Evolving Paradigms in the Clinical Diagnosis and Treatments of Short Stature

Overview

Management of patients with growth disorders is becoming increasingly complex, with a range of medications that may affect a patient’s growth and expanding uses of growth hormone treatment. Pediatric endocrine physicians and nurses must also be able to counsel patients who are not candidates for treatment. This monograph will review medications that have an impact on growth, as well as the conditions for which growth hormone therapy is indicated. Importantly, strategies for working with families with normal variant short stature, for which growth hormone therapy is not indicated, will be discussed.

CME Learning Objectives

At the conclusion of this activity, participants should be able to:

• Identify at least two medications that may inhibit growth in pediatric patients.
• Describe new indications for growth hormone treatment.
• Outline plans for working with patients for whom growth hormone treatment is not indicated.

For questions about this CME activity, please contact cme@VindicoMedEd.com.

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Faculty and Planning Committee

Terri H. Lipman, PhD, CRNP, FAAN Mitchell E. Geffner, MD
Denise Gruccio-Paolucci, MSN, CRNP
Stephen F. Kemp, MD, PhD Medical Writer
Peter A. Lee, MD, PhD Valerie Zimmerman, PhD

External Reviewer

Mitchell E. Geffner, MD

Medical Writer

Valerie Zimmerman, PhD

Disclosures:

In accordance with the Accreditation Council for Continuing Medical Education’s Standards for Commercial Support, all CME providers are required to disclose to the activity audience the relevant financial relationships of the planners, teachers, and authors involved in the development of CME content. An individual has a relevant financial relationship if he or she has a financial relationship in any amount occurring in the last 12 months with a commercial interest whose products or services are discussed in the CME activity content over which the individual has control. Relationship information appears on this page and the next page.

The authors disclose that they do have significant financial interests in any products or class of products discussed directly or indirectly in this activity, including research support.

Faculty members report the following relationship(s):

Terri H. Lipman, PhD, CRNP, FAAN
No relevant financial relationships to disclose.

Denise Gruccio-Paolucci, MSN, CRNP
No relevant financial relationships to disclose.

Stephen F. Kemp, MD, PhD
Consulting Fee: Genentech, Inc., Pfizer, Inc., Sandoz
Speakers’ Bureau: Genentech, Inc., Pfizer, Inc., Sandoz

Peter A. Lee, MD, PhD
Consulting Fee: Novo Nordisk

External reviewer reports the following relationship(s):

Mitchell E. Geffner, MD
Speakers’ Bureau: Eli Lilly, EMD-Serono, Genentech, Inc., Novo Nordisk, Pfizer, Inc., Tercica, Inc., Sandoz
Research Contract: Eli Lilly, Genentech, Inc., Novo Nordisk, Pfizer, Inc., Tercica, Inc.
Advisory Board: EMD-Serono, Genentech, Inc., Pfizer, Inc., Tercica, Inc., Teva Pharmaceuticals
Research Grant: Genentech, Inc., Pfizer, Inc.
Grant Review Board: Genentech, Inc.

Medical writer reports the following relationship(s):

Valerie Zimmerman, PhD
No relevant financial relationship to disclose

Signed disclosures are on file at Vindico Medical Education, Office of Medical Affairs and Compliance.

Target Audience

This program is designed for infectious disease specialists.

Unlabeled and Investigational Usage

The audience is advised that this continuing medical education activity may contain references to unlabeled uses of FDA-approved products or to products not approved by the FDA for use in the United States. The faculty members have been made aware of their obligation to disclose such usage. All activity participants will be informed if any speakers/authors intend to discuss either non-FDA approved or investigational use of products/devices.

Created and published by Vindico Medical Education®, 6900 Grove Road, Building 100, Thorofare, NJ 08086-9447. Telephone: 856-994-9400; Fax: 856-384-6680. Printed in the USA. Copyright© 2009 Vindico Medical Education®. All rights reserved. No part of this publication may be reproduced without written permission from the publisher. The material presented at or in any of Vindico Medical Education® continuing medical education activities does not necessarily reflect the views and opinions of Vindico Medical Education®. Neither Vindico Medical Education® nor the faculty endorse or recommend any techniques, commercial products, or manufacturers. The faculty/authors may discuss the use of materials and/or products that have not yet been approved by the United States Food and Drug Administration. All readers and continuing education participants should verify all information before treating patients or utilizing any product.

This continuing medical education activity is sponsored by Vindico Medical Education.

