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.[1] Growth failure is the term that describes a growth rate below the appropriate growth velocity for age (see image below).
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Growth failure in length and weight with a normal head circumference in an infant with growth hormone deficiency.
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, which are normal nonpathologic variants of growth. 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.
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. GHRH also stimulates somatotroph proliferation. Another signal, which is stimulated by certain growth hormone–releasing peptides (GHRPs), may be present; the receptor for the GHRPs has been identified, and ghrelin, the natural ligand for these receptors, has been identified. The GHRH receptor is a cell surface-associated seven membrane-spanning domain protein linked to a G protein (Gs). It stimulates intracellular cAMP production after ligand-induced activation.
Ghrelin (from the word ghre, a root word in proto-Indo-European languages meaning grow), is unique in that it is a small polypeptide modified at the third amino acid (serine) by esterification of n-octanoic acid. Ghrelin is a gastrointestinal peptide (synthesized in the stomach) which specifically induces GH secretion. The ghrelin receptor is expressed on the anterior pituitary. Somatostatin secreted by the hypothalamus inhibits growth hormone secretion.
When growth hormone pulses are secreted into the systemic circulation, insulin-like growth factor (IGF)–1 is released, either locally or at the site of the growing bone. Growth hormone circulates bound to a specific binding protein (GHBP), which is the extracellular portion of the growth hormone receptor. IGF-1 circulates bound to one of several binding proteins (IGFBPs). The IGFBP that most depends on growth hormone is IGFBP-3.
In 1994, Lindsay et al studied 114,881 school children in Utah.[2] 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%), growth hormone 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.[3] 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, growth hormone 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.
Race
There is no known racial predilection for growth failure; however, in large databases following children treated with growth hormone,[4] white children appear to be over-represented, compared with children of Asian or African descent. This observation is thought to be probably due to referral bias.
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.
History of those with growth failure 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 the percentile at which a child's height is expected to track.
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. The recent increase in the use of electronic medical records has contributed positively in the access to growth data.
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. It is important to note that infancy and adolescence are the two phases of postnatal growth when crossing length/height percentile lines may be observed due to normal physiology. In the first 2 years of life, an infant's height (length) curve may cross the percentile curves up or down in accordance with the child's genetic potential, moving away from the influences of the intrauterine environment. On the other hand, puberty is characterized by a growth spurt. Therefore crossing of the height percentiles between age 2 and the onset of puberty should be noted by the physician and evaluated as needed.
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.
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 growth hormone [GH] deficiency), puberty is delayed.
Look for signs of specific syndromes: Numerous specific syndromes 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.
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.[5]
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).[6]
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 (celiac disease), ulcerative colitis, or regional enteritis (Crohn disease), disorders involving the liver may be present. In inflammatory bowel disease (in particular, Crohn disease), the growth failure may be apparent before other symptoms appear.
Renal disease: Chronic renal failure, renal tubular acidosis. In children, growth failure may precede the diagnosis of chronic renal failure.
Lungs: Cystic fibrosis or severe asthma may be present.
Connective tissue/rheumatologic problems: Conditions such as dermatomyositis or systemic-onset juvenile idiopathic arthritis (JIA) 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. Short stature homeobox-containing gene (SHOX) mutations, haploinsufficiency, or complete absence are associated with growth retardation (OMIM #300582). The SHOX gene is found in the pseudoautosomal region of the X and Y chromosomes. Individuals with SHOX mutation tend to have mesomelic growth retardation (shorter forearms and lower legs), Madelung deformity of the forearm (focal dysplasia of the distal radial physis), cubitus valgus, high arched palate and muscular hypertrophy (short, stocky appearance). SHOX mutations are present in approximately 1-4% of patients who would otherwise have been classified under the category of idiopathic short stature[7] .
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. Overall, 10% of children who are SGA have not caught up in growth by age 2 years.
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.
Growth hormone deficiency: Children who are growth hormone deficient have normal proportions but may appear younger than their age. They have delayed skeletal maturation. Although growth hormone deficiency may be suspected because of damage or malformation of the pituitary gland, in most children diagnosed with growth hormone deficiency, the etiology is idiopathic.
Growth hormone insensitivity (primary IGF-1 deficiency): Sometimes called Laron dwarfism, this disorder appears to be similar to growth hormone deficiency, except that large amounts of growth hormone 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.
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. As the serum total T4 assays measure both bound and unbound ("free") T4, freeT4 test is preferred for screening in most pediatric endocrine clinics.
