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Idiopathic short stature: Definition,

epidemiology, and diagnostic evaluation

Article in Growth Hormone & IGF Research · May 2008

DOI: 10.1016/j.ghir.2007.11.004 · Source: PubMed

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S P E C I A L F E A T U R E

C o n s e n s u s S t a t e m e n t s

Consensus Statement on the Diagnosis

and Treatment of Children with Idiopathic Short
Stature: A Summary of the Growth Hormone
Research Society, the Lawson Wilkins Pediatric
Endocrine Society, and the European Society for
Paediatric Endocrinology Workshop

P. Cohen, A. D. Rogol, C. L. Deal, P. Saenger, E. O. Reiter, J. L. Ross, S. D. Chernausek,

M. O. Savage, and J. M. Wit on behalf of the 2007 ISS Consensus Workshop participants
Department of Pediatric Endocrinology (P.C.), Mattel Children’s Hospital at University of California, Los Angeles, Los Angeles, California 90095;
Department of Pediatrics (A.D.R.), University of Virginia, and ODR Consulting, Charlottesville, Virginia 22911; Endocrinology Service (C.L.D.),
Sainte-Justine Hospital, Montreal, Quebec, Canada H3T 1C5; Department of Pediatrics (P.S.), Albert Einstein College of Medicine, Bronx, New
York 10467; Baystate Children’s Hospital (E.O.R.), Tufts University School of Medicine, Springfield, Massachusetts 01199; Department of
Pediatrics (J.L.R.), Thomas Jefferson University, Philadelphia, Pennsylvania 19107; Department of Pediatrics (S.D.C.), University of Oklahoma
Health Sciences Center, Oklahoma City, Oklahoma 73104; Centre for Endocrinology (M.O.S.), the London School of Medicine and Dentistry,
London E1 2AD, United Kingdom; and Department of Pediatrics (J.M.W.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands

Objective: Our objective was to summarize important advances in the management of children
with idiopathic short stature (ISS).

Participants: Participants were 32 invited leaders in the field.

Evidence: Evidence was obtained by extensive literature review and from clinical experience.

Consensus: Participants reviewed discussion summaries, voted, and reached a majority decision on
each document section.

Conclusions: ISS is defined auxologically by a height below ⫺2 SD score (SDS) without findings of
disease as evident by a complete evaluation by a pediatric endocrinologist including stimulated GH
levels. Magnetic resonance imaging is not necessary in patients with ISS. ISS may be a risk factor for
psychosocial problems, but true psychopathology is rare. In the United States and seven other
countries, the regulatory authorities approved GH treatment (at doses up to 53 ␮g/kg䡠d) for chil-
dren shorter than ⫺2.25 SDS, whereas in other countries, lower cutoffs are proposed. Aromatase
inhibition increases predicted adult height in males with ISS, but adult-height data are not avail-
able. Psychological counseling is worthwhile to consider instead of or as an adjunct to hormone
treatment. The predicted height may be inaccurate and is not an absolute criterion for GH treat-
ment decisions. The shorter the child, the more consideration should be given to GH. Successful
first-year response to GH treatment includes an increase in height SDS of more than 0.3– 0.5. The
mean increase in adult height in children with ISS attributable to GH therapy (average duration of
4 –7 yr) is 3.5–7.5 cm. Responses are highly variable. IGF-I levels may be helpful in assessing com-
pliance and GH sensitivity; levels that are consistently elevated (⬎2.5 SDS) should prompt consid-
eration of GH dose reduction. GH therapy for children with ISS has a similar safety profile to other
GH indications. (J Clin Endocrinol Metab 93: 4210 – 4217, 2008)

0021-972X/08/$15.00/0 Abbreviations: CDGP, Constitutional delay of growth and puberty; GnRHa, GnRH analog;
Printed in U.S.A. ISS, idiopathic short stature; SDS, SD score.