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	Introduction Terri H. Lipman, PhD, CRNP, FAAN Course Chair Professor of Nursing of Children University of Pennsylvania School of Nursing Philadelphia, PA
	Impact of Pharmaceuticals on Growth Stephen F. Kemp, MD, PhD Professor of Pediatrics and Medical Humanities University of Arkansas for Medical Sciences Arkansas Children’s Hospital Little Rock, AR
	The Many Faces of Growth Hormone Treatment: Indications for Growth Hormone Treatment in Pediatrics Peter A. Lee, MD, PhD Professor of Pediatrics, Penn State College of Medicine The Milton S. Hershey Medical Center Hershey, PA Department of Pediatrics, University of Indiana School of Medicine Riley Hospital for Children Indianapolis, IN
	The Child with Normal Variant Short Stature: Working with Families When Treatment Is Not Indicated Denise Gruccio-Paolucci, MSN, CRNP Nurse Practitioner Division of Endocrinology and Diabetes The Children’s Hospital of Philadelphia Philadelphia, PA

Introduction

Heightism is discrimination because of stature. Short stature is second only to obesity as the most common reason for children being teased and bullied in school.¹ Results of a survey of 999 parents who sought genetic counseling revealed that 10% would choose taller stature for their children if they could.² There is societal discrimination against those with short stature. For example, a person 6 ft tall earns nearly $166,000 more during a 30-year career than someone who is 5 feet 5 inches, after controlling for gender, age, and weight.³ In the political arena, since the advent of television, the taller presidential candidate has won every election, with the exception of Jimmy Carter and George W. Bush. It is important, therefore, to acknowledge that heightism exists and that it is a valid concern for both children and parents.

Growth hormone therapy has been available for more than 50 years, and the indications for treatment continue to increase. Growth failure has a multitude of causes including medications that disrupt the growth hormone axis. Practitioners must be knowledgeable about the conditions that cause growth failure and when growth hormone may have an important role in reversing poor growth. All patients with short stature, however, are not candidates for growth hormone therapy. The practitioner’s involvement with these children and their families can be quite beneficial in situations where adaptive measures are more important than medication.

Vindico Medical Education organized a panel of experts to discuss those issues related to short stature and provide guidance to practitioners who work with affected children. The important topics that were presented and are summarized in this monograph include medications that can impact growth, new indications for treatment with growth hormone, and how to work with children with normal variant short stature.

I thank the panel for their contribution to the discussion and to the development of this monograph, which will provide readers with valuable information that can help improve the services they provide to their patients with short stature.

Terri H. Lipman, PhD, CRNP, FAAN
Course Chair

References

1. Voss LD, Mulligan J. Bullying in school: Are short pupils at risk? Questionnaire study in a cohort. BMJ. 2000 Mar 4; 320(7235): 612-613.
2. Hathaway F, Burns E, Ostrer H. Consumers' desire towards current and prospective reproductive genetic testing. Journal of Genetic Counseling. 2009 Apr; 18(2): 137-146.
3. Judge TA, Cable DM. The effect of physical height on workplace success and income: Preliminary test of a theoretical model. The Journal of Applied Psychology. 2004 Jun; 89(3): 428-441.

Impact of Pharmaceuticals on Growth

Stephen F. Kemp, MD, PhD

The growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis defines the myriad effects and interactions of these 2 compounds that are essential for normal growth. This axis can be disrupted by several pharmaceuticals, particularly glucocorticoids, including inhaled as well as oral formulations. In addition, attention deficit hyperactivity disorder (ADHD) stimulant medications may be associated with adverse effects of growth.

Glucocorticoids and Growth

Glucocorticoids are known to affect many steps in the GH/IGF-I axis (Figure 1). They can inhibit growth secretion, GH binding to its receptor (type 1 IGF receptor), production of IGF-I, and the actual growth that occurs at the growth plates.

Understanding the potential for growth inhibition by exogenous glucocorticoids begins with consideration of normal physiologic cortisol (hydrocortisone) production, which is ~7 mg/m²/d and that, in comparison, prednisone is 4 to 5 times more potent. Experience treating patients with congenital adrenal hyperplasia indicates that 15 mg/m²/d to 20 mg/m²/d of hydrocortisone equivalents (about twice the physiologic dose) may suppress the hypothalamic-pituitary-adrenal axis and that growth suppression also can occur with doses in the upper part of this range. Accordingly, practitioners must be aware of the adverse consequences of giving too little hydrocortisone and having undesirable bone age advancement in these patients, and of giving too much hydrocortisone with its associated interference with growth.

