AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Short stature may be the normal expression of genetic potential, in which case the growth rate is normal, or it may be the result of a condition that causes growth failure with a lower-than-normal growth rate. Growth failure is the term that describes a growth rate below the appropriate growth velocity for age.

A child is considered short if he or she has a height that is below the fifth percentile; alternatively, some define short stature as height less than 2 standard deviations below the mean, which is near the third percentile. Thus, 3-5% of all children are considered short. Many of these children actually have normal growth velocity. These short children include those with familial short stature or constitutional delay in growth and maturation. In order to maintain the same height percentile on the growth chart, growth velocity must be at least at the 25th percentile. When considering all children with short stature, only a few actually have a specific treatable diagnosis. Most of these are children with a slow growth velocity.

Pathophysiology

The most rapid phase of human growth is intrauterine. Following birth, a gradual decline in growth rate occurs over the first several years of life. The average length of an infant at birth is about 20 inches, the length at age 1 year is approximately 30 inches, the length at age 2 years is approximately 35 inches, and the length at age 3 years is approximately 38 inches. After age 3 years, linear growth proceeds at the relatively constant rate of 2 inches per year (5 cm/y) until puberty.

Normal growth is the result of the proper interaction of genetic, nutritional, metabolic, and endocrine factors. To a large extent, growth potential is determined by polygenic inheritance, which is reflected in the heights of parents and relatives. Secretion of growth hormone (GH) by the pituitary is stimulated by growth hormone–releasing hormone (GHRH) from the hypothalamus. Another signal, which is stimulated by certain growth hormone–releasing peptides (GHRPs), may be present; the receptor for the GHRPs has been identified, and a possible natural ligand for these receptors has been determined. Somatostatin secreted by the hypothalamus inhibits GH secretion.

When GH pulses are secreted into the systemic circulation, insulinlike growth factor (IGF)–1 is released, either locally or at the site of the growing bone. GH circulates bound to a specific binding protein (GHBP), which is the extracellular portion of the GH receptor. IGF-1 circulates bound to one of several binding proteins (IGFBPs). The IGFBP that is most dependent on GH is IGFBP-3.

A peptide hormone that stimulates GH release, named ghrelin (from the word ghre, a root word in proto-Indo-European languages meaning grow), has been described. This hormone is unique in that it is a small polypeptide modified at the third amino acid (serine) by esterification of n-octanoic acid. Ghrelin appears to be made in the stomach and stimulates GH secretion by binding with its own receptor, which had previously been known to bind synthetic GHRPs. Ghrelin may play a role in regulation of GH at the hypothalamic level, permitting an adequate energy supply for maintenance, growth, and repair.

Frequency

United States

In 1994, Lindsay et al studied 114,881 school children in Utah.¹ After 1 year, 79,495 of the original group were available for evaluation. Of these, 555 (0.7%) had heights that were below the third percentile and a growth rate that was less than 5 cm/y. When examined further, causes for short stature within this group of children included familial short stature (37%), constitutional delay (27%), a combination of familial short stature and constitutional delay (17%), other medical causes (10%), idiopathic short stature (5%), GH deficiency (3%), Turner syndrome (3% of girls), and hypothyroidism (0.5%).

International

Several studies have been conducted to determine the frequency of various causes of short stature. In 1974, Lacey and Parkin evaluated children in Newcastle upon Tyne in England.² They studied 2256 children, 111 of whom were below the third percentile in stature. Of the 98 children that they were able to examine, only 16 had evidence of organic disease causing their short stature. Diagnoses included Down syndrome, cystic fibrosis, chronic renal insufficiency, GH deficiency, juvenile rheumatoid arthritis (treated with glucocorticoid), and Hurler syndrome.

