8/8/23, 13:45 Diagnosis of growth hormone deficiency in children - UpToDate

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Diagnosis of growth hormone deficiency in children

AUTHORS: Erick J Richmond, MD, Alan D Rogol, MD, PhD
SECTION EDITOR: Mitchell E Geffner, MD
DEPUTY EDITOR: Alison G Hoppin, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2023.

This topic last updated: Jan 20, 2022.

INTRODUCTION

Growth hormone (GH) has been available for management of the short stature associated
with GH deficiency (GHD) for more than 60 years [1]; recombinant DNA-derived human GH
(rhGH) has been available since 1985. While availability is no longer a problem, there still
remains a number of difficulties with the diagnosis of GHD, resulting mainly from the lack of
appropriate tools to make (or exclude) the diagnosis reliably.

The incidence of short stature associated with GHD has been estimated to be approximately
1:4000 to 1:10,000 [2-4]. It is the primary indication for human GH treatment in childhood,
which entails years of treatment with subcutaneous injections and substantial cost for the
health care system. Based on these premises, it is clear that an accurate diagnosis is
essential [5,6].

The diagnosis of GHD in children is reviewed here. Related content is in the following
UpToDate topic reviews:

● (See "Causes of short stature".)

● (See "Diagnostic approach to children and adolescents with short stature".)
● (See "Treatment of growth hormone deficiency in children".)

AUXOLOGY

The scientific study of growth and maturation of children (auxology) began some 250 years
ago [7] and is still an indispensable tool in pediatrics. Most pediatric endocrinologists agree
that the foundation for the diagnosis of GHD in childhood is based on a comparison of the
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child's growth pattern with established norms. A consensus view concluded that clinical
assessment of the growth-retarded child is the single most useful parameter in diagnosing
growth disorders and challenged the status of human GH measurements as the diagnostic
"gold standard" [8].

Errors in length or height measurements may be the result of unreliable equipment. For this
reason, all apparatus should be checked frequently. More often, measuring procedures are
at fault, perhaps in the positioning of the subject or in locating proper landmarks. (See
"Measurement of growth in children".)

Neonates and children younger than two years may be difficult to measure accurately; the
neonatometer (length stadiometer) and supine table are the recommended devices to
reduce errors in measuring. The vertical stadiometer is used to measure standing height,
which is recommended for children two to three years or older [9].

Length or height data should be plotted on the appropriate growth chart. Length is for
children measured lying down and should be used up to two to three years of age
( figure 1A-B); height is for children measured standing and should be used for children
over two to three years ( figure 2A-B). The severity of short stature is quantified by
determining the height percentiles or Z-scores from these charts or from calculators for boys
(calculator 1) or for girls (calculator 2).

Height velocity can be calculated from serial height determinations and plotted on
appropriate velocity charts ( figure 3A-B). A period of at least six months is necessary for
reliable calculation of height velocity of children above the age of two years. (See "Diagnostic
approach to children and adolescents with short stature", section on 'Evaluation of growth'.)

MOLECULAR GENETICS OF GROWTH HORMONE DEFICIENCY

Approximately 3 to 30 percent of children with GHD have an affected parent, sibling, or child
[10,11]. Several genetic causes of GHD have been described [3] (see "Causes of
hypopituitarism", section on 'Genetic diseases'):

● POU1F1 gene mutations – The POU1F1 gene (known as Pit1 in rodents) is responsible for
pituitary-specific transcription of genes for GH, prolactin, thyrotropin, and the GH-
releasing hormone (GHRH) receptor [12,13]. Mutations of the POU1F1 gene are
transmitted as autosomal recessive or codominant traits and cause variable peptide
hormone deficiencies with or without anterior pituitary hypoplasia, known as combined
pituitary hormone deficiency (CPHD) type 1 ( MIM #613038) [14-16]. One specific
mutation at the POU1F1 locus has been associated with dominantly inherited isolated
GHD [17].

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● PROP1 gene mutations – PROP1 gene mutations result in failure to activate POU1F1/Pit1
gene expression and probably cause pituitary hypoplasia and/or familial multiple
pituitary hormone deficiency [18]; paradoxical cystic hyperplasia of the pituitary also
has been reported [19]. This is the most common known genetic cause of CPHD type 2
( MIM #262600) [20,21].

● Other transcription factors – In addition to POU1F1/Pit1 and PROP1, other transcription

factors participate in the differentiation of anterior pituitary cells. Mutations in these
genes also cause congenital deficiencies of multiple pituitary hormones, with variable
phenotypes. These include the genes LHX3 (responsible for CPHD type 3; MIM
#221750), LHX4 (CPHD type 4; MIM #262700), HESX1 (CPHD type 5; MIM #182230),
OTX2 (CPHD type 6; MIM #613986), TBX19 (TPIT), SOX2, SOX3 [22-24], and GLI2 [25].

● GHRH receptor gene defects – Children with mutations in the GHRH receptor gene
(GHRHR; MIM 139191) have undetectable GH release during standard provocative
tests and after exogenous GHRH administration, but they respond to GH treatment.