Inhaled glucocorticoids are in widespread use as treatment for allergic rhinitis and asthma, with the advantage of delivering clinically effective doses directly to the target tissues, with minimal systemic absorption. Variable data regarding the potential effect of inhaled glucocorticoids on growth exist. One study showed no differences in growth velocities in patients given either placebo, fluticasone propionate 50 µg/d, or fluticasone propionate 100 µg/d for up to 52 months.¹ In other studies, although daily doses of beclomethasone 100 µg and 200 µg for 2 weeks did not alter urinary free cortisol or cortisol metabolites,² some children who were taking inhaled beclomethasone dipropionate and budesonide for 12 months were shown to experience slight, but not negligible, growth suppression,³ and children treated with inhaled budesonide or beclomethasone for 12 months had lower levels of markers of collagen and bone synthesis.⁴ In addition, in a recent study, children receiving < 400 µg/d of beclomethasone (budesonide equivalent) for 2 years experienced an 18% decrease in height standard deviation score (sds). when the glucocorticoids were tapered, however, a growth spurt was triggered and the height sds returned to starting values.⁵

The National Cooperative Growth Study (NCGS) is an observational database started in 1985, which is part of a long-term longitudinal study following more than 50,000 pediatric patients with growth disorders who are undergoing GH treatment in the United States and Canada. Data from the NCGS showed that children with growth retardation while taking glucocorticoids experienced a doubling in their growth velocity during treatment with GH.⁶ In a small study of 7 children, the magnitude of the response to growth hormone was shown to be inversely proportional to the prednisone dose.⁷ Therefore, treatment with GH can overcome some of this growth suppression.

ADHD Stimulant Medications and Growth

An increasing number of children who are taking ADHD stimulant medications are being referred for short stature. A recent study of approximately 300 children in the Multimodal Treatment Study of Children with ADHD who were followed for up to 3 years found that children taking ADHD stimulant medications experienced slower growth rates after treatment was started.⁸ Results from a literature review of children followed for at least 1 year, however, showed that modestly reduced height and weight velocities during childhood were attenuated over time, and some data suggest normal adult stature is ultimately achieved.⁹ More studies are needed to determine the effects of continuous treatment from childhood to adulthood.

The NCGS database has also served as a resource for investigating ADHD medications being taken by children on GH therapy. Children with ADHD in the NCGS database received ADHD medication at a greater rate than in the general population (83% vs. 56%). This may reflect a bias in the NCGS database toward treated children, or ADHD medications may cause growth failure that results in the referral of these patients for short stature follow-up.¹⁰

Results of a search of the database from its inception through 2004 for patients who were taking medications for ADHD revealed that approximately 47% were classified as having idiopathic growth hormone deficiency, 21% had idiopathic short stature (ISS), 13% had organic causes for short stature, 5% had Turner syndrome, and 14% had other forms of growth suppression.¹⁰ These results were consistent with the general distribution of diagnoses among children in the database who were not taking ADHD medication; accordingly, from these data, ADHD treatment does not appear to be associated with a specific diagnosis. However, trends in the number of children in the database who were taking ADHD medications showed a clear increase with time. By 2004, almost 6% of children in the database were on ADHD stimulant medications. This is consistent with the reported prevalence of ADHD in the pediatric population in the United States ranging from 2% to 18%.^11,12 The increase may reflect the perceived increased prevalence of ADHD in the population in general, which may be the result of improved diagnosis or, conversely, an increased false-positive diagnosis rate.

To further evaluate the relationship between ADHD and short stature, investigators compared NCGS data for GH-treated children with idiopathic GH deficiency (IGHD) or ISS with or without concomitant stimulant treatment for ADHD.¹⁰ Children treated for ADHD (both at baseline and at 1 year of GH treatment) had a statistically significantly lower BMI than the population treated with GH, but who were not treated for ADHD; however, their height SDS and growth velocities were not significantly different from those of their counterparts not treated for ADHD. Comparing children with IGHD and children with ISS separately yielded similar results.

The majority of children who require GH therapy are boys, at a 3:1 boy to girl ratio; however, among children with ADHD who are taking GH, the ratio is even greater; that is, a 9:1 boy to girl ratio. This may reflect that male patients are more likely to be treated with GH than females, similar to male patients being more likely to be treated for ADHD. Combining the 2 male-predominated situations may produce a combined increased prevalence in males.

In summary, the prevalence of ADHD in the NCGS database has increased over the past 20 years. The data reveal that the proportion of children in the NCGS database that are on ADHD medications is within the range in the United States pediatric population that are taking ADHD medications. The increase of treated ADHD patients in the NCGS database may be the result of referral bias. The threshold dose of ADHD medications at which growth can be affected has not been determined; however, practitioners should keep a possible effect on growth under consideration when they are managing children who are on ADHD medications. Currently, “although physicians should monitor height, deficits in height and weight do not appear to be a clinical concern for most children treated with stimulants.”⁹