Copyright © 2008 by The Endocrine Society

doi: 10.1210/jc.2008-0509 Received March 4, 2008. Accepted August 27, 2008.
First Published Online September 9, 2008

4210 jcem.endojournals.org J Clin Endocrinol Metab. November 2008, 93(11):4210 – 4217

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J Clin Endocrinol Metab, November 2008, 93(11):4210 – 4217 jcem.endojournals.org 4211

S hort stature is one of the most common concerns presenting

to pediatric endocrinologists and other physicians caring
for children. A variety of disease states must be considered and
there is a greater perceived disability of short stature in boys
compared with girls, irrespective of social class. Children with
dysmorphic phenotypes, such as skeletal dysplasias or Turner
ruled out in children presenting with severe short stature, yet a syndrome, and those with birth weight or length that are small
large number of such children remain without a definitive diag- for gestational age should be excluded from the ISS diagnostic
nosis and are labeled as having idiopathic short stature (ISS). The category as are children with clearly identified causes of short
Growth Hormone Research Society together with the Lawson stature (e.g. celiac disease, inflammatory bowel disease, juvenile
Wilkins Pediatric Endocrine Society and the European Society chronic arthritis, GHD or GH resistance, hypothyroidism, Cush-
for Pediatric Endocrinology agreed upon the organization of an ing’s syndrome, etc.).
international workshop in 2006 and convened it on October
17–20, 2007, in Santa Monica, CA, to review and weigh avail-
able evidence related to the evaluation and management of chil- Subcategorization
dren with ISS. Leading experts in the field, including represen-
tatives of all international pediatric endocrine societies were ISS should be subcategorized, principally based on auxological
invited to participate in creating a consensus document on the criteria. The main distinction is between children with a familial
topic. Industry supporters of the Growth Hormone Research history of short stature, whose heights are within the expected
Society were invited to send representatives to the meeting. These range for parental target height and those children who are short
individuals participated in all discussions leading to the devel- for their parents. Although the midparental height is commonly
opment of the consensus document and attended sessions pre- calculated by the Tanner method (average of the father’s and
senting the consensus statements but did not participate in the mother’s height plus or minus 6.5 cm), a more accurate estimate
writings of, or vote on, the statements. The workshop partici- can be achieved using a corrected target height SDS, which is
pants identified and addressed key issues employing a previously calculated as 0.72 ⫻ average of father’s and mother’s height SDS
defined model used to achieve consensus statements for the di- and the lower limit of the target height range as corrected target
agnosis and management of adult and pediatric GH deficiency height minus 1.6 SDS (8). It is generally accepted that, on aver-
(GHD) (1–3) and produced this comprehensive statement that age, adult height achieved in children with ISS is below the pa-
integrates clinical practice recommendations for the approach to rental target height (9).
children with ISS. Two discussion documents were prepared by ISS should also be classified by the presence or absence of
the organizing committee (without industry involvement) before bone age delay, indicating the probability of delayed growth and
the workshop, one on the evaluation and the other on the man- puberty. Subcategorization may help to predict adult height,
agement of children with ISS. These two review papers are pub- which would be expected to be greater in a child with delayed
lished separately (4, 5), and the reader is invited to review them maturation. Short individuals with no family history of short
for further details. The workshop followed a rigorous structure stature generally have a lower adult height in comparison with
of breakout group discussion and review of key issues. A writing target height.
group transcribed the group reports and discussion summaries
into a consensus draft that was carefully and critically reviewed
by all participants in a plenary forum on the last day. Participants Evaluation of the Short Child
(except industry delegates) voted and reached a majority decision
on each section of the document. They were sent a polished draft The evaluation of the short child always begins with a careful
for additional comments and gave signed approval to the final medical history, including family and past medical history, and
revision. a comprehensive physical examination, including phenotypic
characteristics, body proportions, and pubertal staging. Specific
attention should be paid to the possibility of consanguinity and
Definition and Epidemiology the timing of puberty in the parents as well as the stature of first-
and second-degree relatives. Birth history should be reviewed for
ISS is defined as a condition in which the height of an individual abnormalities of fetal growth and perinatal complications and
is more than 2 SD score (SDS) below the corresponding mean information collected pertaining to past illness or symptoms of
height for a given age, sex, and population group without evi- chronic disease, medication use, nutritional status, and psycho-
dence of systemic, endocrine, nutritional, or chromosomal ab- social and cognitive development. The child’s and the parents’
normalities (6). Specifically, children with ISS have normal birth perceptions of the problem as well as their levels of concern
weight and are GH sufficient. ISS describes a heterogeneous should be assessed. Every effort should be made to obtain and
group of children consisting of many presently unidentified plot all previous growth measurements on the appropriate chart
causes of short stature. It is estimated that approximately 60 – (10). For evaluation of children less than 5 yr of age, the World
80% of all short children at or below ⫺2 SDS fit the definition Health Organization recommends the use of their recently pub-
of ISS (7). This definition of ISS includes short children labeled lished growth curves (11). For the assessment of older children,
with constitutional delay of growth and puberty (CDGP) and the use of ethnic-specific growth charts, where available, is pre-
familial short stature. The frequency of referral of these children ferred. For children adopted from developing countries, specific
is dependent on the socioeconomic environment; furthermore, charts from the country of origin are advised for the first gen-
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4212 Cohen et al. Consensus Statement on ISS J Clin Endocrinol Metab, November 2008, 93(11):4210 – 4217

