Medical Care
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.
Surgical Care
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.
Consultations
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.
Diet
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]
Activity
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.
Adult with GHRD standing with 3 of his fellow police officers, his affected brother, a visiting US physician (Dr Frank Diamond) and the seated chief.
Prevention
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.
Long-Term Monitoring
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.
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Diagram of the hypothalamic-pituitary-GH/IGF-I axis, showing mutational targets beginning with the GH-releasing hormone receptor (GHRHR), indicated in bold and italicized.
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A 50-year-old woman with GHRD (right) and her 75-year-old mother, indicating premature aging appearance. Photos were taken at the same distance, emphasizing the small size of the subject and relative foreshortening of the facies.
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A 10-year-old Ecuadorian girl with GHRD/Laron syndrome, who was performing at the top of the class, with her classmates.
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15 Ecuadorian children with GHRD due to homozygosity for the E180 splice mutation of the GH receptor, lined up according to descending age from 15 years to 2 years, with 3 normal children standing behind age mates. Note general but not consistent statural correlation with age, most dramatic for the 11-year-old boy, 4th from the left, and his 8-year-old brother holding the ball who is almost the same height.
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A 21-year-old woman and her 23-year-old brother with GHRD/Laron syndrome demonstrating variable effects on growth of the same mutation and the correlation with low levels of IGF-I in IGFBP3. Her height is 100 cm, -11.2 SDS and his height is 134 cm, -6.3 SDS, his IGF-I level is 4 times hers, and his IGFBP3 level is twice hers.
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Adult with GHRD standing with 3 of his fellow police officers, his affected brother, a visiting US physician (Dr Frank Diamond) and the seated chief.
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Six-month, placebo-controlled, double-blind study of rhIGF-I in 16 Ecuadorian children with GHRD, followed by 6 months open label rhIGF-I therapy of the entire group.
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Treatment with rhIGF-I for 1-2 year of children with GH insensitivity. Data are from the references noted as well as package inserts.
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Four subjects with growth hormone (GH) receptor deficiency due to the E180 splice mutation on the GH receptor gene. From left to right, the first woman, age 22 years, was treated from age 4 years, when she had a height standard deviation score (SDS) of -8, to age 14 years with insulinlike growth factor-1 at a dose of 80 µg/kg body weight bid; adult height is -4.3 SDS and body fat percent is 39.8. The other 3 women were treated for 3 years with 120 µg/kg bid and are aged 30, 23, and 27 years with body fat content of 49.3%, 49%, and 54.6% and with heights of 120.7 cm, 120.8 cm, and 118.5 cm, respectively. Females with GH insufficiency who had comparable baseline characteristics and were treated with 120 µg/kg twice daily to adult height in the US trial only reached 112 cm, 121.2 cm, and 120.8 cm. These observations suggest no greater statural attainment with prolonged high-dose therapy than with short-term, high-dose treatment, consistent with the observation of disproportionate advancement of osseous maturation by the higher dose. Courtesy of The Journal of Clinical Endocrinology and Metabolism (Guevara-Aguirre J, Rosenbloom AL, Guevara-Aguirre M, Saavedra J, Procel P. Recommended IGF-I dosage causes greater fat accumulation and osseous maturation than lower dosage and may compromise long-term growth effects. J Clin Endocrinol Metab 98: 839–845, 2013).
Tables
Condition |
Growth failure |
GH |
GH binding protein |
IGF-I |
IGFBP3 |
Genetic |
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GHRD - Recessive forms |
Severe |
Elevated |
Absent-low* |
Very low |
Very low |
GHRD - Dominant negative forms |
Mild-moderate |
Elevated |
Increased |
Very low |
Low-normal |
STAT5b mutation |
Severe |
Elevated |
Normal |
Very low |
Very low |
ALS mutation |
None-moderate |
Normal |
Normal |
Very low |
Very low |
IGF-I gene mutation |
Severe |
Elevated |
Normal |
Absent-high** |
Low-normal |
IGF-I receptor mutation |
Mild-moderate |
Normal-elevated |
Normal |
Normal-elevated |
Normal-elevated |
Acquired |
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GH inhibiting antibodies |
Severe |
Absent |
Normal |
Very low |
Low |
Malnutrition |
None-mild |
Elevated |
Decreased |
Variable |
Variable |
Diabetes mellitus |
None-mild |
Elevated |
Decreased |
Decreased |
Increased |
Renal disease |
Mild-severe |
Normal |
Decreased |
Normal |
Increased |
Hepatic disease |
Mild-severe |
Elevated |
Normal-increased |
Decreased |
Normal |
*Increased in mutations of or near the transmembrane domain of the GH receptor**Absent with partial IGF1 gene deletion; very high with abnormal IGF-I |
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