References

1. Allen DB, Bronsky EA, LaForce CF, Nathan RA, Tinkelman DG, Vandewalker ML, Konig P. Growth in asthmatic children treated with fluticasone propionate. Fluticasone propionate asthma study group. The Journal of Pediatrics. 1998 Mar; 132(3 Pt 1): 472-477.
2. Wolthers OD. Short-term growth and adrenal function in children with asthma treated with inhaled beclomethasone dipropionate hydrofluoroalkane-134a. Pediatric Allergy and Immunology. 2006 Dec; 17(8): 613-619.
3. Allen DB. Influence of inhaled corticosteroids on growth: a pediatric endocrinologist's perspective. Acta Paediatrica. 1998 Feb; 87(2): 123-129.
4. Crowley S, Trivedi P, Risteli L, Risteli J, Hindmarsh PC, Brook CG. Collagen metabolism and growth in prepubertal children with asthma treated with inhaled steroids. The Journal of Pediatrics. 1998 Mar; 132(3 Pt 1): 409-413.
5. Anthracopoulos MB, Papadimitriou A, Panagiotakos DB, Syridou G, Giannakopoulou E, Fretzayas A, Nicolaidou P, Priftis KN. Growth deceleration of children on inhaled corticosteroids is compensated for after the first 12 months of treatment. Pediatric Pulmonology. 1998 May; 132(5): 409-413.
6. Allen DB, Julius JR, Breen TJ, Attie KM. Treatment of glucocorticoid-induced growth suppression with growth hormone. National cooperative growth study. The Journal of Clinical Endocrinology and Metabolism. 1998 Aug; 83(8): 2824-2829.
7. Rivkees SA, Danon M, Herrin J. Prednisone dose limitation of growth hormone treatment of steroid-induced growth failure. The Journal of Pediatrics. 1994 Aug; 125(2): 322-325.
8. Swanson JM, Elliott GR, Greenhill LL, Wigal T, Arnold LE, Vitiello B, Hechtman L, Epstein JN, Pelham WE, Abikoff HB, Newcorn JH, Molina BS, Hinshaw SP, Wells KC, Hoza B, Jensen PS, Gibbons RD, Hur K, Stehli A, Davies M, March JS, Conners CK, Caron M, Volkow ND. Effects of stimulant medication on growth rates across 3 years in the MTA follow-up. Journal of the American Academy of Child and Adolescent Psychiatry. 2007 Aug; 46(8): 1015-1027.
9. Faraone SV, Biederman J, Morley CP, Spencer TJ. Effect of stimulants on height and weight: A review of the literature. Journal of the American Academy of Child and Adolescent Psychiatry. 2008 Sep; 47(9): 994-1009.
10. Frindik JP, Fowlkes JL, Kemp SF, Thrailkill KT, Morales A, Dana K Increasing prevalence of stimulant medication use in children with growth hormone deficiency or idiopathic short stature: An NCGS database analysis summary. Hormone Research. In press.
11. Daley KC. Update on attention-deficit/hyperactivity disorder. Current Opinion in Pediatrics. 2004 Apr;16 (2): 217-226.
12. Center of Disease Control and Prevention. Mental health in the United States: Prevalence of diagnosis and medication treatment for attention-deficit/hyperactivity disorder --- United States, 2003. Morbidity and Mortality Weekly Report. 2005 Sep; 54(34): 842-874.

The Many Faces of Growth Hormone Treatment: Indications for Growth Hormone Treatment in Pediatrics

Peter A. Lee, MD, PhD

Growth hormone therapy has been available for more than 50 years, starting with the use of natural hormone obtained from cadaveric pituitaries. Recombinant growth hormone became available in 1985, coincident with discontinuing the distribution of natural growth hormone in response to contamination of some batches with the Creutzfeld-Jacob virus. There are 11 FDA-approved indications for growth hormone, of which 8 address children with short stature (Table 1). This section of the monograph provides a review of indications for short stature that have been approved since 2000.

Prader-Willi Syndrome

Prader-Willi syndrome causes height problems for most of the patients who have this disorder. In addition, it is the most commonly recognized genetic form of obesity. Seventy percent of cases result from paternally derived chromosome 15q11-13 deletion, 25% from maternal disomy of chromosome 15, and 5% from an imprinting defect. The incidence of Prader-Willi syndrome is 1 in 10,000 to 1 in 15,000.

Slightly more than three-fourths of patients with Prader-Willi syndrome have short stature. More common characteristics include mental deficiency with an intelligent quotient of 65 to 70 (97%), hypogenitalism/hypogonadism (95%), early-onset obesity (94%), infantile hypotonia (94%), and small hands and feet (83%). Characteristic facies include a narrow bifrontal diameter, dolichocephaly, almond-shaped eyes, and triangular mouth (down-turned corners).

Several differences between a child with simple exogenous obesity and a child with Prader-Willi syndrome must be considered, including normal or accelerated growth rate and stature in normal obese children compared with slow growth rate and short stature in children with Prader-Willi syndrome (Table 2).