eration. After that, charts specific to the adopting country seem there is a wide variability in GH and IGF-I values and in their
more appropriate. The physical exam should begin with quan- interpretation among currently available commercial and in-
tification of the degree of growth failure and proportionality house assays. This reflects diverse assay methodology as well as
using arm span, sitting height or upper-to-lower segment ratios, the adequacy and applicability of normative data. In the evalu-
body mass index, and for children under 4 yr of age, measure- ation of a short child, a hypothalamic-pituitary magnetic reso-
ment of the head circumference. Dysmorphic features, which nance imaging is performed in children with confirmed GHD or
may indicate a syndromic diagnosis, should be sought, as should if an intracranial lesion is suspected. If a diagnosis of ISS is made,
signs of chronic illness or endocrinopathy. magnetic resonance imaging is not indicated. Although it is clear
that there is variable GH sensitivity among children with short
stature, the IGF-I generation test, although capable of document-
Screening Tests and Initial Diagnostic Testing ing severe GH insensitivity, cannot currently detect more mod-
erate degrees. Attempts should be made to improve diagnostic
In patients for whom the history and physical exam do not utility by generating better normative data. A search for alter-
suggest a particular diagnosis, screening laboratory tests are in- native indices of GH sensitivity should be encouraged.
dicated. These include a complete blood count, erythrocyte sed-
imentation rate, creatinine, electrolytes, bicarbonate, calcium,
phosphate, alkaline phosphatase, albumin, TSH, and free T4 and Genetic Tests
IGF-I levels. Screening for celiac disease is also recommended. A
karyotype should be performed in all girls with unexplained In situations where a specific genetic diagnosis associated with
short stature, and in short boys with associated genital abnor- short stature is expected (such as Noonan syndrome or GH in-
malities. A bone age x-ray should be obtained and reviewed by sensitivity syndrome), the genes of interest should be examined.
an expert. This gives an indication of the child’s remaining Online resources exist such as Genetest (www.genetests.org),
growth potential and may narrow the differential diagnosis. A which identify laboratories capable of performing these tests.
skeletal survey should be reserved for patients with suspicion of Although routine analysis of SHOX should not be undertaken in
a skeletal dysplasia, such as those with abnormal body propor- all children with ISS, SHOX gene analysis should be considered
tions or a height SDS substantially below midparental height SDS for any patient with clinical findings compatible with SHOX
and should be read by an expert in bone disorders. haploinsufficiency (13).

