Growth Hormone Resistance

Insulin-like growth factor I (IGF-I) is the effector of growth induced by growth hormone (GH). IGF-I deficiency can be the result of GH resistance or insensitivity due to genetic disorders of the GH receptor causing GH receptor deficiency (growth hormone receptor deficiency [GHRD], Laron syndrome) or postreceptor defects, including the principal transduction agent STAT5b, the IGF-I/IGFBP3 stabilizer acid labile subunit (ALS), the IGF-I gene, or the IGF-I receptor.[1]

 Acquired forms of GH insensitivity include the rare GH1 mutation (in which GH inhibiting antibodies develop after a few months of replacement therapy with recombinant GH) and, far more commonly, malnutrition, hepatic disease, renal disease, and diabetes. The table below compares the clinical and biochemical features associated with these various causes of GH resistance.

Table. Features of GH Resistance Causes (Open Table in a new window)

The GH molecule binds to its specific cell surface receptor (GHR), which dimerizes with another GHR molecule so that the single GH molecule is enveloped by 2 GHR molecules. The intact receptor lacks tyrosine kinase activity, but binding of GH and dimerization results in association with JAK2, a member of the Janus kinase family, which results in self-phosphorylation of the JAK2 and a cascade of phosphorylation of cellular proteins. The most critical of these proteins is the signal transducer and activator of transcription 5b (STAT5b), which couples GH binding to the activation of gene expression that leads to the intracellular effects of GH, including synthesis of IGF-I, insulin-like growth factor binding protein 3 (IGFBP3), and ALS.[1]

Hepatic IGF-I circulates almost entirely bound to IGF binding proteins (IGFBPs), with less than 1% being free. The IGFBPs are a family of 6 structurally related proteins with a high affinity for binding IGF. The principal BP, IGFBP3, binds approximately 90% of circulating IGF-I in a large (150-200 kD) ternary complex consisting of IGFBP3, ALS, and the IGF molecule. The ALS stabilizes the IGF–IGFBP3 complex, reduces the passage of IGF-I to the extravascular compartment, and extends its half-life.[1]

IGF binding involves 3 basic types of receptors: the structurally homologous insulin receptor and type 1 IGF receptor and the distinctive type 2 IGF-II/mannose-6-phosphate receptor. In addition to these receptors, hybrid receptors consisting of a dimer from the IGF-I receptor paired with the insulin receptor, are ubiquitous and the respective expression of these receptors varies from tissue to tissue. Although the insulin receptor has a low affinity for IGF-I, IGF-I is present in the circulation at molar concentrations that are 1000 times those of insulin. Thus, even a small insulin-like effect of IGF-I could be more important than that of insulin itself, were it not for the IGFBPs that control the availability and activity of IGF-I. In fact, intravenous infusion of recombinant human IGF-I (rhIGF-I) can induce hypoglycemia, especially in the IGFBP3 deficient state.[2]

The importance of IGF-I in normal intrauterine growth in humans has been demonstrated in a single patient with a homozygous partial deletion of the IGF1 gene,[3] and patients with mutation of the IGF1 gene resulting in high circulating levels of an ineffective IGF-I,[4, 5, 6] and in probands and first-degree relatives with heterozygous mutations of the IGF-I receptor.[7]  Those individuals with IGF1 gene mutations were severely mentally retarded and had growth retardation at birth, indicating dependence of both intrauterine somatic growth and brain development on adequate IGF-I. Those with heterozygous mutations of the IGF-I receptor had more moderate intrauterine growth retardation and inconsistent mental retardation. Individuals with mutations of STAT5b do not appear to have intrauterine growth retardation or impaired brain development; however, because of the central role of STAT5b in multiple cytokine transduction/transcription pathways, these individuals can have serious immunodeficiency problems.[7]

United States data

Very few of the reported cases of GH resistance due to GHRD or the even more rare postreceptor abnormalities come from North America.

International data

Worldwide, approximately 250 individuals have GHRD/Laron syndrome, 10 individuals have homozygous STAT5b mutations, 13 families have IGF-I receptor mutations affecting over 20 individuals, and a comparable number of individuals have homozygous mutations resulting in ALS deficiency; only 3 individuals have been reported with IGF1 gene mutations. Recombinant IGF-I treatment reports include 13 children with GH gene deletion and acquired GH inhibiting antibodies following rhGH therapy. Other forms of acquired GH resistance, due to malnutrition or chronic disease, are common.

