Emerging Paradigms in the Clinical Management of Short Stature

Introduction Short stature in today’s clinical practice Terri Lipman, PhD, CRNP, FAAN Diagnosis and evaluation of the pediatric patient with GH deficiency Ron G. Rosenfeld, MD Growth hormone therapy: Guiding the transition into adulthood David B. Allen, MD Working with families of children with short stature Denise Gruccio-Paolucci, MSN, CRNP

Introduction

Approximately 10,000 to 15,000 children in the United States experience growth failure due to growth hormone deficiency. Growth hormone deficiency may occur singularly or in combination with one or more pituitary hormone deficiencies, and may be total or partial. New data suggest that the relationship between GH and IGF-1 may allow clinicians to dose growth hormone based on measurements of serum IGF-1 levels. With the advent of emerging treatments for short stature, refinements in existing diagnostic and testing modalities are necessary and, while a direct serum IGF-1/GH relationship cannot be used to determine dosages, monitoring IGF-1 is essential during long-term GH therapy and can aid in the correct diagnosis of the cause of growth failure. Additional diagnostic and treatment requirements are also experienced by patients who are transitioning into adolescence and adulthood, presenting a clear need to educate on this complex process. The multidisciplinary management of patients with short stature requires attention and understanding to the perspective of the patient and patient’s family - effective shared decision making is always necessary to provide these patients with the best possible care.

At the Pediatric Endocrinology Nursing Society 2008 annual meeting in Cincinnati, Ohio, an expert faculty shared their years of clinical experience to elaborate on these important topics. This CME monograph is based on the proceedings of this symposium. Vindico Medical Education would like to thank the faculty for sharing their expertise, as well as the Pediatric Endocrinology Nursing Society for their unwavering support.

Tim Hayes, MD, PhD
Medical Director
Vindico Medical Education

Terri Lipman, PhD, CRNP, FAAN Associate Professor of Nursing of Children University of Pennsylvania School of Nursing Pediatric Nurse Practitioner Division of Endocrinology Children’s Hospital of Philadelphia Philadelphia, PA. David B. Allen, MD Faculty, University of Wisconsin School of Medicine and Public Health University of Wisconsin Hospital and Clinics Meriter Hospital, St. Mary’s Hospital Madison, WI. Ron G. Rosenfeld, MD Senior Vice-President for Medical Affairs Lucile Packard Foundation for Children’s Health Professor of Pediatrics, Stanford University Professor of Pediatrics, Oregon Health and Science University Professor of Cell and Developmental Biology, OHSU Chairman of Pediatrics, OHSU (emeritus) Palo Alto, CA. Denise Gruccio-Paolucci, MSN, CRNP Nurse Practitioner Diagnostic and Research Growth Center Division of Endocrinology Children’s Hospital of Philadelphia Philadelphia, PA.

Short stature in today’s clinical practice

Terri Lipman, PhD, CRNP, FAAN

The topic of short stature in today’s clinical practice is timely for all endocrine practitioners. Growth is the basis of pediatrics. As James Tanner wrote in 1986, “Growth is the single most important indication of the health of a child.” ¹

Children with growth disorders are a mainstay of the practice of the pediatric endocrine nurse. These nurses are well versed in the importance of accurate growth assessment and are intricately involved with all aspects of the diagnosis, treatment and management of children with short stature.²

Evidence based practice entails conscientious decision making based on available scientific evidence. A review of the research on the diagnosis and management of children with short stature is discussed in this monograph by Ron Rosenfeld, MD. The treatment indications of children with short stature have changed over the years, with additional populations of children being eligible for growth hormone treatment. David B. Allen, MD, presents the indications for treatment, as well as an overview of treatment for adult growth hormone deficiency. Working with children with short stature and their families presents a variety of complexities and challenges. These issues are examined by Denise Gruccio-Paolucci, MSN, CRNP. Ethical issues related to diagnosis and treatment are incorporated in all of the papers in this monograph.

All children have the right to accurate growth assessment and thorough growth evaluation. — Terri Lipman, PhD, CRNP

All children have the right to accurate growth assessment and thorough growth evaluation. Gender and racial disparities exist in the referral, diagnosis and treatment of children with short stature.^3,4 Endocrine clinicians must not only have knowledge of the current research regarding children with growth disorders, but also have the responsibility to educate primary care practitioners and the lay public on the importance of the identification of all children with short stature who are in need of referral and further evaluation.

References

1. Tanner JM. Normal growth and techniques of growth assessment. Clin Endocrinol Metab. 1986; 15:411-451.
2. Lipman TH, Hench KD, Benyi T, et al. A multicentre randomized controlled trial of an intervention to improve the accuracy of linear growth assessment. Arch Dis Child. 2004; 89:342-346.
3. Grimberg A, Stewart E, Wajnrajch M. Gender of pediatric recombinant human growth hormone recipients in the United States and globally. Clin Endocrinol Metabol. 2008; 1210:2007-2617.
4. August GP, Lippe BM, Blethen SL, et al. Growth hormone treatment in the United States: demographic and diagnostic features of 2331 children. J Pediatr. 1990; 116:899-903.