● Deletions and mutations of the GH1 gene – GH1 ( MIM 139250) is the gene encoding
GH, located on chromosome 17. Gene deletions, frameshift mutations, and nonsense
mutations of GH1 have been described as causes of familial GHD [26].

● Syndrome of bioinactive GH – A diagnosis of the syndrome of bioinactive GH (Kowarski

syndrome; MIM #262650) has been proposed for short children with a phenotype
that resembles that of isolated GHD, with normal or slightly elevated basal GH levels in
combination with low insulin-like growth factor 1 (IGF-1) concentrations that increase
after treatment with exogenous GH. True molecular abnormalities involving a mutant
GH molecule have rarely been reported [27,28].

Other mutations can cause GH insensitivity. The clinical phenotype of GH insensitivity is

similar to that of GHD, but the mechanisms, laboratory findings, and treatment are different.
(See "Growth hormone insensitivity syndromes", section on 'Introduction'.)

CLINICAL PRESENTATION

GHD can be divided into congenital and acquired forms. The single most important clinical
manifestation of GHD is growth failure, and careful documentation of height velocity is
critical to making the correct diagnosis. In some children with congenital GHD or
hypopituitarism, the growth faltering may not be manifested until late infancy, as noted
below.

Congenital — Patients with congenital severe GHD have only a slightly reduced birth length
and may not immediately show growth failure. There is a higher frequency of breech
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presentation and perinatal asphyxia. Neonatal morbidity may include hypoglycemia and
prolonged jaundice.

The clinical presentation depends upon the severity of the GHD. Postnatal growth is
abnormal, and growth failure can occur during the first months of life [29-32] but may not be
obvious until 6 to 12 months of age, by which time the height velocity is definitely slow and
deviates from the normal growth curve, with length measurements often significantly below
the mean. Bone age becomes delayed but is similar to height age, unless there is concurrent
hypothyroidism.

In some cases, congenital GHD is associated with multiple pituitary hormone deficiencies,
which affect the clinical manifestations. When GHD is combined with deficiency of
adrenocorticotropic hormone (ACTH), hypoglycemia may be severe. The combination of GHD
with gonadotropin deficiency can cause microphallus, cryptorchidism, and hypoplasia of the
scrotum.

Some children with congenital GHD have associated pathologic variants in one of several
genes related to pituitary development or hormone formation, or with a structural brain
abnormality. Others have no identifiable cause. (See 'Molecular genetics of growth hormone
deficiency' above and "Causes of short stature", section on 'Growth hormone deficiency'.)

Acquired — Children with acquired GHD present with severe growth failure, delayed bone
age, and increased weight:height ratios. Causes of acquired GHD include intracranial tumors
involving the hypothalamic-pituitary region (eg, craniopharyngioma), cranial irradiation, and
head trauma.

WHICH CHILDREN REQUIRE EVALUATION?

Children with short stature should be evaluated with careful serial measurements of length
or height and compared with reference standards. (See 'Auxology' above.)

The clinical significance of the short stature depends on many factors, especially height
velocity, severity of the short stature, and genetic potential. Many children with moderate
short stature and normal growth (eg, height velocity at least 5 cm/year between four and six
years of age and at least 4 cm/year between six years and puberty) require only a basic
evaluation (including bone age evaluation), as outlined in a separate topic review. (See
"Diagnostic approach to children and adolescents with short stature".)

A more comprehensive evaluation is warranted in children with one or more of the following
features:

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● Growth failure – This is suggested if a height-for-age curve has deviated downward

across two major height percentile curves (eg, from above the 25th percentile to below
the 10th percentile) or if the child is growing slower than the following rates:

• Age two to four years – Height velocity less than 5.5 cm/year (<2.2 inches/year)

• Age four to six years – Height velocity less than 5 cm/year (<2 inches/year)

• Age six years to puberty:

- Height velocity less than 4 cm/year for boys (<1.6 inches/year)

- Height velocity less than 4.5 cm/year for girls (<1.8 inches/year)

● Severe short stature (eg, height ≤-2.5 standard deviations [SD], ie, 0.6th percentile), or
less severe short stature combined with growth failure [33].

● Features that raise concerns for hypothalamic-pituitary dysfunction, either congenital

(eg, hypoglycemia, microphallus, cryptorchidism, or wandering nystagmus) or acquired
(eg, intracranial tumor, cranial irradiation, or head trauma), with decelerating growth,
even if the child's height is within the normal range [8].

● Evidence for deficits in other hypothalamic-pituitary hormones, either congenital or

acquired.

DIAGNOSTIC APPROACH

Once the decision to evaluate a short child has been made, a variety of different tests can be
performed.

The first step is to evaluate for other causes of growth failure, including chronic systemic
disease, hypothyroidism, Turner syndrome (in girls), and skeletal disorders. This is
accomplished through a thorough medical history and physical examination. Laboratory
evaluation should be performed when appropriate, including screens for systemic disease,
undernutrition, inflammation, and thyroid function, and a karyotype in girls to rule out
Turner syndrome. (See "Diagnostic approach to children and adolescents with short stature",
section on 'Laboratory and imaging studies'.)

