Laron's dwarfism: Studies on the nature of the defect

doi:10.1016/S0022-3476(73)80485-8

The Journal of Pediatrics

Volume 83, Issue 2, August 1973, Pages 253-263

https://doi.org/10.1016/S0022-3476(73)80485-8 Get rights and content

Laron's syndrome is characterized by severe dwarfism, high circulating levels of immunoreactive growth hormone, and a failure to generate somatomedin in response to administration of human growth hormone. Studies conducted in a 7 1/2-year-old boy with the syndrome indicate that the hypothalamic-pituitary mechanisms controlling growth hormone secretion are intact. However, those controlling the suppression of growth hormone release seem to be inoperative. The administration of exogenous human growth hormone failed to produce an acute metabolic response as measured by mineral retention, nitrogen retention, somatomedin generation, or release of free fatty acid from adipose tissue; however, an unsustained growth response to long-term administration of human growth hormone was observed. The circulating growth hormone resembled normal human growth hormone immunologically and has the usual prolactin-like activity. These data suggest that the primary defect is tissue unresponsiveness to normal human growth hormone. An abnormality in the structure of growth hormone which is not essential for prolactin activity and immunoreactivity and a slow rate of growth hormone degradation in these patients cannot be excluded by available data.

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Cited by (42)

Genetic causes of proportionate short stature
2018, Best Practice and Research: Clinical Endocrinology and Metabolism
Citation Excerpt :
Nomenclature has been confusing and evolved over time. The early descriptive name of “genetic pituitary dwarfism with high-serum GH” was changed to Laron dwarfism [54], Laron type dwarfism [55], and subsequently Laron syndrome (ls) [56], GH insensitivity, or GHR deficiency [57]. Because GH resistance can be primary or secondary, a consensus classification and nomenclature of GH insensitivity syndromes was published in 1993 [58].
Human growth is a very complex phenomenon influenced by genetic, hormonal, nutritional and environmental factors, from fetal life to puberty. Although the GH-IGF axis has a central role with specific actions on growth, numerous genes are involved in the control of stature. Genome-wide association studies have identified >600 variants associated with human height, still explaining only a small fraction of phenotypic variation. Since short stature in childhood is a common reason for referral, pediatric endocrinologists must be aware of the multifactorial and polygenic contributions to height. Multiple disorders characterized by growth failure of prenatal and/or postnatal onset due to single gene defects have been described. Their early diagnosis, facilitated by advances in genomic technologies, is of upmost importance for their clinical management and to provide genetic counseling. Here we review the current clinical and genetic information regarding different syndromes and hormone abnormalities with proportionate short stature as the main feature, and provide an update of the approach for diagnosis and management.
Fifty seven years of follow-up of the Israeli cohort of Laron Syndrome patients-From discovery to treatment
2016, Growth Hormone and IGF Research
Citation Excerpt :
So the “IGF-I generation test” was born. The name Laron Dwarfism (later changed to Laron Syndrome (LS)) was coined by Elders et al. [9]. Definite evidence for GH resistance was found by liver biopsy in 2 LS patients, showing that I125hGH did not bind to the liver membranes of these patients, in contrast to membranes from controls (taken during renal transplants) [10].
Clinical and laboratory investigations of dwarfed children newly Jewish immigrants from Yemen and Middle East and who resembled patients with isolated growth hormone deficiency were started by our group in 1958. In 1963 when we found that they have high serum levels of hGH, we knew that we had discovered a new disease of primary GH insensitivity. It was subsequently coined Laron Syndrome (LS, OMIM #262500). The etiopathogenesis was disclosed by 2 liver biopsies demonstrating a defect in the GH receptor. Subsequent investigations demonstrated deletions or mutations in the GHR gene. The defect lead to an inability of IGF-I generation, resulting in severe dwarfism, obesity, and other morphologic and biochemical pathologies due to IGF-I deficiency. With the biosynthesis of IGF-I in 1986, therapeutic trials started. Following closely our cohort of 69 patients with LS enabled us to study its features in untreated and IGF-I treated patients. This syndrome proved to be a unique model to investigate the effects of IGF-I dissociated from GH stimulation. In recent studies we found that homozygous patients for the GHR mutations are protected lifelong from developing malignancies, opening new directions of research.
Lessons from 50 years of study of laron syndrome
2015, Endocrine Practice
Citation Excerpt :
In 1966 (1) and in 1968 (2), we described a disease characterized by severe growth retardation, obesity, and small genitalia, resembling congenital growth hormone (GH) deficiency (3) but with high serum GH levels and low to undetectable serum insulin-like growth factor 1 (IGF- 1). This disease was subsequently coined Laron dwarfism (4) and changed later to Laron syndrome (LS; Online Mendelian Inheritance in Man# 262500). The negative feedback between low IGF-1 and the hypothalamic growth hormone (growth hormone–releasing hormone) leads to an increased secretion of pituitary GH (5).
Objective: To describe the characteristics of untreated and recombinant insulin-like growth factor 1 (IGF-1)- treated patients with the Laron syndrome (LS) as seen in our clinic over a period of over 50 years. In 1966, we reported a new disease, characterized by dwarfism (-4 to -10 height standard deviation score) typical facial features, small head circumference, obesity, and small genitalia. They resembled congenital growth hormone (GH) deficiency but had high levels of serum human GH and low IGF-1. Since then, our cohort grew to 69 patients, consisting of Jews of oriental origin, Muslins, and Christians originating from the Middle East or Mediterranean area. Many belong to consanguineous families.