Investigation of the GH-IGF Axis Psychosocial Consequences of ISS

GHD must be excluded to make a diagnosis of ISS. This requires With currently available data, it is difficult to generalize on the
both clinical and biochemical evaluation, because no single test impact of short stature on psychosocial adaptation. Short stature
or set of tests can define GHD. GH testing should be performed may be a risk factor for psychosocial problems, such as social
in any patient with a compatible history and physical examina- immaturity, infantilization, low self-esteem, and being bullied,
tion or a low height velocity or in whom low IGF-I levels are especially for those referred for evaluation. The large interindi-
observed. The majority of experts concur that a patient who is vidual differences in adaptation to short stature and on the im-
short, with normal height velocity, no bone age delay, and a pact of being short may be a function of several risk and pro-
plasma IGF-I level above the mean for age does not require GH tective factors, including parental attitudes and prevailing
testing. A minority recommended pursuing GH testing irrespec- cultural opinions (14). Stress experiences may be frequent, but
tive of IGF-I concentration. The choice of GH stimuli to be used true psychopathology is rare (15). Overall, both clinical and pop-
is highly country dependent, as is the decision to prime with sex ulation studies indicate that most short individuals are function-
steroids. In a child with clinical criteria for GHD, a peak GH ing within the broad range of normalcy; however, it is of note that
concentration less than 10 ng/ml has traditionally been used to extremely short children (⬍⫺2.5 SDS) have not been adequately
support the diagnosis. At the present time, a new GH reference studied.
standard is being introduced that may require a downward ad-
justment of the lower limit of normal. In addition, changes in
assay methodology influence choice of cutoff values for the di- Ethical Principles in the Management of
agnosis of GHD. Measures of spontaneous GH secretion (noc- Children with ISS
turnal or 24-h profiles) are not indicated for routine assessment
of GH status. In contrast, it is strongly recommended that IGF-I The diagnosis and treatment of children with ISS should be under
levels be obtained as part of the evaluation. IGFBP-3 measure- the auspices of pediatric endocrinologists, and management de-
ments add little to the evaluation of short stature except in chil- cisions should be evidence based. The interest of the child is the
dren younger than 3 yr, where low IGFBP-3 levels are helpful in primary concern. One must discourage the expectation that
the diagnosis of GHD (12). Reliable assay performance and ap- taller stature is necessarily associated with positive changes in
propriate normative data are critical for successful use of GH and quality of life. Growth-promoting measures should be effective
IGF-I measurements in clinical practice. It is acknowledged that and should take into consideration the risks, benefits, and treat-
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J Clin Endocrinol Metab, November 2008, 93(11):4210 – 4217 jcem.endojournals.org 4213

ment alternatives including counseling. Treatment must include ment for boys with CDGP with an adult height prediction within
continuous and ongoing evaluation of efficacy and safety as well the normal range. Oxandrolone offers the advantage of oral ad-
as the option of changing the therapy, the dosing strategy, or ministration, but the disadvantages of being weakly androgenic
discontinuation of therapy, when the growth response is poor, and carrying the remote risk of hepatotoxicity.
when an acceptable height is attained, or if the youth withdraws
assent for treatment. The primary goal of treatment is attainment
IGF-I
of a normal adult height. A desired secondary goal is reaching a
In the United States, Japan, and Europe, IGF-I is approved for
normal height during childhood. Physicians are responsible for
short stature with severe IGF deficiency associated with normal
engaging families in discussion that must involve an honest and
GH secretion (or GH insensitivity) (19).
realistic appraisal of treatment expectations for height gain and
In ISS children who do not respond to GH treatment, IGF-I
the variability of clinical outcome (16).
therapy is a theoretical option; however, data are lacking re-
garding efficacy and safety in this population.

