Idiopathic Short Stature

Rose A. Gubitosi-Klug, MD, PhD, Leona Cuttler, MD*Department of Pediatrics, Rainbow Babies and Children’s Hospital,

Case Western Reserve University, 11100 Euclid Avenue,

Room 737, Cleveland, OH 44106, USA

Idiopathic short stature (ISS) is a diagnosis that involves controversy,particularly with regard to its definition and emerging options for itstreatment [1–3]. Because ISS affects a large population of children, under-standing its causes and optimizing its management will have a profoundimpact on child health. This article reviews origins of the diagnosis ISS,current diagnostic criteria, scientific advances in delineating etiologies ofISS, management options for ISS, and implications of managementdecisions for child health.

Emergence of idiopathic short stature as a diagnostic entity

The term ISS has evolved as clinical observations met advances inbiotechnology. In the 1950s, the differential diagnosis of endocrine causesof childhood short staturedstated by Lawson Wilkins, based on clinicalobservation and radiographic analysis of skeletal maturationdincludedhypothyroidism, gonadal aplasia (Turner syndrome), pituitary dwarfism(referring to panhypopituitarism), delayed adolescence, and primordial orgenetic dwarfism [4]. Primordial dwarfism referred to children who weregenerally small from birth or early childhood, and had normal pubertaldevelopment; it was predicted that some of these children might haveisolated deficiency of growth hormone (GH). Difficulty in distinguishingamong pituitary dwarfism, primordial dwarfism, and delayed adolescencewas acknowledged, and is sometimes the case today.

In the 1960s, radioimmunoassays documented low circulating GH levelsnot only in children with panhypopituitarism, but also in some who had

This work was supported in part by Grants from the National Institutes of Health.

Dr. Gubitosi-Klug’s work is supported in part by a National Institutes of Health training

Grant and a grant from the Endocrine Fellows Foundation.

* Corresponding author.

E-mail address: lx15@po.cwru.edu (L. Cuttler).

0889-8529/05/$ - see front matter � 2005 Elsevier Inc. All rights reserved.

doi:10.1016/j.ecl.2005.04.003 endo.theclinics.com

Endocrinol Metab Clin N Am

34 (2005) 565–580

been speculated to have isolated, idiopathic GH deficiency. In the 1970s and1980s, the development of GH stimulation tests revealed that GH deficiencyaccounted for fewer than 1% of children with short stature and suggestedthat GH deficiency occurred in approximately 1 in 4000 to 10,000 children[5]. Several new groups of short children then were identified and cat-egorized as having partial GH deficiency, GH resistance and, representingthe largest group, short stature with normal stimulated GH levels. In the1980s and 1990s, the literature referred to this final group by various terms,including normal variant short stature, short-normal children, non–GH-deficient short stature, and ISS. These terms referred to children with shortstature of unknown cause.

Several developments then spurred consideration of GH treatment asa means to promote growth in children with short stature of unknowncause. These developments included a virtually unlimited supply of re-combinant GH, evidence that GH could promote growth in Turner syn-drome and other disorders not associated with GH deficiency, and reportsof false-positive and false-negative results from GH stimulation tests. Asclinical studies of GH treatment developed, the term ISS emerged asa consistent way to refer to such children in what was considered anunbiased manner [6], although some believe the term to medicalize shortotherwise normal children [1]. A key issue then became operationalizing theterm ISS by selection of inclusion criteria. The criteria varied markedlyamong clinical research studies in terms of degree of short stature, growthrate, bone age, birthweight, and predicted adult height resulting in studies ofheterogeneous populations all considered to have ISS.

Although the definition continues to be controversial, several inclusioncriteria generally are accepted for diagnosis of ISS today: height more thantwo standard deviations (SDs) below the mean, absence of an identifiedunderlying disease process, normal weight for gestational age, normal bodyproportions, good caloric intake, no psychiatric disorder, and peak growthhormone response on standard stimulation test greater than 10 ng/mL [6,7].This approach permits inclusion of familial short stature and constitutionaldelay in growth and development under the rubric of ISS, consistent withsome previous usage [6,8]. It also continues potential clinical heterogeneityin ISS populations. Unsettled issues are whether predicted adult height SDand/or growth velocity should be components of the definition, whether andhow to incorporate family heights, whether to incorporate other indices ofGH secretion or insensitivity (eg, IGF-1 and IGF-BP3) in the definition, andwhich diagnosable disorders must be excluded to justify application of theterm. These issues and ambiguities are important in developing practical,operational criteria for therapeutic interventions.