Serum electrolytes, creatinine, bicarbonate, calcium, phosphate, alkaline phosphatase, albumin: A low bicarbonate level may indicate renal tubular acidosis, which can result in growth failure. Electrolyte levels and/or creatinine 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 growth hormone (GH) dependent. Low values suggest growth hormone deficiency. However, they are also sensitive to other factors such as nutritional state, so a low value alone is not diagnostic of growth hormone 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.
Celiac serology: Screening for celiac disease is considered in applicable patients. Tissue transglutaminase [tTG] immunoglobulin A [IgA] and serum total Ig A are the first line tests. Inclusion of total IgA level helps exclude a false-negative test in a patient with selective IgA deficiency. Additional (IgG based) celiac serology tests are available.
Additional evaluations should be considered on a case-by-case basis, if suggested by the history and physical examination. For example testing for precocious puberty, potential endocrine (such as Cushing's syndrome), skeletal or syndromic causes of short stature. Testing for SHOX gene mutations should be considered as applicable.
Bone age determination: A radiograph of the left hand and wrist can be compared with standards to provide an estimation of skeletal maturation. The most common methods used to determine skeletal age are the Greulich and Pyle Atlas and the Tanner-Whitehouse method. Bone age also provides a determination of growth potential (predicted adult stature may be estimated from the tables of Bayley and Pinneau).
MRI of the head: Patients who are diagnosed with growth hormone 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 growth hormone deficiency have an abnormality of the pituitary gland, such as an ectopic bright spot, an empty sella, or a small sella. Discovery of one of these conditions aids diagnosis of growth hormone deficiency and significantly increases the probability that such a patient requires lifelong growth hormone replacement.
Growth hormone response to insulin has been considered the most reliable test for growth hormone deficiency. For recognition of the diagnosis of growth hormone deficiency, many insurance companies require documenting a failure to demonstrate a growth hormone response (with a growth hormone level >10 ng/mL) to 2 provocative stimuli. Provocative stimuli include insulin-induced hypoglycemia, arginine, levodopa (L-dopa), clonidine, and glucagon.
Over time, the potential growth hormone supply has increased, and the peak growth hormone level considered "adequate" has increased to 10 ng/mL. In true (or classic) growth hormone deficiency, the peak growth hormone response to provocative stimuli is probably less than 5 ng/mL. Children who have classic growth hormone deficiency robustly respond to relatively small doses of growth hormone (especially during the early part of treatment), particularly in terms of growth velocity. However, many patients who have peaks in the 5-10 ng/mL range in response to growth hormone provocative agents may also respond well to growth hormone therapy.[8] In fact, no great difference in terms of response to GH is noted between this group and those whose growth hormone provocative tests are read as adequate (ie, a growth hormone peak >10 ng/mL). This latter category has been called idiopathic short stature.
Because of these issues, in 2003, the US Food and Drug Administration (FDA) approved growth hormone therapy for especially short children (height >2.25 standard deviations below the mean) who are not growth hormone deficient and thus fall into the category of idiopathic short stature. Also, because growth hormone testing with provocative agents uses a cut-off peak growth hormone level of 10 ng/mL, some practitioners have avoided these growth hormone provocative tests. However, the author believes that recognizing children who are severely growth hormone deficient (classic growth hormone deficiency) is valuable because these children may be more at risk for other pituitary hormone deficiencies and are much more likely to need lifelong growth hormone replacement.
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 growth hormone (GH) deficiency, the treatment is growth hormone replacement therapy. In 2003, the FDA approved the use of growth hormone for children who are not growth hormone deficient but who are at least 2.25 standard deviations below the mean for height, who are unlikely to have an adult height above -2 standard deviations, and who have no explanation for their short stature. This disorder has been termed idiopathic short stature.
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.
Guidelines on growth disorders and their treatment by the Drug and Therapeutics Committee and Ethics Committee of the Pediatric Endocrine Society[9]
Use growth hormone (GH) to normalize adult height (AH) and avoid extreme shortness in children and adolescents with growth hormone deficiency (GHD).
Suggest against routine cardiac testing, dual x-ray absorptiometry (DXA) scanning, and measurement of lipid profiles in children and adolescents treated with GH.
Establish a diagnosis of GHD without GH provocative testing in patients possessing all of the following 3 conditions: auxological criteria, hypothalamic-pituitary defect (such as major congenital malformation [ectopic posterior pituitary and pituitary hypoplasia with abnormal stalk], tumor, or irradiation), and deficiency of at least one additional pituitary hormone.
