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Diagnosis of growth hormone deficiency in children

Diagnosis of growth hormone deficiency in children
Literature review current through: Jan 2024.
This topic last updated: Oct 05, 2023.

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 diagnosis of GHD in childhood is based on a comparison of the 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" [7].

Technique – 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 (figure 1). The vertical stadiometer is used to measure standing height, which is recommended for children two to three years or older (figure 2) [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".)

Growth charts – 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 3A-B); height is for children measured standing and should be used for children over two to three years (figure 4A-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 – Height velocity can be calculated from serial height determinations and plotted on appropriate velocity charts (figure 5A-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 [9,10]. Several genetic causes of GHD have been described [3] (see "Causes of hypopituitarism", section on 'Genetic diseases'):

POU1F1 – 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 [11,12]. Pathogenic variants 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) [13-15]. One specific variant at the POU1F1 locus has been associated with dominantly inherited isolated GHD [16].

PROP1 – Pathogenic variants in PROP1 result in failure to activate POU1F1/Pit1 gene expression and probably cause pituitary hypoplasia and/or familial multiple pituitary hormone deficiency [17]; paradoxical cystic hyperplasia of the pituitary also has been reported [18]. This is the most common known genetic cause of CPHD type 2 (MIM #262600) [19,20].

Other transcription factors – In addition to POU1F1/Pit1 and PROP1, other transcription factors participate in the differentiation of anterior pituitary cells. Pathogenic variants in these genes also cause congenital deficiencies of multiple pituitary hormones, with variable phenotypes. These include several syndromic manifestations [21]:

Septo-optic dysplasia (HESX1, SOX2, SOX3, OTX2 and others)

CPHD with sensorineural deafness (MIM #221750, due to LHX3)

CPHD with/without cerebellar defects (MIM #262700, due to LHX4)

Optic nerve hypoplasia, polydactyly, midface defects (MIM #615849, due to GLI2)

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

GH1GH1 is the gene encoding GH, located on chromosome 17. Gene deletions, frameshift variants, and nonsense variants of GH1 have been described as causes of familial GHD [22].

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 [23,24].

Other pathogenic variants 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 presentation and perinatal asphyxia.

The clinical presentation depends upon the severity of the GHD. If GHD is congenital and severe, the diagnosis is relatively easy to confirm. Affected children present with hypoglycemia, microphallus (males), prolonged conjugated hyperbilirubinemia, frontal bossing, midface hypoplasia, hypotonia, central distribution of body fat, high-pitched voice, and very low serum concentrations of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3). Postnatal growth is abnormal, and growth failure can occur during the first months of life [25-28] 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 children, 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:

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 [29].

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 [7].

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 (if not done previously)

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 [7]. 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 [30]. (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 [31].

Between normal pulses of GH secretion, serum GH levels are low, often 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".)

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) [32]

Despite relatively good correlations within groups of patients between GH secretion and IGF-1 concentrations [33-36], there remain substantial problems in assessing GH status by measurement of IGF-1 alone in individual patients [37,38]:

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 [39].

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 [40], diabetes [41], renal failure [40,42], and cancer [43].

Of the six IGFBPs, IGFBP-3 is the major serum carrier protein for IGF-1 [44-46] and the most GH-dependent [47]. 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 [48]. (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 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 maturation, if available). The range varies with the assay used, and results should be interpreted against standards provided by the laboratory performing the test [49]. 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 [50,51].

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 [52].

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 [52].

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.

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) [7,51]:

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 [51,53]. 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 [50,51].

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 [52,54,55].

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 [30,51]. 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 [56,57].

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 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 [50]. Newer published data [58] suggest that assay-specific cutoffs to define GHD may be necessary [50,59]. Specific considerations for the measurement of human GH have been reviewed in detail [60].

Some clinicians also measure a baseline GH level as part of the stimulation test. If that level is in the upper one-half of the unstimulated reference range (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. This is because of an absolute and then relative refractory period after a physiologic GH pulse.

Choice of stimulus – There is general consensus that two different stimuli should be used for most patients [50,52]. 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 [30,51,61]. 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 [61]. 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 [62-65].

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 [61]. 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 [61]. 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 [61,66,67]. 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 (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 [68-70]. Regular insulin is administered intravenously at a dose of 0.05 to 0.1 unit/kg. The maximum GH peak is expected at 15 to 30 minutes after insulin administration. Serum GH is measured at 0, 15, 30, 45, and 90 minutes. However, this test is infrequently used in children because of safety concerns [30]. (See "Growth hormone deficiency in adults", section on 'Insulin-induced hypoglycemia'.)

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

Other – Macimorelin acetate is used for testing adults with suspected GHD, but there are few data in the pediatric population, although it is under study. 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 [51,71]. 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 [52]. 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 [61,72]. 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.)

Imaging — High-quality contrast-enhanced MRI with fine cuts (1 mm) permits excellent visualization of the hypothalamic-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 [73]. Newer techniques may permit imaging without contrast sequences [74].

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 [30]. 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 [74,75]. 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 [75]. 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 pathogenic variants of the gene encoding 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 [76] (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".)

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 pathogenic variants (although these are rare) or by conditions 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.)

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 deficiency of at least one other pituitary hormone, with marked growth failure. (See 'Indications' above.)

Imaging – If GHD is confirmed, 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.)

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Topic 5842 Version 33.0

References

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