Growth Hormone Resistance Treatment & Management

  • Author: Arlan L Rosenbloom, MD; Chief Editor: Stephen Kemp, MD, PhD   more...
 
Updated: Apr 18, 2012
 

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 IGF-I gene mutation is rhIGF-I. Growth failure due to heterozygous mutation of the type I IGF receptor is responsive to rhGH.[22]
  • 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.
  • 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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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.
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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.
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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.[30] 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.[31]

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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' employment has included secretary, teacher, farmer, shopkeeper, lab technician, policeman, or cardiovascular surgeon.

Adult with GHRD standing with 3 of his fellow poliAdult with GHRD standing with 3 of his fellow police officers, his affected brother, a visiting US physician (Doctor Frank Diamond) and the seated chief.
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Contributor Information and Disclosures
Author

Arlan L Rosenbloom, MD  Adjunct Distinguished Service Professor Emeritus of Pediatrics, University of Florida College of Medicine; Fellow of the American Academy of Pediatrics; Fellow of the American College of Epidemiology

Arlan L Rosenbloom, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Epidemiology, American Pediatric Society, Endocrine Society, Florida Pediatric Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Coauthor(s)

Jaime Guevara-Aguirre, MD  Founder and General Director, The Institute of Endocrinology, Metabolism and Reproduction (IEMYR), Ecuador

Jaime Guevara-Aguirre, MD is a member of the following medical societies: Endocrine Society and Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Phyllis W Speiser, MD  Chief, Division of Pediatric Endocrinology, Steven and Alexandra Cohen Children's Medical Center of New York; Professor of Pediatrics, Hofstra-North Shore LIJ School of Medicine at Hofstra University

Phyllis W Speiser, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London)  Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Greece; UNESCO Chair on Adolescent Health Care, University of Athens, Greece

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American Academy of Pediatrics, American College of Endocrinology, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Merrily P M Poth, MD  Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences

Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD  Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas for Medical Sciences College of Medicine, Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

References

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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.
Reported patients with homozygous signal transduction and activator of translation (STAT5b) mutations.
Acid labile subunit (ALS) deficiency from mutations of the ALS gene in 15 patients. IGF-I, IGFBP3, target height, and near adult or adult height are expressed as standard deviation score (SDS). Target height is calculated as the mean parental height SDS.
Reported cases of mutations of the IGF-I receptor in 17 individuals from 7 families.
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.
10-year-old Ecuadorian girl with GHRD/Laron syndrome, who was performing at the top of the class, with her classmates.
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 11-year-old boy, 4th from the left and his 8-year-old brother holding the ball who is almost the same height.
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, and his IGF-I level is 4 times hers and his IGFBP3 level twice hers.
Adult with GHRD standing with 3 of his fellow police officers, his affected brother, a visiting US physician (Doctor Frank Diamond) and the seated chief.
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.
Treatment with rhIGF-I for 1-2 year of children with GH insensitivity. Data are from the references noted as well as package inserts.
Table. Features of GH Resistance Causes
ConditionGrowth failureGHGH binding proteinIGF-IIGFBP3
Genetic
GHRD - Recessive formsSevereElevatedAbsent-low*Very lowVery low
GHRD - Dominant negative formsMild-moderateElevatedIncreasedVery lowLow-normal
STAT5b mutationSevereElevatedNormalVery lowVery low
ALS mutationNone-moderateNormalNormalVery lowVery low
IGF-I gene mutationSevereElevatedNormalAbsent-high**Low-normal
IGF-I receptor mutationMild-moderateNormal-elevatedNormalNormal-elevatedNormal-elevated
Acquired
GH inhibiting antibodiesSevereAbsentNormalVery lowLow
MalnutritionNone-mildElevatedDecreasedVariableVariable
Diabetes mellitusNone-mildElevatedDecreasedDecreasedIncreased
Renal diseaseMild-severeNormalDecreasedNormalIncreased
Hepatic diseaseMild-severeElevatedNormal-increasedDecreasedNormal
*Increased in mutations of or near the transmembrane domain of the GH receptor



**Absent with partial IGF-I gene deletion; very high with abnormal IGF-I



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