Diagnosis and evaluation of the pediatric patient with GH deficiency

Ron G. Rosenfeld, MD

The heights of children are of great importance to their parents. The following case is representative of the current dilemma that clinicians face in the work-up of a child whose parents request treatment for short stature.

A child measures -2.9 standard deviations (SD) in height. His parents are short but within the broad range of normal, -1.5 to -1.8 SD. The child’s insulin-like growth factor-1 (IGF-1) level is low. Is this child short? If so, what is the etiology? Should growth hormone stimulation tests be performed? If so, which ones? Should cranial magnetic resonance imaging (MRI) be performed? Should this child be treated with growth hormone? Will he respond to growth hormone? What if he does not respond to growth hormone? What are the clinician’s options?

The challenge in defining short stature is that any definition is arbitrary rather than based on physiologic principle. Height fits a Gaussian or “normal” distribution. The Gaussian curve for height is tight. A variation in height of 2 SD represents only approximately 7% of stature, yet height outside of this -2SD is frequently defined as short stature. (Figure1)

Height: The True Gaussian Distribution Figure 1. Recreated courtesy of Ron G. Rosenfeld, MD

Following are facts with respect to stature.

• Any statistical definition of short stature is arbitrary.
• The end of the normal range is unknown. Not enough is known (and it is probably impossible) to discriminate between the lower limits of normal and the upper limits of pathology.
• It is neither practical nor desirable to treat every child with short stature.

No matter how many children are treated for short stature, 5% will always lie below the 5^th percentile, and 1.2% will always be below -2.25 SD.

• Response to treatment is variable.
• · Treatment should be directed at children with the most severe growth failure and the greatest likelihood of responding to specific therapy.

Case continued

What is the diagnosis in this child with a -2.9 SD deviation in height? Is it IGF deficiency, given his low level of IGF? Is it growth hormone (GH) deficiency? If so, how is that determination made? Is it something else, such as Prader-Willi syndrome?

Treatment should be directed at children with the most severe growth failure and the greatest likelihood of responding to specific therapy. — Ron G. Rosenfeld, MD

The IGFs are the major mediators of mammalian growth and probably account for approximately two-thirds of total growth in humans. Like other endocrine systems abnormalities ( e.g. primary and secondary hypothyroidism or primary and secondary hypocortisolism), IGF deficiency can be divided into a secondary form that is caused by a defect in GH secretion or production (i.e. GH deficiency) or into a primary form that is the result of a defect at the level of the GH receptor or the GH receptor signaling cascade or the IGF-1 gene. One of the first responsibilities in treating the case patient is to decide, in the context of short stature and a low IGF-1, whether this child has a secondary IGF deficiency for which the appropriate treatment is GH or whether he has a primary IGF deficiency for which several options can be considered. A broad spectrum of GH secretion and sensitivity exists, and clinicians must be able to use all of their clinical tools to begin to understand an individual case.

Performing GH stimulation tests has been controversial for many years and such tests have numerous limitations. They are nonphysiologic; they rely on arbitrary definitions of normal and abnormal; they are age-and puberty-dependent; they depend upon assays of high variability and poor reproducibility; and they are expensive, uncomfortable and in some cases risky.

Nevertheless, GH stimulation tests are the best method to differentiate GH deficiency from GH insensitivity. If a patient is GH deficient, then GH stimulation tests allow for evaluation of other pituitary functions, such as plasma adrenocorticotropin, gonadotrophin or thyroid-stimulating hormone. They also determine the need for a cranial MRI scan, which is unnecessary if a child is not GH deficient. GH stimulation tests may be relevant genetically, in that the decision to evaluate the child for a hereditary disorder rests on the underlying pathology. These tests also predict the responsiveness to GH treatment. Finally, GH stimulation tests help guide management in adults.

GH stimulation tests

More than 34 provocative GH tests have been described in the literature, and more than 189 combinations of protocols have been published. These tests are performed too often with little regard for the age, gender or pubertal status of the patient.

Virtually no data on GH stimulation tests in normal children are available. The lone well-controlled study of GH stimulation tests in children of normal stature was performed at the National Institutes of Health.¹ Of children who were classified as Tanner 1 and who did not receive ethinyl estradiol priming, 61% failed to achieve a GH level of at least 7 ng/mL. These children would be labeled as GH deficient although they are of normal stature. Among pre-pubertal children without sex steroid priming, peak GH levels were as low as 1.9 ng/mL. When these same children were primed with sex steroids, their peak GH levels ranged from 7.2 to 40.5 ng/mL.

The authors concluded that little value exists in performing a GH stimulation test in pre-pubertal children unless they are primed with sex steroids. In the absence of priming, the specificity of these tests is suspicious.

