Endocrinology Metabolism

Short Stature: Non-Endocrine Causes

Are You Sure the Patient Has Short Stature?

Evaluation of the Child with Short Stature

A child who is 2 standard deviations (SD) or more below the mean height for children of that sex and chronological age (and ideally of the same racial-ethnic group) is said to have short stature. A single measurement of height is much less reliable in assessing growth than is the trend over a period of time (at least 6 months); the key finding is slowed growth that progressively deviates from a previously defined growth channel (or percentile) even if within 2 SD of the mean.

Linear growth measurements must be made with an appropriate device, and these measurements (along with those of weight and head circumference) plotted accurately on the appropriate growth chart (see detailed information on growth charts later in this text).

This topic will emphasize the presentation of and diagnostic approach to children with short stature.

Growth Charts

In a child with a growth disorder, examination of his or her growth pattern over time can provide important clues to the correct diagnosis. Accurate measurements, using age- and sex-specific growth charts, are mandatory to make sure that the child is growing at an appropriate rate. Care must be taken to plot the height and weight based on the child's actual chronological age (to the month). Length should be measured in infants until 2 years of age and standing height thereafter if possible (height being slightly less than length at any given time).

Height should be measured using a wall-mounted stadiometer while making sure that the child is shoeless, standing up straight, with his/her feet together and looking directly forward with the eyes and pinnae along the Frankfurt (auriculo-orbital) plane. Infant length should be measured from the crown of the head to the outstretched heel on a firm platform with a fixed head-plate, a moveable footplate, and a mounted ruler.

Clinicians in the U.S. historically have used growth charts that are provided by the Centers for Disease Control and Prevention (CDC). The CDC growth charts represent a “growth reference” that shows how a large cross-section of US infants actually grew between 1970 and the early 1990s. They were based on data from infants whose feeding approximated the mix of practices of that time: ~50% were ever breast-fed and ~33% were breast-fed to 3 months.

In April 2006, the World Health Organization (WHO) released new international growth charts for children aged 0-59 months. Similar to the 2000 CDC growth charts, these charts describe weight for age, length (or stature) for age, weight for length (or stature), and body mass index (BMI) for age. The measurements from birth to 2 years were accrued from 882 infants of high socio-economic status from multiple sites around the world who were exclusively/ predominantly breast-fed for at least 4 months and who continued breast-feeding for at least 12 months. These infants were measured 21 times over 24 months.

These new charts, therefore, show how predominantly breast-fed infants “should grow” under ideal conditions and are considered growth standards. The 2006 WHO international growth charts, rather than the CDC growth charts, are, thus, recommended for children (in the US) <24 months of age. In the US, the CDC growth charts should continue to be used for the assessment of growth in children aged 2 to 19 years. The CDC growth charts are available at http://www.cdc.gov/growthcharts.

Premature infants should have their growth plotted on charts designed to account for their gestational age (i.e., until 24 months for weight, 40 months for length, and 18 months for head circumference). Disease-specific growth charts should be used, when available, for syndromic short stature to compare growth with data from other children with the same disorder [e.g., trisomy 21 (Down syndrome), Turner syndrome, achondroplasia, etc.].

Normal Variants

Familial (genetic) short stature and constitutional short stature are common variations of normal growth. Children with familial short stature have a normal growth rate within their mid-parental target height (MPTH) range (see below), do not have bone age delay, puberty and the pubertal growth spurt occur at a normal age, and adult height is appropriate for the MPTH range. Constitutional delay of growth is suggested by deceleration of length/height in the first 3 years of life, a normal or near-normal height velocity during childhood (2 inches/year), significantly delayed bone age and pubertal development, and adult height within or slightly below the MPTH range.

Constitutional delay of growth is often familial (~50% of the time). Careful questioning of the parents about their childhood growth and pubertal patterns can be helpful. With familial as well as constitutional short stature, reassurance is often all that is needed, although boys with constitutional short stature may profit psychologically from a short course of low-dose testosterone treatment beginning around age 13 years. Note that it is not uncommon for a child to have both familial short stature and constitutional delay.

Abnormal Growth

Children whose linear growth measurements are at the extremes of the growth curve, but associated with a normal rate of growth, are likely to be normal. Conversely, a slow growth rate, irrespective of the actual height percentile (even one that is within the normal range, i.e., > 3rd percentile), is more likely to be abnormal and warrants further evaluation. As noted previously, linear growth must be evaluated over time, preferably over a minimum of 3-6 months, in order to determine velocity and the need for merely ongoing observation or initiation of an evaluation, as only a very small number of potential new disorders will be uncovered during comprehensive (expensive) routine screening of otherwise healthy children with normal height velocity almost regardless of how low a percentile (SDS) along which a child may be tracking. Such testing should proceed only if the height velocity is abnormal for age.

Importantly, linear growth patterns must be viewed in the context of simultaneous weight-tracking, as concomitant weight slow-down vs. weight preservation provides a highly useful diagnostic fulcrum. Additional information can be gleaned from concomitant pubertal delay in the older child, along with dental delay at any age, as well as physical findings to suggest a specific diagnosis.