GHD due to congenital hypopituitarism should be diagnosed without formal GH provocative testing in a newborn with hypoglycemia who does not attain a serum GH concentration above 5 µg/L and has deficiency of at least one additional pituitary hormone and/or the classical imaging triad (ectopic posterior pituitary and pituitary hypoplasia with abnormal stalk).
Recommend against reliance on GH provocative test results as the sole diagnostic criterion of GHD.
Suggest sex steroid priming prior to provocative GH testing in prepubertal boys older than 11 yr and in prepubertal girls older than 10 yr with AH prognosis within -2 SD of the reference population mean in order to prevent unnecessary GH treatment of children with constitutional delay of growth and puberty.
Recommend against the use of spontaneous GH secretion in the diagnosis of GHD in a clinical setting.
Recommend an initial GH dose of 0.16-0.24 mg/kg/wk (22-35 µg/kg/day) with individualization of subsequent dosing.
Suggest measurement of serum insulin-like growth factor-I (IGF-I) levels as a tool to monitor adherence and IGF-I production in response to GH dose changes. Suggest that the GH dose be lowered if serum IGF-I levels rise above the laboratory-defined normal range for the age of pubertal stage of the patient.
During puberty, recommend against the routine increase in GH dose to 0.7 mg/kg/wk in every child with GHD.
Recommend that GH treatment at pediatric doses not continue beyond attainment of a growth velocity below 2-2.5 cm/yr. The decision to discontinue pediatric dosing prior to attainment of this growth velocity should be individualized.
Recommend that prospective recipients of GH treatment receive anticipatory guidance regarding the potential adverse effects of intracranial hypertension, slipped capital femoral epiphysis (SCFE), and scoliosis progression.
Recommend monitoring of GH recipients for potential development of intracranial hypertension, SCFE, and scoliosis progression by soliciting pertinent history and performing a physical examination at every follow-up clinic visit; further testing should be pursued if indicated.
Recommend re-assessment of both the adrenal and thyroid axes after initiation of GH therapy in patients whose cause of GHD is associated with possible multiple pituitary hormone deficiencies (MPHD).
For GH initiation after completion of tumor therapy with no evidence of ongoing tumor, a standard waiting period of 12 mo to establish “successful therapy” of the primary lesion is reasonable, but can also be altered depending on individual patient circumstances.
Recommend that patients with multiple (≥3) pituitary hormone deficiencies regardless of etiology, or GHD with a documented causal genetic mutation or specific pituitary/hypothalamic structural defect except ectopic posterior pituitary, be diagnosed with persistent GHD.
Recommend re-evaluation of the somatotropic axis for persistent GHD in persons with GHD and deficiency of only one additional pituitary hormone, idiopathic isolated GHD (IGHD), IGHD with or without small pituitary/ectopic posterior pituitary, and after irradiation.
Suggest that measurement of the serum IGF-I concentration be the initial test of the somatotropic axis if re-evaluation of the somatotropic axis is clinically indicated.
Recommend GH provocative testing to evaluate the function of the somatotropic axis in the transition period if indicated by a low IGF-I level.
Suggest that GH treatment be offered to individuals with persistent GHD in the transition period. There is evidence of benefit; however, the specifics of the patient population that benefits, the optimal time to re-initiate treatment, and the optimal dose are not clear.
Because there is overlap in response between dosing groups, suggest initiating GH at a dose of 0.24 mg/kg/wk, with some patients requiring up to 0.47 mg/kg/wk.
Recommend the use of IGF-I therapy to increase height in patients with severe primary IGF-I deficiency (PIGFD).
Recommend a trial of GH therapy before initiating IGF-I for patients with unexplained IGF-I deficiency. Patients with hormone signaling defects known to be unresponsive to GH treatment can start directly on IGF-I replacement; these include patients with very low or undetectable levels of GH-binding protein (GHBP) and/or proven GH receptor (GHR) gene mutations known to be associated with Laron syndrome/GH insensitivity syndrome (GHIS), GH-neutralizing antibodies, STAT5b gene mutations, and IGF1 gene deletion or mutation.
Suggest an IGF-I dose of 80-120 µg/kg BID. Similar short-term outcomes were seen with 80 and 120 µg, but published studies had limitations, and there is no strong evidence supporting superiority of one dose over the other.
Growth hormone (GH) is approved by the FDA for treatment of growth failure caused by the following: growth hormone deficiency, Turner syndrome, chronic renal insufficiency, intrauterine growth failure with postnatal growth failure, Noonan syndrome, Prader-Willi syndrome, idiopathic short stature and SHOX mutations.