Reproducibility

The reproducibility of GH stimulation tests was assessed by Tauber and colleagues in 1997.² Children who were labeled as GH deficient were retested as adults. More than 80% of children who had organic GH deficiency were GH deficient when retested as adults. In contrast, 70% of children who were identified as having idiopathic GH deficiency passed a GH stimulation test as adults, almost certainly because they were improperly labeled as GH deficient as children. (Figure 2)

GHST: Reproducibility in Adult Life Figure 2. Adapted from Tauber, M et al. JCEM. 1997;82:352-356

Guidelines for MRI

The clinical presentation and laboratory findings should guide the decision to perform an MRI scan. Little indication exists for performing an MRI scan in short children with normal GH levels. Performing an MRI scan in lieu of a GH stimulation test subjects children who may not be GH deficient to an expensive and often frightening test with little value in establishing a diagnosis for the short stature of the patient.

Should the case patient be treated?

Whether or not to treat the case patient is a complex question. Over the past 20 years a logical conundrum has developed; that is, if a clinician approaches children with short stature logically, then he or she should reach one of two possible conclusions: (1.) GH therapy should be reserved for those children with unequivocal GH deficiency, or (2.) clinicians should accept that auxology plus clinical responsiveness, and not necessarily the underlying diagnosis, should be the determining factor in the decision to treat.

Will this child respond to GH?

If the diagnosis has been established properly, then the child with true GH deficiency will show a good response to GH. — Ron G. Rosenfeld, MD

If the diagnosis has been established properly, then the child with true GH deficiency will show a good response to GH.

Growth response was measured in centimeters per year in GH responsiveness curves that were constructed using postmarketing databases representing several thousand children with the diagnosis of idiopathic GH deficiency.³ An enormous variability in response was observed, with height velocity ranging from 20 cm/yr to no growth response, even though GH therapy was maintained for 1 year.

What if the child does not respond to GH?

Responsiveness should be checked regularly. If a child is not responding, then the clinician should check and recheck compliance. Clinicians should also (1) look for intercurrent illness, (2) consider the rare possibility of antigrowth hormone antibodies, and (3) re-evaluate the diagnosis of GH deficiency, especially if sex steroid priming was not used.

What are the options in poorly responsive patients?

In poorly responsive patients, treatment can be stopped, or other avenues explored.

These approaches may or may not comply with FDA approval, depending upon the specific clinical setting. First, the dosage of GH can be increased. In the case of our patient who is -2.9 SD in height, IGF-1 treatment or a combination of GH and IGF-1 can be considered. Epiphyseal fusion can be delayed by various means, including estrogen antagonists, inhibitors of the enzyme aromatase which is necessary to convert precursor steroids to estrogen, or the use of Gn RH agonists or antagonists . These strategies are reasonable to consider on a case-by-case basis.

In children with GH deficiency, for example, the improvement in growth rate was greater with 0.05 mg/kg/day of GH than with 0.025 mg/kg/day.⁴ (Figure 3)

GHRX: Gain in Height SDS Figure 3. Recreated courtesy of Ron G. Rosenfeld MD

In a randomized study in which the dosage of GH was titrated to the serum IGF-1 level and compared with conventional dosing, children with GH deficiency or idiopathic short stature had larger gains in height with dosing targeted to an IGF-1 z score of +1.5 to +2.5 SD than with conventional dosing or dosing targeted to a lower IGF-1 z score (-0.5 to +0.5). In each dose group, children with GH deficiency had a greater response to therapy than children with idiopathic short stature. For example, on the highest GH dosage, children with idiopathic short stature had gains in height that were equal to those of children with GH deficiency treated conventionally.⁵

Historically, GH has been dosed on a weight basis, but dose adjustments based on GH sensitivity, IGF sensitivity and growth velocity may become the norm if more data confirm the superiority of this approach.

Finally, we are approaching an era in which recombinant IGF-1 alone or in combination with GH may be used to augment growth in a number of situations in which GH alone has not been effective.Trials of these approaches have just begun and their results are awaited with great interest by caregivers and patients alike.

Summary

Proper treatment depends on proper diagnosis. Serum IGF-1 levels are invaluable in the evaluation of short children, provided that the child is not suffering from a malabsorption or other causes of weight loss which places the child below the 10^th percentile for weight. GH stimulation tests, although imperfect and lacking specificity, have a high sensitivity for GH deficiency. For maximum value, the prepubertal child should be primed first with sex steroids. Any child who is treated with GH should be monitored carefully for growth rate and serum IGF-1 levels.