A useful starting-off point to guide the differential diagnosis is a bone age which is delayed in children with constitutional short stature and various systemic and endocrine causes of growth failure and typically more so in pathological situations. On the other hand, the bone age is usually not delayed when growth failure is caused by familial short stature or genetic syndromes.

How do you know a child is growing normally?

Physiology of Growth

Hormonal regulation of human growth involves the growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis. There is also clearly a genetic contribution to human growth. This is discussed further under normal (parental growth and development history) and abnormal growth patterns (Turner syndrome and SHOX deficiency). GH is important in promoting somatic growth and in regulating body composition and muscle and bone metabolism. Some of these GH effects are direct actions whereas others, specifically linear growth, is mediated via IGF-I.

The original "somatomedin (alternatively termed IGF) hypothesis" postulated that somatic growth was controlled by pituitary GH and mediated by circulating IGF-I produced exclusively by the liver. The discovery in the late 1980’s that most tissues produce IGF-I, supporting a role of autocrine/paracrine IGF-I, led investigators to modify the original hypothesis to what is known today as the "dual effector" theory.

Experiments using gene deletions and transgenic technologies have revealed new information that again has led investigators to revisit the hypotheses. These experimental studies have shown that, while the liver is the principal source of IGF-I in the circulation, hepatic IGF-I is not required for postnatal body growth. This finding indicates that autocrine/paracrine, but not liver-derived (endocrine) IGF-I, is the major determinant of postnatal somatic growth. However, lack of liver-derived IGF-I results in disproportional organ growth.

Analysis of adult height by genome-wide association studies (GWAS) has led to the discovery of >200 loci associated with variation in adult height and highlights the polygenic nature of human continuous traits. Of these associations, the most important appears to be the Short Stature Homeobox Gene on X-chromosome (SHOX), also dubbed the master height gene. The SHOX gene encodes a transcription factor that contains a homeodomain (a protein sequence that binds DNA) similar to that found in many other transcription factors. The protein is expressed during early embryogenesis at the ends of certain long bones suggesting a role for this transcription factor in chondrogenesis (see below).

Growth Velocity

A newborn's size is determined by its intra-uterine environment, which is influenced by maternal size, nutrition, general health, and social habits, such as smoking or drinking alcohol. Thus, an “overnourished” mother can have a heavier and longer baby and an “undernourished” mother can have a lighter and shorter baby than otherwise dictated by family growth genetics. The average weight of a newborn is 3.25 kilograms (7.25 pounds) and the average length is 50 centimeters (19.7 inches). After birth, the growth rate becomes more dependent on the infant's genetic background.

Important physiological phenomena, known as catch-up and catch-down growth, occur in the first 18 months of life. In two-thirds of children, the growth rate percentile shifts after birth until the child reaches his or her genetically determined height percentile. Some children (born too small because of uterine fetal constraint) move upward (catch-up) on the growth chart because they have tall parents, whereas others (oversized at birth because of excessive maternal nutrition during the pregnancy) move downward (catch-down) on the growth chart because they have short parents. By 18 to 24 months of age, most children's stature has shifted to their genetically determined percentiles. Thereafter, growth typically proceeds along the same percentile until the onset of puberty (see Table 1).

Table 1.

Normal Growth Velocity at Various Ages

Genetic Potential

Determination of the MPTH is a critical first step in the assessment of a child’s stature, and obtaining accurate parental height measurements is essential when determining the MPTH. A large proportion of parents who bring their children for a consultation with a pediatric endocrinologist make a significant error in reporting their own heights. Since parental height often determines the extent of a work-up and/or therapeutic intervention, it is the opinion of the authors that parents’ heights should be directly measured whenever possible.

The MPTH is a child's projected adult height based on the heights of his or her parents. Sex-specific calculations are shown in Table 2. For both genders, 1.7 inches on either side of the calculated MPTH is ~1 SD while 3.3 inches on either side is ~2 SD. By calculating the percentile and range for the MPTH, it can be determined if a child is growing on a percentile that is within or outside this range.

Table 2.

Mid-Parental Target Height Formulas

What Else Could the Patient Have?

Turner syndrome (TS)

What you should be alert for in the history

Any short girl, especially if growing slowly with the deceleration beginning early in life, has TS until proven otherwise. Birth lengths are typically in the lower portion of the normal range. Fifty per cent of girls with TS have heights <5th %ile by age 1.5 years and 75% by age 4 years, irrespective of karyotype. The timing of growth failure is more variable in the presence of an iso-X-chromosome or a mosaic karyotype. Regardless, on average, height is <5th %ile for 5 years before the diagnosis of TS is made.

Furthermore, ~15% of girls with TS have some evidence of spontaneous gonadarche, e.g., breast development. One of the most common historical findings is frequent bouts of otitis media often requiring placement of pressure-equalizing tubes. This frequently results in conductive hearing loss. Note that sensori-neural hearing loss occurs in 50% of adult women with TS. Autoimmune diseases such as Hashimoto thyroiditis, celiac disease, and inflammatory bowel disease also occur with heightened predilection in patients with TS and can contribute to poor growth. Overall intelligence is generally normal although mild neuropsychological issues are frequent, including attention deficit/hyperactivity disorders, abnormalities of executive functioning, and disturbances of visuo-spatial processing manifesting as difficulty in mathematics and being able to reverse parallel-park.