Race-related demographics

Among the approximately 250 affected individuals with GHRD identified worldwide, about two thirds are Semitic and half of the rest are of Mediterranean or South Asian origin. The Semitic group includes the Arab, Oriental, or Middle Eastern Jewish population and the largest group, the genetically homogeneous 100+ Conversos in Ecuador (Jews who converted to Christianity during the Inquisition).

The identification of an Israeli GHRD patient of Moroccan origin with the E180splice mutation found in the Ecuadorian patients indicated the Iberian provenance of this mutation, which readily recombined in the isolated communities of these 16th century immigrants established in the southern Ecuadorian Andes. Recently, additional patients with the E180splice mutation on the same genetic background have been identified in Chile and Brazil and in siblings from Mexico residing in the US, indicative of a common founder.[1]

The 10 individuals with STAT5b mutation include Kuwaiti siblings, 2 related and 2 unrelated Argentinians, 1 patient from Turkey, and 2 siblings from Brazil.[11]

ALS mutations were reported in Kurds, several unrelated Spanish patients, Norwegian/German siblings, and patients of Turkish, Argentinian, Ashkenazi Jewish, Pakistani, mixed European, and Mayan origin.[13, 14, 15, 16, 17, 18, 19]

Families with mutations of the IGF-I receptor were of Dagestani, European, and Japanese origin.[7, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30]

Sex-related demographics

Among patients observed from the original description of GHRD by Laron, Pertzelan, and Mannheimer in 1966[31] until 1990, a normal sex ratio was noted. The initial report of 20 cases from a single province in Ecuador included only 1 male, but subsequent observations from an adjacent province indicated a normal sex ratio, and a few more males were subsequently identified in the initial province.[8, 32] The abnormal sex ratio for that locus (M/F = 1/4) remains unexplained.

Age-related demographics

Newborns with GHRD are instantly recognizable to family members with previous experience because of the foreshortened facies and prominent brow. This is a curious finding, because intrauterine growth is not dependent on GH-GHR interaction.

Long-term prognosis appears normal for GHRD, and postreceptor defects with the exception of STAT5b. In fact, subjects with GHRD, despite obesity, have enhanced insulin sensitivity and do not develop diabetes and may be protected from cancer, as well.[33]

Individuals with STAT5b mutation probably have a reduced life expectancy as a result of chronic pulmonary disease.

Mortality/Morbidity

Children younger than 7 years with GHRD had twice the mortality of their unaffected siblings in a large Ecuadorian cohort, with causes of death not being different and typical of the environment (meningitis, diarrhea, pneumonia).[8]

Lean to fat mass ratios determined by dual energy x-ray absorptiometry are markedly reduced in studies of Ecuadorian and Israeli patients (who together account for more than half of known cases).[8, 9] Total and LDL cholesterol levels are elevated, likely reflecting decreased activity of the hepatic LDL receptor that is under direct GH influence.

Longevity after early childhood appears normal, although as with GH deficiency, there is an old-young appearance due to wrinkling and sagging of the face.

At least 50% of infants and children with GHRD have overt symptoms of hypoglycemia, including convulsions, and many without a clinical history of symptoms demonstrate quite low blood glucose levels with ordinary fasting. Retardation associated with severe recurrent hypoglycemia has only been noted in one instance. A somewhat increased mental retardation rate of 13.5% in an international treatment study series, and wide variability of intellectual capabilities in the Israeli population with GHRD that did not correlate with hypoglycemia histories, are observations that are not controlled by concurrent studies of unaffected family members, and they likely reflect the frequent association of this disorder with consanguinity. Controlled studies in the Ecuadorian cohort failed to demonstrate intellectual impairment or impaired school performance.[10]

The ALS and STAT5b mutations are not associated with intellectual impairment, because, as with GHRD (and as has long been known with congenital GH deficiency), intrauterine IGF-I production is not impaired and presumably GH independent. As noted earlier, IGF1 gene mutations result in severe mental retardation, and heterozygous IGF-I receptor mutations have no retardation to moderate retardation.

