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 (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 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.^[1]

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 IGF-I gene^[2] , a patient with mutation of the IGF-I gene resulting in high circulating levels of an ineffective IGF-I^[3] , and in 17 probands and first-degree relatives with heterozygous mutations of the IGF-I receptor (homozygous mutations are presumably fatal).^{[4, 5, 6, 7, 8, 9]}

Whereas those individuals with IGF-I gene mutations were severely mentally retarded and growth retarded 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 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.^[10]

Frequency

United States

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

International

Worldwide, approximately 250 individuals have GHRD/Laron syndrome, 6 individuals have homozygous STAT5b mutations, 7 families have heterozygous IGF-I receptor mutations, 15 individuals have homozygous mutations resulting in ALS deficiency, and only 2 individuals have IGF-I 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.

Mortality/Morbidity

Children younger than 7 years with GHRD have 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). Adults in this population appear to have an increased risk of cardiovascular disease, which is similar to the increased risk in adults with GH deficiency.^[11] 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).^{[11, 12]} Total and LDL cholesterol levels are elevated, likely reflecting decreased activity of the hepatic LDL receptor that is under direct GH influence. Longevity of survivors, in the absence of cardiovascular disease, 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 can 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.^[13]

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,

IGF-I gene mutations result in severe mental retardation, and heterozygous IGF-I receptor mutations have none to moderate retardation.

Reproductive capability is normal. Women require cesarean delivery.

Race

Among the approximately 250 affected individuals 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 and the largest group, the genetically homogeneous 70+ Conversos in Ecuador (the Jewish who converted to Christianity during the Inquisition).

The identification of an Israeli patient of Moroccan origin with the E180 splice 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 E180 splice mutation on the same genetic background have been identified in Chile and Brazil, likely of the same origin. Among those who are not of Semitic, South Asian, or Mediterranean origin, there is wide ethnic representation, including Northern European, Eurasian, East Asian, African, and Anglo-Saxon (Bahamas).^[1]

The 6 individuals with STAT5b mutation include Kuwaiti siblings, 2 unrelated Argentinians, 1 patient from Turkey, and 1 patient from the Caribbean.^[10]

ALS mutations were reported in 3 Kurdish brothers, 3 unrelated Spanish patients, 3 Norwegian/German siblings, and individual patients of Turkish, Argentinian, Ashkenazi Jewish, Pakistani, mixed European, and Mayan origin.^{[14, 15, 16, 17, 18, 19]}

Families with heterozygous mutations of the IGF-I receptor were of Dagestani, European, and Japanese origin.^{[4, 5, 6, 7, 8, 9]}

Sex

Among patients observed from the original description of the syndrome by Laron, Pertzelan, and Mannheimer in 1966^[20] 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.^{[11, 21]} The abnormal sex ratio for that locus remains unexplained.

Age

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.