Methods: Molecular genetic investigations revealed that these patients had deletions or mutations in the GH receptor gene, but only individuals homozygous for this defect express the disease, coined “Laron syndrome” (LS; Online Mendelian Inheritance in Man# 262500).
Results: During childhood, LS patients grow slowly, have a retarded bone age and sexual development, but reach full sexual development. The treatment of LS is recombinant IGF-1, which stimulates the linear growth but increases the degree of obesity. Adult-age patients with congenital IGF-1 deficiency are protected from cancer but can develop insulin resistance, glucose intolerance, diabetes, and cardiovascular disease. Due to pathologic changes in the brain related to the type of molecular defect in the GH receptor, they vary in their intellectual capacity. A number of LS patients marry, and with help of pregestational genetic diagnosis, have healthy children.
Conclusion: LS is a unique disease model presenting a dissociation between GH and IGF-1 activity.
Abbreviations:
GH = growth hormone
hGH = human growth hormone
IGF-1 = insulin-like growth factor 1
LS = Laron syndrome
rIGF-1 = recombinant IGF-1
SDS = standard deviation score
Reduced hepatic growth hormone (GH) receptor gene expression and increased plasma GH binding protein in experimental uremia
1994, Kidney International
Reduced hepatic growth hormone (GH) receptor gene expression and increased plasma GH binding protein in experimental uremia. In uremia, reduced longitudinal growth and decreased hepatic insulin-like growth factor-I (IGF-I) secretion despite elevated GH serum levels point to an insensitivity to the action of GH. The molecular basis that accounts for this insensitivity could comprise decreased GH receptor expression in the target organs for GH or binding of GH in the circulation to substances that compete with the receptor. To address this hypothesis, the abundance of hepatic GH receptor mRNA was measured by solution hybridization RNase protection assay in uremic female Spra-gue-Dawley rats, following two-stage 5/6 nephrectomy, and in pair-fed and in ad libitum-ted sham-operated controls; rat GH binding protein (GHBP) plasma concentration was measured by a sensitive direct RIA. Uremia was associated with a 50% decrease of hepatic GH receptor expression compared to pair-fed controls, which themselves showed a 25% reduction of hepatic GH receptor mRNA abundance when compared to ad libitum-ted controls. Plasma GHBP levels in uremia were markedly higher than in both control groups. Treatment with recombinant human GH (rhGH) (10 IU/kg body wt per day s.c. for 10 days) led to a comparable induction of IGF-I plasma levels and weight gain in uremia and pair-fed controls, indicating that the insensitivity to GH in uremia can be overcome by large rhGH doses. Subcutaneous rhGH injections did not significantly alter the hepatic GH receptor transcript abundance or plasma GHBP levels in any of the groups. Methylprednisolone (6 mg/kg body wt per day given for 10 days) significantly suppressed weight gain and food conversion ratio in all experimental groups, accompanied by a 50% reduction of plasma GHBP, but without a consistent effect on hepatic GH receptor mRNA abundance or circulating IGF-I. This study demonstrates that experimental uremia in rats leads to a decreased expression of hepatic GH receptor mRNA. This decrease is partly due to a reduced nutritional intake but also involves other as yet unidentified mechanisms. Circulating GHBP is increased in the uremic state and could potentially compete for ligand binding to the receptor. We hypothesize that both these alterations contribute to GH insensitivity in uremia.
Stimulation of statural growth by recombinant insulin-like growth factor I in a child with growth hormone insensitivity syndrome (Laron type)
1992, The Journal of Pediatrics
We studied the effects of 9 months of treatment with twice-daily subcutaneous injections of insulin-like growth factor I (IGF-I), 120 μg/kg per dose, in a 9.7-year-old child with growth hormone insensitivity syndrome, in whom short-term studies had suggested that IGF-I might promote linear growth. Height velocity increased from 6.5 cm/yr (+1.7 SD score) to 11.4 cm/yr (+8.8 SD score). Serum concentrations of IGF-I increased from pretreatment values of 9±2 μg/L to a peak of 347±26 μg/L after 2 hours. Serum concentrations of IGF-II were unchanged. Basal but not stimulated growth hormone concentrations were decreased. During the first 12 days of treatment, serum concentrations and the 24-hour urinary excretion of urea nitrogen were decreased by 28% and 10%, respectively (p<0.05), there was a 2.4-fold increase in urinary excretion of calcium (p<0.001), and creatinine clearance and urine volume increased by 22% and 55%, respectively (p<0.02). The changes in serum levels of urea nitrogen and in urinary calcium and creatinine clearance were still evident at 10 weeks. Fasting and postprandial serum glucose concentrations remained normal. We conclude that IGF-I given as twice-daily subcutaneous injections is effective in stimulating statural growth without producing the hypoglycemia and hyperglycemia observed when IGF-I is infused continuously.
Molecular basis of Laron dwarfism
1991, Trends in Endocrinology and Metabolism
An autosomal recessive disorder, Laron-type dwarfism, results from peripheral unresponsiveness to growth hormone. Mutations in the growth hormone receptor have recently been identified in this syndrome. Analysis of patients with Laron-type dwarfism should provide insight into the mechanisms of hormone receptor binding and signal transduction pathways of this receptor, which belongs to a new class of transmembrane receptors.

