During childhood, linear growth is one of the most sensitive markers of health. Normal growth is the integrated response to numerous stimulatory and inhibitory signals. A body of evidence suggests growth occurs as a discontinuous process known as saltatory growth. Saltatory growth can be envisioned as frequent small increments in growth separated by periods of no growth. As the ratio of stimulatory to inhibitory signals increases, these saltatory steps occur more frequently and, possibly, with greater magnitude, resulting in an increased growth velocity.
Linear growth velocity in healthy children varies significantly with age and pubertal status. This is illustrated by the growth velocity curves (Figure 1, see page 178).' Peak growth velocity of 25 cm per year occurs during the first year of life. The growth rate slows considerably during the second year of life and gradually reaches a prepubertal rate of 5 to 6 cm per year by ages 6 to 7. Growth velocity slows to its prepubertal nadir in the year prior to the onset of the pubertal growth spurt.
During puberty, the growth velocity rises to a robust 9 cm per year. This pattern of growth is seen in most healthy children. However, numerous conditions affect this growth pattern. In addition, there are normal variants of growth. One important normal variant growth pattern is constitutional delay. Constitutional delay represents a pattern of growth delay beginning as a toddler associated with delayed or prolonged pubertal growth response. Children exhibiting this pattern of growth are typically termed "late bloomers." This growth pattern seems to be heritable, as there is commonly a family history of similar growth patterns. The causes of this growth pattern are not known.
GROWTH HORMONE AXIS
Linear growth in humans is regulated by many hormonal factors. These factors include growth hormone (GH), insulin-like growth factors (IGFs), thyroid hormone, and sex hormones. GH is secreted by the pituitary gland in a pulsatile fashion. GH secretion is stimulated by GH-releasing hormone, produced in the hypothalamus, and ghreHn, produced in the stomach and hypothalamus. Growth hormone release is inhibited by somatostatin, also produced in the hypothalamus.
GH promotes linear growth through actions at the liver and the epiphyseal growth plate. In the liver, GH stimulates the secretion of IGF-I and its carrier proteins, IGF binding protein-3 and acid labile subunit. These carrier proteins prolong the half-life of IGF-I and facilitate its transport to target tissues.
Because of the pulsatile nature of GH secretion, random measurements of GH are not useful in assessing the activity of the GH axis. Measurement of GH by frequent serum sampling has been shown to be a useful predictor of GH function. However, this method is not easily applicable to clinical practice. Measurement of serum IGF- 1 levels can provide a useful assessment of the GH axis. Because the serum half-life of IGF-I is longer than that of GH, IGF-I provides an estimate of GH function. IGF-I values show a slow increase during childhood, with peaks during the pubertal growth spurt. This pattern is similar to the post-infantile linear growth curve. Both IGF-I and GH have growth-promoting actions at the local tissue level, including the growth plate.
Short stature may be defined using statistical analysis of the distribution of heights at various ages. A person with short stature has a height more than two standard deviations below the mean (-2 SD or below). By this definition, approximately 2.5% of children have short stature. The most recent growth charts use data from Third National Health and Nutrition Examination Survey and are available through the Centers for Disease Control and Prevention.2
Growth Velocity Curve Boys)
Numerous studies have shown children and adults affected by short stature are at a disadvantage compared with their peers. During childhood, short children are at risk for being ostracized by their peers and juvenilized by adults.3-4 Studies have shown short stature in adults affects the social and economic arenas. Short adults have a reduced marriage rate and lower-perceived competence. Short adults are also more likely to be injured in car accidents, because safety devices are designed for average-sized people.5
IDIOPATHIC SHORT STATURE
Idiopathic short stature (ISS) is, by definition, short stature without a known etiology. This definition excludes the known causes of short stature, which include various forms of GH deficiency, certain genetic conditions such as Turner and Noonan syndromes, skeletal dysplasias such as achondroplasia, and chronic illnesses such as renal failure and inflammatory bowel disease. (See Sidebar 1, page 179.) ISS also excludes normal variations in growth pattern, such as constitutional delay of growth and development.
ISS includes familial and non-familial short stature, which likely are caused by a number of different mechanisms. As further research identifies new causes of short stature, small subsets of the ISS group will be removed from this category. Therefore, we are limited in our ability to describe the cause of short stature in children with ISS by the current diagnostic tools.