The tension between considering ISS to be a disorder, as opposed tonormal variation, underlies much of the controversy surrounding the termand its use as a medical diagnosis. Elements of this tension are bothdiagnostic and conceptual. It can be argued that height is a normally

566 GUBITOSI-KLUG & CUTTLER

distributed characteristic, with some biologically normal individuals beingbelow a statistically defined limit (eg, 2 SD from the mean). Thus, concernhas been raised that some normal children with what traditionally has beenconsidered familial short stature or constitutional delay of growth anddevelopment might be classified as having ISS, suggesting that they havea disorder. On the other hand, ISS likely includes some children with whatappears to be familial short stature or constitutional delay but who will befound through scientific advances to have distinct biochemical or geneticdisorders. Conceptually, a central issue is lack of knowledge about the pointat which short stature (ie, independent of diagnosis) represents a conditionthat is disabling or problematic enough to be considered a disorderwarranting therapeutic intervention.

Advances in identifying molecular causes of idiopathic short stature

Recent research has attempted to identify subgroups of children withspecific defects in the GH–IGF-1-bone axis and other factors that influencegrowth (Fig. 1, Table 1). Advances in understanding the cellular pathwaysthat influence growth have resulted in several potential targets of dysfunction.

After secretion from the pituitary, GH binds to the GH receptor (GHR)in peripheral tissues, leading to receptor dimerization and activation of thetyrosine kinase, Janus kinase 2 (JAK 2). JAK2 then phosphorylates severalmembers of the STAT family (signal transducers and activators oftranscription), including STATs 1, 3, 5a, and 5b. Although not thought tobe the sole intermediate of GH gene regulation, STAT phosphorylationleads to translocation of activated cytoplasmic proteins to the nuclear mem-brane where gene regulation events related to GH action occur, includingsynthesis of IGF-1 and IGF-binding proteins (IGFBPs).

Investigations of individual cases of very short children have confirmeddisorders in the GH–IGF-1 axis that otherwise might be classified as ISS(see Table 1). Relative insensitivity to GH appears to characterize several ofthese defects.

Growth hormone receptor mutations or deletions can yield defectiveGHR, leading to poor GH binding and GH insensitivity (as in classicalLaron Syndrome, which is associated with low circulating levels of GHbinding protein, the extracellular domain of the GHR). Although Laronsyndrome generally is not considered a form of ISS, milder forms of GHRdysfunction have been identified in children who otherwise appear to haveISS [8–12]. In addition, a patient has been identified with a mutation in theintracellular domain of the GHR, resulting in decreased transmembranesignaling to STAT 5 [13]. Moreover, postreceptor defects are possible;a STAT 5b mutation has been identified in a patient with short stature andbiochemical parameters associated with GH insensitivity [14]. Beyond GHsignaling, mutations of the IGF-1 gene [15] or its receptor [16] have beenidentified in individuals with prenatal and postnatal growth failure.

567IDIOPATHIC SHORT STATURE

In addition to activating STAT 5, GH also can activate the extracellularsignal-regulated kinase pathway (ERK). Recently, two novel mutations inthe GH1 gene were described in two children with ISS [17]. The children hadnormal GH secretion and normal STAT 5 activation; however, the ERKsignal transduction was diminished. The effects of ERK in GH signaling arenot yet well defined, but such studies suggest a potential role. In contrast,other GH1 mutations lead to bioinactive GH [18,19].

Fig. 1. The complex regulation of linear growth involves several pathways, including the GH-

IGF-1 axis, direct effects of GH on bone metabolism, SHOX gene alteration of bone growth,

and many others. In children who otherwise might be considered to have ISS, genetic defects

have been found at multiple steps of the GH-IGF-1 pathway (labeled 1 to 5) as well as in the

SHOX gene (6) (see Table 1). In IGF-1 generating cells, GH (1) binds to the GHR (2), leading

to receptor dimerization and functional receptors at the cell surface membrane. These active

receptors then stimulate the associated JAK2, which undergoes autophosphorylation and

phosphorylates the GHR. The GHR-JAK2 complex activates other signaling pathways

including STAT (3) and ERK. STAT translocation to the nucleus induces transcription of the

IGF-1 gene, which results in the generation of circulating IGF-1 (4). IGF-1 interacts with IGF-1

receptors (5), leading to linear growth. ERK activation leads to nuclear translocation and

immediate early gene transcription, but is not linked to IGF-1 gene transcription. The SHOX

gene (6) is present in bone marrow fibroblasts; its functional effect is not known. Other factors

involved in the regulation of growth are not specified in this figure, which focuses only on

currently identified sites of defects.

568 GUBITOSI-KLUG & CUTTLER

Table 1

Genetic alterations identified in cases of idiopathic short stature

Gene involved Genetic alterationa Functional effect

Total no. of cases

reported [Ref.]