References

1. Marin G, Domene HM, Barnes KM, Blackwell BJ, Cassorla FG, Cutler GB Jr. The effects of estrogen priming and puberty on the growth hormone response to standardized treadmill exercise and arginine-insulin in normal girls and boys. J Clin Endocrinol Metab. 1994; 79:537-541.
2. Tauber M, Moulin P, Pienkowski C, Jouret B, Rochiccioli P. Growth hormone (GH) retesting and auxological data in 131 GH-deficient patients after completion of treatment. J Clin Endocrinol Metab. 1997;82:352-356.
3. Bakker B, Frane J, Anhalt H, Lippe B, Rosenfeld RG. Height velocity targets from the National Cooperative Growth Study for first-year growth hormone responsiveness in short children. J Clin Endocrinol Metab. 2008; 93:352-357.
4. Cohen P, Bright GM, Rogol AD, Kappelgaard AM, Rosenfeld RG. Effects of dose and gender on the growth and growth factor response to GH in GH-deficient children: implications for efficacy and safety. J Clin Endocrinol Metab. 2002; 87:90-98.
5. Cohen P, Rogol AD, Howard CP, Bright GM, Kappelgaard AM, Rosenfeld RG. Insulin-like growth factor-based dosing of growth hormone therapy in children: a randomized, controlled study. J Clin Endocrinol Metab. 2007; 92:1480-1486.

Growth hormone therapy: Guiding the transition into adulthood

David B. Allen, MD

For children and adolescents receiving growth hormone (GH) therapy, determining whether height goals have been met, when and how to discontinue treatment, and whether to transition to adult therapy is a complex process.

Since variability exists in etiology and levels of GH deficiency, a child’s body may or may not resume hormone production and normal maturation after therapy ends. Trial periods off therapy are taken to retest for hormone production and assess for continuing therapy.

When severe GH deficiency persists after height goals are met, an extended period off therapy can result in adverse consequences, leading to low bone mineral density, abnormal body composition, and lower quality of life in terms of energy level and other observed measures. Such factors should be considered when deciding whether and when to terminate therapy and for how long.

The majority of patients on GH therapy are children with isolated GH deficiency. For these otherwise healthy children, the primary purpose of therapy is to increase height. —David B. Allen, MD

The majority of patients on GH therapy are children with isolated GH deficiency. For these otherwise healthy children, the primary purpose of therapy is to increase height. Because normal GH secretion and growth patterns are often restored at puberty, termination of therapy, observation and retesting are recommended. When not accompanied by other hormone deficiencies or magnetic resonance imaging (MRI) evidence of CNS abnormalities, post-pubertal GH secretion is usually normal and no adverse effects occur upon treatment termination. Continuing therapy only until height is within the normal range, rather than when maximum height is achieved, is a legitimate goal.

Beyond medical concerns, the wishes of the patient and family and the cost of therapy affect when therapy is terminated.

In patients with severe GH deficiency, often accompanied by other pituitary hormone deficiencies and CNS abnormalities, continuing therapy into adulthood has benefits. Rather than implementing a trial period off therapy as the patient approaches adulthood, clinicians may be justified in continuing therapy without interruption in patients with multiple pituitary hormone deficiencies or structural abnormalities. Alternatively, therapy may be stopped for 1 to 2 years before re-assessing GH secretion and other indicators of GH deficiency (e.g. body composition, lipid levels).

In patients with moderate risk for adult deficiency, a trial off therapy and a period of evaluation for untoward effects may be warranted.

When starting GH therapy, patients and families should be counseled on the probable need for continuing therapy into adulthood in patients with severe GH deficiency. Because of the variability in the profiles of patients with GH deficiency, decision-making on when to stop therapy and whether and when to resume it must be individualized.

Issues in terminating GH therapy and transitioning to adult therapy

It is important to consider when to begin a trial off of GH therapy. Other issues include how to evaluate a patient for adult therapy, whether to pause in therapy for a longer period of evaluation, when to start adult therapy and transitioning to a new health care provider.

GH: Multiple sites of action

GH has important metabolic actions as children develop into adults and affects linear growth by increasing epiphyseal growth.¹ GH is important for normal bone metabolism and maintenance of bone mineral density. It increases osteoclast differentiation and activity and osteoblast activity. GH increases bone mass by means of endochondral bone formation. (Figure 1)

GH: Multiple Sites of Action Figure 1. Adapted from Allen DB. Growth Hormone Treatment: Lifshitz F, ed Pediatric Endocrinology. 4th ed 2003: 87-111.

GH has important actions on the preservation of muscle mass, affecting how the body regulates energy use. Effects on muscle include increased amino acid transport and nitrogen retention. It also may affect muscle fiber distribution and increases the amount of metabolically active tissue, leading to increased energy expenditure.

GH promotes the use of fat as an energy source. It has acute insulin-like effects, which are followed by increased lipolysis, inhibition of lipoprotein lipase, stimulation of hormone-sensitive lipase, decreased glucose transport and decreased lipogenesis. These effects allow the body to effectively use fat as an energy source and help preserve muscle mass through times of illness, stress and aging.

