and both height and weight are decreased. In the United States, poor nutrition may lead to growth retardation, especially in infants and young toddlers. Poor nutrition may result from parental lack of dietary knowledge, an age-inappropriate diet, or dieting.
Psychosocial dwarfism is often difficult to distinguish from idiopathic growth hormone deficiency (GHD). Patients and/or parents may display aberrant social behavior, patients may exhibit bizarre eating and drinking habits, and abnormal GH stimulation tests usually return to normal upon the patient's removal from a negative home environment.
ENDOCRINE CAUSES OF SHORT STATURE
Endocrine causes of short stature are glucocorticoid excess, thyroid hormone deficiency, poorly controlled diabetes, sexual precosity, and iatrogenic causes. Thyroid hormone deficiency has nonspecific symptoms such as weakness, lethargy, decreased appetite, cold intolerance, constipation, dry skin, mild-to-severe obesity, and developmental delay age <2 years. These children have short stature, females may have galactorrhea, delayed or precocious puberty, and sella turcica enlargement.
Iatrogenic causes can be from drugs, such as high-dose estrogens, high-dose androgens, glucocorticoids, methylphenidate, and dextroamphetamines. Poorly controlled diabetes causes increased levels of counterregulatory hormones including GH and can result in low insulin-like growth factor-1 (IGF-1) levels. It is important to note that impaired growth only occurs in patients with poorly controlled diabetes. Alternatively, optimal glycemic control can increase IGF-1 and decrease GH levels.
GHD or nonresponsiveness and IGF-1 deficiency or nonresponsiveness cause short stature (Figure 1). GH deficiency etiologies can be congenital/genetic (decreased secretion, resistance/nonresponsiveness) or acquired (decreased secretion resistance/nonresponsiveness. Hereditary causes are multiple pituitary hormone deficiency—the most common form is caused by paired-like homeobox 1 gene mutations. Embryologic causes are associated with midline central nervous system (CNS) defects with septo-optic dysplasia being the most severe phenotype caused by HESX homeobox 1 gene mutations. Acquired disease is typically organic in nature (infiltrative disease, trauma, irradiation, inflammatory/autoimmune disease), accounting for 13% of all GH deficiency. In pediatric populations, 13% of all GH deficiency is organic, with 54% attributable to a CNS tumor.
GH resistance can be classified as either primary GH insensitivity or acquired GH insensitivity. Primary GH insensitivity symdromes are associated with hereditary/congenital defects. They can be quantitative and qualitative GH receptor defects—such as Laron-type dwarfism—postreceptor defects, or primary defects in IGF-1 synthesis. Acquired GH syndromes are characterized by antibodies to GH or its receptor or a GH insensitivity due to liver disease or malnutrition.
Patients with Laron-type dwarfism experience greatly reduced IGF-1 and IGF-BP3 levels and elevated GH levels. It can be treated with high-dose GH and IGF-1.
WHEN TO EVALUATE
Auxologic findings of suspected growth abnormalities include abnormally slow growth rate, downwardly crossing height percentiles after age 2 years, height significantly below genetic potential, and height <3rd precentile. To make a diagnostic evaluation, physicians must perform a history and physical examination, conduct radiographic studies, laboratory tests (blood and urine), and endocrine stimulation tests.
Some considerations to bear in mind when initially approaching the diagnosis of suspected growth abnormalities are pregnancy history, general history, growth history, and family history (Table 3).
The physical exam must include accurately measured and plotted height and weight assessment, head circumference, assessment of body proportions (upper:lower segment ratio), pubertal status, and syndrome-associated features. Radiographic studies of suspected growth abnormalities should include skeletal age and pituitary imaging if indicated. Skeletal age investigation provides information on maturation delay or acceleration, as well as potential for future growth. Pituitary imaging studies include a lateral skull radiograph for signs of calcifications and head computed tomography or magnetic resonance imaging (MRI) for anatomical evaluation of the hypothalamus and pituitary gland. Common abnormalities of pituitary-hypothalamic structure as observed on MRI are severe hypoplasia of sella turcica and pituitary gland with absence of normal T1-weighted post- pituitary, absence or severe hypoplasia of pituitary stalk, or nodular T1-weighted hyperintensity at the level of the infundibulum.
