Growth hormone insensitivity syndromes

INTRODUCTION — Growth hormone insensitivity (GHI) is a group of inherited disorders in which there is a reduction in or absence of the biologic effects of growth hormone (GH) despite normal or above normal production and secretion of GH. These disorders are characterized by growth failure and normal or increased circulating levels of GH, in contrast with GH deficiency. In addition, many affected individuals also have low circulating levels of GH-binding protein (GHBP; which is equivalent to the shed extracellular-binding domain of the GH receptor) and is measured in a commercially available clinical test reflecting the number of GH receptors. (See "Diagnosis of growth hormone deficiency in children".)

The classic model of GHI is in patients with Laron syndrome, caused by mutations in the GH receptor gene. However, subsequent experience has shown that there is a spectrum of GHI caused by a variety of defects along the GH-insulin-like growth factor 1 (IGF-1) axis (figure 1). These disorders will be discussed in this topic review.

A growing body of literature suggests that some patients with idiopathic short stature often have a component of GH resistance, which may call for alternative treatment approaches such as adjusting GH doses based on IGF-1 levels. These considerations are discussed in a separate topic review. (See "Growth hormone treatment for idiopathic short stature".)

PATHOPHYSIOLOGY AND CLINICAL MANIFESTATIONS — GHI can be caused by loss-of-function mutations in the growth hormone (GH) receptor gene or in its downstream mediators, the most important of which is insulin-like growth factor 1 (IGF-1). These syndromes are characterized by normal or elevated levels of GH and low levels of IGF-1 (except for IGF-1 receptor mutations, in which IGF-1 levels are normal or high) (table 1).

Growth hormone receptor mutations (Laron syndrome) — Laron syndrome (MIM #262500), the most common known cause of genetically mediated GHI, is characterized by severe postnatal growth failure [1]. It is caused by homozygous or compound heterozygous mutations in the GH receptor gene; a variety of mutations have been identified, most of which affect the extracellular GH-binding region of the receptor [2-4], while others affect the transmembrane and intracellular domains [5].

Patients with homozygous loss-of-function mutations in the GH receptor gene have severe growth failure, with a mean adult height in one report of 119 cm (47 inches) in females and 124 cm (49 inches) in males [6]. However, there is wide variability in adult height, ranging in another series from -2.2 to -12 standard deviations (SD) [7,8].

Other clinical features of Laron syndrome include small head circumference, characteristic facies with saddle nose and prominent forehead, delayed skeletal maturation, small genitalia and testes, short limb length compared with trunk length, and abnormal body composition, with osteopenia and obesity (picture 1 and table 2) [9,10]. Intellectual development is normal or only modestly impaired. Unlike patients with IGF-1 deficiency (described below), there is minimal disturbance of prenatal growth.

Patients with Laron syndrome also have metabolic abnormalities including hyperlipidemia and episodes of hypoglycemia, especially during infancy. Data are conflicting on the risk of insulin resistance. An Ecuadorian cohort displays less insulin resistance and lower rates of diabetes than relatives without Laron syndrome, despite higher percentage of body fat [11,12]. On the other hand, reports from an Israeli cohort suggest increased risk for insulin resistance [10,13,14]. Possible explanations for the apparent difference in diabetes among these two populations with Laron syndrome include differences in environment (lifestyle, diet, etc), differences in serum IGF-1 levels, differences in the specific GH receptor mutation, or differences in genetic risk for diabetes in their underlying gene pool. Understanding the differences in energy intake and expenditure may give insight to more fundamental aspects of energy balance.

Moreover, individuals with Laron syndrome appear to have much lower cancer rates than healthy controls. Experimental evidence from animal models and in vitro studies suggest that the low levels of IGF-1 in Laron syndrome are responsible for the reduced susceptibility to cancer and for increased longevity [11,15].