One condition that could be considered a component of ISS is GH neurosecretory dysfunction. This condition can best be diagnosed by low cumulative GH levels measured in frequent serum samples during a period of 12 to 24 hours. Application of this test to a population of children with short stature in the clinical setting is not practical. As such, this cause of short stature can be missed by the current, clinically-relevant, diagnostic tools. Short stature associated with intrauterine growth retardation could also be categorized as a form of ISS, though this type of short stature is now a separately approved indication by the Food and Drug Administration (FDA) for GH treatment.
The most important diagnostic tools for the evaluation of short stature continue to be a thorough history and physical examination. The history should include a number of areas: birth history including birth weight, growth patterns of the patient and family members, clues suggesting pituitary or thyroid dysfunction, psychosocial or nutritional deprivation, and symptoms of chronic illness. Examination of the growth chart and determination of parental height are crucial components of the history. The physical examination should focus on the presence of dysmorphisms suggestive of chromosomal abnormalities or syndromes, midline defects such as cleft palate and bind uvula, body proportions, signs of chronic illness, and features of endocrine abnormality, such as myxedema or Cushingoid features. Laboratory screening for chronic illness should include a hemogram, electrolytes, calcium, phosphorus, creatinine, liver function tests, erythrocyte sedimentation rate, albumin, urinalysis, and stool for ova, parasites, and excess fat. Because of the importance of thyroid hormone in normal growth and the frequency of hypothyroidism in children, thyroid function should be evaluated by measuring free thyroxine and thyroid-stimulating hormone. Screening for celiac disease with antibody to tissue transglutaminase may also be considered. Further screening may be directed by the history and physical examination.
Growth velocity should be monitored for a period of 6 months, with careful attention to accuracy of height measurements. A bone-age radiograph of the left hand and wrist should be obtained. The bone age is extremely delayed in severe hypothyroidism and significantly delayed in children with GH deficiency and constitutional delay of growth and development. Bone age is equivalent to chronologic age in children with familial short stature and primordial short stature.
IGF-I and IGFBP-3 levels in serum have been used as screens of GH function. The relative plasma half-lives of these compounds provide an estimate of integrated GH secretion. Children with IGF-I levels greater than -1 SD are unlikely to have GH deficiency.6 Low levels of IGF-I and IGFBP-3 are accepted by some as sufficient evidence of GH deficiency in the absence of hypothyroidism and under-nutrition. The presence of random GH levels greater than 10 ng/mL in an individual with low IGF-I would suggest GH resistance and would eliminate consideration of GH-stimulation testing.
GH-stimulation testing has been used as a measure of GH deficiency. Peak GH responses less than 10 ng/mL, after provocation by two separate stimuli, are diagnostic of GH deficiency. GH-stimulation testing has been fraught with problems of poor reproducibility, low specificity, and low sensitivity. Testing children with poor growth multiple times has produced conflicting results. In addition, children with normal growth have had abnormal test results. Finally, a number of patients with slow growth, low levels of IGF-I, and low integrated GH levels have had normal results on provocative GH testing.
Therapy with recombinant human growth hormone (rhGH) was approved in 1985 for short stature caused by GH hormone deficiency. Since then, rhGH has been approved for the treatment of short stature in five non-GH-deficient conditions: Turner Syndrome, short stature in patients with intrauterine growth retardation, chronic renal insufficiency, short stature in Prader-Willi syndrome, and idiopathic short stature.
The use of rhGH in ISS has been the focus of both ethical and financial controversies. Multiple natural history studies report that children with ISS will have short stature as adults. Hintz et al.7 showed GH treatment in children with ISS resulted in an increase in final height of 5 cm when compared with predicted height. A larger increase of 9 cm was seen when the final height of treated patients was compared with historical controls. Finkelstein et al.8 performed a meta-analysis of GH therapy in 40 patients with ISS and concluded adult height was increased by 4 to 6 cm in those treated with GH. However, they estimated the cost of treatment at $35,000 per inch.
In May 2003, the FDA approved the use of rhGH in ISS. To obtain approval for this indication, a placebo-controlled trial of rhGH upon final height was performed. The results of this trial showed a small but convincing effect of rhGH on final height.9 Subsequent final height trials with higher doses and more frequent administration showed increases in final height of 7 cm above pre-treatment predicted height. In addition, more than 90% of participants achieved heights in the normal range. The fact that patients with ISS respond to rhGH therapy suggests that the etiology of ISS may be inadequate GH secretion or inadequate GH action that can be overcome by supra-physiologic GH doses.