Characteristic findings on physical examination

Approximately 50% of girls with TS have no or very subtle dysmorphic features which contributes to the delay in diagnosis. Short stature, preferentially affecting the upper segment, is often the diagnostic feature that brings these girls to medical attention. Most older girls will fail to develop breasts and menstrual periods secondary to primary ovarian failure, although pubic and axillary hair development is normal, albeit on the late side. Dysmorphic features, if present, should be evident, at least to some degree, at birth. Webbed neck occurs in only 25% of cases.

Other classical, but fairly infrequent, findings include: multiple nevi; strabismus and ptosis; increased carrying angles (cubitus valgus); short (most commonly fourth) metacarpals (brachymetacarpia) and metatarsals (brachymetatarsia); low posterior hairline; a broad chest with the illusion of widely-spaced nipples; cardiac abnormalities reflecting predominantly left-sided disease including bicuspid aortic valve, coarctation of the aorta, and hypoplastic left heart syndrome, along with an elongated transverse aortic arch, (occurring in up to 50% of affected girls as gleaned by cardiac MRI/MRA and representing the most common cardiac abnormality associated with TS), hypertension, and dissecting aortic aneurysm; and renal abnormalities such as horseshoe kidney and duplicated collecting systems. Advanced dentition may also occur.

Expected results of diagnostic studies

TS occurs in ~1:2000 live female births. The diagnosis should be easily confirmed by peripheral blood karyotype and suspected if gonadotropins (FSH to a greater degree than LH) are elevated as is clearly evident in infancy and then generally after age 10 years. Elevations are more difficult to detect in between these ages because of changes in feedback sensitivity between ovarian hormones and the pituitary gland. Girls with TS are not thought to have GH deficiency, although testing performed after age 10 years is often associated with poor responses presumably because of lack of endogenous estrogen priming.

Diagnosis confirmation

The cardinal diagnostic test is a chromosomal karyotype (for sex determination). The prevalence of the causative anomalies is as follows: 60% 45,X; 15% mosaics including 45,X/46,XX and 45,X/46,XY; 10% structural abnormalities of the X-chromosome including 46,X,i(Xq) (isochromosome Xq); and 5% other unusual patterns.

Small for Gestational Age (SGA)

What you should be alert for in the history

There is no universal definition of SGA, but most pediatric endocrinologists employ the statistical definition of birth length and/or weight < 5th %ile for gestational age. Various historical data sets exist, including those of Usher and McLean for infants born at sea level, Lubchenco for infants born one mile above sea level, and, most recently, from a cross-sectional sample of birth data from Pediatrix Medical Group.

Characteristic findings on physical examination

Other than persistent post-natal growth failure, the physical examination of a former SGA infant is usually normal. An exception occurs when the SGA is the result of a specific syndrome, e.g., Russell-Silver syndrome (RSS), features of which include pre- and post-natal growth failure (with the latter, at least initially, affecting weight more than linear growth), a small triangular facies (with a high-arched forehead that tapers to a small jaw), micrognathia, prominent nasal bridge, down-turning corners of the mouth, and asymmetry (most easily seen in limb circumference and/or length).

Expected results of diagnostic studies

Standard biochemical testing, including GH testing, is usually normal in the former SGA infant with persistent growth failure. Serum IGF-I levels may be low for chronological age, but may be difficult to interpret in the setting of concomitant poor weight gain.

Diagnosis confirmation

For the specific RSS etiology of SGA, ~50% have imprinting defects at chromosome 11p15 (involving loss of function of the IGF-II locus) and 7-10% of patients have maternal uniparental disomy (UPD) involving chromosome 7. Recently, the first case of an IGF2 variant (c.191C→A, p.Ser64Ter) with evidence of pathogenicity in a multi-generational family with four members who have growth delay was reported. The phenotype affects only family members who have inherited the variant through paternal transmission, consistent with the maternal imprinting status of IGF-II. The severe growth restriction in affected family members suggests that IGF-II affects both pre- and post-natal growth.

Noonan syndrome (NS)

What you should be alert for in the history

Noonan syndrome is a developmental disorder belonging to the “RAS-opathies”, a group of clinically and genetically related syndromes. It occurs in 1:1,000 to 1:2,500 live births and is usually inherited in an autosomal dominant disorder with no gender predominance. The most common historical clues for NS include a known similarly affected parent and, in the child, short stature, pulmonic stenosis, cryptorchidism in boys, and characteristic facies (see below).