Post-growth hormone receptor mechanisms — In addition to GH receptor gene mutations, GHI can occur through mutations in the post-GH receptor signaling pathway. A number of mechanisms have been described and summarized in a review [16]:

Abnormal growth hormone receptor signal transduction — Several patients have been described with GHI caused by a homozygous missense mutation in the gene encoding signal transducer and activator transcription 5B (STAT5B) (MIM #245590), which is essential for normal signaling of the GH receptor [17-20]. Patients with this condition have severe postnatal growth failure and immune dysregulation, which is probably because STAT5B also mediates signal transduction triggered by various immune ligands, such as interleukin-2 (IL-2), interleukin-4 (IL-4), and colony-stimulating factor 1 (CSF1) [21].

In various acquired conditions associated with growth failure, including malnutrition and inflammatory diseases, the relative GH resistance appears to be mediated by downregulation of STAT5B and Janus kinase 2 (JAK2) signaling [22].

Defects of IGF-1 synthesis — Mutations in the gene encoding IGF-1 cause a unique syndrome of GHI (MIM #608747) that overlaps with the phenotype of microcephalic primordial dwarfism. Complete absence of IGF-1 is probably lethal in humans, but individuals have been described with deletions in the insulin-like growth factor 1 gene (IGF1) causing partial loss of function [23-25].

Unlike patients with GH receptor mutations (Laron syndrome), patients with IGF1 gene mutations have prenatal growth failure, microcephaly, significant neurocognitive deficits, sensorineural hearing loss, and normal levels of IGFBP-3. These observations confirm that IGF-1 has an important role in fetal growth as well as brain development, whereas the role of GH during fetal development is less clear [23].

One study found an association between idiopathic short stature and increased methylation of two promoter regions for the IGF1 gene; these epigenetic changes are predicted to reduce the individual's sensitivity to GH [26]. (See "Causes of short stature", section on 'Idiopathic short stature'.)

Defective transport/clearance of IGF-1 — Another GHI syndrome is mediated by deficiency of the insulin-like growth factor-binding protein acid-labile subunit (IGFALS; MIM #615961). This protein is important for the stabilization of the IGF-1-IGFBP-3 complex, forming a three-part (ternary) complex in the circulation. Affected individuals usually have delayed onset of puberty and slow pubertal progression but only minimal slowing of linear growth [27,28]. They have increased plasma levels of GH, normal levels of GH-binding protein (GHBP; the extracellular portion of the GH receptor), and very low levels of IGF-1 and IGFBP-3, which remain low after administration of recombinant GH.

The human pregnancy-associated plasma protein A2 gene (PAPPA2) encodes a metalloproteinase that cleaves IGFBP-3 and IGFBP-5. Mutations in the PAPPA2 gene have been reported in patients with postnatal growth retardation with heights ranging from -1.0 to -3.8 SD (MIM #619489) [29]. Affected patients have elevated total serum IGF-1 levels (similar to those with IGF-1 resistance) but low serum free IGF-1 levels.

IGF-1 resistance — Mutations in the gene encoding the receptor for insulin-like growth factor 1 (IGF-1) have been reported in infants presenting with pre- and postnatal growth failure (MIM #270450) [30-32]. These mutations are thought to result in partial loss of function of the IGF-1 receptor, and the phenotype is variable with normal or only mildly abnormal cognitive development; some patients have microcephaly, sensorineural hearing loss, and insulin resistance that develops during adolescence. Unlike the other GHI syndromes, circulating levels of IGF-1 are normal or elevated. Since most affected patients are born small for gestational age, recombinant human GH treatment has been used; however, growth response is highly variable and close monitoring of serum IGF-1 levels is recommended [33].