Criteria for Treating Children with ISS

GnRH analogs (GnRHa)
Auxological Monotherapy with GnRHa in both sexes has shown a small
The height criteria for consideration of therapy vary based on and variable effect on adult height gain and is generally not rec-
geographical and clinical parameters. In the United States and ommended. Concerns have been raised regarding potential ad-
seven other countries, the regulatory authorities have approved verse effects of GnRHa, including on short-term bone mineral
GH treatment for children shorter than ⫺2.25 SDS (1.2 percen- density (20) and on the psychological consequences of delaying
tile). Among this working consensus group, opinions regarding puberty (21). Combination therapy with GnRHa and GH, how-
the appropriate height below which GH treatment could be con- ever, has potential value if the GnRHa is used for at least 3 yr.
sidered ranged from ⫺2 to ⫺3 SDS. Age should be taken into
account when deciding to initiate treatment. It is felt that the Aromatase inhibitors
optimal age for initiating treatment is 5 yr to early puberty; most Aromatase inhibition may facilitate growth in the presence of
studies on the GH therapy of children with ISS examined children androgens, whereas bone age advancement is slowed due to in-
older than 3– 4 yr. hibition of estrogen production. An increase in predicted adult
height has been shown in males with ISS (22), but adult height
Biochemical data are not available. There is insufficient evidence for its use in
There are no accepted biochemical criteria for initiating GH females with ISS. The long-term efficacy and safety of aromatase
treatment in ISS. inhibitors in males with ISS has not been demonstrated. The
results of ongoing studies on combined treatment with GH and
Psychological aromatase inhibitors show that combination treatment for at
The clinician should weigh the degree of short stature and the least 2 yr slows down the tempo of bone age acceleration and
coping capacity of the child. Therapy would generally not be increases predicted adult height (23). Long-term follow-up of
recommended for the short child who is unconcerned about his/ these patients is still required.
her stature; alternatively, the clinician may be more likely to
consider medical or psychological intervention for the child who
Psychological counseling
seems to suffer from his/her shortness. The psychological bene-
Psychosocial interventions to support the adaptation process
fits of GH therapy in such children have yet to be proven (14).
to short stature and to enhance personal resources for coping
However, robust measures to prove the psychological value of
with stress experiences as well as social action to reduce preju-
GH therapy in such children remain elusive, at least in part
dices are worthwhile to consider instead of or as an adjunct to
because of the recognized limitations in quantitating out-
hormone treatment (14). No data have been reported about the
comes (17).
effect of such interventions.

The Role of GH Treatment Alternatives

Are There Specific Therapies for Various
Anabolic steroids Patient Subtypes?
Oxandrolone has been shown to increase height velocity in
the short term in several controlled studies but does not signif- In children with CDGP, whose puberty and bone age are sub-
icantly increase predicted or measured adult height. Low-dose stantially delayed and who are taller than ⫺2.5 height SDS, tes-
testosterone therapy causes short-term acceleration of linear tosterone is the appropriate therapy in boys, where this clinical
growth with minimal or no advancement of bone age or de- picture is far more prevalent than in girls. In late-maturing girls,
crease in adult height potential. Although both of these drugs are low-dose estrogens represent a theoretical option; however,
useful in males with CDGP with mild to moderate short stature there are no published data to support its use. In ISS children
(⬎⫺2.5 SDS) (18), testosterone is the most appropriate treat- where CDGP is unlikely, GH therapy could be considered.
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4214 Cohen et al. Consensus Statement on ISS J Clin Endocrinol Metab, November 2008, 93(11):4210 – 4217

The Role of Predicted Adult Height in the individual patient. In most children with ISS, the change in height
Decision to Treat with GH SDS will provide the best indicator of response, but height ve-
locity, height velocity SDS, and the change in height velocity
The predicted adult height may be inaccurate in individuals but (centimeters per year or SDS) all have utility, and are sometimes
can be helpful together with other criteria (family pubertal his- superior, in assessing response when interpreted in light of the
tory and midparental target height) in deciding to treat with GH. patient’s clinical situation. Long-term auxological parameters
In a longitudinal study of ISS subjects, bone age delay had an that define the success of therapy include adult height SDS, adult
impact on the accuracy of prediction. In children with a bone age height SDS minus height SDS at start of GH, adult height minus
delay around 2 yr, the average adult height was close to the predicted height, and adult height minus target height. Long-
predicted height, and in those with no bone age delay, adult term psychosocial and metabolic outcomes should be evaluated
height surpassed the initial prediction substantially, although if in registries for these patients.
the bone age was delayed by more than 2 yr, adult height was
considerably below predicted height (24).