Adult GH deficiency syndrome

Untreated adult GH deficiency results in an abnormal body composition. Lacking the lipolytic actions of GH, the body accumulates fat mass, particularly intra-abdominal fat, and loses lean muscle mass. Bone mineralization is diminished, causing low bone mineral density. GH deficiency is also associated with impaired lipid metabolism, which causes high levels of LDL cholesterol, low levels of HDL cholesterol and elevated triglycerides.

A reduced quality of life is also observed with GH deficiency. Family members may note a marked diminution in energy level, initiative and feeling of well-being in an adult who has not received GH therapy.

Adult GH therapy reverses these effects. In a double-blind ,placebo-controlled trial of growth hormone replacement in adults, a computed tomographic scan at L3-L4 level after 26 weeks of recombinant GH therapy revealed a marked diminution in subcutaneous and visceral fat, producing an overall better health profile in terms of insulin sensitivity and cardiovascular risk.² The 10 patients with adult-onset GH deficiency were studied for body composition, metabolic parameters and well-being. GH replacement also resulted in marked improvements in bone mineral metabolism and psychiatric symptoms.

Early guidance on therapy, termination and transitioning to adult therapy

The majority of patients on GH therapy are children with isolated GH deficiency. For these otherwise healthy children, the primary purpose of therapy is to increase height. —David B. Allen, MD

In most endocrinology practices, GH therapy is routinely provided until growth is finished. However, in at least a subset of patients, this practice may be unwarranted. When beginning therapy for a child with very short stature, the clinician’s goal is to prevent a disabling short stature. Treatment is aimed at children achieving normal height, not at making short children tall.

Most children who are treated have idiopathic GH deficiency, with no other hormonal deficiencies and no abnormalities on cranial MRI. They are short-statured, grow slowly and fail GH provocation tests. It is highly likely that these children will not need adult treatment. However, when other hormonal deficiencies or other organic causes of GH deficiency are evident, it is more likely that the child will require adult GH therapy.

In preparing the family for the evaluation process, clinicians discuss when they may take the child off of GH therapy. In cases of partial or non-organic isolated GH deficiency, a clinician may attempt early trials of GH discontinuation. When GH deficiency is mild, no other deficits exist and it is certain that GH deficiency is not permanent, a clinician may attempt a trial off of GH therapy when the child has attained normal height for his age, to allow sufficient time for growth rate evaluation.

Particularly when tests of GH secretion have been borderline, not all children remain GH deficient throughout childhood and adolescence, and families are often receptive to a trial off therapy with close observation. More commonly, clinicians discontinue therapy when a child is at the onset of puberty. Puberty is the most likely explanation for children transitioning from deficiency to adolescent GH normalcy. Early trials of stopping GH therapy are less likely to be successful when no other hormonal deficiencies are present.

For children with isolated GH deficiency who remain on therapy through early adolescence, clinicians may consider terminating therapy at near attainment of the therapeutic goal for adult height. Even if still mildly deficient, a child may experience additional growth after termination. Most patients in whom clinicians stop therapy are no longer GH deficient and continue to grow normally.

Etiologies of GH deficiency

In classic organic structural GH deficiency, MRI reveals a small pituitary gland; pituitary hormone deficiencies are multiple. The classic facial appearance includes a small midface. Children who have a clear organic, structural or genetic explanation for their deficiency have a high likelihood of lifelong dependency on GH.

More typically, children present with short stature and delayed bone age and do not pass the GH stimulation test. Their cranial MRI is normal, and they respond well to treatment. This type of patient with idiopathic GH deficiency constitutes the majority of those being treated with GH. When retested at a later age, up to ~ 70% are no longer GH deficient.³

Treatment endpoint: Normal or maximum height?

Because many children or teens normalize in their endogenous GH secretion and growth, it is difficult to determine when therapy should be reassessed. From a medical standpoint, this decision is dependent upon the underlying diagnosis of GH deficiency. In isolated GH deficiency with a normal cranial MRI, 30% to 70% of children or teens treated for GH have a normalization of GH tests with puberty. For these children, it is advisable to reassess the diagnosis at this time to potentially prevent years of unnecessary injections and cost.

Other variables influence the timing of cessation of height-promoting GH therapy. In a questionnaire survey to pediatric endocrinologists, clinicians were asked how growth rate and bone age affect their decisions to continue or discontinue GH therapy.⁴

When the family wants to continue ongoing GH therapy, most clinicians would terminate therapy in a short statured child if the bone age is more advanced and the growth rate is slow. When the bone age is younger and growth is fast, although the child is taller, most physicians would continue therapy.

The clinician response markedly changes if the family wants to discontinue treatment, illustrating how medical decision-making is also driven by psychosocial benefits of treatment. For the same children, while only 2% of physicians would discontinue treatment for the taller child if the parents wanted to continue, almost half would recommend terminating treatment if the parents wanted to discontinue.

In general, if families want to continue treatment, then most physicians will continue, although the additional small amount of height achieved at the later stages of GH therapy is costly. At this point, dosages increase as a child’s growth slows and as he or she gains weight. Physicians tend to value even small gains in final height, although an additional 20% in cost may be required to gain the last 1% to 3% of adult height.