Characteristic findings on physical examination

The diagnosis is usually made on clinical grounds. Short stature occurs in up to 83% of children with NS [mean adult male height is 64 inches (162.5 centimeters) and mean adult female height is 60 inches (152.7 centimeters)]. Characteristic facial features include broad, high forehead; hypertelorism; micrognathia; low-set, posteriorly rotated ears with a thick helix; high-arched eyebrows; short neck with excess nuchal skin; epicanthal folds; downward-slanting palpebral fissures; and low posterior hairline. Associated congenital heart defects are typically right-sided, e.g., pulmonic stenosis, but may also be extra-cardiac, e.g., hypertrophic obstructive cardiomyopathy. Other clinical manifestations include: pectus deformities, scoliosis, cryptorchidism, lymphatic abnormalities, coagulopathies, cognitive/learning disabilities, and ptosis.

Expected results of diagnostic studies

Standard biochemical testing is generally normal in individuals with NS. Investigations of the GH-IGF-I axis yield variable results.

Diagnosis confirmation

The molecular basis of RAS-opathies is dysregulation of the RAS-MAPK pathway and 15 different genes affecting this pathway have been identified. Of these 15 genes, 11 have been found to be involved in NS or NS-like conditions, with mutations in PTPN11 the cause in ~50 % of the cases. The other genes are SOS1, CBL, BRAF, RAF1, SHOC2, MAP2K1, RIT1, NRAS, KRAS, and RRAS. Mutations in PTPN11 are particularly associated with pulmonic stenosis, short stature, and the typical facies of the condition, whereas mutations in SOS1 (the next most commonly involved gene in ~17% of cases) are associated with the characteristic facies and cardiac abnormalities, but less so with growth disorders. Mutations in RAF1 (3-~17% of cases) are associated with hypertrophic cardiomyopathy. KRAS (<5%) is associated with the most severe phenotype.

SHOX Deficiency

What you should be alert for in the history

Short stature and poor height velocity are the most consistent findings in the setting of SHOX deficiency. The SHOX gene is located in the pseudo-autosomal region of both the X and Y chromosomes and encodes a transcription factor, i.e., a homeodomain protein, that controls cartilage formation. The majority of defects (~60-70%) are heterozygous deletions of one whole copy of SHOX gene from X or Y chromosome. Haploinsufficiency of the SHOX gene may cause what otherwise appears to be idiopathic short stature (ISS) or can manifest as Leri-Weill dyschondrosteosis. Homozygous SHOX mutations are associated with the severe form of dwarfism known as Langer mesomelic dysplasia.

Characteristic findings on physical examination

In its mildest form, affected patients manifest variable degrees of short stature, with greater shortening of limbs than trunk. The limb shortening preferentially involves the middle segment (mesomelia) of the forearms and lower legs. There may also be a high-arched palate, micrognathia, Madelung deformity (bayonet wrist), radial and tibial bowing, cubitus valgus, and a “stocky” appearance with calf muscle hypertrophy and increased BMI. Importantly, some subjects are merely short with no other abnormalities. SHOX deficiency is said to be the cause of idiopathic short stature (ISS) in 1-4% of cases (see below).

Expected results of diagnostic studies

Radiographic abnormalities, when present, may include altered osseous alignment at the wrist, “pyramidization” (wedging) of the carpal bones, triangularization of the radial head, lucency of the ulnar border of the radius, radial/tibial bowing, metacarpal/metatarsal shortening, metaphyseal flaring, exostoses of the proximal tibia/fibula, abnormal tuberosity of the humerus, abnormal femoral neck, and a coarse trabecular pattern.

Diagnosis confirmation

SHOX gene testing is commercially available (cost ~$400) and should be considered for a short child with any of the following, especially in combination: a clinical diagnosis or family history of Leri-Weill or Madelung wrist deformity, disproportionate short stature with limbs shorter than trunk, bowing or shortening of the forearms or lower legs (may be quite subtle), high-arched palate, cubitus valgus, short 4th metacarpal or other skeletal feature of Turner syndrome or Leri-Weill syndrome, muscular hypertrophy of the calves (or increased limb circumferences), increased BMI (reflecting “stocky” body habitus), and/or diagnostic radiological signs (see above).

Chondrodystrophies

What you should be alert for in the history

Chondrodystrophies refer to a group of skeletal disorders caused by genetic mutations that affect the development of cartilage. Many are associated with reduced lifespan. Some forms are inherited in an autosomal recessive fashion, while others, such as achondroplasia and its milder variant, hypochondroplasia, are inherited in an autosomal dominant manner, so that there may be a parent or close relative similarly affected. New mutations account for ~50% of cases. Short stature, disproportion of limbs and/or spine, and/or abnormally large head size, with abnormal radiographs are frequently apparent in the newborn period or certainly by later infancy.

Characteristic findings on physical examination

The cardinal findings of the most noteworthy chondrodystrophy, achondroplasia, include rhizomelia (proximal shortening of arms and legs), limitation of elbow extension, trident configuration of the hands, genu varum (bowed legs), thoraco-lumbar gibbus in infancy, exaggerated lumbar lordosis which develops when walking begins, a large head with frontal bossing, and mid-face hypoplasia. The average height of adult males with achondroplasia is 4 feet 4 inches (131 centimeters) and of adult females 4 feet 1 inch (124 centimeters). Short stature in individuals with hypochondroplasia is less severe than in those with achondroplasia and the condition is often not recognized until early to mid-childhood or, in some cases, not until adulthood.