If there is no evidence of these disorders, then the possibility of GHD should be investigated
with the following tests:

● Insulin-like growth factor 1 (IGF-1)

● Insulin-like growth factor binding protein-3 (IGFBP-3)
● Bone age

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GHD is effectively excluded in children with a normal bone age and height velocity. In this
case, provocative testing for GHD is not required.

When GHD is congenital and near complete, the diagnosis is relatively easy to confirm
because affected children present with severe growth failure, delayed bone age, and very
low serum concentrations of GH, IGF-1, and IGFBP-3 [8]. For patients with all of these clinical
characteristics, it is reasonable to make the diagnosis of GHD without performing GH
stimulation testing.

Milder degrees of growth faltering and decreased IGF-1 and IGFBP-3 levels are consistent
with GHD but are also consistent with other causes of growth failure, including poor
nutrition. (See 'IGF-1 and IGFBP-3' below.)

If not explicable on the basis of undernutrition, low IGF-1 and/or IGFBP-3 levels are strongly
suggestive of a diagnosis of GHD, but this should be confirmed by provocative GH testing. In
addition, a magnetic resonance imaging (MRI) of the hypothalamic-pituitary region (with and
without contrast) is recommended for children with suspected GHD [34]. (See 'Growth
hormone stimulation tests' below and 'Imaging' below.)

TESTING FOR GROWTH HORMONE DEFICIENCY

Assessment of pituitary GH production is difficult because GH secretion is pulsatile, with the

most consistent surges during stages 3 and 4 of sleep. The regulation of GH secretion
involves at least two well-studied hypothalamic factors, GH-releasing hormone (GHRH;
stimulatory) and somatostatin (inhibitory). In addition, GH secretion is influenced by multiple
other peptides and neurotransmitters, including ghrelin (stimulatory) produced both in the
hypothalamus and in the stomach, which causes stimulation of GHRH [35].

Between normal pulses of GH secretion, serum GH levels are often low, below the limits of
sensitivity of most conventional assays. Thus, measurement of a random serum GH level is
not helpful in diagnosing GHD and is used only to exclude the possibility of GH insensitivity.

Because of these issues, the diagnosis of GHD is made with a combination of clinical
assessment and auxology, insulin-like growth factor 1 (IGF-1) and insulin-like growth factor
binding protein-3 (IGFBP-3) levels, and GH stimulation tests.

IGF-1 and IGFBP-3 — The determination of IGF-1 and IGFBP-3 levels has become a widely
used tool in the diagnostic evaluation of growth disorders. IGF-1 is the mediator of the
majority of the growth-promoting actions of GH. (See "Physiology of insulin-like growth
factor 1".)

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Test characteristics — Two benefits of measurement of serum concentrations of IGF-1 and

IGFBP-3 are:

● Their concentrations often reflect the integrated concentration of secreted GH

● Unlike the pulsatile secretion of GH, IGF-system peptides are stable during the day
(serum half-lives of 12 to 16 hours) [36]

Despite relatively good correlations with groups of patients between GH secretion and IGF-1
concentrations [37-40], there remain substantial problems in assessing GH status by
measurement of IGF-1 in individual patients [41,42]:

● Normal IGF-1 values in children younger than three years may be very low and, in some
cases, may be below the lower limit of detection of the assay. As a result, the normal
range overlaps with that for GHD. Newer assays using mass spectrometry may resolve
this issue [43].

● Inadequate nutrition lowers IGF-1 concentrations despite normal or even elevated

levels of GH.

● Serum IGF-1 levels may be low in conditions other than GHD, such as GH insensitivity,
hypothyroidism [44], diabetes [45], renal failure [44,46], and cancer [47].

Of the six IGFBPs, IGFBP-3 is the major serum carrier protein for IGF-1 [48-50] and the most
GH-dependent [51]. IGFBP-3 levels are less nutritionally dependent and are more
discriminatory than those of IGF-1 in the lower end of the normal range. Although levels of
both IGF-1 and IGFBP-3 normally increase with age, IGFBP-3 is a better screening test for
GHD than IGF-1 in younger children because it is easier to distinguish low-normal levels of
IGFBP-3 in young children from truly low levels [52]. (See "Physiology of insulin-like growth
factor 1".)

Interpretation of results — For patients with growth failure or severe short stature, we
interpret the results of this testing as follows:

● Moderately or severely reduced IGF-1 and IGFBP-3 (eg, <-2 standard deviations [SD])
with delayed bone age:

• In most cases, the possibility of GHD should be explored by provocative GH testing,

if other causes of low IGF-1 and IGFBP-3, such as poor nutrition, have been
excluded. (See 'Growth hormone stimulation tests' below.)