LABORATORY EVALUATION OF GROWTH FAILURE
The following are initial screening studies to be conducted in the evaluation of growth failure: complete blood count; erythrocyte sedimentation rate; electrolytes and serum chemistry panel; thyroid function studies (free thyroxine and thyroid-stimulating hormone [TSH]); urinalysis and renal function tests; IGF-1, IGF-binding protein 3 [IGFBP3], and GH-BPs; karyotype/chromosomes (females); and celiac disease antibodies.
Indications for assessment of GH secretion are neonatal hypoglycemia or microphallus, inadequate growth rate, growth failure after cranial irradiation, and decreased IGF-1/IGFBP3 levels.
PATIENT IDENTIFICATION FOR THERAPY
It is cumbersome and expensive to assess GH secretion, and there is no definitive test for GH deficiency.7 Therefore, the diagnosis is based on a combination of clinical and laboratory data, with the initial screening based on auxologic data and associated physical findings or organic deficits. Then, patients with physical criteria consistent with GHD should undergo screening tests and GH-stimulation testing.
Table 4 shows the efficiency of provocative GH testing. Criteria for the diagnosis of GHD has changed over the years. With regard to GH secretion, GH should be measured every 5 to 30 minutes for 24 hours. In the late 1960s, normal GH response was thought to be 5 ng/mL. By the 1970s, peak GH was considered 7 ng/dL, and in the late 1980s, it was 10 ng/mL. GH secretion assessment is performed through physiologic tests, exercise stimulation, sleep, urinary excretion, and serial sampling.
GHD THERAPY
Human GH (hGH) was first used in 1958, however, it was in very limited supply. In 1962, the National Pituitary Agency was established, and at that time, 3,000 patients were being treated with hGH—only about half of eligible patients. In 1985, Jakob-Creutzfeldt infection occurred from hGH treatment, prompting the introduction of recombinant hGH (rhGH) later that year. By 1986, 6,000 patients were being treated with rhGH.
Today, GH therapy is Food and Drug Administration approved for GHD (pediatric in 1985, adult in 1997); growth deceleration in chronic renal failure (1996); Turner's syndrome (1997); Prader-Willi syndrome (2000); children who are small for gestational age or with intrauterine growth restriction who fail to catch up by age 2 years; idiopathic short stature (2003); and Noonan syndrome (2007).
The current perspective on the diagnosis of GH deficiency or inadequacy is that the patient must have demonstrated inadequate GH secretion on at least two diagnostic tests, inadequate growth rate, bone age X-rays that indicate residual growth potential, and all other etiologies ruled out. There are contraindications to GH therapy. For example, GH should not be used in patients with closed epiphyses or in those with active neoplasia, and GH therapy should be discontinued if evidence of neoplasia develops. Somatropin when reconstituted with bacteriosatic water for injection, USP (benzyl alcohol preserved) should not be used in patients with a known sensitivity to benzyl alcohol.
Endocrinologists should be aware of the safety concerns associated with GH therapy. These are glucose intolerance, peripheral edema/lymphedema, intracranial hypertension, slipped capital femoral epiphysis, and secondary neoplasms (following solid tumors). The theory that GH therapy is associated with leukemias has been disproven.
PUBERTY AND PUBERTAL DISORDERS
Puberty (Figures 2 to 4) is defined as the stage of development in which sexual maturation and growth are complete, and therefore, individuals have the capacity to reproduce. For girls, the average age of onset is 10 to 11 years (range, 8–13 years), and for boys, it is 11 to 12 years (range, 9–14 years). The initial sign of puberty in girls is breast development and testicular enlargement (volume, >3.0 cm3, length >2.5 cm) in boys. The average age of menarche has been decreasing.8 In 1963 to 1970, the average age was 12.75 years, in 1988 to 1994, it was 12.53 years, and in 1999 to 2002, it was 12.34 years.