Bowing of the legs typically develops during early childhood, but often improves spontaneously with age and some affected individuals may also have microcephaly. Adult heights of men with hypochondroplasia range from 4 feet 6 inches to 5 feet 5 inches (138 centimeters to 165 centimeters), and 4 feet 2 inches to 4 feet 11 inches (128 centimeters to 151 centimeters) for adult women.

Expected results of diagnostic studies

Diagnosis of specific chondrodystrophies is typically based on a combination of clinical and unique radiological criteria.

Diagnosis confirmation

Specific genetic mutations responsible for various chondrodystrophies are becoming increasingly delineated. For example, >99% of individuals with achondroplasia have one of two point mutations in the FGFR3 gene [~98% have G380R substitution (G -->A) and ~1% a G --> C at nucleotide 1138]. FGFR3 mutations are also the most frequent cause hypochondroplasia.

Idiopathic Short Stature (ISS)

What you should be alert for in the history

ISS refers to short stature often equivalent to the degree seen in children with GH deficiency and other causes of growth failure, but associated with normal GH stimulation test results and no defined etiology. Height velocity may be normal or low. It is essentially a diagnosis of exclusion of known syndromes, SGA, or other existing indications for GH treatment, and is likely a heterogeneous state resulting from familial/genetic factors, subtle abnormalities of the GH-IGF-I axis, and/or abnormalities of the growth plate.

Characteristic findings on physical examination

There are typically no distinguishing phenotypic features.

Expected results of diagnostic studies

Basic diagnostic testing is normal, although serum levels of IGF-I may be low for age in some patients.

Diagnosis confirmation

There is no specific confirmatory diagnostic test for this heterogeneous condition.

Management and Treatment of the Disease

Turner syndrome

The short stature of girls with TS, although not due to GH deficiency, responds well to GH treatment, with GH first approved for use in this condition by the FDA in 1996. As ascertained from TS-specific growth charts, the average height of untreated girls with TS is ~4 feet 8 inches (142.5 centimeters) whereas, after ~5 years of GH treatment, increases, on average, by 4 inches (10 centimeters). More so in the past, low doses of anabolic steroids were used adjunctively with GH. Newer evidence suggests potentially better height outcomes if GH can be started in the toddler age range even before an affected girl becomes significantly short. No unusual safety signals have been reported with GH use in this population, although concerns remain regarding possible induction of diabetes, worsening of scoliosis, and cardiac issues.

Ovarian failure, associated with premature menopause in utero, is treated with female hormone replacement. In the past, this was accomplished with oral therapies such as Premarin (estrogen) alone for one year frequently not commenced until ages 13-15, followed by the addition of Provera (progesterone) to allow menstruation and provide uterine protection against endometrial cancer. A more modern approach involves transdermal estrogen by (cut) patch allowing for more physiological dosing and an earlier age of treatment initiation without fear of disproportionate bone age advancement because of availability of lower estrogen doses than are available in pills.

Small for Gestational Age

GH therapy was FDA-approved in 2001 at doses up to 0.48 mg/kg/wk for treatment of short stature of children born SGA who fail to show catch-up growth to the 5th percentile by 2 yr of age (GH testing not required). GH treatment normalizes stature and increases final height above baseline height prediction (with the resultant growth response being dose-related). Despite the potential use of considerably higher dosing compared to that recommended for children with GH deficiency, GH treatment does not increase risk for metabolic syndrome (for which former SGA children are inherently prone) or cause any unusual safety signals. Note that there appears to be a higher risk of precocious and/or rapid-tempo puberty that is intrinsic to having been born SGA (and not caused by GH) and may require addition of a gonadotropin-releasing hormone agonist to the treatment regimen.

Noonan syndrome

Although patients with NS are not GH-deficient, research studies have shown that, after long-term GH treatment, boys with NS gain an average of almost 4 inches (~9.5 centimeters) and girls 3.6 inches (9.0 centimeters) or 1.5 SD over their original predicted height. Accordingly, GH was approved for use in children with NS at a dose of up to 0.462 mg/kg/wk in 2007. No unusual safety signals have been reported. Note that the start of puberty is often delayed in adolescents with NS.

SHOX Deficiency

GH was approved by the FDA in 2006 at a dose of 0.35 mg/kg/wk for the treatment of short stature or growth failure in children with simple SHOX deficiency whose epiphyses are not closed. Once again, no unusual safety signals have been noted.

Chondrodystrophies

Most chondrodystrophies have no specific treatment, although GH is FDA-approved for treatment of SHOX deficiency (see previous paragraph on SHOX deficiency). GH usage in patients with achrondroplasia has not been proven to have long-term efficacy. Surgical leg-lengthening procedures, e.g., Ilizarov distraction osteogenesis, have been performed successfully resulting in gains of 12-14 inches (30.5-35.5 centimeters).

In achondroplasia, Phase 2 multi-center and multi-national trials are currently underway to evaluate the potential benefit of a long-acting once-daily subcutaneous analog of cartilage natrurietic peptide (CNP), which inhibits FGFR3-mediated stimulation of the MAPK signaling pathway and, in mouse models of achondroplasia, has resulted in improved growth.