Overall, patients with Prader-Willi syndrome have a greater ratio of fat mass to lean body mass than do obese patients, with the difference reaching and maintaining significance after 12 years of age.¹ In addition, a significantly higher percentage of body fat than that seen in their unaffected obese counterparts is consistent for both boys and girls with Prader-Willi syndrome.² One of the effects of growth hormone therapy is a shift in body composition, and this also occurs in children with Prader-Willi syndrome who are treated with growth hormone.³ In a controlled study, 1 group of children with Prader-Willi syndrome was treated with growth hormone 0.33 mg/kg/d for 2 years. A second group was treated with growth hormone 0.66 mg/kg/d starting in the second year. The lean mass:fat mass ratio was significantly greater in the group receiving growth hormone in the first year compared with that in patients who had not yet started therapy (P=.004). An additional benefit of growth hormone therapy in patients with Prader-Willi syndrome is its dramatic effect on the typical phenotype seen in these patients. In fact, after GH therapy, it may be difficult to distinguish a GH-treated person with the disorder from a person without the condition.

Risks associated with growth hormone treatment in Prader-Willi syndrome have been suggested to include scoliosis. The prevalence of scoliosis is, however, considerably higher in untreated patients with Prader-Willi syndrome (30% to 80% depending on age) compared with the general population (3%).⁴ In fact, a recent multicenter randomized controlled trial showed no difference in onset of scoliosis or curve progression between growth hormone-treated children and controls.⁵ In addition, because patients with Prader-Willi syndrome often have the complications of obesity including glucose intolerance and type 2 diabetes, children with Prader-Willi syndrome and growth hormone deficiency should be monitored for glucose intolerance during growth hormone treatment.

Another concern relates to several deaths that have been reported in children with Prader-Willi syndrome who were taking growth hormone therapy.⁶ Therapeutic risk cannot be conclusively assessed at this time; however, because no population-based studies or multicenter trials suggest that the death rate, which is 3%/year in patients with Prader-Willi syndrome who do not take growth hormone, is increased with growth hormone therapy. However, assessment before therapy and surveillance during therapy are recommended to control risks.^7,8 Before therapy, sleep apnea, respiratory distress, and adrenal insufficiency should be assessed. Respiratory distress should continue to be monitored during therapy and a sleep study should be repeated 3 to 6 months after starting therapy. Cortisol status should be monitored during stress while on therapy, for example, when the child is ill, because these patients may not have a typical symptomatic response to stress.

Small for Gestational Age (SGA)

By definition, the child born small for gestational age (SGA) has a length or weight =2 standard deviations below the mean for his gestational age. Because intrauterine growth retardation (IUGR) refers to a deviation and reduction in the expected fetal growth pattern, not all IUGR infants are SGA; similarly, not all small fetuses are growth-restricted.

Diagnosis of SGA is based on physical findings. There are many potential fetal, maternal, and placental etiologies including infection, malnutrition, chromosomal abnormalities, and toxins. In addition, in 40% of cases, the pathology is not identified. Accordingly, some SGA individuals may not respond as well as others to growth hormone therapy.

Compensatory growth generally occurs in these children, and the prognosis is better for children who do not have dysmorphic features. Up to 90% of non-dysmorphic children born SGA reach normal stature, with at least 80% achieving a height within the normal range in the first 6 months and 90% by age 2 years.^9,10 Growth rates for SGA children may be normal, accelerated, or subnormal. Insulin-like growth factor-I (IGF-I) levels and IGF binding protein-3 (IGFBP-3) levels vary from low to normal. Bone age is not predictive of growth potential; it may advance rapidly, particularly around the time of the onset of puberty, without appropriate concomitant growth.

For the 10% of SGA children who continue to be classified as short stature beyond the age of 3 years, growth hormone therapy can help them achieve catch-up growth in early childhood, maintain that growth, and achieve normal adult height. In the Nordinet International Outcome Study, SGA children started on growth hormone at a lower height (>-3 standard deviation score [SDS]) than did children with either congenital (< -3 sds) or acquired growth hormone deficiency (< 2.5 sds) who were also in the study. their 1-year and 2-year response to gh therapy, however, paralleled that of the other children, reaching < -2.5 sds at the end of 2 years (lee pa, et al, unpublished results).

In a study of 79 SGA boys and girls who were treated with growth hormone for 5 years, almost all of the children reached a height percentile within the normal range and were projecting toward their target height (Figure 1).¹¹ Importantly, the change in height SDS curves after 2 years of therapy show that, regardless of dose, response to growth hormone treatment is better when a child is started on treatment at an earlier age. With SGA children, therefore, if the child’s growth has not allowed him or her to reach a normal percentile by 2 years of age, the child is not going to catch up spontaneously. Accordingly, growth hormone treatment should be started at that time.

In summary, for SGA children whose height has not reached the normal range by the age of 2 years, growth hormone therapy should be considered. A standard workup for short stature should be performed. Practitioners should remember that SGA does not exclude growth hormone deficiency. If the rate of growth is normal, GH testing may not be indicated. In addition, IGF-I and IGFBP-3 values provide baseline markers that can be useful in monitoring growth hormone therapy. Finally, bone age is unreliable for adult height prediction in SGA.