Delayed puberty. Delayed puberty is considered when there are no signs of breast development in females aged >13 years, no signs of testicular enlargement in males aged >14 years, when puberty begins but does not progress appropriately, and when >5 years have lapsed between the first signs of puberty and menarche. Etiologies of delayed puberty in boys and girls are either constitutional delay (accounts for 50% in males, 20% in females), gonadal pathology (10% males, 40% females), hypothalamic-pituitary (30% males, 30% females), and systemic pathology (10% for both).
Gonadal pathology consists of primary hypogonadism (hypergonadotrophic hypogonadism with increased leutinizing hormone [LH] and follicle-stimulating hormone [FSH] levels) or secondary or central hypogonadism (hypogonadotrophic hypogonadism with decreased LH/FSH.
Primary amenorrhea. Primary amenorrhea is uncommon, affecting fewer than three out of 100 girls. Constitutional delay is the most common etiology, and clinicians must always first consider pregnancy. Etiologies of primary amenorrhea include primary ovarian pathology (eg, gonadal dysgenesis, including Turner syndrome, polycystic ovary syndrome [PCOS], idiopathic hypogonadism, postradiation/chemotherapy ovarian failure, and autoimmune hypogonadism), genital tract anomalies, androgen insensitivity/testicular feminization, hypothalamic-pituitary hypogonadism (acquired or congenital), stress, other endocrinopathies, and medications.
Evaluation of the patient will include a physical exam (ie, pubertal status, external genitalia, signs of virilization), laboratory tests (ie, qualitative human chorionic gonadotropin; prolactin, TSH, gonadotrophins), adrenal androgens if evident virilization, karyotype if Turner stigmata is present, a pelvic sonogram, and a Pap test and screen for sexually transmitted diseases if the patient is sexually active.
Patient management should begin with reassurance and education, a progesterone challenge with medroxyprogesterone (Provera, [UpJohn and Pharmacia] by mouth daily for 5 days or one intramuscular injection). If no withdrawal bleeding within 7 to 10 days after the challenge, proceed with full evaluation. If withdrawal bleeding occurs, observation is appropriate but oral contraceptives may be started.
Evaluation of delayed puberty. The evaluation of delayed puberty should include:
- Leutinizing hormone releasing hormone (LHRH)/gonadotropin-releasing hormone (GnRH) stimulation test,
- Administration of IV LHRH,
- LH and FSH are then measured for 120 minutes after LHRH.
Adequate responses are defined as five to 10 times LH or two to three times FSH elevation above baseline. Note that menstrual bleeding may occur 1 to 2 days after the test.
Again, treatment of delayed puberty should begin with supprt and reassurance. The clinician is charged with preventing the potential short- and long-term psychological, personality, and social handicaps associated with delayed puberty. The physician should consider a short course of sex steroid hormone supplementation. If a permanent condition is apparent, sex steroid hormone replacement is definitely indicated.
Treatment of hypogonadism. In girls, treatment involves daily ethinyl estradiol for the first 21 days of the month, until breakthrough bleeding occurs. At this time, start cycling with a progesterone agent on days 12 to 21 of the month to mimic a normal menstrual period. Alternatively, an estradiol patch 0.0375—0.1 mg twice weekly plus progesterone cycling when appropriate is prescribed.
In boys, testosterone esters, such as enanthate and cypionate are given intramuscularly every 2 to 4 weeks. Androderm (Watson) is a daily nonscrotal testosterone skin patch, and Androgel (Solvay) and Testim (Auxillium) are gel preparations.