GH1 Single heterozygous point mutations:

Ile179Met Reduction in ERK activation 1 [17]

Arg77Cys Bioinactive GH 1 [18]

Asp112Gly Bioinactive GH 1 [19]

GHR Homozygous point mutations:

Frameshift leading to premature stop codon and

truncated GHR (GHR1-449)

Loss of STAT5 signaling 2 [13]

Other: 5 nonsense, 2 frame shift, 8 splice,

4 missense

d 23 [9,11]

Compound heterozygous point mutations:

Glu44Lys and Arg161Cys Reduced GH binding 1 [12]

Other: 1 additional described d 1 [11]

Single heterozygous point mutations:

Arg211His Reduced number of GHRs 1 [12]

Cys122stop Reduced number of GHRs 1 [12]

Glu244Asp Aberrant subcellular localization 1 [12]

Other: 4 missense d 7 [10,12]

STAT5b Homozygous point mutation:

Ala630Pro Aberrant transcription of IGF-1/IGFBP3 1 [14]

(continued on next page)

569

IDIO

PATHIC

SHORTSTATURE

Table 1 (continued )

Gene involved Genetic alterationa Functional effect

Total no. of cases

reported [Ref.]

IGF-1 Homozygous partial deletion:

IGF-1 Deficiency of IGF-1 1 [15]

IGF-1R Compound heterozygous point mutations:

Arg108Gln and Lys115Asn Decreased IGF-1R function 1 [16]

Single heterozygous point mutations:

Arg59stop Reduced number of IGF-1Rs

SHOX Deletion:

His229–Leu232 d 3 [16]

SHOX d 1 [25]

Single heterozygous point mutations:

1 nonsense, 1 missense 6 [23,25]

a Specific genetic alteration is listed when functional effect is known. If functional effect is unknown, the alterations are grouped.

570

GUBIT

OSI-K

LUG

&CUTTLER

Because partial GH insensitivity may be a potential contributor to ISS, atleast in part through the mechanisms described, it will be important todevelop sensitive and reliable clinical, genetic, or pharmacogenetic tests forassessing sensitivity to GH [20–22].

Mutations in the short stature homeobox-containing gene (SHOX gene)also have been described in some patients with ISS [23]. SHOX is located inthe pseudoautosomal regions of the X chromosome and encodes a tran-scription factor highly expressed in bone marrow fibroblasts and in othertissues. Although the function of the SHOX gene product is not known,gene defects have been linked to Leri-Weill syndrome dyschondrosteosis. Inaddition, functionally significant SHOX mutations have been identified in1% to 2% of children with ISS [24,25]. It has been suggested that screeningfor this defect should be restricted to those with short limbs and radiologicalabnormalities of the hand (triangularization of distal radial epiphysis,pyramidalization of distal carpal row, or lucency of the distal ulnar borderof the radius) [26].

Thus, molecular research, sparked by advances in identifying cellularmechanisms underlying linear growth, is chipping away at identifying causesof ISS. The potential role of these emerging data in treatment decisions willbe discussed. The extent to which molecular defects will be found to underlieshort stature for the vast population of children with ISS remains to bedetermined.

Management of idiopathic short stature

Current management options for ISS include recommending that thechild not embark on any pharmacological treatment or recommendingtreatment with agents designed to modify growth directly (eg, GH) orindirectly by altering the tempo of puberty and epiphyseal closure (eg, sexsteroids, gonadotropin-releasing hormone [GnRH] agonists, and aromataseinhibitors).

The natural history of ISS is important in management decisions. Interms of height, natural history data are complicated by heterogeneity ofconditions commonly included under the rubric ISS. Without therapeuticinterventions, height SD scores of those with ISS increases from 2.1 to 3.1SDs below the mean during childhood to 0.7 to 2.7 SDs below the mean byadulthood. The overall observed gain in height is 0.5 to 1.9 SDs [27]. Thisgain may reflect the inclusion of children with constitutional delay in growthand development in studies. Height predictions based on bone ages mayover- or underestimate adult height. The Bayley-Pinneau method, com-monly used in the United States, may overestimate adult height in malesby 3.1 cm [28]. In terms of psychosocial adjustment, children with ISS,including those presenting to endocrinologists for evaluation, generally donot show impairment of psychological well-being [29–32]. It has beenquestioned whether subpopulations with extreme short stature may have

571IDIOPATHIC SHORT STATURE

more impairment, but data are lacking. Tall stature, particularly in males,may confer economic and cultural advantages [33,34].

Decisions to use pharmacological therapy generally rest on the degree ofshort stature, the predicted adult height, whether delayed puberty isconsidered a contributor to short stature, and the physician’s interpretationof available data on morbidity of short stature and efficacy of treatment.For some regimens (eg, sex steroids for children with delayed puberty), thetreatment goal is short-term growth acceleration coincident with pubertalinduction. For others (eg, GH), the goal is generally an increase in adultheight.