Outcome of GH Therapy in Children with ISS

The Role of Current Height in the Decision to
The mean increase in adult height attributable to GH therapy
Treat with GH
(average duration of 4 –7 yr) in children with ISS is 3.5–7.5 cm
The shorter the child, the more consideration should be given to compared with historical controls (26, 27), with patients’ own
treatment with GH. The U.S. Food and Drug Administration pretreatment predicted adult heights (28), or with nontreatment
(FDA)-approved cutoff in the United States (and seven other control or placebo control groups (29, 30).
nations) is ⫺2.25 SDS, whereas in other countries lower cutoffs Responses are highly variable and are dose dependent. Con-
are proposed. Children whose heights are below ⫺2.0 SDS and cern has been raised that higher GH doses (⬎53 ␮g/kg䡠d) may
who are more than 2.0 SDS below their midparental target height advance the bone age and the onset of puberty (31), but this has
and/or have a predicted height below ⫺2.0 SDS are also believed not been found in other studies (32).
by some experts to warrant treatment consideration. Multiple factors affect the growth response to GH, many of
which are unknown. Children who are younger or heavier, who
receive higher GH doses, and who are shortest relative to target
Defining the Response to GH Treatment height have the best growth response. These factors account for
approximately 40% of the variance in growth response. Adult
Short-term auxological features that suggest a successful first- height outcome is influenced negatively by age at start and pos-
year response to GH treatment in individual patients include a itively by midparental height, height at start, bone age delay, and
change in height SDS of more than 0.3– 0.5, a first-year height the first-year response to GH (23, 24). The utility of baseline and
velocity increment of more than 3 cm/yr, or a height velocity SDS treatment-related biochemical data including IGF-I has not been
of more than ⫹1. Restoration to a more normal height during validated in long-term studies, but 2-yr studies suggest that the
childhood is an important consideration. Mathematical models rise in IGF-I correlates with short-term height gain (30).
can be used to estimate responses to therapy with the selected
dose (25).

Biochemical features Monitoring for Efficacy and Safety in GH-

Serial IGF-I measurements during GH therapy are useful to Treated Children with ISS
assess efficacy, safety, and compliance and have been proposed
as a tool for adjusting the GH dose. No other biochemical tests Children treated with GH should be monitored for height,
are routinely recommended in GH-treated ISS patients. weight, pubertal development, and adverse effects at 3- to
6-month intervals. Regular monitoring for scoliosis, tonsillar
Psychological features hypertrophy, papilledema, and slipped capital femoral epiphysis
An important rationale for treatment with GH is the assump- should be performed as part of the regular physical exam during
tion that it will improve quality of life. Validated instruments follow-up visits. We recommend that after 1 yr, the response to
sensitive to the specific domains that are affected in short chil- therapy be assessed by calculating height velocity SDS as well as
dren and that are easily administered in the clinic are needed but the change in height SDS. Pubertal stage should be assessed reg-
are not currently recommended as part of routine care. ularly, and bone age may be obtained periodically to reassess
height prediction and for consideration of intervention to modify
the tempo of puberty. IGF-I levels may be helpful in guiding GH
Interpretation of Outcome Measures dose adjustment, but the significance of abnormally elevated
Assessing the Success of GH Treatment IGF-I levels remains unknown. Thus far, no instances of elevated
blood glucose in GH-treated patients with ISS have been re-
Short-term outcome measures (i.e. ⬍2 yr) must take into account ported, but there is controversy regarding the need for routine
the age, pubertal status, and degree of growth retardation of the monitoring of glucose metabolism.
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GH Treatment Adjustment Strategies Cost/Benefit Analysis