Mortality/Morbidity

• Short stature has been thought to have far-reaching effects on psychological well-being, including poor academic achievement (despite normal intelligence, healthy family dynamics, and high socioeconomic status) and behavioral problems (eg, anxiety, attention-seeking actions, poor social skills).
• Morbidity related to the underlying cause of the growth failure may also be observed. 
• Some studies involving children who have not been seen in a clinic that treats short stature (and, therefore, may represent a different patient population) have challenged the notion that short stature has psychological implications. At the present time, this issue is not completely resolved.
• Mortality rates in children with growth failure relate to the underlying cause of the growth failure. Mortality is not related to growth failure itself; rather, it is related only to the cause of the growth failure.

Sex

The sex distribution of children treated with growth hormone is about 3 boys for every girl. Recent work in this area suggests that this is mostly due to a referral bias, either from parents themselves or from the referring physician.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

History of those with short stature should focus on the following areas:

• Birth weight and birth length: One of the issues in the differential diagnosis is intrauterine growth retardation, which should be apparent from the birth history.
• Parents' heights: In order to evaluate a child's genetic potential, calculation of the sex-adjusted midparental height (ie, target height) is helpful. The sex-adjusted midparental height is calculated by adding 2.5 inches to (for boys) or subtracting 2.5 inches from (for girls) the mean of the parents' heights; it represents the most statistically probable adult height for the child, based on parental contribution. By calculating the percentile for this midparental target height, one can determine at what percentile a child's height is expected to fall.
• Timing of puberty in parents: Constitutional delay in growth and maturation may have a family history. Most mothers can remember their age at menarche (average age, 12-12.5 y). Eliciting pubertal history from a father is more difficult because no specific landmark is recognized. Evidence of delayed puberty may include continuing to grow after high school or not shaving until age 20 years or older.
• Previous growth points
• • The most useful part of a workup for growth failure is observing the growth pattern. Previous growth data may be obtained from physicians' offices, schools, or marks that have been kept on a door or wall at home.
  • If the growth rate is normal (approximately 2 inches/y [5 cm/y] from age 3 y to puberty), the cause of the child's short stature is likely one of the normal variants, and the child does not actually have growth failure.
  • If the growth rate is low, growth failure is present, and a pathological cause for the growth failure is more likely.
  • Children with constitutional delay in growth and maturation often appear to be growing slowly just before the pubertal growth spurt; they may be confused with children who have actual growth failure.
• The child's general health: Ruling out a chronic disease or poor nutrition as a cause of growth failure is important. Worldwide, malnutrition is probably the most likely cause of growth failure.

Physical

The following items in the physical examination are targeted toward assessing growth failure:

