Growth Failure

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Practice Essentials

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.

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. 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.

Epidemiology

Frequency

United States

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

History of those with growth failure should focus on the following areas:

Physical

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

Causes

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

Laboratory Studies

See the list below:

Imaging Studies

See the list below:

Other Tests

See the list below:

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 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.

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.

Guidelines Summary

Guidelines on growth disorders and their treatment by the Drug and Therapeutics Committee and Ethics Committee of the Pediatric Endocrine Society [9]

Medication Summary

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.

Somatropin (Humatrope, Nutropin AQ, Genotropin, Norditropin, Omnitrope, Saizen, Tev-Tropin, Zorbtive)

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.

Class Summary

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.

Oxandrolone acetate (Oxandrin)

Clinical Context:  Synthetic testosterone derivative. A weak androgen that cannot be aromatized to estrogen.

Class Summary

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

Mecasermin (Increlex)

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.

Class Summary

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.

Leuprolide acetate (Lupron)

Clinical Context:  Suppresses ovarian and testicular steroidogenesis by decreasing LH and FSH levels.

Class Summary

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.

Letrozole (Femara)

Clinical Context:  Letrozole is an aromatase inhibitor, which interferes with the conversion of androgen to estrogen.

Class Summary

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.

Further Outpatient Care

See the list below:

Prognosis

See the list below:

Patient Education

See the list below:

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?

Author

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

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Growth failure in length and weight with a normal head circumference in an infant with growth hormone deficiency.

Growth failure in length and weight with a normal head circumference in an infant with growth hormone deficiency.