• If the growth failure is severe, bone age is significantly delayed, and IGF-1 and
IGFBP-3 are definitively low (eg, <-2 SD), it is reasonable to make the diagnosis of
GHD without performing GH stimulation testing, especially in the setting of known

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hypothalamic-pituitary disease and/or its treatment (eg, brain surgery and/or

radiation).

● Somewhat low IGF-1 and IGFBP-3 (eg, between 0 and -2 SD) – The decision about
whether to perform provocative GH testing depends on individual patient
characteristics, including the severity of growth failure, degree of bone age delay, and
whether the low levels can be explained by other factors, such as poor nutrition.

● Clearly normal IGF-1 and IGFBP-3 (SD ≥0); ie, in the upper one-half of the normal
range – GHD is extremely unlikely, and no further testing is required.

If the results of IGF-1 and IGFBP-3 are discordant, IGF-1 takes precedence, except for infants
and young children, in whom IGFBP-3 should guide the decision about further testing. IGF-1
and IGFBP-3 levels should be interpreted against reference ranges that are standardized for
sex and age (or better, by stage of sexual development, if available). The range varies with
the assay used, and results should be interpreted against standards provided by the
laboratory performing the test [53]. Consideration of norms based on bone age rather than
chronologic age has also been recommended.

Growth hormone stimulation tests

Indications — Provocative (stimulation) GH testing is indicated for most patients to confirm

a diagnosis of GHD. Because this testing has limitations, the results should not be used as
the sole diagnostic criterion and should be interpreted in the context of auxologic findings,
bone age, and IGF-1 and IGFBP-3 concentrations [54].

Provocative GH testing is not necessary for selected patients in whom other clinical criteria
are sufficient to make the diagnosis of GHD, including those with the following conditions:

● Pituitary abnormality (secondary to a congenital anomaly, tumor, or irradiation) and a

known deficiency of at least one other pituitary hormone, as well as auxologic criteria
[55].

● Newborn with a congenital pituitary abnormality (ectopic posterior pituitary and

pituitary hypoplasia with abnormal stalk) or known deficiency of a pituitary hormone,
along with hypoglycemia, at which time a simultaneous serum GH concentration is <5
mcg/L [55].

● Infant or young child with extreme short stature (eg, height <-3 SD), normal nutrition,
significantly reduced IGF-1 (eg, <-2 SD) and IGFBP-3, and delayed bone age. This is the
classic presentation of congenital and severe GHD, and most experts agree that
provocative testing is not required to make the diagnosis.

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Provocative testing also is not necessary for short children with a normal bone age and
height velocity or for those with clearly normal levels of IGF-1 and IGFBP-3. These findings
are sufficient to exclude GHD without provocative testing. (See 'Which children require
evaluation?' above and 'Interpretation of results' above.)

Limitations — Provocative GH testing has a number of limitations ( table 1) [8]:

● The tests are nonphysiologic.

● The cutoff level of "normal" is arbitrary and may depend on the specific provocative
agent used.

● The interpretation of the test results depends upon age and sex hormone
concentrations [56]. Children with constitutional delay of growth and puberty may have
low GH results on provocative testing in the absence of true GHD (ie, false-positive
results). Administration of sex steroids for a few days prior to the provocative GH
testing (known as "priming") reduces the chance of a false-positive result, as discussed
below.

● Adiposity (as measured by body mass index) also influences GH response to the
stimulation test, such that obese children show diminished GH responses to all stimuli
[55,57,58].

● The tests rely upon GH assays of variable accuracy.

● The tests are expensive, uncomfortable, and carry some risks.

● Test reproducibility has not been adequately documented.

● The ability of the tests to discriminate between normal short children and children with
partial GHD is limited.

Because of these limitations, it is clear that there is no real "gold standard" for the diagnosis
of GHD [34]. Nonetheless, GH stimulation testing is a valuable diagnostic tool when
combined with auxologic data and measurements of IGF-1 and IGFBP-3. The peak GH
response to provocative testing is also a useful predictor of response during the first year of
treatment with GH [59,60].

Technique — Measurement of GH secretory reserve relies upon the use of physiologic or

pharmacologic stimuli.

● General protocol – The stimulation tests are performed after an overnight fast. After
the pharmacologic agent is administered, serum samples are collected at intervals
designed to capture the peak stimulated GH level; the expected time to this peak varies

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depending on the stimulus. Traditionally, most pediatric endocrinologists defined a

"normal" response by a serum GH concentration of >10 mcg/L, but a cutoff of 7.5
mcg/L is often used for modern assays and is used in some countries [54]. Newer
published data [61] suggest that assay-specific cutoffs to define GHD may be necessary
[54,62]. Specific considerations for the measurement of human GH have been reviewed
in detail [63].

Some clinicians also measure a baseline GH level as part of the stimulation test. If that
level is relatively high (eg, between 5 and 10 mcg/L), this suggests that GHD is unlikely
and that subsequent GH values after stimulation, even if the values are all <10 mcg/L,
may not necessarily reflect true GHD.