Clinical Context:
Recombinant DNA origin GH. In children whose epiphyses are not yet fused, GH therapy usually results in a significant increase in growth velocity (averaging 10-11 cm/y during the first year of therapy in GH deficiency and 7-9 cm/y during the first year in other disorders). Response wanes each year, but growth velocity continues to be faster than pretreatment rates.
These agents are used for physiologic replacement of growth hormone 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.
Clinical Context:
Recombinant human IGF-1 indicated for long-term treatment of growth failure in children with severe (ie, basal IGF-1 and height SD scores ≤ -3, normal or elevated GH level) primary IGF-1 deficiency (primary IGFD). IGF-1 is essential for normal growth of children's bones, cartilage, and organs by stimulating glucose, fatty acids, and amino acid uptake into tissues. IGF-1 is the principal hormone for statural growth and directly mediates GH effect. Primary IGFD is characterized by lack of IGF-1 production despite normal or elevated GH levels.
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.
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.
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 3 years may result in increases in adult height prediction by as much as 3 inches or more. Actual adult height data are pending, although these data are just beginning to appear.
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 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 growth hormone (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.
What is growth failure?What is the pathophysiology of growth failure?What is the prevalence of growth failure in the US?What is the global prevalence of growth failure?What is the mortality and morbidity associated with growth failure?What are the racial predilections of growth failure?What are the sexual predilections of growth failure?Which clinical history findings are characteristic in growth failure?How is height assessed during the physical exam for growth failure?How is proportionality assessed during the physical exam for growth failure?How is pubertal status assessed during the physical exam for growth failure?Which syndromes with short stature should be considered in the physical exam of growth failure?What causes growth failure?What is the role of chronic disease and systemic disorders in the etiology of growth failure?Which syndromes are associated with growth failure?What is the role of target tissue defects to the etiology of growth failure?What are endocrine causes of growth failure?What are the differential diagnoses for Growth Failure?What is the role of lab tests in the workup of growth failure?What is the role of imaging studies in the workup of growth failure?What is the role of growth hormone provocation testing in the workup of growth failure?How is growth failure treated?Which specialist consultations are beneficial to patients with growth failure?What are the Pediatric Endocrine Society guidelines on growth failure?Which medications are used in the treatment of growth failure?Which medications in the drug class Aromatase Inhibitor are used in the treatment of Growth Failure?Which medications in the drug class Gonadotropin Releasing Hormone Analog are used in the treatment of Growth Failure?Which medications in the drug class Insulinlike growth factor are used in the treatment of Growth Failure?Which medications in the drug class Androgen are used in the treatment of Growth Failure?Which medications in the drug class Growth Hormone are used in the treatment of Growth Failure?What is included in the long-term monitoring of growth failure?What is the prognosis of growth failure?What is included in the patient education about growth failure?
Neslihan Gungor, MD, Associate Professor of Pediatrics, Division of Endocrinology, Louisiana State University School of Medicine in Shreveport; Pediatric Endocrinologist, LSU Children’s Hospital
Disclosure: Nothing to disclose.
Specialty Editors
Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London), Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Greece; UNESCO Chair on Adolescent Health Care, University of Athens, Greece
Disclosure: Nothing to disclose.
Chief Editor
Sasigarn A Bowden, MD, Associate Professor of Pediatrics, Section of Pediatric Endocrinology, Metabolism and Diabetes, Department of Pediatrics, Ohio State University College of Medicine; Pediatric Endocrinologist, Associate Fellowship Program Director, Division of Endocrinology, Nationwide Children’s Hospital; Affiliate Faculty/Principal Investigator, Center for Clinical Translational Research, Research Institute at Nationwide Children’s Hospital
Disclosure: Nothing to disclose.
Additional Contributors
Thomas A Wilson, MD, Professor of Clinical Pediatrics, Chief and Program Director, Division of Pediatric Endocrinology, Department of Pediatrics, The School of Medicine at Stony Brook University Medical Center
Disclosure: Nothing to disclose.
Acknowledgements
In memory of Stephen Kemp, MD, PhD, a distinguished and beloved mentor, physician, and professor. A unique role model for inspiration, kindness and knowledge.
References
[Guideline] New York State Department of Health. Growth, body composition, and metabolism. New York (NY): New York State Department of Health; 2007 Nov.
Hintz RL. Disorders of growth. Brunwald E, Fauci AS, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 13th ed. New York, NY: McGraw-Hill Medical Publishing Division; 1994.
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