Other conditions — Several other genetic conditions associated with GHI have been identified:

●In most patients with Noonan syndrome, short stature is mediated by constitutive activation of mitogen-activated protein kinases (MAPK) pathways and inhibition of STAT5b [34]

●Decreased synthesis of GH receptors in Pygmies [35]

●Disordered GH receptor degradation [36]

●Abnormalities in the nuclear factor kappa-B (NFKB) pathway [37]

EPIDEMIOLOGY — Laron syndrome, characterized by severe GHI, has been reported in several hundred patients worldwide, the majority of whom have ancestry from the Mediterranean, Middle East, or South Asia regions, including a large cohort living in Ecuador [8,38]. A history of consanguinity is common, consistent with an autosomal recessive pattern of inheritance. The other causes of GHI have been reported in few patients, so the epidemiology and geographical distribution is not clear. However, familial aggregation and a family history of consanguinity are still common.

EVALUATION — The initial evaluation of a child with short stature requires distinguishing between children with common nonpathologic causes such as constitutional delay of growth or familial short stature, those with a non-endocrine cause of growth failure (eg, Crohn disease), and those with an endocrine cause of short stature who might benefit from hormonal treatment. The general approach to this assessment is discussed in a separate topic review. (See "Diagnostic approach to children and adolescents with short stature".)

Evaluation of a child for GHI involves the following steps (algorithm 1):

●Suspect GHI in patients with severe growth failure (height <-3 standard deviations [SD]) and low insulin-like growth factor 1 (IGF-1) levels. In young children, measurement of insulin-like growth factor-binding protein 3 (IGFBP-3) may be more informative. (See 'IGF-1 and IGFBP-3' below.)

●Exclude causes of secondary IGF-1 deficiency, including undernutrition, hepatic disease, and growth hormone (GH) deficiency, through a focused clinical evaluation.

●Supportive evidence may come from measuring basal GH concentrations and GH-binding protein (GHBP), or from the results of an IGF-1 generation test, which involves measuring the IGF-1 response to administered GH (but is not a standardized test for use in clinical practice). These tests may help to confirm the diagnosis and/or to indicate the level of the defect. Patients with post-GH receptor defects have distinct clinical and biochemical patterns (table 1). (See 'Growth hormone concentration' below and 'Growth hormone-binding protein' below and 'IGF-1 generation test' below.)

●Confirm the diagnosis with molecular genetic testing, if available. The timing and selection of molecular testing depends upon the level of clinical suspicion (severity of growth failure and degree of reduction of IGF-1 and IGFBP-3 concentrations), as well as access to molecular testing. (See 'Molecular testing' below.)

IGF-1 and IGFBP-3 — In a child with severe growth failure, low insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP-3) concentrations suggest the possibility of GH deficiency and also GHI. However, interpretation of these tests requires caution:

●In normal young children (<3 years old), relatively low levels of IGF-1 are the norm, so this finding is not diagnostic of GH deficiency or GHI in this age group. Other causes of (transient) low IGF-1 levels include poor nutritional status, hypothyroidism, and renal failure, so these causes must be excluded to make the diagnosis of GHI. In normal children, IGF-1 levels rise two- to fourfold during puberty as a result of increased production during that time. IGF-1 and GH reach maximal levels around the time of peak height velocity [39].

●Levels of IGFBP-3 may be more informative because they are less likely to vary with age, nutritional status, and chronic illness. IGFBP-3 is low in most of the GHI syndromes (table 1). An exception is in patients with an insulin-like growth factor 1 gene (IGF1) mutation, who have elevated IGFBP-3 levels, with low IGF-1 levels. This possibility should be considered in patients with severe prenatal growth failure. (See "Diagnosis of growth hormone deficiency in children", section on 'IGF-1 and IGFBP-3' and 'Defects of IGF-1 synthesis' above.)

Growth hormone concentration — A high basal GH level supports the diagnosis of GHI but is not diagnostic and should be interpreted with caution. A normal basal GH level is not suspicious for GHI unless the patient also has severe growth failure (height <3 SD below the mean).

