Diagnostic Considerations

GHRD is clinically indistinguishable from severe GHD. Serum GH concentrations, however, are elevated or briskly responsive to stimulation; baseline values are less likely to be elevated in adults than in children. Serum GHBP levels are low to unmeasurable in most forms of GHRD, those that involve the extracellular domain of the GH receptor. IGFBP3 levels are also low and IGF-II concentrations are elevated. IGF-I generation tests are not necessary for diagnosis and may be misleading. STAT5b mutations result in a similar clinical picture, but with normal GHBP and IGFBP3 concentrations, and in problems with immunocompetence (recurrent and chronic infections). ALS mutations are also associated with normal GHBP, markedly reduced IGFBP3 and IGF-I concentrations, unmeasurable ALS, and a relatively mild growth retardation. IGF-I mutations and heterozygous IGF-I receptor mutations are distinguished by their causing intrauterine growth retardation.

Differential Diagnoses

Workup

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Media Gallery

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.
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.
A 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 the 11-year-old boy, 4th from the left, and his 8-year-old brother holding the ball who is almost the same height.
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.
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.
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.
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).

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Table. Features of GH Resistance Causes

Table. Features of GH Resistance Causes

Condition	Growth failure	GH	GH binding protein	IGF-I	IGFBP3
Genetic
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
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 receptorAbsent with partial IGF1* gene deletion; very high with abnormal IGF-I

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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, Pediatric Endocrine Society, Society for Pediatric Research, Florida Chapter of The American Academy of Pediatrics, Florida Pediatric Society, International Society for Pediatric and Adolescent Diabetes

Disclosure: Nothing to disclose.

Coauthor(s)

Jaime Guevara-Aguirre, MD Professor, Department of Diabetes and Endocrinology, University of San Francisco, Quito Ecuador; 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, Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Specialty Editor Board

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 Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, American College of Endocrinology

Disclosure: Nothing to disclose.

Chief Editor

Robert P Hoffman, MD Professor and Program Director, Department of Pediatrics, Ohio State University College of Medicine; Pediatric Endocrinologist, Division of Pediatric, Endocrinology, Diabetes, and Metabolism, Nationwide Children's Hospital

Robert P Hoffman, MD is a member of the following medical societies: American College of Pediatricians, American Diabetes Association, American Pediatric Society, Christian Medical and Dental Associations, Endocrine Society, Midwest Society for Pediatric Research, Pediatric Endocrine Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Growth Hormone Resistance Differential Diagnoses

Diagnostic Considerations

Differential Diagnoses

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