GH has been used to treat patients with GH deficiency since the 1960s. GH was originally extracted from cadaveric pituitary glands. In 1985, several cases of Creutzfeldt-Jakob disease were identified and attributed to pituitary-derived GH.10 That year, recombinant human growth was approved by the FDA. Because of the concern about Creutzfeldt-Jakob disease, and because mGH was a product of a new technology, recombinant DNA technology, the makers of mGH were required to develop surveillance studies to monitor adverse events in rhGH-treated patients.
Overall, these studies have demonstrated the safety of rhGH. Concerns that have arisen about GH promoting malignancy have been greatly reduced by the results from these large surveillance databases.11 Recently, the deaths of seven children with Prader-Willi Syndrome have raised concern about GH therapy for this condition. However, the role that GH therapy played in these deaths is difficult to determine. Known side effects and complications of GH include injection site discomfort, musculoskeletal pain, reduced insulin sensitivity, pseudotumor cerebri, progression of scoliosis, and hypothyroidism.
Idiopathic short stature represents a group of conditions that are not definable by current biochemical criteria but usually respond to GH therapy. Natural-history studies confirm adult height will be short in untreated ISS individuals. Children and adults with short stature have disadvantages compared with their peers. The evidence for benefit from treatment of children with idiopathic short stature is strong. Numerous studies, now including a placebo-controlled study, have demonstrated the positive effect of GH treatment on final height. The effect of GH treatment is quantitatively similar to results seen in other non-GH-deficient conditions. Although currently very expensive, rhGH treatment is relatively safe.
GH treatment of children with idiopathic short stature should not be withheld because of our inability to explain the etiology or because of the inadequacy of our current diagnostic tests. Continued efforts to delineate specific causes of poor growth in ISS individuals may result in our being able to predict subsets of individuals who will respond well to GH and subgroups who may be considered for other treatments, such as IGF-I or a combination of IGF-I and IGFBP-3.
1. Tanner JM, Davies PS. Clinical longitudinal standards for height and height velocity for North American children. J Pediatr. 1985; 107(3):317-329.
2. National Centers for Health Statistics. 2000 CDC Growth Charts; United States. Available at: http://www.cdc.gov/growthcharts. Accessed January 9, 2003.
3. Sandberg DE, Kranzler J, Bukowski WM, Rosenbloom AL. Psychosocial aspects of short stature and growth bormone therapy. J Pediatr. 1999;135(1):133-134.
4. Voss LD, Mulligan J. Bullying in school: are short pupils at risk? Questionnaire study in a cohort. BMJ. 2000;320(7235):612-613.
5. Beuse NM, Hollowell WT, Summers L, et al. The 5(th) percentile dummy in a 56 kmph full-frontal barrier crash test. Anna Proc Assoc Adv Automat Med. 2002;46: 387-409.
6. Hintz RL. Management of disorders of size. In: Molecular and Cellular Pediatrie Endocrinology. Handwerger S, ed. Totowa, NJ: Humana Press; 1999:124-139.
7. Hintz RL, Attie KM, Baptista J, Roche A; Genentech Collaborative Group. Effect of growth hormone treatment on adult height of children with idiopathic short stature. JV Engl J Med. 1999;340(7):S02-507.
8. Finkelstein BS, Imperiale TF, Speroff T, et al. Effect of growth hormone therapy on height in children with idiopathic short stature: a meta-analysis. Arch Pediatr Adolesc Med. 2002;156(3):230-240.
9. Cutler G, Enas G, Hintz R, Quigley C, MacGillivray M. Humatrope® (somatropin [rDNA origin] for injection) treatment of pediatrie patients with non-growth hormone-deficient short stature. Presented at: Food and Drug Administration Fjidocrinologic & Metabolic Drugs Advisory Committee meeting. June 10, 2003. Available at: http://www.fda.gov/ohrms/ dockets/ac/03/slides/3957S 1 .htm. Accessed January 9, 2003.
10. Hintz RL. The prismatic case of CreutzfeldtJakob disease associated with pituitary growth hormone treatment. J Clin Endo Metab. 1995;80(8):298-2301.
11. Maneatis T, Baptista J, Connelly K, Blethen S. Growth hormone safety update from the National Cooperative Growth Study. J Pediatr Enáocrinol Melab. 2000;13(Suppl 2):1035-1044.