Because the STAT5b pathway is important in immune function, 9 of 10 reported individuals with functional mutation of the STAT5b have had severe immunologic problems or chronic pulmonary disease; the initially reported patient was awaiting lung transplantation.[11]

Reproductive capability has been normal in the GHRD population. Women require cesarean delivery.

With IGF-I therapy, parents and patients are instructed to observe for and report adverse effects. Parents and patients are also instructed to recognize the signs and symptoms of hypoglycemia, how to treat hypoglycemia, and, when deemed appropriate, how to monitor blood sugar at home.

For patient education resources, see the Thyroid & Metabolism Center and Oral Health Center, as well as Growth Hormone Deficiency, Growth Hormone Deficiency in Children, Growth Failure in Children, Growth Hormone Deficiency FAQs, and Growth Hormone Deficiency Medications.

The clinical features of GHRD are not different than those of severe GH deficiency. Postreceptor abnormalities differ from GHRD in not having hypoglycemia, because the counter-regulatory effects of GH are not impaired. IGF-I mutations differ from GHRD with severe mental retardation, sensorineural deafness, micrognathia, microcephaly, and intrauterine growth retardation. Heterozygous IGF-I receptor mutations have no or mild-to-moderate effect on brain development, but they do result in intrauterine growth retardation.

A single case report exists of a homozygous mutation resulting in severe prenatal and postnatal growth failure with malformations in a Lebanese child born of parents who were first cousins who were unaffected by their heterozygosity.[34]

Clinical characteristics of GHRD and STAT5b mutation

The clinical features with GHRD and STAT5b mutation are not distinguishable from those of severe GH deficiency.

ALS deficiency has modest, at most, effect on growth, without any other phenotypic features.[13, 14, 15, 16, 17, 18, 19] IGF-I mutations result in severe intrauterine and postnatal growth failure, deficient brain development in utero, and severe mental retardation, deafness, and micrognathia.[3, 4, 5, 6] Heterozygous IGF-1 receptor mutations result in varying degrees of intrauterine and postnatal growth retardation, microcephaly, and normal to moderately retarded cognitive development.[7, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30]

Clinical characteristics of GHRD

Growth characteristics include typically normal birth weight and birth length; growth failure from birth with growth velocity half of normal; height deviation that correlates with (low) serum levels of IGF-I and IGFBP-3; adult stature -4 to -12 standard deviations below normal mean; delayed bone age, but advanced for height age; and small hands and feet.

Craniofacial characteristics include sparse hair before age 7; frontotemporal hairline recession all ages; prominent forehead (bossing); head size more normal than stature with impression of large head; "setting sun sign" (sclera visible above iris at rest) 25% in children younger than 10 years (which, together with the craniofacial disproportion, can lead to impression of hydrocephalus and unnecessary workup); hypoplastic nasal bridge, shallow orbits; decreased vertical dimension of face; blue scleras; prolonged retention of primary dentition with decay; normal permanent teeth that may be crowded; absent 3rd molars; sculpted chin; unilateral ptosis; and facial asymmetry (15%, only reported in GHRD).

Musculoskeletal/body composition features include: hypomuscularity with delay in walking; avascular necrosis of femoral head (in 25% of those with GHRD); high-pitched voices in all children, most adults; thin, prematurely aged skin; limited elbow extensibility after 5 years of age; children underweight to normal for height, most adults overweight for height; and marked decrease of ratio of lean mass to fat mass compared to normal at all ages.

Metabolic characteristics include hypoglycemia (fasting), increased cholesterol and LDL-C levels, and decreased sweating.

Sexual development characteristics include small penis in childhood with normal growth with adolescence, delayed puberty, and normal fertility.

More than 50 mutations in the GHR gene have been described in the approximately 250 known patients with GHRD. The report of the characterization of the GHR gene included the first description of a genetic defect of the GHR, a deletion of exons 3, 5, and 6. Recognition that the exon 3 deletion represented an alternatively spliced variant without functional significance resolved the dilemma of explaining deletion of nonconsecutive exons.