Low-dose sex steroids

For many years, low doses of androgens have been used to treat male shortstature caused by constitutional delay in growth and development [35]. Thegoals are generally to relieve peer-related psychosocial stress associated withdelayed puberty and to enhance growth. In boys with constitutional delay ofgrowth and development, low-dose, short-term parenteral testosterone (eg,six injections of 50 mg/m2 of repository testosterone at monthly intervals)does not alter adult height (although high doses may cause early epiphysealclosure and reduced adult height). Thus, in cases of ISS that suggestconstitutional delay of growth and development, parenteral testosterone maybe utilized. Oral testosterone preparations are avoided because of adverseeffects. Constitutional delay rarely occurs in girls, but low doses of estrogencan, similarly, be given in this situation.

Gonadotropin-releasing hormone agonist

In contrast to sex steroids, GnRH agonists have been used to a limiteddegree in children with ISS, the goal being prolonged growth by inhibitionof pubertal development and delay in epiphyseal closure. In studies of thistreatment, GnRH agonist was used alone or in combination with GH. Ina placebo-controlled trial, GnRH agonist therapy alone, given for a mean of3.5 years, caused a 0.6 SD (4.2 cm) gain in near adult height [36]. Treatment,however, also resulted in decreased accretion of bone mineral density [36];therefore, the approach is not recommended for adolescents with normallytimed puberty. Studies involving a combination of GnRH agonist and GHtreatment for 3 years suggest a gain in predicted adult height [37]. Final dataon height, bone mineral density, cost-effectiveness, and potential adverseeffects of combined GnRH agonist–GH therapy, however, are not yetavailable.

Aromatase inhibitors

Exploiting the importance of estrogen in mediating epiphyseal closure,recent studies with aromatase inhibitors have been undertaken in boys with

572 GUBITOSI-KLUG & CUTTLER

constitutional delay of growth and development. Administration of tes-tosterone and letrozole, a potent P450-aromatase inhibitor, delayed bonematuration and increased predicted adult height by 5.1 cm over an 18-month follow-up, compared with controls treated with testosterone alone[38]. Long term data, however, are not yet available.

Growth hormone

The use of GH to treat children with ISS is an important clinical issue,particularly given approval of the treatment by the US Food and DrugAdministration (FDA) in 2003 [39]. Several studies have documentedincreases in growth velocity in a high proportion of children with ISS duringthe first 1 to 2 years on GH therapy. Long-term outcome on adult height,however, had been unclear. A recent meta-analysis found a gain of 4 to 6 cmin adult height after an average of 5.3 years of GH treatment [40]. Aseparate systematic analysis by the Cochrane group also concluded that GHcan increase short-term growth and (near) final height, although treatedindividuals remain relatively short compared with peers [41]. A randomized,double-blind, placebo-controlled trial of GH in children with ISS founda 3.7 cm average gain in adult height, with mean treatment duration of4.4 years, using a GH dose regimen (0.22 mg/kg per week in three divideddoses) [42] that would be considered low today. The effect of GH is dose-dependent, and there is evidence that daily GH injections at higher doses(approximately 0.37 mg/kg per week divided into six daily doses) canaugment height gain to 7 cm [43]. With regard to the psychological impactof GH therapy on children with ISS, no study has demonstrated objectiveimprovement [31,44].

The FDA approval of GH is for children with ISS whose current heightsare more than 2.25 SDs below the mean and with ‘‘associated growth ratesunlikely to permit attainment of adult height in the normal range, inpediatric patients whose epiphyses are not closed and for whom diagnosticevaluation excludes other causes associated with short stature that should beobserved or treated by other means’’ [39]. The approved dose is up to 0.37mg/kg per week.

Potential risks of GH therapy have been reviewed [3]. Over the 20 yearssince recombinant human GH was approved for use in children with GHdeficiency, its safety profile has been considered relatively low-risk, withadverse effects reported in fewer than 3% of recipients [3]. Recognizedadverse effects include edema and pseudotumor cerebri, gynecomastia,hyperinsulinism or elevated blood glucose, and potentially an increase innevi. The development of anti-GH antibodies that attenuate the growthresponse is extremely rare. Arthralgia and carpal tunnel syndrome are lesscommon in children than in adults receiving GH. Slipped capital femoralepiphyses and worsening of scoliosis can occur in rapidly growing children,including those on GH. Some children with Prader-Willi syndrome have

573IDIOPATHIC SHORT STATURE

died after receiving GH, many associated with respiratory abnormalities andobesity [3]. Long-term risks of GH in ISS are not clear, but the associationof elevated serum IGF-I or abnormal ratio of IGF-I to IGFBP3 withmalignancies of breast, prostate, and colon has raised concern, particularlyas GH doses have increased over those considered routine 20 years ago.Monitoring of IGF-1 and IGF-BP3 levels is recommended for children onGH therapy, the goal being to maintain these in the normal range.