Idiopathic Short Stature

GH was first approved in the US for treatment of children with ISS in 2003 at a dose of up to 0.37 mg/kg/wk. This new indication restricts treatment to children who are >2.25 SD below the mean for age and sex, i.e., the shortest 1.2% of children, and who are predicted to have adult heights <5 feet 3 inches (<160 centimeters) and <4 feet 11 inches (<149.9 centimeters) for men and women, respectively.

In the research trials leading to the FDA approval, including parallel dose-comparison and placebo-controlled studies, most patients reached the normal height range during childhood. More specifically, 62% of patients who attained adult height in the higher dose group (0.37 mg/kg/wk) gained more than 2 inches (more than 5 centimeters) over their baseline height prediction while 31% gained more than 4 inches (more than 10 centimeters) over their baseline height prediction. In most reports, no unusual safety signals have been reported (see SGA above).

Controversies have recently arisen concerning possible long-term risks of GH treatment as reported by investigators from the multi-national European study [Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE)]. A total of 6928 former GH-treated children (now >18 years old) with a history of either idiopathic isolated GH deficiency (n = 5162), neurosecretory dysfunction (n = 534), ISS (n = 871), or having been born SGA (n = 335) who started treatment with recombinant human GH between 1985 and 1996 were re-contacted by questionnaire now as adults.

Over the past 2 years, there have been two published studies from a French subset of this larger group that reported that: (1) mortality rates were increased in this population of adults, especially in those who had received the highest GH doses (>0.35 mg/kg/wk), with specific effects found in terms of death due to bone tumors or cerebral hemorrhage, but not for all cancers and (2) there was an increased risk of hemorrhagic stroke in young adults. Subsequent analysis of the full cohort refuted the initial findings related to mortality, while we await a similar analysis concerning the stroke question.

Furthermore, the results of both sub-analyses can be further questioned because of at least three key additional design flaws. First, there were low response rates to the questionnaires (45%) that likely reflect increased responder bias with lack of responses from healthy subjects. Second, information regarding cause of death was taken from death certificates and not medical records (the former often omitting the precipitating event for the death, e.g., a car accident leading to a cerebral hemorrhage). Third, prevalence comparisons were made to similar outcomes in populations of healthy controls as opposed to non-GH-treated young adults with the same underlying diagnoses without which there is no way to separate the effect of the treatment from the disease. For example, having been born SGA itself predisposes to future metabolic syndrome. Additionally, if the adults in question with organic GH deficiency were no longer receiving GH, the GH deficiency itself can be a predisposing factor for adult cardiovascular disease. Although stroke is a potential serious complication that warrants further investigation, the Growth Hormone Research Society takes the position that, currently, the available evidence is insufficient to raise this as a concern with families before starting GH treatment in children. That all said, caution about long-term safety of GH is wise and further studies are needed.

What’s the Evidence?/References

Cohen, P, Rogol, AD, Deal, CL. "Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop". J Clin Endocrinol Metab. vol. 93. 2008. pp. 4210-7.

(This article provides the most recent consensus statement on the diagnosis and treatment of idiopathic short stature.)

Rogol, AD, Lawton, EL., Lohr, JA. "Body measurements". Pediatric Outpatient Procedures. JB Lippincott. 1991. pp. 1.

(This article describes the importance of body measurements in the diagnosis of conditions related to short stature.)

Sisley, S, Trujillo, MV, Khoury, J, Backeljauw, P.. "Low incidence of pathology detection and high cost of screening in the evaluation of asymptomatic short children". J Pediatr. vol. 163. 2013. pp. 1045-51.

(Rational guidelines for evaluating short stature.)

Salmon, W D, Daughaday, WH.. "A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro". J Lab Clin Med. vol. 49. 1957. pp. 825-36.

(Seminal article identifying IGF-1 as a growth factor.)

Green, H, Morikawa, M, Nixon, T.. "A dual effector theory of growth hormone action". Differentiation. vol. 29. 1985. pp. 195-8.

(Seminal article on the direct and indirect actions of GH.)

Sjogren, K, Liu, JL, Blad, K, Skrtic, S, Vidal, O, Wallenius, V, LeRoith, D, Tornell, J, Isaksson, OG, Jansson, JO, Ohlsson, C.. "Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but it is not required for postnatal growth in mice". Proc Natl Acad Sci. vol. 96. 1999. pp. 7088-92.

(Role of IGF-I in postnatal growth.)

Wang, J, Zhou, J, Powell-Braxton, Bondy C.. "Effects of Igf1 gene deletion on postnatal growth patterns". Endocrinology. vol. 140. 1999. pp. 3391-4.

(Role of IGF-I in postnatal growth.)

"National health and nutrition examination survey. Clinical growth charts". U. S. Dept. of Health and Human Services, Centers for Disease Control and Prevention. http:/www.cdc.gov/nchs/about/major/nhanes/growthcharts/Clinical_charts.htm.

(Clinical growth charts.)