Notably, most short patients with normal GH levels do not have one of these GHI syndromes and are classified as having idiopathic short stature rather than GHI. However, lesser degrees of GH resistance may play a role in idiopathic short stature (figure 1). Most of these patients with idiopathic short stature are not eligible for treatment with recombinant IGF-1 based on treatment recommendations, which are described below. Such patients may respond to GH therapy, but they may require adjustment of the GH dose to achieve therapeutic IGF-1 levels. These patients can be considered to have mild (partial) GHI, since levels of IGF-1 may rise to some degree after GH administration, but require doses higher than are typically used for treatment of GH deficiency [40]. (See "Growth hormone treatment for idiopathic short stature", section on 'Dose adjustment for IGF-1 levels'.)

Growth hormone-binding protein — Testing for GHBP can be used to further investigate the possibility of Laron syndrome, especially if molecular testing is not available. Testing for GHBP is commercially available.

In patients with clinical characteristics of severe GHI and normal or elevated circulating GH levels, 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, but GHBP levels are normal or high if the GH receptor mutation affects the transmembrane or cytoplasmic domain of the GH receptor [41,42]. GHBP levels also are normal in patients with GHI due to post-receptor defects.

Molecular testing — For patients who meet the clinical and laboratory parameters outlined above, we suggest testing for mutations in the genes that cause GHI. The first priority is testing for a mutation in the GH receptor gene (Laron syndrome) since this is the most common cause of GHI. Other tests can be selected as indicated by the clinical and biochemical profile (table 1). These include evaluation for IGF1 gene mutations in individuals with severe prenatal growth failure and elevated IGFBP-3 levels (see 'Defects of IGF-1 synthesis' above), or signal transducer and activator of transcription 5B (STAT5B) gene mutations in patients who also have immunodeficiency (see 'Abnormal growth hormone receptor signal transduction' above). Testing that focuses on specific mutations is limited by the known causes of GHI.

Specific testing for these mutations is available through some clinical laboratories, which are listed on the Genetic Testing Registry website. Whole-exome sequencing (WES) also may be used and sometimes discovers mutations not identified by candidate-gene methods [43,44]. However, interpretation of the WES results can be challenging since the pathogenicity of a novel variant is often unclear [45]. Decisions about whether and how to perform molecular testing should be made by a specialist in these disorders. GH stimulation testing usually is not necessary, because the basal levels of GH are normal or high in patients with GHI, distinguishing them from individuals with GH deficiency. If GH stimulation testing is performed, the GH response to stimulation is usually robust.

IGF-1 generation test — If molecular testing is not available, an insulin-like growth factor 1 (IGF-1) generation test can be used to confirm the diagnosis of GHI and helps to predict responsiveness to recombinant IGF-1 therapy. This consists of a brief trial of GH administration for approximately one week. In patients with GHI, the low baseline IGF-1 will not rise after exogenous administration of GH for four to nine days [10]. However, the protocols for performing this test have not been standardized, the levels of IGF-1 achieved are quite variable, and it may be difficult to obtain insurance authorization for the GH required for this short course of therapy [41,46]. Therefore, this is not used routinely to evaluate patients with suspected GHI. Nonetheless, this test can be helpful in clarifying the diagnosis in conjunction with the clinical and other laboratory findings described above.

DIAGNOSIS — GHI should be suspected in patients with severe growth failure (height <-3 standard deviations [SD]) and low insulin-like growth factor 1 (IGF-1) and/or insulin-like growth factor-binding protein 3 (IGFBP-3) levels. Causes of secondary IGF-1 deficiency, including undernutrition, hepatic disease, and GH deficiency, should be excluded through a focused clinical evaluation.

The diagnosis can be confirmed by molecular genetic testing for mutations in the GH receptor gene (Laron syndrome) or other genes that affect post-GH receptor signaling (algorithm 1). (See 'Molecular testing' above.)

If molecular testing is not available, a clinical diagnosis of GHI can be made on the basis of a strong clinical phenotype and compatible biochemical testing (table 1), ideally including supportive tests such as GH concentrations, GH-binding protein (GHBP), and/or an IGF-1 generation test. (See 'IGF-1 generation test' above.)