In contrast to the alternatively spliced variant lacking exon 3, the first mutation of this exon has been described in a typical GHR-deficient patient with heterozygosity for a nonsense mutation in exon 4, and family studies indicate that heterozygosity for the exon 3 mutant has no effect. In addition to the original exon 5, 6 deletion, another deletion of exon 5 has been described, along with numerous nonsense mutations, missense mutations, frame shift mutations, splice mutations, and a unique intronic mutation resulting in insertion of a pseudo-exon. A number of other mutations have been described that are either polymorphisms or have not occurred in the homozygous or compound heterozygous state.[24]

The point mutations that result in severe GH insensitivity when present in the homozygous state or as a compound heterozygote are all associated with the typical phenotype of severe GHD. All but a few of the defects result in absent or extremely low levels of GH binding protein (GHBP). Noteworthy is the D152H missense mutation that affects the dimerization site, thus permitting the production of the extracellular domain in normal quantities but failure of dimerization at the cell surface, which is necessary for signal transduction and IGF-I production. Two defects that are close to (G223G) or within (R274T) the transmembrane domain result in extremely high levels of GHBP. These defects interfere with the normal splicing of exon 8, which encodes the transmembrane domain, with the mature GHR transcript being translated into a truncated protein that retains GH binding activity but cannot be anchored to the cell surface.[35]

The intronic mutation present in the heterozygous state in a mother and daughter with relatively mild growth failure (both with standard deviation score [SDS] for height -3.6), and resulting in a dominant negative effect on GHR formation, is not associated with other phenotypic features of GH deficiency. This splice mutation preceding exon 9 results in an extensively attenuated, virtually absent intracellular domain.[36]

Japanese siblings and their mother have a similar heterozygous point mutation of the donor splice site in intron 9, also resulting in mild growth failure compared to GHRD but with definite, although mild, phenotypic features of GHD.[37] GHBP levels in the Caucasian patients were at the upper limit of normal with a radiolabeled GH binding assay and in Japanese patients the levels were twice the upper limit of normal using a ligand immunofunction assay. These heterozygous GHR mutants transfected into permanent cell lines have demonstrated increased affinity for GH compared to the wild-type full-length GHR, with markedly increased production of GHBP. When cotransfected with full-length GHR, a dominant negative effect results from overexpression of the mutant GHR and inhibition of GH-induced tyrosine phosphorylation and transcription activation. Naturally occurring truncated isoforms have also shown this dominant negative effect in vitro.

A novel intronic point mutation was discovered in a highly consanguineous family with 2 pairs of affected cousins with GHBP-positive GH insensitivity and severe short stature, but without the facial features of severe GHD or GHRD. This mutation resulted in a 108-bp insertion of a pseudo-exon between exons 6 and 7, predicting an in-frame, 36-residue amino acid sequence in a region critically involved in receptor dimerization.[38]

Homozygous mutations described in the patients with STAT5b dysfunction have been associated with consanguinity.[11] By 2010  16 discrete mutations of the ALS gene had been reported in 21 individuals from 16 families, all resulting in absence of ALS and very low levels of IGF-I and IGFBP3 in the circulation, but modest, at worst, effects on growth.[13, 14, 15, 16, 17, 18, 1] Seven discrete heterozygous mutations of the IGF-I receptor have been described, resulting in varying degrees of intrauterine and postnatal growth retardation, microcephaly, and mental retardation (from none to moderate).[6, 17, 18, 19, 20, 21] Thus far, only 4 mutations previously noted for the IGF1 gene have been described.[3, 4, 5, 6]

Cardiovascular risk may be increased in GHRD, similar to that seen with GH deficiency in adults, and associated with increased total and LDL cholesterol levels.

While pregnancy is uncomplicated in GHRD, delivery requires cesarean delivery.

Infants, toddlers, and preschool children with GHRD appear to be at greater risk of death from prevalent infections than unaffected siblings.

Obesity, particularly in females, becomes a serious problem with aging but has not been associated with insulin resistance, diabetes, or increased cancer risk, as is seen in unaffected populations and unaffected relatives.[33]

Please refer to Hyposomatotropism and Short Stature for the complete workup for growth failure. Note the following:

• GH is elevated in childhood in GHRD but may be normal in adults; response to stimulation is above normal in children and adults. See Table in the Background section for other conditions.

• IGF-I and IGFBP3 are very low in GHRD. See Table in the Background section for other conditions.

• GHBP is low or absent in GHRD, except for mutations at the transmembrane region, which result in increased GHBP. See Table in the Background section for other conditions.

• Home blood glucose monitoring may be considered for infants and young children to monitor for hypoglycemia (typically controlled by frequent feeding).