Grummer-Strawn, LM, Reinold, C, Krebs, NF. "Use of World Health Organization and CDC growth charts for children aged 0-59 months in the United States". MMWR Recomm Rep. vol. 59. 2010. pp. 1-15.

(Clinical growth charts.)

Needlman, RD., Behrman, RE. "Growth and development". Nelson Textbook of Pediatrics. Saunders. 2003.

(Normal growth and development.)

Aceto, TJ, Dempsher, DP, Garibaldi, L, Becker, KL. "Endocrine and metabolic dysfunction in the growing child and aged". Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. 2001. pp. 1784-808.

(Abnormal growth and development.)

Karlberg, J, Luo, ZC.. "Estimating the genetic potential in stature". Arch Dis Child. vol. 82. 2000. pp. 270.

(Determination of height based on genetic potential.)

Labarta, JI, Ruiz, JA, Molina, I, De Arriba, A, Mayayo, E, Longás, AF.. "Growth and growth hormone treatment in short stature children born small for gestational age". Pediatr Endocrinol Rev. vol. 6. 2009. pp. 350-7.

(Efficacy of GH use in children born small for gestational age.)

Poduval, A, Saenger, P.. "Safety and efficacy of growth hormone treatment in small for gestational age children". Curr Opin Endocrinol Diabetes Obes. vol. 15. 2008. pp. 376-82.

(Safety of GH use in children born small for gestational age.)

Divall, SA, Radovick, S.. "Growth hormone and treatment controversy; long term safety of rGH". Curr Pediatr Rep. vol. 1. 2013. pp. 128-32.

(Perspective on long-term safety of GH.)

Begemann, M, Zirn, B, Santen, G, Wirthgen, E, Soellner, L, Büttel, HM, Schweizer, R, van Workum, W, Binder, G, Eggermann, T.. "Paternally inherited IGF2 mutation and growth restriction". N Engl J Med. vol. 373. 2015. pp. 349-56.

(The role of IGF-II and Russell-Silver syndrome.)

Usher, R, McLean, F.. "Intrauterine growth of live-born Caucasian infants at sea level: standards obtained from measurements in 7 dimensions of infants born between 25 and 44 weeks of gestation". J Pediatr. vol. 74. 1969. pp. 901-10.

(Growth charts for children born small for gestational age.)

Lubchenco, Lo, Hansman, C, Dressler, M, Boyd, E.. "Intrauterine growth as estimated from liveborn birth-weight data at 24 to 42 weeks of gestation". Pediatrics. vol. 32. 1963. pp. 793-800.

(Growth charts for children born small for gestational age.)

Olsen, IE, Groveman, SA, Lawson, ML, Clark, RH, Zemel, BS.. "New intrauterine growth curves based on United States data". Pediatrics. vol. 125. 2010. pp. e214-e224.

(Intrauterine growth charts.)

Saenger, P, Wikland, KA, Conway, GS, Davenport, M, Gravholt, CH. "Recommendations for the diagnosis and management of Turner syndrome". J Clin Endocrinol Metab. vol. 86. 2001. pp. 3061-9.

(Consensus on the diagnosis and management of Turner syndrome.)

Bondy, CA.. "Turner syndrome 2008". Horm Res. vol. 71. 2009. pp. 52-6.

(Review of Turner syndrome.)

Padidela, R, Camacho-Hübner, C, Attie, KM, Savage, MO.. "Abnormal growth in Noonan syndrome: genetic and endocrine features and optimal treatment". Horm Res. vol. 70. 2008. pp. 129-136.

(Review of Noonan syndrome.)

Romano, AA, Allanson, JE, Dahlgren, J, Gelb, BD, Hall, B, Pierpont, ME, Roberts, AE, Robinson, W, Takemoto, CM, Noonan, JA.. "Noonan syndrome: Clinical features, diagnosis, and management guidelines". Pediatrics. vol. 126. 2010. pp. 746-59.

(Management guidelines in Noonan syndrome.)

Dahlgren, J.. "GH therapy in Noonan syndrome: Review of final height data". Horm Res. vol. 72. 2009. pp. 46-8.

(Final height data for Noonan syndrome patients treated with GH.)

Binder, G.. "Short stature due to SHOX deficiency: Genotype, phenotype, and therapy". Horm Res Paediatr. vol. 75. 2011. pp. 81-9.

(SHOX deficiency review.)

Blum, WF, Crowe, BJ, Quigley, CA, Jung, H, Cao, D, Ross, JL, Braun, L, Rappold, G. "Growth hormone is effective in treatment of short stature associated with short stature homeobox-containing gene deficiency: Two-year results of a randomized, controlled, multicenter trial". J Clin Endocrinol Metab. vol. 92. 2000. pp. 219-28.

(GH therapy in SHOX deficiency.)

Hagenäs, L, Hertel, T.. "Skeletal dysplasia, growth hormone treatment and body proportion: comparison with other syndromic and non-syndromic short children". Horm Res. vol. 60. 2003. pp. 65-70.

(GH therapy in skeletal dysplasias.)

Kanaka-Gantenbein, C.. "Present status of the use of growth hormone in short children with bone diseases (diseases of the skeleton)". J Pediatr Endocrinol Metab. vol. 14. 2001. pp. 17-26.