Idiopathic Short Stature

Idiopathic short stature (ISS) is not a specific diagnosis; rather, it is a definition of height for children who are not growth hormone-deficient and who were not born SGA. It includes patients with familial short stature and constitutional delay of growth in puberty who meet the FDA-established height criteria, that is, >2.25 SDS below the mean height for their age and gender. It has been hypothesized that three-fourths of patients with short stature are in this category. These patients will likely respond to growth hormone, which is indicated in cases that fulfill the following criteria established by the FDA:

• Height < -2.25 sds
• Growth rate that is unlikely to attain an adult height within the normal range
• No diagnosis of growth hormone deficiency
• Open epiphyses

Short Stature Homeobox-containing Gene on the X-chromosome Deficiency

An estimated 2% to 5% of patients in the ISS category have Short Stature Homeobox-containing Gene on the X-chromosome (SHOX) deficiency. Patients with Turner syndrome, which was approved as an indication for growth hormone therapy in 1996 and which also has a SHOX mutation involved, have a similar deficiency in height, and responses to growth hormone are also similar among patients with Turner syndrome patients and patients with SHOX gene deficiency.¹²

The role of the SHOX gene is not completely understood, although many advances have been made since its discovery in 1997. It is known to encode a transcription factor that contains a protein homeodomain, which binds DNA in a specific manner and achieves its effects through the formation of complexes with other transcription factors. The target genes and specific mechanism of action are unknown. The gene appears to be involved in cartilage and bone formation; accordingly, findings characteristic of SHOX gene deficiency involving bony malformations similar to those seen in Turner syndrome are stigmata-related to SHOX.

Patients with SHOX gene deficiency who are treated with growth hormone show significantly improved growth compared with untreated patients with SHOX deficiency. Growth patterns are similar to those for treated patients with Turner syndrome for both height velocity and height standard deviation scores.¹³

Noonan Syndrome

Noonan syndrome was first recognized as a unique entity in 1963 by Noonan and Ehmke.¹⁴ Similar to patients with Prader-Willi syndrome, patients with Noonan syndrome have a variety of health issues that may include multiple malformations, the most severe of which is congenital heart disease, present in approximately 50% of affected persons. Patients with Noonan syndrome have some characteristics similar to patients with Turner syndrome. Cardinal features include unusual facies (hypertelorism, down-slanted eyes, and webbed neck), short stature, and pectus carinatum or pectus excavatum chest deformities. Some individuals have mental retardation, bleeding diathesis, and skeletal, neurologic, genitourinary, lymphatic, eye, and skin findings. Accordingly, the most significant health problems in these patients may not be their height.

Both sporadic and autosomal dominant cases have been identified. Mutations in 4 specific genes (and their frequencies) have been shown to be associated with clinically diagnosed Noonan syndrome:

• PTPN11 (~50%)
• SOS1 (~10%)
• RAF1 (~3%-17%)
• KRAS (~1%)

The PTPN11 mutation may be associated with inadequate generation of IGF-I during growth hormone therapy¹⁵ and a reduced growth response to long-term growth hormone treatment has been reported.¹⁶ A recent study, however, found similar responses to growth hormone therapy in children with Noonan syndrome with and without the mutation.¹⁷ Growth hormone has also been used successfully to treat patients with Noonan syndrome with other mutations and most children achieve a height within the normal range for their age. As with other conditions, children with multiple problems must receive multidisciplinary care targeting the improvement of not only their physical health, but also their social and psychological health.

In summary, growth hormone therapy has a valuable role in the management of people with short stature emanating from many etiologies. The variable manifestations of these conditions emphasize the obligation for practitioners to understand and apply current best practices aimed at improving their patients’ overall health and quality-of-life.

