Clinical and Ethical Issues In Managing Idiopathic Short Stature Addressed in New Guidelines

Pediatric Endocrine Society offers updated recommendations for use of growth-promoting hormone therapy and related medications in children.

Written by Adam Marcus

With Adda Grimberg, MD and Tamara L Wexler, MD, PhD

New guidelines from the Pediatric Endocrine Society (PES) seek to help clinicians better manage children when treatment with growth hormone and related medications are under consideration to augment idiopathic short stature. The guidelines appear in the latest issue of Hormone Research in Paediatrics.

The Guidelines for Growth Hormone and Insulin-Like Growth Factor-1 Treatment in Children and Adolescents,1 updated from 2003, reflect the continuing controversy over how to diagnose, categorize and treat growth failure in children, according to the authors, reporting on behalf of the PES Drug and Therapeutics Committee and Ethics Committee.   

Among the major changes in the recommendations,1 recombinant insulin-like growth factor-1 (IGF-1) should be considered a front-line therapy for children eligible for treatment with growth-boosting hormones. 

Consider severity of hormonal insufficiency 

“There are strong supporting evidence and general agreement regarding the restoration of hormonal normalcy in children with a severe deficiency of growth hormone (GH) or IGF-I,” said Adda Grimberg, MD, a pediatric endocrinologist at the University of Pennsylvania Perelman School of Medicine, who led the guidelines panel.

“More complex is issues related to the use of GH treatment to increase growth rates and heights of otherwise healthy short children with either idiopathic short stature (ISS) or partial isolated idiopathic GH deficiency (GHD), who are distinguished from each other only by their GH testing results,” Dr. Grimberg told EndocrineWeb.

“Because ISS remains a controversial indication, and diagnostic challenges often blur the distinction between ISS, GHD, and primary IGF-I deficiency [PIGFD], this guideline statement focused on these 3 diagnoses and added recombinant IGF-I therapy to the GH guidelines for the first time,” Dr. Grimberg added.

Idiopathic short stature is defined as height less than 2.5 standard deviations below the mean—a definition that applies to roughly 500,000 children in the United States.2

These children do not have a deficiency in growth hormone, yet some respond to treatment with a synthetic form of growth hormone approved by the Food and Drug Administration in 2003. Since then, the agency also has approved IGF-1 for use in children with severe PIGFD.

An estimated 4,000 to 10,000 children in the United States have true growth hormone deficiency. 3 Although many of them can attain a normal height with treatment, the therapy is not universally effective. 

7 key guideline changes

The panel of experts from the United States and Canada reserved its strongest recommendations for 7 areas:

An area of particular concern for families considering growth-promoting medication for a child is the expense. Growth hormone therapy costs as much as $50,000 for every inch of height gained—a hefty price tag that “is difficult to justify for those in whom it is unclear if there are benefits of treatment,” the authors wrote.  However, most health plans consider treatment for GHD a medical necessity and may offer reimbursement.

Even so, short stature is not a disease, and adult height is not necessarily linked to a better quality of life, the panelists stressed that clinicians should not feel they have to prescribe medication.

“No treatment at all is also a very reasonable option,” stated the authors. “Psychological counseling should always be offered for patients suffering due to their stature, either in addition to or instead of hormone treatment as appropriate, although the efficacy of counseling for short stature has not been rigorously evaluated.”

Dr. Grimberg said future research should focus on developing better outcome measures for the treatment of short stature—including quality of life—and more refined diagnostic tests.

“Evidence-based practice innovation will be hampered without clearly defining what we are trying to achieve and whom we are studying,” she said.

Clinical considerations regarding GH guidelines in Peds

“The guidelines1 carefully detailed the manner in which existing research on growth hormone (GH) deficiency in pediatrics was analyzed, and some of the limitations inherent in comparing studies,” said Tamara L Wexler, MD, PhD,  director of the Pituitary Center at NYU Langone Medical Center in New York, NY.