It would be desirable to identify subpopulations of children most likely tobenefit from GH. Reliable clinical predictors of GH response for in-dividuals, however, have not been identified to date, although a delayedbone age is associated with greater final adult height in GH recipients. In thefuture, pharmacogenetics addressing variation in the GHR [45] or othermediators of GH action may assist in determining individual GH dose–response kinetics.

Future possibilities

Future potential treatment modalities include IGF-1 therapy for forms ofpartial GH insensitivity and combinations of the therapies describedpreviously (eg, GH and aromatase inhibitors). Psychological counselingalso may play a role, alone or in combination with pharmacotherapy.

Implications of management decisions

Because ISS is a relatively common condition, decisions about itsmanagement will have profound implications for child health. On the onehand, medical intervention has the potential to benefit large numbers ofchildren. On the other, medical intervention has the potential for un-necessary treatment, with social and economic costs.

The impactofFDAapprovalofGHfor the treatmentof ISS is not clear.Thecurrent FDA approval criterion of children with heights more than 2.25 SDsbelow the mean includes the shortest 1.2% of US children (or approximately410,000 US children). The FDA approval also involves ‘‘growth rates unlikelyto permit attainment of adult height in the normal range.and.diagnosticevaluation exclud[ing] other causes [of] short stature that should be observedor treated by other means.’’ It is unclear how these relatively subjective criteriaare to be applied. Furthermore, if even a small increase in eligibility criteria isadopted formally or becomes customary,manymore childrenwould be eligiblefor treatment (eg, eligibility at a height of the third percentile or belowwould translate into approximately 1,025,000 potentially eligible children inthe United States). Moreover, off-label use potentially could expand thepopulation further.With such high numbers, it is a challenge to determinewho,among potentially eligible children, should be treated [1,2].

The ability to predict the degree to which individual children will respondfavorably to GH is imprecise. In the future, molecular studies likely will

574 GUBITOSI-KLUG & CUTTLER

elucidate some genetic predictors of GH responsiveness [45]; however, theseanalyses may simply indicate which children are more or less sensitive toGH, thus guiding relative dosing rather than providing absolute principleson who should or should not receive treatment.

For these reasons, it is important to consider the goals and implicationsof treatment. These issues pertain to any treatment for ISS, but are ad-dressed here in the context of GH therapy.

Defining therapeutic benefit for idiopathic short stature

It was critical to establish whether GH in standard doses could alter adultheight in ISS. With evidence now showing a statistically significant effect, themore perplexing challenge is to determine whether the height gain is beneficialand warrants increasing use of treatment. Defining benefit in the context ofISS may include the degree of height gain, the impact on psychosocialstatus and quality of life, and the relationships of risk and costs to benefit.

Such assessments are difficult without strong evidence of broad psy-chosocial dysfunction in ISS or improvement in psychosocial well-being (orquality of life) because of treatment [31,32,44,46], and without reliablepredictors of responsiveness in individuals. Objective data do not exist onthe degree of short stature that generally constitutes a disability or sig-nificant disadvantage, or on the degree of height gain that materially alterslives. The degree to which a given height gain is seen as a benefit may dependon family attitudes, gender, and the magnitude of the gain in relation to theheight likely to be attained without treatment (eg, a 2-inch gain in height fora male who otherwise would be 5’1’’ may have different impact than thesame gain for one who otherwise would be 5’5’’).

Estimating a baseline height that is considered disabling and below whichtreatment is needed would be helpful in decision-making but may not befeasible. Further, regardless of the cut-off point set, arguments likely wouldcontinue that others marginally taller are not materially different and thusentitled to the same treatment.

Potential population effects

Ideally, treatment for a disease reduces morbidity for those affected, or,barring an increased incidence of the condition, reduces the problem posedby the condition for society. If significant numbers of potentially eligiblechildren receive GH (or another treatment) and increase their heights asa result, this may establish a new standard of care for both the medical andlay communities. Although potentially useful for individual recipients, thismay result in pressure for others with more marginal short stature to receivetreatment. Moreover, if treatment is effective in increasing heights of thecurrent shortest 1%–2% of children, this will create a new group of childrenwho populate the lowest 1%–2% of height [47].

575IDIOPATHIC SHORT STATURE

Potential costs

Currently, GH costs have been estimated at $40/mg, with yearly costs of$5000 to $40,000 (approximate mean $18,000 to $20,000 annually) [1], anda full multi-year course of treatment to cost up to $300,000 [43]. These veryhigh overall costs are similar to those routinely incurred and accepted forconditions such as renal failure and cancer, and so the controversy regardingcosts for GH in ISS relate more to morbidity of the untreated condition inrelation to benefits than to costs alone. The difficulty, again, is quantifyingthe benefits derived from GH for ISS. Data suggest that the high cost of GHmay be offset by enhanced earnings or career success of taller individuals orthose who were taller during adolescence [33,34]; however, earnings andcareer success are not typically considered in such analyses of benefit.