● Choice of stimulus – There is general consensus that two different stimuli should be
used for most patients [54,55]. In a patient with known pathology of the central
nervous system, other pituitary hormone defects, or a genetic defect, one test is
sufficient to establish the diagnosis [34,64]. The pharmacologic stimulants that have
the highest specificity (fewest false-positive results) and are most commonly used
clinically are:

• Clonidine – Clonidine stimulates GH by several mechanisms, including the

stimulation of GHRH via alpha-adrenergic pathways. It is administered orally at a
dose of 5 mcg/kg (maximum 250 mcg), and serum GH is measured at 0, 30, 60 and
90 minutes; peak GH secretion typically occurs approximately one hour after the
stimulus is given [64]. Clonidine may cause modest hypotension and hypoglycemia,
so patients should be monitored for these problems during the test. This stimulant
is thought to have relatively good specificity, although estimates of this test's
sensitivity and specificity vary [65-68].

• Arginine – An intravenous infusion of 0.5 g/kg body weight (to a maximum of 40 g)

is given over 30 minutes, and serum GH is measured at 0, 30, 60, 90, and 120
minutes [64]. The maximum GH peak is expected at approximately 60 minutes.
There are no side effects from this test, but overdoses have been described. GH
secretion can be enhanced (and therefore false-positive results reduced) by adding
a dose of L-Dopa orally just prior to the administration of arginine [64]. However, L-
Dopa is not available in the United States. L-Dopa also can be used alone but is a
relatively weak stimulant of GH release.

• Glucagon – Administration of glucagon causes transient hyperglycemia, which in

turn stimulates endogenous insulin secretion, followed by controlled hypoglycemia
and consequent GH secretion [64,69,70]. It is less risky than insulin-induced
hypoglycemia (described below) and is a good choice for infants and young
children. Glucagon is administered subcutaneously at a dose of 0.03 mg/kg
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(maximum 1 mg), and serum samples are drawn at intervals between one and three
hours after the stimulus. Peak GH secretion occurs between two and three hours
after glucagon administration; side effects are mild and transient and include
nausea, vomiting, sweating, or headaches.

• Insulin-induced hypoglycemia – Insulin-induced hypoglycemia is a potent stimulant

of GH release and is therefore among the most specific tests for GHD [71-73].
However, this test is less commonly used in children because of safety concerns
[34]. (See "Growth hormone deficiency in adults", section on 'Insulin-induced
hypoglycemia'.)

Arginine, glucagon, and insulin also provide information about the hypothalamic-
pituitary-adrenal axis.

Macimorelin acetate is used for testing adults with suspected GHD, but there are no
data in the pediatric population. The performance of this and other provocative tests is
discussed separately. (See "Growth hormone deficiency in adults", section on
'Provocative tests'.)

● Sex steroid priming – Administration of sex steroids prior to the GH stimulation test
(known as "priming") increases the response to the stimulus and diminishes the
possibility of a false diagnosis of GHD [74]. The clinical utility of priming has not been
fully established, but guidelines recommend priming before provocative GH testing in
prepubertal boys older than 11 years and prepubertal girls older than 10 years [55].
Priming is most useful for otherwise healthy patients with mild growth failure (eg,
predicted adult height within -2 SD of the mean) because it may reduce false-positive
results for GH stimulation testing and thus help distinguish mild GHD from
constitutional delay of growth and puberty.

● Other considerations – Stimulation testing with the combination of GHRH and

arginine improves the evaluation for patients with multiple pituitary hormone
deficiencies to determine the level of the secretory defect [64,75]. However, it is not
useful in making a diagnosis of GHD in children with isolated idiopathic GHD (which
accounts for most children with GHD), because these children have a defect in
hypothalamic regulation of pituitary GH secretion and are expected to respond
normally to GHRH. GHRH is not available in the United States.

If the child is also hypothyroid, the tests of GH secretion should be postponed until
thyroxine is adequately replaced. GH secretion may be subnormal merely as a result of
the hypothyroidism. Thus, hypothyroidism should be excluded before performing GH
stimulation tests. (See 'Diagnostic approach' above.)

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Imaging — High-quality contrast-enhanced magnetic resonance imaging (MRI) with fine

cuts (1 mm) permits excellent visualization of the hypothalamo-pituitary stalk
(infundibulum). On T1-weighted imaging, a clear demarcation can be made between the
adenohypophysis (after two months of age) and the neurohypophysis, which appears as
hyperintense [76].

After the clinical and biochemical diagnosis of GHD is made, it is essential to obtain an MRI
of the brain with narrow cuts through the hypothalamic-pituitary area [34]. This imaging is
important to exclude the possibility of a pituitary tumor; it also permits diagnostic
characterization by showing the presence or absence of morphologic abnormalities such as
anterior pituitary hypoplasia, pituitary stalk agenesis, and posterior pituitary ectopia.