TREATMENT — Treatment should be considered for patients with severe growth failure due to GHI whose epiphyses are open. Treatment should be started as soon as the GHI is identified for optimal effect. The approach to treatment depends on whether a specific cause of the GHI has been established and on the type of defect (table 1). Treatment options include a trial of recombinant growth hormone (GH) or recombinant insulin-like growth factor 1 (IGF-1).

Trial of growth hormone — For children with GHI and IGF-1 deficiency diagnosed by clinical criteria but not established by molecular testing, we suggest a trial of GH therapy for three to six months (algorithm 1) [41]. Some of these children have partial GHI and may respond to GH if given at relatively high doses. Efficacy of GH is indicated by increased serum levels of IGF-1 (ideally into the upper one-half of the normal range) and increased height velocity (eg, increases the height velocity by at least 2.5 cm/year). (See "Treatment of growth hormone deficiency in children", section on 'Dose adjustment based on IGF-1 response'.)

If GH is effective, it is preferable to IGF-1. This is because GH is often more effective for patients with partial GHI, has a better safety profile (both short and longer term), and is more convenient. Children who do not respond to exogenous GH can then move on to IGF-1 treatment.

Recombinant IGF-1

●Indications – Recombinant human insulin-like growth factor 1 (IGF-1; mecasermin) is a recommended treatment for children with severe primary IGF-1 deficiency, whether due to mutations in the GH receptor, post-GH receptor signaling pathway, or IGF1 gene [41]. Accepted indications for treatment in this population are: two years of age or older with open epiphyses and height and basal IGF-1 standard deviations (SD) both ≤-3. It is contraindicated in patients with active or history of malignancy [47].

Patients with proven gene defects that cause GHI can start directly on IGF-1 replacement [41]; these include pathologic mutations in the GH receptor gene (Laron syndrome), signal transducer and activator of transcription 5B (STAT5B) gene, or IGF1 gene. Recombinant IGF-1 may also be used in children with primary GH deficiency due to a GHI gene deletion who have developed neutralizing antibodies during treatment with GH, causing an acquired GHI [48,49].

IGF-1 replacement should not be used for patients with GHI due to established IGF-1 receptor gene mutations, as they are unlikely to respond. There is no known treatment for growth failure in these patients.

If the cause of GHI has not been established, we suggest a trial of GH therapy before initiating IGF-1 replacement [41]. This is because some patients with clinical features of GHI may respond to GH treatment. (See 'Trial of growth hormone' above.)

●Dose and administration – Guidelines suggest starting recombinant human IGF-1 at a dose of 80 to 120 mcg/kg twice daily [41]. The dose should be given 20 minutes after a carbohydrate-containing meal or snack to avoid hypoglycemia. The treatment is typically continued until height velocity has decreased to <2 cm/year, which corresponds to closure or near-closure of the epiphyses.

●Efficacy – The effects of IGF-1 treatment on children with severe primary IGF-1 deficiency were examined in an open-label study of 76 children treated for up to 12 years [49]. Height velocity increased from a mean of 2.8 cm/year at baseline to a mean of 8 cm/year during the first year of treatment. Height velocity remained above baseline for up to eight years. However, this growth response was less than that typically attained in GH-deficient children receiving standard doses of GH therapy. After long-term IGF-1 treatment, most patients do not experience sufficient catch-up growth to bring their height into normal range. This treatment also results in rapid catch-up growth of head circumference and normalization of metabolic abnormalities such as hyperlipidemia and insulin resistance [9].

IGF-1 has also been effectively used for patients with GHI caused by mutations in the IGF1 gene, resulting in increased linear growth and beneficial effects on body composition, including increased bone mineral density [50,51]. (See 'Defects of IGF-1 synthesis' above.)