It is important to question when growth is adequate and how to balance the expense and inconvenience of treatment with the therapeutic objective. —David B. Allen, MD

It is important to question when growth is adequate and how to balance the expense and inconvenience of treatment with the therapeutic objective. Most clinicians would agree that treating short stature to avoid a disabling short adult height is appropriate. However, continuing to treat beyond average height may be considered cosmetic enhancement. Cost should be considered because relative costs for the amount of height gained increases exponentially at a later age. For example, at ages 17 and 18, the cost of treatment per centimeter of growth is $13,000.⁵

For otherwise healthy children who receive only GH, normal rather than maximum height can be considered a reasonable goal. In terms of medical treatment of impairment, a rightful claim exists for treatment into the normal adult range and out of the disabling range. But it can be argued that no strong claim exists for a child to become taller than others in the normal range. In addition, no data supports improved psychological outcomes with the addition of inches within the normal range. For instance, no data demonstrates that making a child 5’8” rather than 5’6” will improve long-term quality of life. In addition, parental expectations may not justify third-party or publicly supported prolonged treatments to increase height. (Figure 2)

GH Therapy for Height Figure 2. Adapted from Allen D.B. Pediatric 1999;104:1004-1010

Evaluating for adult GH deficiency

Radovick and colleagues created a useful algorithm to evaluate if an adolescent will need lifelong GH therapy.⁶ (Figure 3) When multiple pituitary hormone deficiencies or a clear structural reason for GH deficiency exists, the probability of persistent deficiency into adulthood is high. In this case, it is recommended that the child not be taken off therapy but rather be transitioned to adult GH therapy. Children at high risk include those with acquired or congenital multiple pituitary hormone deficiencies, congenital idiopathic GH deficiencies with structural abnormality or a confirmed genetic mutation affecting hormone production.

Evaluation for Persistant Adult GHD Figure 3. Modified from Radovick, S.,Dival, S. JCEM 2007; 92:1195-1200

Children with idiopathic isolated GH deficiency have a low probability of deficiency persisting into adulthood. However, many patients are in a middle ground. They may have a structural lesion or perhaps one other hormonal deficiency. Many children have differing levels of loss of function of endocrine systems. These children have a moderate probability of persistent deficiency into adulthood and include those with acquired GH deficiency from radiation therapy, surgery or idiopathic multiple pituitary hormone deficiency. In these situations, clinicians recommend a period off of GH therapy to determine the degree of adult deficiency. As indicated on the algorithm chart, insulin-like growth factor 1 level can be a useful screening device in determining which adolescents to retest for GH production.

GH-free period

Safety is a crucial consideration when deciding to transition a child to adult therapy and determining the length of the transition. Two studies in which a long GH-free period was examined resulted in differing conclusions due to the different types of patients enrolled.

In Mauras and colleagues’ study,⁷ 58 adolescents with childhood GH deficiency, a large proportion of whom had isolated idiopathic GH deficiency, were randomized to GH therapy or placebo for 2 years. All of the participants had been retested before the study and were positive for GH deficiency. After 2 years, no difference existed between the groups in lipid and carbohydrate metabolism, body composition, bone mineral density, cardiac function, muscle strength or quality of life indicators. The investigators concluded that GH therapy can be safely discontinued in adolescents for at least 2 years.

Attanasio and colleagues conducted a study in which 58 late adolescents (mean age, 19 years old) who were more severely affected were enrolled; 80% had multiple pituitary hormone deficiencies.⁸ All had completed pediatric GH treatment at final height and were randomized to receive one of two different dosages of GH or placebo for 2 years. In the treatment arm, significant differences in body composition existed, with increased lean body mass and decreased fat mass and an absence of LDL and HDL cholesterol disturbances. The authors of the study introduced the concept that when two-dimensional growth or statural height is complete, the children have not yet fully finished “three-dimensional” development to target adult body composition. The authors concluded that for a GH-deficient child to develop completely requires GH treatment after near-final height is achieved, and that a long period off of therapy can be harmful to the child.

Carroll and colleagues⁹ evaluated whether ceasing GH therapy in adolescents with severe GH deficiency had adverse consequences. At completion of linear growth, 12 patients continued on GH and 12 patients ceased treatment. The patients who were treated had a 6% increase in lean body mass after 1 year of treatment, whereas the patients who were untreated had a decline that approached 2%.

IGF-1 level and testing for GH production

In contrast to children in whom interpreting the IGF-1 is problematic, once puberty has ended IGF-1 level is a reasonable indicator of the integrity of the GH system. After a period of observation in patients off of GH therapy for 1 to 3 months, if IGF-1 levels are borderline or lower, a repeat testing for GH production is necessary.

It must be noted that tests that are useful in children will not be applicable in adults. Clonidine is not a useful secretagogue in adult patients. Insulin tolerance testing, glucagon or GH-RH-arginine testing are useful agents in adults to test for GH secretion.