• Lipid profile is appropriate for adults with GHRD.

• Mutational analyses should be obtained in consultation with one of the few laboratories analyzing the GH-IGF-I axis.

A left hand and wrist radiograph can be used to assess osseous maturation as is done with any other growth disorder. 

A hip radiograph series may be indicated to assess for Legg-Perthes disease (aseptic necrosis of the capital femoral epiphysis).

Patients being treated with rhIGF-I may need radiographic studies of the upper airway to screen for the common adverse effect of lymphoid hyperplasia, which often requires tonsillectomy/adenoidectomy. 

Brain imaging studies may be required because of the adverse effect of intracranial hypertension.

The only specific treatment available for patients with genetic disorders causing GH resistance with growth failure due to GHRD, STAT5b mutations, ALS mutations, or IGF1 gene mutation is rhIGF-I.

Growth failure due to heterozygous mutation of the type I IGF receptor is responsive to rhGH.[23]  

For those with secondary forms of GH resistance, other than that due to GH inactivating antibodies in rhGH-treated patients with GH1 gene deletion who require rhIGF-I treatment, the underlying cause (eg, malnutrition, liver disease) should be identified and treated appropriately.

Infants with GHRD may require more frequent feedings to avoid hypoglycemia. Nocturnal cornstarch feeding as is used for glycogen storage disease may help prevent fasting hypoglycemia. 

Periodic blood sugar monitoring is necessary for some patients with GHRD and for patients who are receiving rhIGF-I therapy.

At least 1 of 10 of patients treated with rhIGF-I requires a tonsillectomy/adenoidectomy as a result of the adverse effect of lymphoid hyperplasia. 

All mothers with GHRD require cesarean delivery.

Dental or orthodontic consultation may be needed for dental crowding, delayed eruption, or misalignment.

Nutritional consultation may be needed for children with inadequate intake, and to promote the high-protein, low-fat diet that appears to enhance response to IGF-I and reduce the common development of obesity with rhIGF-I treatment.

Treatment with rhIGF-I often requires ENT consultation for lymphoid hyperplasia, snoring, and hypoacusis and may require tonsillectomy/adenoidectomy.

Ophthalmologic or neurologic consultation may be needed for patients treated with rhIGF-I who develop headache as a possible sign of benign intracranial hypertension.

Prolonged fasting in patients with GHRD should be avoided, particularly in young children. Postreceptor defects are not associated with hypoglycemia. The already compromised growth of children with GHRD may be further compromised by poor appetite or social circumstances limiting nutrition. French investigators reported a patient with poor intake who grew normally in the hospital while receiving tube feeding, without rhIGF-I supplementation.[39] Three of the placebo-treated subjects in the Ecuadorian trial of rhIGF-I grew as well as those receiving rhIGF-I during the 6-month control period, presumably because of nutritional support provided by the investigators.[40]

The only limitations on physical activity are related to stature and the risk of hypoglycemia with prolonged fasting and exertion in GHRD. No limitations in putting in a full day of schoolwork, farming, or other occupations have been noted. Ecuadorian patients' occupations have included secretary, teacher, farmer, shopkeeper, lab technician, policeman, and cardiovascular surgeon.

Genetic counseling regarding mode of transmission, the contribution of consanguinity, and the risk of future offspring having conditions causing GH resistance is an important aspect of education and prevention.

Children receiving recombinant human rhIGF-I therapy need to be monitored at least every 3 months for adverse effects and should have trough (before next injection) IGF-I levels measured soon after starting treatment and annually.

Families of treated children also require intense nutritional counseling to minimize the development of obesity and to enhance the therapeutic effect of rhIGF-I.

Adults with GHRD also require nutritional counseling and exercise encouragement to reduce the risk of obesity and should have lipids monitored and hyperlipidemia treated as necessary.

Human IGF-I was synthesized by recombinant DNA techniques in 1986 and preparations of rhIGF-I for subcutaneous injection became available in 1990. The initial manufacturers in Japan (Fujisawa) and Sweden (Kabi) provided rhIGF-I for approximately 70 children with GHRD internationally and a handful of GH gene deletion patients with acquired GH insensitivity due to GH inactivating antibodies developing after treatment with rhGH.