• Height (or length) and weight: A determination of weight is not difficult; height (standing) or length (lying down) should be measured with care. Using a single steady stadiometer and obtaining more than one measurement provides accurate values.
• • Taking accurate measurements of length requires attention to the following:
  • • An accurate measuring device should be used. For infants, the device should consist of a board with a yardstick attached (or embedded), a stationary head plate, and a movable footplate.
    • Gently stretch the child. The heels, buttocks, shoulders, and the back of the head should touch the base of the device, and the soles of the feet should be perpendicular to the base of the device.
    • Repeating the measurement 2-3 times (and taking an average of these measurements) improves the accuracy of the measurement.
  • When taking height measurements, the following should be addressed:
  • • Always have the child barefoot or in stocking feet. The heels, buttocks, and shoulders should be in contact with the wall or the measuring device.
    • The child should be standing with heels together, feet slightly spread.
    • The child should look straight ahead. This is called having the head in the Frankfurt horizontal plane, which is a plane represented in the profile by a line between the lowest point on the margin of the orbit and the highest point on the margin of the auditory meatus.
    • At the time of the measurement, have the child hold a deep breath.
    • Use proper equipment. The ideal device for height measurement is a stadiometer, which may be mounted on the wall, with an arm that moves vertically. The arm is placed on the head, and the height can be read from a counter or from a ruler on the wall. If a stadiometer is not available, good height measurements may be obtained from a yardstick (or meter stick) attached to the wall and a device that makes a right angle with the wall and the child's head. The floppy arm devices mounted on weight scales are inherently variable and frequently yield inaccurate measurements. A height measurement can be determined using this device, but even more attention is required.
    • For precise height determinations, measure the child 2-3 times and take the mean. If the first 2 measurements agree, they should be considered accurate.
    • In order to minimize diurnal variation in height, always measure the child at the same time of day.
• Proportionality: Inspect the child for proportionality of limbs and trunk. If disproportion is suspected, the following measurements may be taken:
• • Arm span: Measure outstretched arms from fingertip to fingertip. In children of European origin, the arm span should approximate the height. In comparisons of people of Asian, European, and African heritage, Asians had proportionally shorter arms, Europeans had intermediate-length arms, and Africans had significantly longer arms.
  • Lower segment (LS): Measure from the symphysis pubis to the floor.
  • Upper segment (US): Subtract the LS from the height.
  • The US/LS ratio is calculated by dividing the US by the LS. In children of European origin, this ratio is about 1.7 at birth and decreases to 1 at about age 10, where it remains throughout adulthood. In comparisons of people of Asian, European, and African heritage, Asians had proportionally shorter legs (therefore, larger US/LS ratios), Europeans had intermediate length legs, and Africans had significantly longer legs.
• Pubertal status: Puberty should be staged using the Tanner staging system. In constitutional delay as well as many pathological causes of short stature (including GH deficiency), puberty is delayed.
• Look for signs of specific syndromes: A number of specific syndromes exist that include short stature and slow growth velocity.
• • For Turner syndrome, look for webbing of the neck (pterygium colli), a wide carrying angle (cubitus valgus), a low hairline, a high-arched palate, short fourth metacarpals, and multiple nevi.
  • Noonan syndrome and Russell-Silver syndrome, among others, should be considered.
  • Examine for disproportion of limbs to trunk when considering the possibility of skeletal dysplasias.
  • Other syndromes may be present as well.

Causes

The following are possible causes of growth failure (slow growth velocity):