Dosage is usually selected and adjusted by weight. If the growth The average ultimate height gain attributable to GH treatment in
response is considered inadequate, the dose may be increased. children with ISS, as well as the cost, are known (10,000 –20,000
There are no definitive data concerning the long-term safety of dollars/cm), but the short- and long-term benefits for the indi-
doses higher than 50 ␮g/kg䡠d in children with ISS. The upper limit vidual and society are unclear (26). It is presently not known
of GH dosage used in other pediatric conditions is approximately whether, and how, a gain in height relates to change in quality of
70 ␮g/kg䡠d (28, 33), but the possibility of using such doses varies life. Therefore, GH treatment for children with ISS should be put
in terms of national health economics. In the United States, the in the context of the health budget for the specific country. At the
current FDA-approved doses for GH in ISS are up to 0.3– 0.37 current time, data demonstrating improved quality of life, better
mg/kg 䡠 wk (34). In the future, growth prediction models may psychological health, etc. have not yet been collected in well-
improve GH dosing strategies. IGF-I levels may be helpful in controlled studies. Therefore, recommendations for treatment
assessing compliance and GH sensitivity; levels that are consis- that increases adult height should be balanced with the high cost
tently elevated (⬎2.5 SDS) should prompt consideration of GH of these therapies.
dose reduction. Recent studies on IGF-based dose adjustments in
ISS demonstrated increased short-term growth when higher IGF
targets were selected, but this strategy has not been validated in
The Definition of GH Nonresponsiveness
long-term studies with respect to safety, cost effectiveness, or
adult height (31). The expected result of GH treatment in ISS is an increase in height
SDS and height velocity resulting in increased adult height. Be-
cause there is a continuum of GH responses, the definition of
nonresponsiveness is arbitrary. Suggested criteria for poor first-
Consideration of Adding Puberty Modulators year response include height velocity SDS less than ⫹1 or change
If height prediction is below ⫺2.0 SDS at the time of pubertal in height SDS less than 0.3– 0.5, depending on age. Emerging
onset in either sex, the addition of GnRHa may be considered as tools for the definition of GH treatment failures include predic-
discussed above (35, 36). Alternatively, in males, aromatase in- tion modeling and age- and gender-specific growth-response
hibitors may be an option (22). However, long-term efficacy and charts (39). If the growth response is lower and compliance is
safety data are not available for either of these interventions. assured, among the options considered may be increasing the
Also, the impact of delayed puberty on somatic and psycholog- dose of GH. IGF-I values can be used to assess compliance and
ical development is not known. We do not recommend aro- sensitivity to GH. If after 1–2 yr and higher doses of GH, the
matase inhibitors for girls. growth rate is still inadequate, GH treatment should be stopped
and alternative therapies could be entertained.

Duration of GH Treatment Future Studies

There are two schools of thought about the duration of treat- Future studies on the management of children with ISS should
ment. One is that treatment should stop when near adult height involve three major areas. The first is improvement in diagnostic
is achieved (height velocity ⬍2 cm/yr and/or bone age ⬎16 yr in tools to categorize the different subpopulations who fall within
boys and ⬎14 yr in girls). Alternatively, therapy can be dis- the definition of ISS and their response to therapy. These would
continued when height is in the normal adult range (above ⫺2 include molecular genetics, proteomics, and pharmacogenom-
SDS) or has reached another cutoff for the reference adult pop- ics, better measures of GH and IGF-I sensitivity, and improved
ulation (for example, in Australia, the 10th percentile; elsewhere, prediction models. The second area should involve psychosocial
the 50th percentile). Stopping therapy is influenced by patient/ instruments, interventions, and outcomes. A third area is the
family satisfaction with the result of therapy or ongoing cost- conduct of well-controlled studies on the use of adjunctive phar-
benefit analysis or when the child wants to stop for other reasons. macological interventions such as the combination of GH and
GnRHa, aromatase inhibitors, or IGF-I.