Eventually, the 3 manufacturers stopped production of rhIGF-I because of the limited market. Subsequently, a company licensed by Genentech (Tercica Inc, Brisbane, California) obtained orphan drug approval of their rhIGF-I (mecasermin, [Increlex]) from the US Food and Drug Administration (FDA) in late 2005. Soon thereafter, an equimolar preparation of rhIGF-I and rhIGFBP3 (mecasermin rinfabate [Iplex], Insmed Inc, Glen Allen, Virginia) was approved by the FDA. In addition to the purported pharmacokinetic advantage permitting once daily injection for the latter preparation, a lower risk for hypoglycemia was proposed.[41] As a result of legal action, Iplex is no longer available for growth therapy; this is not a problem because the preparation was less effective than rhIGF-I alone.[42]

Pharmacokinetic profiles done at doses of 40, 80, and 120 mcg/kg suggested a plateau effect for circulating IGF-I concentrations between 80 and 120 mcg/kg per dose. It was considered that the carrying capacity of the IGFBPs was saturated at this level.[43] In a randomized, double-blind, placebo-controlled trial, 17 prepubertal Ecuadorian patients were given IGF-I at 120 mcg/kg SC bid for 6 months, following which all subjects received IGF-I. The 9 placebo-treated patients had a modest but not significant increase in height velocity from 2.8 ± 0.3 to 4.4 ± 0.7 cm/y, accounted for by 3 individuals with 6-month velocities of 6.6-8 cm/y.[40]

This response was attributed to improved nutritional status as noted with nutrition-induced catch up growth by Crosnier et al[39] in their GHRD patient with anorexia. For those receiving IGF-I, the height velocity increased from 2.9±0.6 to 8.8±0.6 cm/y and all 16 patients had accelerated velocities during the second 6-month period when all were receiving IGF-I.

In the comparison of growth response of the 22 Ecuadorian GHRD patients treated with rhIGF-I and 11 GHD patients treated with rhGH in the same setting and with comparable growth impairment, growth velocity increase in those with GHRD over the first year of treatment with IGF-I was 63% of that with GH treatment of GHD; in the second year the increment was less than 50% of that with GH-treated GHD.[43] The difference in growth response between GHRD treated with IGF-I and that treated with GHD was consistent with the hypothesis that 20% or more of GH-influenced growth is due to the direct effects of GH on growing bone.[44]

The collective experience of treating the rare conditions in which responsiveness to GH is severely impaired includes approximately 150 individuals, mostly with GHRD, and fewer than 10% with GH inactivating antibodies. The growth velocity increment in the first year was 4.3 cm in the European[45] and mecasermin (Genentech/Tercica) study populations,[46] and 5.6 cm in the Ecuadorian population,[43] all groups receiving comparable doses of rhIGF-I administered twice daily. In the Israeli population given a single injection of a comparable total daily dose, the increment was only 3.6 cm.[47]

Height SDS improvement in the first year of treatment paralleled these increments at 0.7, 0.8, and 0.6 for the twice daily rhIGF-I in the European, Ecuadorian, and International-mecasermin groups, respectively, and 0.2 for the Israeli population. The stimulatory effect on growth wanes rapidly after the first year, with only modest continued improvement. Among 76 patients treated for a mean 4.4 years, overall height SDS improvement was 1.4.[46]

In a three-year study comparing 80 µg/kg rhIGF-I twice daily in 7 subjects to 120 µg/kg twice daily in 14 subjects, no differences in height velocity were seen, but osseous maturation increased rapidly in the higher dose and correlated with the increase in percentage of body fat and with adrenal size increase. Thus, the commonly used dosage of 120 µg/kg twice daily was considered excessive, disproportionately accelerating osseous maturation probably from the combined effects greater accumulation of body fat and inappropriate adrenal growth, compromising adult height potential.[48]

That growth failure due to GH insensitivity cannot be corrected with endocrine IGF-I replacement is not explained by concomitant IGFBP3 deficiency. Substantial tissue delivery is reflected in profound effects on adipose tissue, facies, and lymphoid tissue in treated patients (see below).