If GH use for ISS significantly increases overall health costs, insurers mayrespond by developing more restrictive eligibility criteria or eliminating GHfrom their formularies. If GH becomes a discretionary item, there will likelybe disparities in access to it, even for those with clear-cut needs. If the price ofGH declines substantially, much of the high-profile controversy surroundingits use would fade; however, such a scenario only would highlight theintrinsic difficulty of decisions based on strictly medical grounds.

Costs also can involve burden of treatment and risks. GH appears to berelatively safe, although long-term effects are not yet fully known. Withseveral examples of medications found to pose serious risks after years ofuse, consideration of potential therapeutic benefits in relation to unknownlong-term risk is reasonable.

Application of advances in molecular analyses of idiopathic short statureto decision-making

Anticipated advances that uncover molecular causes of what now istermed ISS or that identify factors predicting responsiveness to GH areexciting scientifically, but it is not clear whether they will alter treatmentissues substantively. The proportion of children currently diagnosed with ISSwhose stature may be attributed to these conditions is not yet known, anda substantial population with idiopathic conditions likely will remain. Also, ithas been argued that children with ISS whose heights are comparable to thosewith known disease entities (eg, Turner syndrome) should not be deniedtreatment because of absence of a more distinct diagnosis. If one accepts thisargument and considers degree of short stature rather than presence/absenceof a disease entity as the central issue in treatment, then delineation ofunderlying molecular disorders should not be central to the rationale fortreatment. In addition, in the absence of treatments that target specificmolecular abnormalities, it is possible that ascertainment of underlyingmolecular defects will help to predict relative responsiveness to existingtherapeutic modalities, rather than providing absolute treatment indications.

576 GUBITOSI-KLUG & CUTTLER

Culture and attitudes

Culture and attitudes are bound up tightly in considerations about GHtreatment for ISS, and this fuels controversy about the distinction betweendisease management and cultural enhancement. Economic and socialadvantages of tall stature in Western culture are documented [33,34], andthe attitudes of families, physicians, and insurers likely contribute toprescribing practices [48,49]. Thus, demand for GH may be susceptible tomolding by attitudinal factors in addition to physiological ones.

Potential approaches

If GH were used routinely for a large population of children with ISS,there are potential problems as discussed previously. However, to developguidelines that categorically deny GH to all children with ISS is not realistic,would deny it for some who truly need and would benefit from it, and mightlead to GH as a discretionary treatment similar to orthodontia. Thechallenge to physicians managing children with ISS is to develop reasonableapproaches that accept the inherent ambiguity of the situation, allowingGH treatment but limiting its scope. To do so, possible considerations indecision-making include:

� Incorporating predicted heights in considerations of whom to treat(even taking into account the potential overprediction of height in somesituations). This might identify children unlikely to attain adult heightwithin the normal range.

� Consider limited periods of GH treatment (eg, 1 to 3 years) to narrowgaps in relation to peers and bring children into a range closer to 2 SDsfrom the mean. This also may address economic analyses that suggestthat height during adolescence is a key predictor of future earnings inmales) [33].

� Consider limiting treatment until target height (if within the normalrange) is reached.

� Consider limiting treatment duration in late adolescence, when gains inheight are relatively small in relation to costs.

� Develop criteria to differentiate between those in whom initial GHtreatment is deemed successful and worthy of continuation, and thosein whom it is not successful and should be stopped. Although thisapproach is desirable, it may be difficult to implement, because manychildren have an increase in growth during early phases of GHtreatment (suggesting that therapeutic trials are not likely to effectivelydifferentiate subgroups), and because it would require evidence thatinitial growth response predicts overall gains, Furthermore, it is possiblethat poor response could lead to higher dose, rather than to treatmentwithdrawal.

577IDIOPATHIC SHORT STATURE

Summary

GH is a central part of the therapeutic armamentarium. Yet, it isimportant to use it wisely to avoid the pitfalls discussed. Although thisdiscussion of treatment implications focuses on GH, it is likely that GH isonly the beginning of treatment options for ISS. Decisions made for GH willhave impact on child health and will have repercussions for future therapies.

References

[1] Freemark M. Editorial. Growth hormone treatment of idiopathic short stature: not so fast.

J Clin Endocrinol Metab 2004;89(7):3138–9.

[2] Cuttler L, Silvers JB. Growth hormone treatment for idiopathic short stature: implications

for practice and policy. Arch Pediatr Adolesc Med 2004;158(2):108–10.