(GH therapy in skeletal dysplasias.)

Deodati, A, Cianfarani, S.. "Impact of growth hormone therapy on adult height of children with idiopathic short stature: systematic review". BMJ. vol. 342. 2011. pp. c7157.

(GH therapy in children with ISS.)

Keni, J, Cohen, P.. "Optimizing growth hormone dosing in children with idiopathic short stature". Horm Res. vol. 71. 2009. pp. 70-4.

(IGF-I based GH therapy in ISS.)

LaFranchi, S.. "Congenital hypothyroidism: etiologies, diagnosis, and management". Thyroid. vol. 9. 1999. pp. 735-740.

Fava, A, Oliverio, R, Giuliano, S. "Clinical evolution of autoimmune thyroiditis in children and adolescents". Thyroid. vol. 19. 2009. pp. 361-67.

(Review of autoimmune thyroiditis in children.)

Richmond, EJ, Rogol, AD.. "Growth hormone deficiency in children". Pituitary. vol. 11. 2008. pp. 115-20.

(Review of children with GHD.)

Lee, PD., Greenswag, LR, Alexander, RC.. "Endocrine and metabolic aspects of Prader-Willi syndrome". Management of Prader-Willi Syndrome. Springer-Verlag. 1995. pp. 32-57.

(Review of PWS.)

Miller, J, Silverstein, J, Shuster, J, Driscoll, DJ, Wagner, M.. "Short-term effects of growth hormone on sleep abnormalities in Prader-Willi syndrome". J Clin Endocrinol Metab. vol. 91. 2006. pp. 413-7.

(GH use in PWS.)

de Lind van Wijngaarden, RF, Otten, BJ, Festen, DA, Joosten, KF, de Jong, FH, Sweep, FC, Hokken-Koelega, AC.. "High prevalence of central adrenal insufficiency in patients with Prader-Willi syndrome". J Clin Endocrinol Metab. vol. 93. 2008. pp. 1649-54.

(Risk of adrenal insufficiency in PWS.)

Backeljauw, P, Bang, P, Dunger, DB, Juul, A, Le Bouc, Y, Rosenfeld, R.. "Insulin-like growth factor-I in growth and metabolism". J Pediatr Endocrinol Metab. vol. 23. 2010. pp. 3-16.

(Review of IGF-I in growth and metabolism.)

Chan, LF, Storr, HL, Grossman, AB, Savage, MO.. "Pediatric Cushing’s syndrome: clinical features, diagnosis, and treatment". Arq Bras Endocrinol Metabol. vol. 51. 2007. pp. 1261-71.

(Review of Cushing syndrome.)

Bastepe, M, Jüppner, H.. "GNAS locus and pseudohypoparathyroidism". Horm Res. vol. 63. 2005. pp. 62-74.

(Review of pseudohypoparathyroidism.)

Vasques, GA, Arnhold, IJ, Jorge, AA.. "Role of the natriuretic peptide system in normal growth and growth disorders". Horm Res Paediatr.. vol. 82. 2014. pp. 222-9.

(The role of CNP as a treatment for short stature associated with chondrodystrophies.)

Carel, JC, Ecosse, E, Landier, F, Meguellati-Hakkas, D, Kaguelidou, F, Rey, G, Coste, J.. "Long-term mortality after recombinant growth hormone treatment for isolated growth hormone deficiency or childhood short stature: preliminary report of the French SAGhE study". J Clin Endocrinol Metab. vol. 97. 2012. pp. 416-25.

(GH and risk of mortality.)

Sävendahl, L, Maes, M, Albertsson-Wikland, K, Borgström, B, Carel, JC, Henrard, S, Speybroeck, N, Thomas, M, Zandwijken, G, Hokken-Koelega, A.. "Long-term mortality and causes of death in isolated GHD, ISS, and SGA patients treated with recombinant growth hormone during childhood in Belgium, The Netherlands, and Sweden: preliminary report of 3 countries participating in the EU SAGhE study". J Clin Endocrinol Metab. vol. 97. 2012. pp. E213-7.

(GH and risk of mortality.)

Poidvin, A, Touzé, E, Ecosse, E, Landier, F, Béjot, Y, Giroud, M, Rothwell, PM, Carel, JC, Coste, J.. "Growth hormone treatment for childhood short stature and risk of stroke in early adulthood". Neurology. vol. 83. 2014. pp. 780-6.

(GH and risk of stroke.)

Geffner, ME, Santen, R, Kopchick, J.. "Statement from the Pediatric Endocrine Society, the Endocrine Society, and the Growth Hormone Research Society. Re: Growth hormone treatment for childhood short stature and risk of stroke in early adulthood (Poidvin, et al.". Neurology. vol. 83. 2014. pp. 780-6.

(GH and risk of stroke.)

"Growth Hormone Safety Workshop Position Paper: a critical appraisal of recombinant human growth hormone therapy in children and adults". Eur J Endocrinol. 2015 Nov 12. pp. EJE-15-0873.

(A current review of the safety of GH.)

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