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 (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.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.
Pathophysiology
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.
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.
IGF binding involves 3 types of receptors: the structurally homologous insulin receptor and type 1 IGF receptor and the distinctive type 2 IGF-II/mannose-6-phosphate receptor. 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.
Clinical Presentation
The clinical features of GHRD are not different than those of severe GH deficiency. Post receptor abnormalities differ from GHRD in not having hypoglycemia, because the counter-regulatory effects of GH are not impaired. As noted above, 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-moderate effect on brain development, but they do result in intrauterine growth retardation.
- Craniofacial characteristics
- 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% < 10 years of age (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, may be crowded; absent 3rd molars
- Sculpted chin
- Unilateral ptosis, facial asymmetry (15%); (only reported in GHRD])
- Musculoskeletal/body composition
- Hypomuscularity with delay in walking
- Avascular necrosis of femoral head (25% of 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; marked decrease of ratio of lean mass to fat mass, compared to normal, at all ages
- Metabolic
- Hypoglycemia (fasting)
- Increased cholesterol and LDL-C levels
- Decreased sweating
- Sexual development
- Small penis in childhood; normal growth with adolescence
- Delayed puberty
- Normal reproduction
GH is elevated in childhood in GHRD, but may be normal in adults; above normal response to stimulation in children and adults. See Table in Background section for other conditions
IGF-I and IGFBP3 are very low in GHRD. See Table in Background section for other conditions.
GHBP is low or absent in GHRD, except for mutations at the transmembrane region, which will result in increased GHBP. See Table in Background section for other conditions.
Home blood glucose monitoring may be considered for infants and young children to monitor intervention for hypoglycemia (typically 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.
Imaging Studies
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 upper airway due to the common adverse effect of lymphoid hyperplasia.
Brain imaging studies may be required because of the adverse effect of intracranial hypertension.
Treatment and Management
The only specific treatment available for patients with genetic disorders causing GH resistance with growth failure due to GHRD, STAT5b mutations, ALS mutations, or IGF-I gene mutation is rhIGF-I. Growth failure due to heterozygous mutation of the type I IGF receptor is responsive to rhGH.
For those with secondary forms of GH resistance, the underlying cause (eg, malnutrition, liver disease) should be identified and treated appropriately.
Infants with GHRD/Laron syndrome may require more frequent feedings to avoid hypoglycemia.
Periodic blood sugar monitoring is necessary for some patients with GHRD and for all patients who are receiving rhIGF-I therapy.
GHBP is low or absent in GHRD, except for mutations at the transmembrane region, which will result in increased GHBP. See Table in Background section for other conditions.
Home blood glucose monitoring may be considered for infants and young children to monitor intervention for hypoglycemia (typically 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.
Imaging Studies
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 upper airway due to the common adverse effect of lymphoid hyperplasia.
Brain imaging studies may be required because of the adverse effect of intracranial hypertension.
Treatment and Management
The only specific treatment available for patients with genetic disorders causing GH resistance with growth failure due to GHRD, STAT5b mutations, ALS mutations, or IGF-I gene mutation is rhIGF-I. Growth failure due to heterozygous mutation of the type I IGF receptor is responsive to rhGH.
For those with secondary forms of GH resistance, the underlying cause (eg, malnutrition, liver disease) should be identified and treated appropriately.
Infants with GHRD/Laron syndrome may require more frequent feedings to avoid hypoglycemia.
Periodic blood sugar monitoring is necessary for some patients with GHRD and for all patients who are receiving rhIGF-I therapy.
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