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^*: Studies at the University of Arkansas Medical Center were supported in part by United States Public Health Service Grants, NS07638 and AM 12011; studies at Harbor General Hospital were supported by United States Public Health Service Grant AM 05638; clinical studies performed at Washington University School of Medicine were supported by United States Public Health Service Grant 2 R01 AM0156 from the National Institute of Arthritis and Metabolic Diseases.

^*: Recipient of a Career Program Award 5K3-HD-23-325.

^**: Recipient of a Clinical Research Center Research Grant RR 00036.

^***: Recipient of United States Public Health Service Grant HD04270.

^****: Recipient of Career Program Award 5K3-AM 18415.

View full text

Original articleLaron's dwarfism: Studies on the nature of the defect*

Lancet

J. Pediatr.

Am. J. Med.

J. Biol. Chem.

Am. J. Clin. Nutr.

Metabolism

Genetic pituitary dwarfism with high serum concentration of growth hormone; a new inborn error of metabolism

Isr. J. Med. Sci.

Pituitary dwarfism with high serum levels of growth hormone

Isr. J. Med. Sci.

Genetic aspects of pituitary dwarfism due to absence or biological inactivity of growth hormone

Isr. J. Med. Sci.

Administration of growth hormone to patients with familial dwarfism with high plasma immunoreactive growth hormone: Measurement of sulfation factor, metabolic and linear growth responses

J. Clin. Endocrinol. Metab.

Defective sulfation factor generation: A possible etiological link in dwarfism

Trans. Assoc. Am. Physicians

Dwarfism with elevated levels of plasma growth hormone

N. Engl. J. Med.

Familial prenatal dwarfism with elevated serum immunoreactive growth hormone levels and endorgan unresponsiveness

Maandschr. Kindergeneeskd.

Primary plasma growth factor deficiency (sulfation factor and thymidine factor) presenting as hyposomatotrophic dwarfism

Radiographic atlas of skeletal development of the hand and wrist

Original article
Laron's dwarfism: Studies on the nature of the defect*