In commenting on growth hormone replacement in the pediatric population, it’s instructive to refer to the adult guidelines on GH treatment4 as well as the EndoScan, Growth Hormone: the Goldilocks Effect, Dr. Wexler said. “In general, there are more situations in which GH treatment is indicated for children and adolescents, than for adults (as discussed later).”

“The lack of available diagnostic tests has received increasing focus in trying to establish GH recommendations,” said Dr. Wexler. As such, the authors cautioned against reliance solely on strict criteria for GH deficiency from provocative testing, raising the question of whether this might impact updates to adult guidelines,4 as well, she told EndocrineWeb. “In adults, provocative testing is considered unnecessary when there is a known reason for GHD, such as pituitary tumor,4 and in the presence of 3 or more pituitary deficiencies whereas in children and adolescents, provocative testing is considered unnecessary when at least 1 pituitary deficiency, beyond short stature, is present (guideline 2.1.1).1

“The transition from adolescence to adulthood is also addressed, with the recommendation that select patients be tested again for GH deficiency in adulthood after one month off GH replacement; this is line with the adult guidelines,”4 said Dr. Wexler.

Proceed to provocative testing

“However, the recommendation is to proceed to provocative testing if IGF-1 is low. IGF-1 is an imperfect screen as an IGF-1 level in the normal range can be seen in individuals with GHD diagnosed by provocative testing,” she said. “In adults, a normal IGF-1 level does not exclude GHD but does mandate provocative testing to establish a diagnosis. There are cases in which repeating provocative testing may be reasonable even in the face of an IGF-1 that falls within the age-matched normal range.”

“Interestingly, the authors specifically included ISS as well as GHD and PIGF1D,” said Dr. Wexler.  “In discussing adult height as a primary outcome, the ISS encompassed a heterogenous population.” Also, the term idiopathic short stature was used differently across studies, and in some cases, ISS encompassed a host of contributors to short stature, including familial short stature, constitutional delay of growth and puberty, or of unknown causes,5-7 she said. “It has been suggested that ISS should not include FSS or CDGP,5 and decisions regarding treatment should be decided individually. 

The guidelines, by Dr. Grinspoon and her colleagues, “offers a useful guide to current thinking on GH use in children and adolescents, as well as in interpreting existing evidence,” Dr. Wexler told EndocrineWeb.

These used guidelines on managing short stature in children are the first on the subject to follow methodology from the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) group and the first to be endorsed by the ethics committee of the Pediatric Endocrine Society.

Those interviewed had no conflicts of interest to disclose.

To review the full guidelines, go to: Horm Res Paediatr.

Sources

  1. Grimberg A, DiVall SA, Polychronakos C et al. Guidelines for Growth Hormone and Insulin-Like Growth Factor-I Treatment in Children and Adolescents: Growth Hormone Deficiency, Idiopathic Short Stature, and Primary Insulin-Like Growth Factor-I Deficiency Horm Res Paediatr 2016;86:361-397
  2. American Association of Clinical Endocrinologists Position Statement Growth Hormone Usage in Short Children. Available at https://www.aace.com/files/position-statements/shortchildren.pdf. Accessed January 30, 2017.
  3. Sinha SK. Short Stature. Medscape Website]. Available at: http://emedicine.medscape.com/article/924411-overview. Accessed on January 31, 2017.
  4. Molitch MEClemmons DRMalozowski SMerriam GRVance ML. Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(6):1587-609.

  5. Pedicelli S,  Peschiaroli E, Violi E, Cianfarani S. Controversies in the Definition and Treatment of Idiopathic Short Stature (ISS). J Clin Res Pediatr Endocrinol. 2009;1(3):105–115.

  6. Jameson LJ, De Groot L. Endocrinology: Adult and Pediatric, 2-Volume Set. 7th ed. Philadelphia, Pennsylvania: Saunders; 2015.

  7. Oxford Textbook of Endocrinology and Diabetes. 2nd Ed. Wass JAH, Stewart PM, eds. New York, New York: Oxford University Press;2011.

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