References

1. Brambilla P, Bosio L, Manzoni P, Pietrobelli A, Beccaria L, Chiumello G. Peculiar body composition in patients with prader-labhart-willi syndrome. The American Journal of Clinical Nutrition. 1997 May; 65(5): 1369-1374.
2. Bekx MT, Carrel AL, Shriver TC, Li Z, Allen DB. Decreased energy expenditure is caused by abnormal body composition in infants with prader-willi syndrome. The Journal of Pediatrics. 2003 Sep; 143(3): 372-376.
3. Myers SE, Carrel AL, Whitman BY, Allen DB. Sustained benefit after 2 years of growth hormone on body composition, fat utilization, physical strength and agility, and growth in prader-willi syndrome. The Journal of Pediatrics. 2000 Jul; 137(1): 42-49.
4. Diepstraten A, Linge B, Swierstra B. Afwijkingen van de wervelkolom. In: Kinderorthopedie. 2nd ed. Maarssen, The Netherlands: Elsevier gezondheidszorg: 2001; 43-47.
5. de Lind van Wijngaarden RF, de Klerk LW, Festen DA, Duivenvoorden HJ, Otten BJ, Hokken-Koelega AC. Randomized controlled trial to investigate the effects of growth hormone treatment on scoliosis in children with prader-willi syndrome. The Journal of Clinical Endocrinology and Metabolism. 2009 Apr; 94(4): 1274-1280.
6. Lee PDK. Growth hormone and mortality in prader-willi syndrome. Growth, Genetics & Hormones. 2006 Jun; 22(2): 17-23.
7. Butler MG, Garg U. Cortisol levels in prader-willi syndrome support changes in routine care. American Journal of Medical Genetics Part A. 2009; 149A(2): 138-139.
8. 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. The Journal of Clinical Endocrinology and Metabolism. 2008 May; 93(5): 1649-1654.
9. Karlberg JP, Albertsson-Wikland K, Kwan EY, Lam BC, Low LC. The timing of early postnatal catch-up growth in normal, full-term infants born short for gestational age. Hormone Research. 1997; 48: Suppl 1: 17-24.
10. Albertsson-Wikland K, Karlberg J. Postnatal growth of children born small for gestational age. Acta paediatrica. Supplementum. 1997 Nov; 423: 193-195.
11. Sas T, de Waal W, Mulder P, Houdijk M, Jansen M, Reeser M, Hokken-Koelega A. Growth hormone treatment in children with short stature born small for gestational age: 5-year results of a randomized, double-blind, dose-response trial. The Journal of Clinical Endocrinology and Metabolism. 1999 Sep; 84(9): 3064-3070.
12. Leka SK, Kitsiou-Tzeli S, Kalpini-Mavrou A, Kanavakis E. Short stature and dysmorphology associated with defects in the SHOX gene. Hormones (Athens, Greece). 2006 Apr-Jun; 5(2): 107-118.
13. 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. The Journal of Clinical Endocrinology and Metabolism. 2007 Jan; 92(1): 219-228.
14. J. A. Noonan, D.A. Ehmke. Associated noncardiac malformations in children with congenital heart disease. [Abstract]. Journal of Pediatrics. 1963; 63: 468-470.
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Case Presentations

Denise Gruccio-Paolucci, MSN, CRNP

The following case presentations illustrate a few scenarios that often occur in the lives of families dealing with a child’s normal variant short stature (NVSS).

Case 1

Jack is a 10-year-old boy with constitutional delay. His height is just under the 5th percentile, where it has been since he was 6 years of age. Jack and his parents receive constant comments about his size in social situations. Jack’s mother lamented to her practitioner, “I have never been in a position where I felt that I was as completely frustrated and powerless as I was recently when we went to a restaurant. The waitress was trying to be nice and asked Jack, `How old are you?’ When Jack replied, ‘I’m 10,’ she said, ‘Ten?! Oh, my goodness! You look the same size as my 6-year-old.’” Jack’s mother said she froze, and eventually said to the waitress, “What you’re saying is not doing us any favors, and I would appreciate it if we’d stop this conversation about stature.” This is an example of what these families endure.

Issue: Children struggle in social situations and parents feel an obligation to rescue their child.

Case 2

Reed is a 5-year-old boy with familial short stature (FSS), whose height has consistently been at the 3rd percentile. The family is coming for a fourth opinion regarding Reed’s situation. The father, who was also very short as a child, asserts that he does not want his son to experience what he experienced as a short child. The discussion further revealed that the father continues to have unresolved issues about his own short stature, which he appears to be implanting in his son. This exemplifies that the issue with children in such situations is not about treatment, but rather about how the parents define and regard short stature themselves.

Issue: Parents may have their own issues related to short stature which may influence how they themselves perceive the situation at hand and how they parent their child around the topic of short stature.

Case 3

Anthony is a 14-year-old high school freshman who had constitutional delay and just recently started to grow. His height has now reached the 25th percentile, after spending most of his time in middle school below the 5th percentile. Anthony is self-assured, athletic, capable, and personable. At his final visit, he was asked to describe his middle school experience and he replied, “Incredibly frustrating.” He went on, “It was something I couldn’t do anything about. I was good in sports. I was good in school… but I was just so frustrated about my size.” Despite his eventual growth, he will always associate his middle school experience with negativity.

Issue: Short stature during childhood impacts how children and adolescents identify themselves.

Case 4

Jill is a charming 11-year-old girl. Her height is just under the 5th percentile and her predicted adult height is 5’. Her mother, who is 5’5”, openly says in front of the child, “We need to do something about this. Let’s face it, she’s not going to have a normal life with this height. Will she be able to drive a car?!”