An MRI is helpful in the prediction of permanent GHD. In one study, GH secretion was
reevaluated after completion of GH treatment in young adults with childhood-onset GHD
[77]. GHD was permanent in children with congenital hypothalamic-pituitary abnormalities
on MRI scans, while children without hypothalamic-pituitary abnormalities frequently
showed normalization of GH secretion at the completion of GH treatment.

An MRI may also provide evidence of severe GHD if the diagnosis of pituitary stalk
interruption syndrome is made [77]. This entity consists of ectopic neurohypophysis,
interrupted pituitary stalk, and hypoplastic adenohypophysis and has been associated with
severe GHD.

If an MRI is not available, computed tomography (CT) of the head is sufficient to screen for a
pituitary tumor.

GROWTH HORMONE INSENSITIVITY

GH insensitivity is a group of inherited disorders in which there is a reduction or absence of

the biologic effects of GH despite normal or above-normal production of GH. GH insensitivity
should be suspected in patients with growth failure and low insulin-like growth factor 1 (IGF-
1) and insulin-like growth factor binding protein-3 (IGFBP-3) levels, but normal or increased
circulating levels of GH, and lack of response to GH ( algorithm 1).

The classic GH insensitivity syndrome is also known as Laron syndrome (formerly, Laron
dwarfism), in which mutations of the GH receptor cause severe postnatal growth failure.
Lesser degrees of GH resistance may play a role in a small percentage of cases of idiopathic
short stature [78] (see "Growth hormone treatment for idiopathic short stature", section on
'Dose adjustment for IGF-1 levels'). This disorder is discussed in a separate topic review. (See
"Growth hormone insensitivity syndromes".)

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SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Growth hormone
deficiency and other growth disorders".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th
grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topic (see "Patient education: My child is short (The Basics)")

SUMMARY AND RECOMMENDATIONS

● Pathogenesis – Growth hormone deficiency (GHD) can be caused by a variety of

genetic mutations (although these are rare) or by processes affecting hypothalamic or
pituitary function. GHD may be isolated or may occur in association with deficiencies of
other pituitary hormones. (See 'Molecular genetics of growth hormone deficiency'
above and 'Clinical presentation' above.)

● Candidates for evaluation – GHD should be suspected in patients with marked short
stature (more than 2.5 standard deviations [SD] below the mean) and/or marked
growth failure (height velocity less than the 25th percentile for age), or more moderate
degrees of short stature and growth failure with decelerating growth (without
alternative explanation). It should also be suspected in children with signs or
symptoms of hypothalamic-pituitary dysfunction with decelerating growth. (See 'Which
children require evaluation?' above.)

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● Diagnostic approach – GHD is primarily a clinical diagnosis, based upon auxologic

features and confirmed by biochemical testing.

• Clinical evaluation – The first step is to evaluate for causes of growth failure other
than GHD, including chronic systemic disease, hypothyroidism, Turner syndrome (in
girls), and skeletal disorders. This is accomplished through a thorough medical
history and physical examination. Laboratory evaluation should be performed when
appropriate. (See 'Which children require evaluation?' above and "Diagnostic
approach to children and adolescents with short stature".)

• Initial testing – Patients with suspected GHD should be screened with radiographic
measurement of bone age, insulin-like growth factor 1 (IGF-1), and insulin-like
growth factor binding protein-3 (IGFBP-3). We interpret the results of IGF-1 and
IGFBP-3 testing as follows (see 'Interpretation of results' above):

- Clearly normal IGF-1 and IGFBP-3 (SD ≥0; ie, in the upper one-half of the normal
range) – GHD is extremely unlikely, and no further testing is required.

- Somewhat low IGF-1 (eg, SD between 0 and -2) and IGFBP-3 – Moderate
suspicion of GHD. The decision about whether to perform provocative GH
testing depends on individual patient characteristics, including the severity of
growth failure, degree of bone age delay, and whether the low levels of IGF-1
and IGFBP-3 can be explained by other factors, such as poor nutrition.

- Moderately or severely reduced IGF-1 (eg, SD <-2) and IGFBP-3 with delayed
bone age – Strong suspicion of GHD. In most cases, the possibility of GHD
should be explored by provocative GH testing, if other causes of low IGF-1 and
IGFBP-3, such as poor nutrition, have been excluded. (See 'Growth hormone
stimulation tests' above.)

● Additional tests for selected patients

• Stimulation tests – GH stimulation tests are required to make a definitive diagnosis

of GHD in children with suspected isolated GHD (ie, with no evidence of other
pituitary hormone deficiencies); testing with two different provocative tests is
recommended to establish the diagnosis. Clonidine, arginine, and glucagon are
common choices in children. Hypothyroidism should be excluded first by
performing thyroid function tests. Provocative GH testing has a number of
limitations ( table 1). (See 'Growth hormone stimulation tests' above.)

GH stimulation testing is not necessary for selected patients in whom other clinical
criteria are sufficient to make the diagnosis of GHD, including those with a known
pituitary abnormality (congenital anomaly, tumor, or irradiation) and known
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deficiency of at least one other pituitary hormone, with marked growth failure. (See
'Indications' above.)