Side effects include the following:

• Episodes of hypoglycemia, which may be severe, are common in infants and children with GHRD. In contrast to the hypoglycemia of GHD, which is corrected by GH replacement therapy, IGF-I treatment enhances the risk in children with GHRD. Hypoglycemia has been the most common early adverse event, reported in 49% of subjects in the largest series, including 5% with seizures.[46]

• In a 6-month placebo-controlled study, hypoglycemia was reported in 67% of those receiving placebo and 86% of those treated with rhIGF-I, an insignificant difference.[40] Fingerstick blood glucose measurements in 23 subjects residing on a research unit documented frequent hypoglycemia before breakfast and lunch, which did not increase in frequency with rhIGF-I administration. Five of the subjects participated in a crossover placebo-controlled study for 6 months with a 3-month washout period with fasting glucose determinations done thrice daily by caregivers for the entire 15-month study. The percentage of glucose values < 50 mg/dL was 2.6% on placebo and 5.5% on rhIGF-I—not a significant difference.[46] In practice, hypoglycemia appears reasonably controllable with adequate food intake.

• Pain at the injection site is common. Injection site lipohypertrophy is frequent, affecting at least one third of subjects; this is the result of failure to rotate injections, and injection into the lumps can attenuate growth response.

• The inotropic effect of IGF-I results in asymptomatic tachycardia in all treated patients, which clears after several months of continued use.

• Benign intracranial hypertension or papilledema has been noted in approximately 5% of IGF-treated subjects. While headache is frequent, the placebo-controlled study found no difference between those receiving placebo injections and those receiving IGF-I.

• Parotid swelling and facial nerve palsy have been described.

• Lymphoid tissue hypertrophy occurs in upwards of one fourth of patients, with hypoacusis, snoring, and tonsillar/adenoidal hypertrophy that required surgical intervention in more than 10% of patients. Thymic hypertrophy was noted in 35% of subjects having regular chest radiographs. Some of these side effects may be more frequent than reported because they take time to develop; for example, snoring incidence in the first year for the 25 subjects treated longest in the mecasermin study was only 4%, but increased to 65% for the entire period.[46]

• Anti-IGF-I antibodies have developed in approximately half of the patients treated with IGF-I during the first year of treatment, but these have had no effect on response.[40, 46]

• Transient elevation of liver enzymes has also been noted.

• Anaphylaxis has been reported.[49]

• Coarsening of facial features reminiscent of acromegaly has been noted in many patients, particularly those of pubertal age.

• In contrast to the increase in lean body mass and decreasing percentage of body fat that occurs with GH treatment of GHD, both lean and fat mass increase with rhIGF-I therapy, particularly at the higher dosages given.[43, 48] Mean body mass index (BMI) increased from +0.6 SDS to +1.8 SDS during 4-7 years of treatment with rhIGF-I in the European multicenter trial, and severe obesity has occasionally occurred.[45] BMI measurement may not accurately reflect the degree of obesity, which can be a doubling or tripling of body fat as demonstrated by dual energy x-ray absorptiometry.[9]

• Whether there might be long-term mitogenic effects of extended therapy with rhIGF-I in growing children is not known. The role of IGF-I in carcinogenesis as an anti-apoptotic agent favoring the survival of precancerous cells, increased cancer risk in hypersomatotropic states, and the evidence for aberrant tissue effects in patients treated with rhIGF-I dictate a need for long-term follow-up of these patients.[50, 51]

Class Summary

rhIGF-I is a member of the somatomedin polypeptide hormones. IGF-I mediates the anabolic and growth-promoting effects of GH. Endogenous IGF-I is required for normal intrauterine growth and brain development. This intrauterine IGF-I is not GH dependent. GH dependent IGF-I is also required for normal extra uterine growth, but not brain development. GH stimulation of IGF-I production in liver (endocrine secretion) and peripheral tissues (autocrine/paracrine secretion) accounts for approximately 50% of normal growth. Mecasermin (Increlex) is the only rhIGF-I product available in the United States.

Mecasermin (Increlex)

Recombinant human insulinlike growth factor-I (rhIGF-I). Used to treat children with growth hormone insensitivity or resistance due to receptor deficiency (GHRD, Laron syndrome), in whom a GH receptor mutation results in inability to synthesize IGF-I in the liver or peripheral tissues or due to postreceptor genetic defects interfering with IGF-I synthesis and also for children with GH gene deletion who develop blocking antibodies against recombinant GH. Increlex has not been studied in children younger than 2 y.