[3] Wilson TA, Rose SR, Cohen P, et al. Update of guidelines for the use of growth hormone

in children: the Lawson Wilkins Pediatric Endocrinology Society Drug and Therapeutics

Committee. J Pediatr 2003;143(4):415–21.

[4] Wilkins L. The diagnosis and treatment of endocrine disorders in childhood and

adolescence. Baltimore (MD): Charles C. Thomas; 1950.

[5] Lindsay R, Feldkamp M, Harris D, et al. Utah Growth Study: growth standards and the

prevalence of growth hormone deficiency. J Pediatr 1994;125(1):29–35.

[6] Ranke MB. Towards a consensus on the definition of idiopathic short stature. Horm Res

1996;45(Suppl 2):64–6.

[7] Pasquino AM, Albanese A, Bozzola M, et al. Idiopathic short stature. J Pediatr Endocrinol

Metab 2001;14(Suppl 2):967–74.

[8] Attie KM. Genetic studies in idiopathic short stature. Curr Opin Pediatr 2000;12(4):400–4.

[9] Metherell LA,Akker SA,Munroe PB, et al. Pseudoexon activation as a novelmechanism for

disease resulting in atypical growth-hormone insensitivity. Am J Hum Genet 2001;69(3):

641–6.

[10] Sanchez JE, Perera E, Baumbach L, et al. Growth hormone receptor mutations in children

with idiopathic short stature. J Clin Endocrinol Metab 1998;83(11):4079–83.

[11] Woods KA, Dastot F, Preece MA, et al. Phenotype: genotype relationships in growth

hormone insensitivity syndrome. J Clin Endocrinol Metab 1997;82(11):3529–35.

[12] GoddardAD,DowdP, Chernausek S, et al. Partial growth hormone insensitivity: the role of

growth-hormone receptor mutations in idiopathic short stature. J Pediatr 1997;131:S51–5.

[13] Milward A, Metherell L, Maamra M, et al. Growth hormone (GH) insensitivity syndrome

due to a GH receptor truncated after Box1, resulting in isolated failure of STAT 5 signal

transduction. J Clin Endocrinol Metab 2004;89(3):1259–66.

[14] KofoedEM,HwaV, Little B, et al. Growth hormone insensitivity associated with a STAT5b

mutation. N Engl J Med 2003;349(12):1139–47.

[15] Woods KA, Camacho-Hubner C, Savage MO, et al. Intrauterine growth retardation and

postnatal growth failure associated with deletion of the insulin-like growth factor I gene.

N Engl J Med 1996;335(18):1363–7.

[16] Abuzzahab J, Schneider A, Goddard A, et al. IGF-I receptor mutations resulting in intra-

uterine and postnatal growth retardation. N Engl J Med 2003;349(23):2211–22.

[17] Lewis MD, Horan M, Millar DS, et al. A novel dysfunctional growth hormone variant

(Ile179Met) exhibits a decreased ability to activate the extracellular signal-regulated kinase

pathway. J Clin Endocrinol Metab 2004;89(3):1068–75.

[18] Takahashi Y, Kaji H, Okimura Y, et al. Short stature caused by a mutant growth hormone

with an antagonistic effect. Endocr J 1996;43:S27–32.

578 GUBITOSI-KLUG & CUTTLER

[19] Takahashi Y, Shirono H, Arisaka O, et al. Biologically inactive growth hormone caused by

an amino acid substitution. J Clin Invest 1997;100(5):1159–65.

[20] Hindmarsh PC. Commentary. Standard and low-dose IGF-1 generation tests and

spontaneous growth hormone secretion in children with idiopathic short stature. Clin

Endocrinol (Oxf) 2004;60:161–2.

[21] Blair J, Camacho-Hubner C, Miraki Moud F, et al. Standard and low-dose IGF-1

generation tests and spontaneous growth hormone secretion in childrenwith idiopathic short

stature. Clin Endocrinol (Oxf) 2004;60:163–8.

[22] Grupposo P. The clinical laboratory evaluation of GH responsiveness. J Clin Endocrinol

Metab 2002;87(2):466–8.

[23] Rao E, Weiss B, Fukami M, et al. Pseudoautosomal deletions encompassing a novel

homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat

Genet 1997;16(1):54–63.

[24] Binder G, Schwarze C, Ranke MB. Identification of short stature caused by SHOX defects

and therapeutic effect of recombinant human growth hormone. J Clin Endocrinol Metab

2000;85:245–9.

[25] Rappold GA, Fukami M, Niesler B, et al. Deletions of the homeobox gene SHOX (short

stature homeobox) are an important cause of growth failure in children with short stature.

J Clin Endocrinol Metab 2002;87:1402–6.

[26] BinderG, RankeMB,MartinD. Auxology is a valuable instrument for the clinical diagnosis

of SHOX haploinsufficiency in school-age children with unexplained short stature. J Clin

Endocrinol Metab 2003;88(10):4891–6.