• Imaging – If GHD is confirmed, magnetic resonance imaging (MRI) of the

hypothalamic-pituitary area is recommended to rule out tumors, investigate for
structural causes of GHD, and evaluate the severity and prognosis of the deficiency.
(See 'Imaging' above.)

Use of UpToDate is subject to the Terms of Use.

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46. Powell DR, Rosenfeld RG, Baker BK, et al. Serum somatomedin levels in adults with
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53. Examples of reference ranges from commonly used laboratories are available in the Int
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64. Richmond EJ, Rogol AD. Growth hormone deficiency in children. Pituitary 2008; 11:115.

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65. Lanes R, Hurtado E. Oral clonidine-an effective growth hormone-releasing agent in

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66. Fraser NC, Seth J, Brown NS. Clonidine is a better test for growth hormone deficiency
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70. Leong KS, Walker AB, Martin I, et al. An audit of 500 subcutaneous glucagon stimulation
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pituitary disease. Clin Endocrinol (Oxf) 2001; 54:463.
71. Kaplan SL, Abrams CA, Bell JJ, et al. Growth and growth hormone. I. Changes in serum
level of growth hormone following hypoglycemia in 134 children with growth
retardation. Pediatr Res 1968; 2:43.
72. Root AW, Rosenfield RL, Bongiovanni AM, Eberlein WR. The plasma growth hormone
response to insulin-induced hypoglycemia in children with retardation of growth.
Pediatrics 1967; 39:844.

73. Raiti S, Davis WT, Blizzard RM. A comparison of the effects of insulin hypoglycaemia and
arginine infusion on release of human growth hormone. Lancet 1967; 2:1182.
74. Marin G, Domené HM, Barnes KM, et al. 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.
75. Maghnie M, Salati B, Bianchi S, et al. Relationship between the morphological evaluation
of the pituitary and the growth hormone (GH) response to GH-releasing hormone Plus
arginine in children and adults with congenital hypopituitarism. J Clin Endocrinol Metab
2001; 86:1574.
76. Dietrich RB, Lis LE, Greensite FS, Pitt D. Normal MR appearance of the pituitary gland in
the first 2 years of life. AJNR Am J Neuroradiol 1995; 16:1413.

77. Maghnie M, Strigazzi C, Tinelli C, et al. Growth hormone (GH) deficiency (GHD) of
childhood onset: reassessment of GH status and evaluation of the predictive criteria for
permanent GHD in young adults. J Clin Endocrinol Metab 1999; 84:1324.

78. David A, Hwa V, Metherell LA, et al. Evidence for a continuum of genetic, phenotypic,
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Rev 2011; 32:472.

Topic 5842 Version 32.0

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GRAPHICS

Length-for-age percentiles, males 0 to 24 months, WHO growth

standards

WHO: World Health Organization.

Reproduced from: Centers for Disease Control and Prevention based on data from the WHO Child Growth
Standards.

Graphic 67950 Version 6.0

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Length-for-age percentiles, females 0 to 24 months, WHO growth

standards

WHO: World Health Organization.

Reproduced from: Centers for Disease Control and Prevention based on data from the WHO Child Growth
Standards.

Graphic 80511 Version 4.0

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Stature-for-age percentiles, males 2 to 20 years, CDC growth

charts: United States

CDC: Centers for Disease Control and Prevention.

From National Health Center for Health Statistics in collaboration with the National Center for Chronic
Disease Prevention and Health Promotion (2000).

Graphic 63399 Version 7.0

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Stature-for-age percentiles, females 2 to 20 years, CDC growth

charts: United States

CDC: Centers for Disease Control and Prevention.

From National Health Center for Health Statistics in collaboration with the National Center for Chronic
Disease Prevention and Health Promotion (2000).

Graphic 77249 Version 6.0

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8/8/23, 13:45 Diagnosis of growth hormone deficiency in children - UpToDate

Height velocity in American males 2 to 19 years

Height velocity by age for American males. The main set of curves (black lines)
is centered on the population with average timing of peak growth velocity
(around 13.5 years for males) and show an approximate trajectory for
individual children with this average pubertal timing. The 2 other curves
outline a trajectory (50 th percentile) for a child with "early" (solid blue) or "late"
(solid orange) timing of peak growth velocity.
Other height velocity curves have been developed that reflect population
averages (eg, Kelly A, JCEM 2014, not shown here). Those curves are
substantially flatter than the trajectory followed by any individual patient. They
are based on data from a more recent and ethnically diverse population of
children and are valuable for understanding overall growth patterns in the

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population but are less appropriate for evaluation of the growth of an

individual patient.

SD: standard deviations.

Reproduced with permission from: Tanner JM, Davies S. Clinical longitudinal standards for height and
height velocity for North American children. J Pediatr 1985; 107:317. Copyright © 1985 Elsevier.