Transitioning patients with probable persistent deficiency.

In a patient with unquestioned severe GHD and multiple pituitary hormone deficiencies accompanied by CNS abnormalities, it is more clear that transition straight into adult GH therapy can be appropriate. Physicians should monitor clinically or discharge those with mild or no deficiency, respectively.

When a patient appears at risk for metabolic consequences, a clinician should discuss the risks and benefits of continuing GH treatment. —David B. Allen, MD

For patients with probable deficiency, the patient perceptions and preferences become important. Clinicians recommend an ongoing evaluation of lipid levels and body composition and perhaps quality of life indicators to determine where a patient falls in the spectrum of GH deficiency. When a patient appears at risk for metabolic consequences, a clinician should discuss the risks and benefits of continuing GH treatment. Patients at low risk for adverse effects should continue to be monitored.

The amount of GH required for metabolic indications is less than that needed during childhood growth. Clinicians begin adult dosing of GH at one-fourth to one-third of the childhood dose. In adults, women require almost twice as much as men to boost IGF-1 levels into the normal range; therefore, titration of dose should be individualized and account for gender.

Transitioning care to an adult endocrinologist may be a challenge in institutions where pediatric and adult endocrine divisions do not work together closely. It is important to cultivate relationships with adult endocrinologists who have a particular interest in children with multiple pituitary hormone deficiencies, and it can be useful to invite them to the clinic to familiarize them with all aspects of treatment of children with severe GH deficiency.

Conclusion

Termination of GH therapy and transitioning to adult GH therapy can be complex and requires an individualized approach to each patient’s therapy. Growth hormone therapy is beneficial to adults with severe GH deficiency. It has beneficial effects on body composition, exercise capacity, skeletal integrity and quality of life.

Most children with isolated GH deficiency do not remain GH deficient after puberty and are not at risk for adult GH deficiency syndrome. In these patients, termination of GH therapy, observation and retesting for IGF-1 and GH production is recommended. In children with multiple pituitary hormone deficiencies or structural or genetic causes for their deficiency, continuous GH therapy may be justified. Children falling between these two extremes merit post-treatment observation including periodic monitoring of IGF-1 levels, body composition, and lipid metabolism as indicated to detect possible adult GH deficiency.

References

1. Allen DB. Growth hormone treatment. In: Lifshitz F, ed. Pediatric Endocrinology. 4th ed. 2003:87-111.
2. Bengtsson BA, Eden S, Lonn L, et al. Treatment of adults with growth hormone (GH) deficiency with recombinant GH. J Clin Endocrinol Metab. 1993;76:309-317.
3. Tauber M, Moulin P, Pienkowski C, Jouret B, Rochiccioli P. Growth hormone (GH) retesting and auxological data in 131 GH-deficient patients after completion of treatment. J Clin Endocrinol Metab. 1997;82:352-356.
4. Cuttler L, Silvers JB, Singh J, Tsai AC, Radcliffe D. Physician decisions to discontinue long-term medications using a two-stage framework: the case of growth hormone therapy. Med Care. 2005;43:1185-1193.
5. Allen DB. Issues in the transition from childhood to adult growth hormone therapy. Pediatrics. 1999;104:1004-1010.
6. Radovick S, DiVall S. Approach to the growth hormone-deficient child during transition to adulthood. J Clin Endocrinol Metab. 2007;92:1195-1200.
7. Mauras N, Pescovitz OH, Allada V, et al. Limited efficacy of growth hormone (GH) during transition of GH-deficient patients from adolescence to adulthood: a phase III multicenter, double-blind, randomized two-year trial. J Clin Endocrinol Metab. 2005;90:3946-3955.
8.Attanasio AF, Shavrikova E, Blum WF, et al. Continued growth hormone (GH) treatment after final height is necessary to complete somatic development in childhood-onset GH-deficient patients. J Clin Endocrinol Metab. 2004;89:4857-4862.
9.Carroll PV, Drake WM, Maher KT, et al. Comparison of continuation or cessation of growth hormone (GH) therapy on body composition and metabolic status in adolescents with severe GH deficiency at completion of linear growth. J Clin Endocrinol Metab. 2004;89:3890-3895.

Working with families of children with short stature

Denise Gruccio-Paolucci, MSN, CRNP

Uncovering a patient’s past experience with the health care system and validating the family’s attitudes about the significance of short stature are essential to creating a successful partnership between the patient, family and health care professionals. — Denise Gruccio-Paolucci, MSN, CRNP

Working effectively with children who present with short stature requires an understanding of the patient’s perspective as well as that of the patient’s family. Uncovering a patient’s past experience with the health care system and validating the family’s attitudes about the significance of short stature are essential to creating a successful partnership between the patient, family and health care professionals.