[27] Wit JM, Kamp GA, Rikken B. Spontaneous growth and response to growth hormone

treatment in children with growth hormone deficiency and idiopathic short stature. Pediatr

Res 1996;39(2):295–302.

[28] Bramswig J, Fasse M, HolthoffM, et al. Adult height in boys and girls with untreated short

stature and constitutional delay of growth and puberty: accuracy of five different methods

of height prediction. J Pediatr 1990;117(6):886–91.

[29] Zimet GD, Owens R, DahmsW, et al. Psychosocial outcome of children evaluated for short

stature. Arch Pediatr Adolesc Med 1997;151(10):1017–23.

[30] Theunissen NC, Kamp GA, Koopman HM, et al. Quality of life and self-esteem in children

treated for idiopathic short stature. J Pediatr 2002;140(5):507–15.

[31] Radcliffe DJ, Pliskin JS, Silvers JB, et al. Growth hormone therapy and quality of life in

adults and children. Pharmacoeconomics 2004;22(8):499–524.

[32] Sandberg DE, Bukowski WM, Fung CM, et al. Height and social adjustment: are extremes

a cause for concern and action? Pediatrics 2004;114(3):744–50.

[33] Persico N, Postlewaite A, Silverman D. The effect of adolescent experience on labor market

outcomes: the case of height. Working paper number 03–036. Philadelphia: Penn Institute

for Economic Research; 2003.

[34] Grumbach MM. Growth hormone therapy and the short end of the stick. N Engl J Med

1988;319:238–41.

[35] Rosenfield RL, Cuttler L. Growth and maturation. In: DeGroot LJL, editor. Endocrinol-

ogy. Philadelphia: WB Saunders; 2006, in press.

[36] Yanovski JA, Rose SR, Municchi G, et al. Treatment with a luteinizing hormone-releasing

hormone agonist in adolescents with short stature. N Engl J Med 2003;348(10):908–17.

[37] Kamp GA, Mul D, Waelkens JJ, et al. A randomized controlled trial of three years growth

hormone and gonadotropin-releasing hormone agonist treatment in childrenwith idiopathic

short stature and intrauterine growth retardation. J Clin Endocrinol Metab 2001;86(7):

2969–75.

[38] Wickman S, Sipila I, Ankarberg-Lindgren C, et al. A specific aromatase inhibitor and

potential increase in adult height in boyswith delayed puberty: a randomised controlled trial.

Lancet 2001;357(9270):1743–8.

579IDIOPATHIC SHORT STATURE

[39] FDA. FDA talk paper: FDA approves humatrope for short stature. Available at: http://

www.fda.gov. Accessed August 23, 2003.

[40] Finkelstein BS, Imperiale TF, Speroff T, et al. Effect of growth hormone therapy on height

in children with idiopathic short stature: a meta-analysis. Arch Pediatr Adolesc Med 2002;

156(3):230–40.

[41] Bryant J, Cave C, Milne R. Recombinant growth hormone for idiopathic short stature in

children and adolescents. Cochrane Database Syst Rev 2003;4:CD004440.

[42] Leschek EW, Rose SR, Yanovski JA, et al. Effect of growth hormone treatment on adult

height in prepubertal children with idiopathic short stature: a randomized, double-blind,

placebo-controlled trial. J Clin Endocrinol Metab 2004;89(7):3140–8.

[43] Wit JM, Rekers-Mombarg LT. Final height gain by GH therapy in children with idiopathic

short stature is dose dependent. J Clin Endocrinol Metab 2002;87(2):604–11.

[44] Downie A, Mulligan J, McCaughey E, et al. Psychological response to growth hormone

treatment in short normal children. Arch Dis Child 1996;75(1):32–5.

[45] Dos Santos C, Essioux L, Teinturier C, et al. A common polymorphism of the growth

hormone receptor is associated with increased responsiveness to growth hormone. Nat

Genet 2004;36(7):720–4.

[46] Voss L. Short normal stature and psychosocial disadvantage: a critical review of the

evidence. J Pediatr Endocrinol Metab 2001;14(6):701–11.

[47] Lantos J, Siegler M, Cuttler L. Ethical dilemmas in growth hormone therapy. JAMA 1989;

261:1020–4.

[48] Cuttler L, Silvers JB, Neuhauser D, et al. Physician management of short stature in

childhood: a national study of physician recommendation patterns. JAMA 1996;276(7):

531–7.

[49] Finkelstein B, Silvers JB, Neuhauser D, et al. Insurance coverage, physician recommenda-

tions, and access to emerging treatments: growth hormone therapy for childhood short

stature. JAMA 1998;279:663–8.

580 GUBITOSI-KLUG & CUTTLER