Graphic 96367 Version 9.0

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8/8/23, 13:45 Diagnosis of growth hormone deficiency in children - UpToDate

Height velocity in American females 2 to 19 years

Height velocity by age for American females. The main set of curves (black
lines) is centered on the population with average timing of peak growth
velocity (around 11.5 years for females) and show an approximate trajectory
for individual children with this average pubertal timing. The 2 other curves
outline a trajectory (50 th percentile) for a child with "early" (solid blue) or "late"
(solid orange) timing of peak growth velocity.
Other height velocity curves have been developed that reflect population
averages (eg, Kelly A, JCEM 2014, not shown here). Those curves are
substantially flatter than the trajectory followed by any individual patient. They
are based on data from a more recent and ethnically diverse population of
children and are valuable for understanding overall growth patterns in the

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8/8/23, 13:45 Diagnosis of growth hormone deficiency in children - UpToDate

population but are less appropriate for evaluation of the growth of an

individual patient.

SD: standard deviations.

Reproduced with permission from: Tanner JM, Davies S. Clinical longitudinal standards for height and
height velocity for North American children. J Pediatr 1985; 107:317. Copyright © 1985 Elsevier.

Graphic 96366 Version 8.0

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Limitations of provocative testing for growth hormone deficiency in

children

Pharmacologic testing is not physiologic

Normality is arbitrarily defined, if defined at all

Reproducibility in both normal and abnormal children is poor, even when the same test is
performed

Age and sex steroid hormone status affect the response

Nutritional adequacy and body composition (particularly, adiposity) can affect response

There is no standard serum growth hormone assay, and there are large interassay variations
among the assays in use

All of the tests are costly

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Evaluation for suspected growth hormone insensitivity in a

child

GH: growth hormone; IGF-1: insulin-like growth factor 1; IGFBP-3: insulin-like

growth factor-binding protein 3; GHBP: growth hormone-binding protein.

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* Refer to UpToDate topic reviews on the diagnostic approach to short stature

and diagnosis of GH deficiency in children.

¶ Trials of GH or IGF-1 should be performed only if the epiphyses are open. An

adequate growth response is an increase in height velocity by at least 2.5
cm/year. Children whose epiphyses are nearly closed may not achieve this
degree of growth response, even if they have GH deficiency or insensitivity.

Δ In a patient with suspected GH insensitivity, the possibility of Laron syndrome

can be assessed by molecular testing for pathogenic homozygous or compound
heterozygous mutations in the GH receptor gene. Laron syndrome is the most
common form of severe GH insensitivity. Alternatively, the possibility of GH
insensivity can be supported by measuring basal GH levels and GHBP or
performing an IGF-1 generation test (IGF-1 response to a brief trial of
recombinant GH). The results of the IGF-1 generation test are not always useful,
because the protocols for performing this test have not been standardized and
the levels of IGF-1 achieved are quite variable.

◊ In patients with clinical characteristics of severe GH insensitivity and a normal

or elevated circulating GH level, a low level of GHBP strongly supports a
diagnosis of Laron syndrome, but normal levels are uninformative. This is
because patients with Laron syndrome have low GHBP levels only if the GH
receptor mutation affects the extracellular binding domain, whereas GHBP
levels are normal or high if the GH receptor mutation affects the
transmembrane or cytoplasmic domain of the GH receptor.

§ Adequate growth response to GH confirms GH deficiency. If the growth

response is inadequate, consider the possibility of an IGF-1 receptor mutation.

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Contributor Disclosures
Erick J Richmond, MD Speaker's Bureau: Merck [Growth hormone]; NovoNordisk [Growth hormone];
Pfizer [Growth hormone]; Sandoz [Growth hormone]. All of the relevant financial relationships listed
have been mitigated. Alan D Rogol, MD, PhD Consultant/Advisory Boards: Anteres [Androgens];
Ascendis [Growth]; BioMarin [Growth]; Comprehensive Drug Testing [Anti-doping]; Lumos [Growth];
Pfizer [Growth]; Tolmar [Growth and androgens]; United States Anti-Doping Agency [Anti-doping];
World Anti-Doping Agency [Anti-doping]. All of the relevant financial relationships listed have been
mitigated. Mitchell E Geffner, MD Grant/Research/Clinical Trial Support: Adrenas [Congenital adrenal
hyperplasia]; Diurnal [Congenital adrenal hyperplasia]; Neurocrine Biosciences [Congenital adrenal
hyperplasia]; Novo Nordisk [Growth]; Spruce Biosciences [Congenital adrenal hyperplasia].
Consultant/Advisory Boards: Adrenas [Congenital adrenal hyperplasia]; Aeterna Zentaris [Growth];
Eton [Congenital adrenal hyperplasia]; Neurocrine Biosciences [Congenital adrenal hyperplasia]; Novo
Nordisk [Growth]; Nutritional Growth Solutions [Growth]; Pfizer [Growth]; Spruce Biosciences
[Congenital adrenal hyperplasia]. Other Financial Interest: McGraw-Hill textbook royalties [Pediatric
endocrinology]. All of the relevant financial relationships listed have been mitigated. Alison G Hoppin,
MD No relevant financial relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

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