PRECOCIOUS PUBERTY
Precocious puberty is when puberty begins early and progresses early. It should be noted that the onset of puberty is beginning earlier. The traditional definition is before age 8 years in girls and less than 9.5 years in boys. The idiopathic type is the most common, and upon evaluation, height age, weight age, and bone age will all be advanced. Early closure of epiphyseal growth plates in these patients results in adult short stature below genetic potential.
Gonadotropin (Gn)-dependent precocious puberty involves the premature activation of the hypothalamic-pituitary-gonadal axis. Gn-independent precocious puberty involves the secretion of sex steroids independent of pituitary Gn release (Figure 7).
Differential diagnosis. GnRH-dependent precocious puberty can be idiopathic in nature, due to CNS lesions (hypothalamic hamartoma or malignancies), secondary to GnRH-independent precocious puberty, ectopic chorionic gonadotropin (hCG)-secreting tumor, or from miscellaneous causes.
The diagnosis involves adrenal and gonadal tests. Adrenal tests include congenital adrenal hyperplasia (21-hydroxylase or 11-hydroxylase deficiency) and gonadal tests for McCune-Albright syndrome (somatic mutation in GNAS1) or testotoxicosis (activating mutation of LH receptor).
Diagnostic evaluation will include a history and physical exam of height, weight, arm span, upper:lower segment ratio, skin, hair, thyroid and neurological findings, breast and pubic hair staging, an inspection of vaginal mucosa, and testicular size. Hormonal testing will include baseline elevation of FSH and FSH response to GnRH provocative testing.
LH levels are consistent with early puberty (LH/FSH ratio > 1.0), estradiol/testosterone levels may rise to the early pubertal range, TSH to rule out hypothyroidism, plasma 17hydroxyprogesterone and dehydroepiandrosterone sulfate (DHEAS). Other tests can include bone age/skeletal survey, a pelvic ultrasound, and an MRI of the brain.
Males and females receive the same evaluation, except for in males, add testosterone, 17-OH progesterone, beta hcg, and specialized testing for LH-receptor mutation.
THERAPY
Therapy should treat the underlying cause of precocious puberty with a GnRH analogue (leuprolide acetate [Lupron, Abbott Labs], histrelin acetate [Supprelin, Indevus]). Therapy should be monitored by testing plasma estradiol/testosterone levels, evaluating growth velocity, and checking for breast/testicular size regression.
PREMATURE ADRENARCHE
Premature adrenarche is defined as the development of pubic hair before age 7 years in white girls and age 6 in black girls. Early maturation of the adrenal zona reticularis should be checked, and these children will have higher levels of basal and stimulated DHEA levels compared with prepubertal children.
Linear growth velocity and skeletal maturation is slightly advanced in these children, and acne and axillary odor may be present. There will be no evidence of systemic virilization. The clinician must exclude adrenal neoplasm and enzymatic defects.
The patient history will include a racial and ethnic background, with intrauterine growth restriction, family history of type 2 diabetes, hypertension, and PCOS putting patients into a higher risk group. Twenty percent of patients who have precocious puberty present with premature adrenarche. A baseline bone age should be obtained and androgens tested (DHEAS, androstenedione, 17-OH progesterone, free testosterone, fasting lipid panel, sex hormone–binding globulin). Radiographic imaging to rule out CNS or adrenal pathology should be reserved in a minority of cases.
Premature adrenarche is found independent of the hypothalamic pituitary gonadal axis and a biochemical evidence can be seen as early as 6 years in normal children (increased basal DHEAS, relative increase in adrenocorticotropic hormone). The mechanism is not known.
PREMATURE THELARCHE
Premature thelarche may be symmetrical or unilateral and is not accompanied by other signs of puberty. The child will have normal estrogen levels and height, bone age is normal or slightly advanced, ovarian cyst is rare, and it may be the first sign of precocious puberty.
Katrina L. Parker, MD, is Director, Pediatric Endocrinology, at the University of Texas Medical Branch Galveston. She may be reached at kaparke1@utmb.edu.
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