Issue: A parent’s definition of short stature and the value they place on stature impacts their response to their child with short stature.

The Child with Normal Variant Short Stature: Working with Families When Treatment Is Not Indicated

Denise Gruccio-Paolucci, MSN, CRNP

In pediatrics, short stature is a common problem and while there are treatments available for short stature resulting from hormone deficiencies, there are also cases of short stature that are not indicative of a medical problem and therefore medical treatment or therapies are not indicated. There is always a population of children considered short who fit the classification of normal variant short stature (NVSS). NVSS can be either familial short stature (FSS), in which case a child is short because of the family’s genetics, or constitutional delay of growth (CDG), in which case a child is a “late bloomer” and may be short during childhood, but will ultimately reach a height consistent with their genetic potential.

Despite being some of the healthiest patients seen by endocrinology providers, caring for them can be very challenging due to their need for ongoing reassurance and guidance. The way practitioners can best help this group of patients is to provide them with valuable tools, tips, and recommendations to help guide them and their parents in handling issues encountered related to short stature. Often, such patients see their endocrinology provider more frequently than their primary care provider, which puts the endocrinology practitioner in a position to talk directly to the child and the family about the issues of FSS or CDG.

Key Issues When Working with Patients with NVSS

While the duration of a child’s short stature is dependent on whether they have familial short stature or constitutional delay, parents must realize that the issue of short stature will not resolve immediately. It is essential to help parents frame their expectations around this reality. Parents often feel frustrated by the lack of a solution, which in turn leads to lingering doubt about whether a medical problem has been missed.

Goals for Working with Families of NVSS Children

There are 2 goals in working with families of children with NVSS:

1. The family will have a clear understanding of NVSS that is reality-based and accurate.
2. The family and child will be empowered to effectively handle issues regarding short stature.

Tips for Working with Families of NVSS Children

Suggestions for providers encompass three primary objectives:

1. Outline realistic expectations and present a longitudinal view of NVSS
2. Provide ongoing education and reassurance
3. Offer tangible parenting tips

1. Outline realistic expectations and a long-term view of constitutional growth delay and familial short stature
Most parents frame their child’s childhood by the school year. Practitioners can use that framework to outline realistic expectations, explaining to the parents what is most likely going to happen in the sixth, seventh, and eighth grades, and emphasizing to the child with constitutional growth delay that this discrepancy may narrow before it widens, while it may not with children with NVSS. These conversations should be started by the fourth or fifth grade, which is an ideal time to prepare parents for what to expect when the child reaches middle and high school.

2. Provide ongoing reassurance
Growth velocity data reviewed at each visit can provide tangible evidence to reassure the parents. If the child is measured accurately at every visit, the practitioner can reassure the parent that the child is growing at a normal velocity. Providing this information at every visit can help to counteract the doubt parents often have about their child’s growth.

3. Offer parenting tips
Parenting the child with short stature can be challenging. Providing tips can be one of the most valuable ways to help families.

1. Reinforce the importance of consistency between parents
   As with all parenting issues, there must be consistency. A father may leave the child at soccer practice saying, “If that kid says one more thing about your height, just knock him over. It’s okay.” The mother may have a totally different approach and tell the child before the next practice, “Before we go to soccer, let’s think about what might happen when Scott tells you that you’re short and why haven’t you grown since Wednesday when he saw you last. How are you going to handle that if it happens? Let’s talk about it.” Parents must agree on a unified approach to handling issues that develop.


2. Emphasize the benefit of positive role modeling
   Regardless of their ages, children sense and model their parents’ behavior. If the father reacts to a comment about his child by becoming argumentative and hostile, then this provides a negative example for the child.


3. Encourage role play
   Role play can help children anticipate situations that may develop. Comments in the restaurant or on the soccer field cannot be controlled, but the child can work to control his responses. Discuss and role play hypothetical situations and work with the child to develop approaches to handle such situations.


4. Facilitate parental self-awareness of feelings related to stature
   Families must be reminded that, despite how the situation affects them as parents or how they may have been affected by their own personal experiences, they must stay focused on the child. Caution parents to avoid retelling their own negative childhood experiences in front of the children, regardless of the child’s age. If the parents are openly talking in the practitioner’s office, they are probably openly talking outside of the visit as well.


5. Suggest the development of a “response toolkit”
   A “response toolkit” is one of the best support mechanisms that can be given to parents. Suggest that families work with their child to “practice” responses. The best responses are ones that are: (1) polite yet assertive, never rude, (2) easy to remember even in situations of high anxiety, and (3) comfortable for a child to use. Work with the child to come up with a short list of responses that he or she can use in social situations when comments are made about stature.

In summary, treating children with NVSS requires a comprehensive approach that can provide the child and his or her family with the knowledge, mind-set, and tools necessary to minimize the adverse situations that are imposed on the child.