• Familial short stature: Children with familial short stature have a history of parents with short stature. They have a normal growth velocity (thus, they do not exhibit true growth failure). Bone age is not delayed. These children have puberty at a normal time and most often finish their growth with a short adult height.
• Constitutional delay in growth and maturation: This entity is sometimes called delayed puberty. Children with constitutional delay have a normal birth weight, and during the first year of life, their growth slows. For most of the period of linear growth (approximately age 3 y to puberty), they maintain an adequate growth velocity. Bone age is usually delayed, and puberty is late, giving a longer time for prepubertal growth, which usually results in a normal adult height. Children with constitutional delay may have a family history of the same. Usually, these children do not exhibit growth failure (a slow growth velocity); however, a period of slow growth velocity usually occurs during the first year of life, and, just before the onset of puberty, growth velocity is again slow (especially when compared with peers who are in the midst of their pubertal growth spurt).
• Malnutrition: Worldwide, malnutrition is probably the most common cause of growth failure and is usually poverty related. In developed countries, nutritional deficiencies are more often the result of self-restricted nutrient intake. Often, poor weight gain is more striking than short stature.
• Chronic disease, systemic disorders
• • Nervous system: Microcephaly may be a feature.
  • Circulatory system: Cyanotic heart disease may be present.
  • Gastrointestinal system: Gluten enteropathy, ulcerative colitis, or regional enteritis (Crohn disease) may be present. In inflammatory bowel disease (in particular, Crohn disease), the growth failure may be apparent before other symptoms appear.
  • Liver, chronic renal failure: People with renal tubular acidosis may present with growth failure without any other features.
  • Lungs: Cystic fibrosis may be present.
  • Connective tissue: Dermatomyositis may be present.
• Psychosocial dwarfism
• Chromosomal abnormalities: In particular, Turner syndrome (45,X) and Down syndrome (trisomy 21) have growth failure as a part of the syndromes. Growth charts specific for these syndromes are available.
• Other syndromes (nonchromosomal): Syndromes that have growth failure as a feature include Noonan syndrome, Russell-Silver syndrome, and Prader-Willi syndrome.
• Target tissue defects
• • Intrauterine growth retardation: The category of intrauterine growth retardation describes children who have birth weights less than 5.5 lb at full term or who are small for gestational age (SGA) if born preterm. Numerous etiologies for this condition are contained in this category, including fetal alcohol syndrome and placental insufficiency syndromes. In some of these conditions, spontaneous "catch-up" growth occurs, while in others, growth rate remains slow.
  • Bone and cartilage disorders: The most common disorder of bone and cartilage is achondroplasia, which is recognizable by frontal bossing, lumbar lordosis, and short limbs. Other skeletal disorders are less easily recognized, such as hypochondroplasia, which may be diagnosed radiologically. Patients with hypochondroplasia also have short limbs, but the disproportion is subtle and may be apparent only with careful measurements of arm span and US and LS. Both of these disorders are due to mutations of the fibroblast growth factor receptor 3.
• Endocrine causes
• • Thyroid hormone deficiency (hypothyroidism): Thyroid hormone is absolutely necessary for normal growth. With hypothyroidism, the growth rate is extremely slow, and with replacement of thyroid hormone, catch-up growth is rapid. Although hypothyroidism is often suspected based on history and physical examination findings, cases have also been reported in which the signs and symptoms are subtle. Because of the possibility of subtle signs, evaluation of thyroid hormone levels in all children with slow growth is advised.
  • GH deficiency: Children who are GH deficient have normal proportions but may appear younger than their age. They have delayed skeletal maturation. Although GH deficiency may be suspected because of damage or malformation of the pituitary gland, in most children diagnosed with GH deficiency, the etiology is idiopathic.
  • GH insensitivity (primary IGF-1 deficiency): Sometimes called Laron dwarfism, this disorder appears to be similar to GH deficiency, except that large amounts of GH are produced but levels of IGF-1 are low. This is a rare condition, except in populations where the gene is present with a greater frequency (eg, in Ecuador).
  • Glucocorticoid excess (Cushing syndrome, Cushing disease): Children with glucocorticoid excess almost always have growth failure as part of the presentation.
  • Androgen excess: When prepubertal children are exposed to excessive amounts of androgen, the growth velocity increases in the short term, but epiphyseal fusion occurs early, resulting in premature slowing of growth velocity, usually resulting in a short adult height. Causes of androgen excess include exposure to exogenous androgen, precocious puberty, and congenital adrenal hyperplasia.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Glucocorticoid excess (Cushing syndrome), endogenous and exogenous

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Thyroxine (T4) and thyroid-stimulating hormone (TSH): T4 and TSH levels are important to rule out hypothyroidism and to screen for panhypopituitarism as a cause for short stature and growth failure.
• Serum electrolytes: A low bicarbonate level may indicate renal tubular acidosis, which can result in growth failure. Electrolyte levels out of the reference range may indicate renal failure. Hypokalemic alkalosis may indicate Bartter syndrome.
• CBC count and sedimentation rate: These tests may be helpful if inflammatory bowel disease is suspected.
• IGF-1 and IGFBP-3: Both IGF-1 and the binding protein IGFBP-3 are GH dependent. Low values suggest GH deficiency. However, they are also sensitive to other factors such as nutritional state, so a low value alone is not diagnostic of GH deficiency.
• Karyotype: Girls with otherwise unexplained short stature should have karyotype determined to rule out Turner syndrome. Although Turner syndrome is diagnosed in many girls from signs present on physical examination, some girls with Turner syndrome have short stature as the only recognizable feature. In particular, girls with mosaic karyotypes or karyotypes with isochromosomes tend to exhibit fewer signs specific to Turner syndrome.