This article illustrates the varied clinical presentations of children with short stature, providing a glimpse of a day at the Diagnostic and Research Growth Center, Division of Endocrinology, at the Children’s Hospital of Philadelphia from a provider’s perspective. Strategies to assess the needs of patients and families and for building effective working relationships with providers are discussed.

Patient presentations vary

Patients who are referred for a growth evaluation generally fall into four major categories:

• Healthy children who happen to have short stature
• Children who do not really have short stature
• Children with short stature and complex medical problems
• Children with short stature secondary to a life-threatening illness

Three cases illustrate the varied presentation of children who present to the growth center and how short stature can have different meanings depending on individual circumstances.

Case 1.

A 13-year-old survivor of neuroblastoma

Brian is a 13-year-old boy with a history of neuroblastoma, growth hormone deficiency and primary gonadal failure. His major concern is his small testes. He wants to be a wrestler but feels that the size of his testes is noticeable in his wrestling outfit. He is also concerned that he is infertile. Despite treatment with growth hormone, he learns that his predicted adult height is estimated to be approximately 5’0”.

What does short stature mean in this scenario? For Brian, being short is another disappointment as well as a source of resentment. It is a reminder of the damage that cancer has caused.

Case 2.

A 13-year-old boy with a family who distrusts medical care

Kyle is a 13-year-old boy who presents with extreme short stature (3 to 4 standard deviations below the mean) and no puberty. His mother said, “We don’t do the doctor thing.” She has not taken Kyle to well-child visits, and he has not been seen by a primary care physician for approximately 6 or 7 years. No growth records are available. The family says, “He is not really that short, and he will eventually grow. Besides, he’s so healthy that he couldn’t have a medical problem.”

What does short stature mean to this family? They believe that short stature is not a problem, but it has yet to become a social issue for Kyle. Although the referral to the center is for short stature, the larger, overarching issue is the family’s distrust of the health care system.

Case 3.

A 15-year-old boy with a history of craniopharyngioma

Gary is a 15-year-old boy who was diagnosed at age 12 with a craniopharyngioma, leaving him with hypopituitarism and blindness. He is now 5’3”. He is concerned about his height and wants to immediately begin growth hormone therapy postoperatively and is frustrated that he must wait for his condition to stabilize.

For Gary, feeling tall again would allow him to preserve one aspect of his previous identity. Treatment for short stature would give him a sense of control and offer the potential for a positive outcome.

These three cases demonstrate how short stature, the ability to grow taller and growth hormone therapy are rarely isolated issues for families. Often, these issues exist among many layers of issues and circumstances that the family faces.

Assessing family needs

To learn as much as possible about how to help families of patients with short stature, health care providers should begin with five basic questions:

1. Who is worried?

Determining the level of concern of the patient, as well as that of the mother, father and pediatrician, provides a picture of what each interested party is experiencing and gives each family member an opportunity to express concerns.

2. What is the patient’s medical history?

Everyone is defined by past experiences, especially families who have faced chronic or life-threatening illness. The issue of short stature for a patient who has survived cancer, radiation and a bone marrow transplant is different than for someone who has had no significant contact with the health care system.

3. Have previous contacts with the health care system been positive or negative?

It is critical to uncover a family’s response to health care.

4. Why is the family concerned?

Although often a family’s concern is primarily about stature, particularly families of patients who have had cancer may fear what an evaluation may uncover. Families may also be concerned about what the treatments involve, or alternatively, may worry that no treatment will be recommended.

5. What led to the referral for a growth evaluation?

Posing this question to families sometimes elicits interesting responses. Often the referral is initiated from a pediatrician or specialist, but sometimes the response is, “We’re here because the boy next door was started on growth hormone a year ago, and we’ve watched how he’s grown.”

Strategies for working with families

Several strategies foster better care of patients and their families:

Listen with intent. By asking the five basic questions and finding out a family’s perspective, health care providers often can tailor effective interventions and working styles.

Be flexible. Being flexible about the approach to dealing with families is critical.

Identify emotional needs of the family in addition to a patient’s physical needs.

Separate parents’ issues from a patient’s issues to ensure optimum treatment.

Ask about goals and expectations. Sometimes parents present with clear goals, including the delivery system through which they want to have growth hormone administered. Determining which goals are realistic is essential.

Recognize and respect the value they place on stature. Sometimes, as in the second case, the medical view may be different from the family’s perspective. — Denise Gruccio-Paolucci, MSN, CRNP

Recognize and respect the value they place on stature. Sometimes, as in the second case, the medical view may be different from the family’s perspective.

Families typically come to their appointments with fear, uncertainty, confusion and hope. Often they have a strong desire to convince the health care provider that a real problem exists. Although health care providers have a growth chart to show the child’s height relative to statistical norms, frequently mothers are compelled to explain how short their child is compared to others.

Families usually have many questions. If health care providers are effective, then families will leave the appointment with a clear sense of their options, realistic goals, validation of their feelings and an effective working relationship with health care professionals.