Possible GH Side Effects

Conclusions
The possible side effects in GH-treated children with ISS are
similar to those previously reported in children receiving GH ISS represents a significant clinical entity within the pediatric
therapy for other indications (37). However, the frequency of endocrinology practice, and multiple therapeutic interventions
adverse events is generally less (38). No long-term adverse effects may be considered for these patients after appropriate evaluation
have been documented. Posttreatment surveillance with focus on has been conducted. Further clinical research and development
cancer prevalence and metabolic side effects is recommended, is warranted to optimize the management of these children and
but the feasibility of such studies is unclear. to ensure that treatments are safe and beneficial.
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4216 Cohen et al. Consensus Statement on ISS J Clin Endocrinol Metab, November 2008, 93(11):4210 – 4217

Acknowledgments References

Consensus Workshop participants include David Allen, University of 1. 1998 Consensus guidelines for the diagnosis and treatment of adults with
Wisconsin School of Medicine and Public Health, Madison, WI; Ivo growth hormone deficiency: summary statement of the Growth Hormone Re-
Arnhold, Universidade de Sao Paulo, Sao Paulo, Brazil; Peter Bang, search Society Workshop on Adult Growth Hormone Deficiency. J Clin En-
docrinol Metab 83:379 –381
Karolinska Institute, Stockholm, Sweden; Fernando Cassorla, University
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Industry nonvoting participants included Eli Lilly and Co.; Barbara
growth hormone (GH) deficiency from childhood to young adulthood: asso-
Lippe, Genentech; Ann-Marie Kappelgaard, Novo Nordisk A/S; Mireille ciation to low GH dependency of IGF-II and presence of circulating IGFBP-3
Bonnemaire, Ipsen, Ltd.; George Bright, Tercica, Inc.; and Jose Cara, 18-kilodalton fragment. J Clin Endocrinol Metab 90:6028 – 6034
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Address all correspondence and requests for reprints to: Pinchas clinical indicators of SHOX haploinsufficiency. J Med Genet 44:306 –313
Cohen, M.D., Professor and Chief of Endocrinology, Mattel Children’s 14. Visser-van Balen H, Geenen R, Kamp GA, Huisman J, Wit JM, Sinnema G
Hospital at UCLA, David Geffen School of Medicine at UCLA, 10833 Le 2007 Long-term psychosocial consequences of hormone treatment for short
Conte Avenue MDCC 22-315, Los Angeles, California 90095-1752. stature. Acta Paediatr 96:715–719
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E-mail: [email protected].
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The Consensus Workshop was organized and supported by the 16. Allen DB, Fost NC 2004 Growth hormone for short stature: ethical issues
Growth Hormone Research Society, the Lawson Wilkins Pediatric En- raised by expanded access. J Pediatr 144:648 – 652
docrine Society, and the European Society of Pediatric Endocrinology 17. Ross JL, Sandberg DE, Rose SR, Leschek EW, Baron J, Chipman JJ, Cassorla
and supported in part by unrestricted education grants from Eli Lilly and FG, Quigley CA, Crowe BJ, Roberts K, Cutler Jr GB 2004 Psychological
Co., Ferring, Genentech, Ipsen, JCR Pharmaceuticals, Novartis, Novo adaptation in children with idiopathic short stature treated with growth hor-
Nordisk, Pfizer, and Tercica. mone or placebo. J Clin Endocrinol Metab 89:4873– 4878
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Nordisk and received grant support from Pfizer, Genentech, and Eli Lilly 902–910
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and a speaker for Novo Nordisk. P.S. is a consultant to Sandoz. E.O.R.
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tant to Eli Lilly and Co. S.D.C. is a consultant for Tercica. M.O.S. is a 22. Hero M, Wickman S, Dunkel L 2006 Treatment with the aromatase inhibitor
consultant to Ipsen. J.M.W. is a consultant to Ipsen, Eli Lilly, and Tercica letrozole during adolescence increases near-final height in boys with consti-
and received grant support from Pfizer, Novo Nordisk, Ferring, and tutional delay of puberty. Clin Endocrinol (Oxf) 64:510 –513
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