Imaging Studies

• MRI of the head: Patients who are diagnosed with GH deficiency should undergo MRI of the head to rule out a brain tumor, such as a craniopharyngioma. As many as 10% of children diagnosed with a craniopharyngioma present with growth failure as the only sign. Also, approximately 15% of patients with GH deficiency have an abnormality of the pituitary gland, such as an ectopic bright spot, an empty sella, or a small sella.
• Bone age determination: A radiograph of the left wrist can be compared with standards to provide an estimation of skeletal maturation. Bone age also provides a determination of growth potential (predicted adult stature may be estimated from the tables of Bayley and Pinneau).

Other Tests

• GH provocative testing: GH response to insulin is considered the most reliable test for GH deficiency. For recognition of the diagnosis of GH deficiency, many insurance companies require documenting a failure to demonstrate a GH response (with a GH level >10 ng/mL) to 2 provocative stimuli. Provocative stimuli include insulin-induced hypoglycemia, arginine, levodopa (L-dopa), clonidine, and glucagon.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Treatment is directed at the cause of the growth failure. If the child is diagnosed with hypothyroidism, treatment is thyroid hormone replacement. Likewise, if the child is diagnosed with GH deficiency, the treatment is GH replacement therapy. In 2003, the FDA approved the use of GH for children who are not GH deficient but who are at least 2.25 SD below the mean for height, who are unlikely to have an adult height above -2 SD, and who have no explanation for their short stature. This disorder has been termed idiopathic short stature.

Consultations

Although a primary care physician often initiates the workup, the child is usually referred to an endocrinologist for a more detailed investigation of possible causes for growth failure.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

GH is approved by the Food and Drug Administration (FDA) for treatment of growth failure caused by the following: GH deficiency, Turner syndrome, chronic renal insufficiency, intrauterine growth failure with postnatal growth failure, Prader-Willi syndrome, and idiopathic short stature.

Drug Category: Growth Hormone

These agents are used for physiologic replacement of GH deficiency and are used pharmacologically as a growth-promoting agent in patients with Turner syndrome, chronic renal insufficiency, intrauterine growth failure, Prader-Willi syndrome, or idiopathic short stature.

Drug Category: Androgen

Oxandrolone, along with GH, has been used in Turner syndrome to potentiate the growth-promoting effect of GH.

Drug Category: Insulinlike growth factor

IGF-I (mecasermin) has been approved by the FDA for primary severe IGF-I deficiency. Some children with idiopathic short stature may have a degree of growth hormone insensitivity; these children may benefit from treatment with IGF-I. Clinical studies are presently in progress to determine whether this hypothesis is correct.

Drug Category: Gonadotropin Releasing Hormone Analog

Gonadotropin-releasing hormone analog has been occasionally used to try to slow the onset and progression of puberty, thus resulting in a longer time for growth. Studies have demonstrated a small, but statistically significant, increase in predicted adult height. The effect seems to be greater if early puberty is is interrupted with this therapy. Part of the problem of using this therapy is that children who are experiencing short stature are troubled by being different, and delaying puberty beyond a normal point is also making them different from their peers.

Drug Category: Aromatase Inhibitor

Maturation of the skeleton has been shown to be the result of estrogen in both boys and girls. Studies have shown that inhibiting conversion of androgen to estrogen for a period of 2 years may result in increases in adult height prediction by as much as 2 inches. Actual adult height data are pending.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• While the cause of growth failure is being investigated, most practitioners prefer to reevaluate patients at intervals of 3 months. This amount of time also permits repeated growth measurements, which then allows an estimation of growth velocity.

Prognosis

• Prognosis for adult stature depends on the cause of the growth failure. Initiating therapeutic intervention is important before the patient has closure of the epiphyses with the concomitant finishing of the growth process. If a diagnosis of hypothyroidism or GH deficiency is made, replacement of the deficient hormone usually results in a period of rapid catch-up growth, with subsequent normal growth until epiphyseal fusion.