●Safety – Recombinant IGF-1 may induce hypoglycemia, particularly in younger children and in those with hypoglycemic episodes prior to the initiation of treatment. To avoid this, each dose should be given after a carbohydrate-containing meal or snack [41]. In the study cited above [49], hypoglycemia occurred in 40 percent of subjects and was severe in 9 percent, and 5 percent of the subjects had at least one hypoglycemic seizure. Other side effects included adenotonsillar hypertrophy (22 percent) and intracranial hypertension (4 percent), both of which have been reported with GH treatment [52].

A few allergic reactions to mecasermin, including anaphylaxis, have been reported [53,54]. One such patient had negative skin testing to the drug and was treated with a desensitization protocol [54]. Despite these precautions, this patient developed recurrent allergic reactions after three additional weeks of treatment with mecasermin.

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".)

SUMMARY AND RECOMMENDATIONS

●Pathophysiology and laboratory features – Growth hormone insensitivity (GHI) can be caused by loss-of-function mutations in the growth hormone (GH) receptor or in its downstream mediators, including insulin-like growth factor 1 (IGF-1). These rare syndromes are characterized by normal or elevated levels of GH and low levels of IGF-1 (except for mutations of the IGF-1 receptor, in which IGF-1 levels are increased or normal) (table 1). (See 'Pathophysiology and clinical manifestations' above.)

Most short patients with normal GH levels do not have one of these GHI syndromes and are classified as having idiopathic short stature rather than GHI. However, lesser degrees of GH resistance may play a role in idiopathic short stature (figure 1). Most of these patients with idiopathic short stature are not eligible for treatment with recombinant IGF-1. (See 'Evaluation' above and "Growth hormone treatment for idiopathic short stature", section on 'Dose adjustment for IGF-1 levels'.)

●Identifying the cause – Causes of GHI and their clinical features are listed in the table (table 1).

•Laron syndrome – Laron syndrome is the most common cause of GHI and caused by mutations in the GH receptor gene. Affected patients have severe postnatal growth failure, characteristic facies, and metabolic abnormalities (picture 1 and table 2). Most patients are from populations with Mediterranean or Middle Eastern ancestry (including a population in Ecuador), and a family history of consanguinity is common. (See 'Growth hormone receptor mutations (Laron syndrome)' above.)

Laron syndrome should be suspected in patients with severe growth failure and low IGF-1 and insulin-like growth factor-binding protein 3 (IGFBP-3) levels, especially if GH levels are normal or increased, the GH-binding protein (GHBP) level is low, and an IGF-1 generation test is subnormal (algorithm 1). The diagnosis should be confirmed through genetic testing where available. These tests can also help to identify and categorize other causes of primary GHI (table 1). (See 'Evaluation' above and 'Diagnosis' above.)

•IGF1 gene mutation – In patients with marked prenatal growth failure, an IGF1 gene mutation should be considered. Like patients with GH receptor mutations, these patients will have normal or increased levels of GH and low IGF-1 levels. Unlike patients with GH receptor mutations, the plasma IGFBP-3 level is elevated (table 1). (See 'Defects of IGF-1 synthesis' above.)

●Management

•Cause unknown/partial GHI – If the cause of GHI has not been established, we suggest a trial of GH therapy before considering IGF-1 replacement (algorithm 1) (Grade 2C). Some of these children have partial GHI and may respond to GH (if given at higher doses than for the typical patient with GH deficiency), manifested as increased height velocity and IGF-1 concentrations. If GH is effective, it is preferable to IGF-1. Patients who do not respond can proceed to treatment with IGF-1. (See 'Trial of growth hormone' above.)

•Severe GHI – For children two years of age or older with severe GHI (defined as height and basal IGF-1 ≤-3 standard deviations [SD], with normal or elevated levels of GH) due to Laron syndrome or most other known defects, we recommend treatment with IGF-1 (mecasermin) rather than GH or no treatment (Grade 1B). Hypoglycemia is a common side effect of recombinant IGF-1, particularly in younger children. IGF-1 is ineffective for patients with IGF-1 receptor mutations. (See 'Treatment' above.)