Patient Education

• For excellent patient education resources, visit eMedicine's Growth Hormone Deficiency Center. Also, see eMedicine's patient education articles Growth Failure in Children, Growth Hormone Deficiency, Understanding Growth Hormone Deficiency Medications, and Growth Hormone Deficiency FAQs.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• The most significant medicolegal pitfall is overlooking a CNS tumor with growth failure as its manifestation. Although CNS tumors also often produce neurological symptoms, such as headache with nausea and vomiting or visual changes, 10% of children diagnosed with craniopharyngioma present with growth failure as the only symptom. Importantly, these children are presenting with growth failure (a slow growth velocity) and not just short stature.
• Delayed diagnosis of a treatable cause of growth failure is another pitfall. Once the epiphyses are fused, correction of the cause of the growth failure does not result in further growth.

Special Concerns

• Children with short stature are frequently teased. Western culture is more accepting of short stature in girls than in boys, a concept that is imbedded in the language. Short girls are often described as petite or cute, whereas terms used to describe short boys are more often pejorative. Studies of children with GH deficiency have shown that these children tend to have normal intelligence but demonstrate poor school performance. They also tend to have more abnormalities on the child behavior checklist. GH therapy results in improvement.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Lindsay R, Feldkamp M, Harris D. Utah Growth Study: growth standards and the prevalence of growth hormone deficiency. J Pediatr. Jul 1994;125(1):29-35. [Medline].
2. Lacey KA, Parkin JM. Causes of short stature. A community study of children in Newcastle upon Tyne. Lancet. Jan 12 1974;1(7846):42-5. [Medline].
3. Carrel AL, Allen DB. Effects of growth hormone on body composition and bone metabolism. Endocrine. Apr 2000;12(2):163-72. [Medline].
4. Grimberg A, Kutikov JK, Cucchiara AJ. Sex differences in patients referred for evaluation of poor growth. J Pediatr. Feb 2005;146(2):212-6. [Medline].
5. Hindmarsh PC, Brook CG. Short stature and growth hormone deficiency. Clin Endocrinol (Oxf). Aug 1995;43(2):133-42. [Medline].
6. Hintz RL. Growth hormone treatment of idiopathic short stature. Horm Res. 1996;46(4-5):208-14. [Medline].
7. Hintz RL. Disorders of growth. In: Brunwald E, Fauci AS, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 13^th ed. New York, NY: McGraw-Hill Medical Publishing Division; 1994.
8. Horner JM, Thorsson AV, Hintz RL. Growth deceleration patterns in children with constitutional short stature: an aid to diagnosis. Pediatrics. Oct 1978;62(4):529-34. [Medline].
9. Kojima M, Hosoda H, Date Y. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. Dec 9 1999;402(6762):656-60. [Medline].
10. Kojima M, Hosoda H, Matsuo H. Ghrelin: discovery of the natural endogenous ligand for the growth hormone secretagogue receptor. Trends Endocrinol Metab. Apr 2001;12(3):118-22. [Medline].
11. Stabler B, Clopper RR, Siegel PT, et al. Academic achievement and psychological adjustment in short children. The National Cooperative Growth Study. J Dev Behav Pediatr. Feb 1994;15(1):1-6. [Medline].
12. Stabler B, Siegel PT, Clopper RR, et al. Behavior change after growth hormone treatment of children with short stature. J Pediatr. Sep 1998;133(3):366-73. [Medline].
13. Tanner JM. Fetus into Man: Physical Growth from Conception to Maturity. Cambridge, Mass: Harvard University Press; 1990.
14. Tanner JM. Normal growth and techniques of growth assessment. Clin Endocrinol Metab. Aug 1986;15(3):411-51. [Medline].

Article Last Updated: Nov 16, 2007