Alternative titles; symbols
SNOMEDCT: 38196001; ICD10CM: E34.321; ORPHA: 633; DO: 9521; MONDO: 0009877;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5p13.1-p12 | Laron dwarfism | 262500 | Autosomal recessive | 3 | GHR | 600946 |
A number sign (#) is used with this entry because of evidence that Laron syndrome, also known as growth hormone insensitivity syndrome, is caused by homozygous or compound heterozygous mutation in the growth hormone receptor gene (GHR; 600946) on chromosome 5p.
Laron syndrome is an autosomal recessive disorder characterized by marked short stature that results from failure to generate insulin-like growth factor I (IGF1; 147440) in response to growth hormone (GH; 139250). GH levels are normal or increased. The disorder is caused by dysfunction of the growth hormone receptor.
A Laron syndrome-like phenotype associated with immunodeficiency (245590) is caused by a postreceptor defect, i.e., mutation in the STAT5B gene (604260).
Patients with mutations in the GHR gene that cause only partial insensitivity to growth hormone have a form of short stature (604271).
Dysfunction of GHR is characterized by clinical hyposomatotropism manifest by short stature, delayed bone age, and occasionally blue sclerae and hip degeneration. Additional features include delayed bone maturation and the absence of bone dysplasias and chronic diseases. Laron syndrome patients have low IGF1 despite normal or increased levels of GH. The GH is functionally normal by the criteria that it reacts normally with a variety of antisera and binds normally to GH receptors. IGF1 is low in GHIS, and exogenous GH does not induce an IGF1 response or restore normal growth. Plasma levels of GH-binding proteins (GHBP), which are derived from the extracellular domain of GHR, are often low. Cultured fibroblasts from patients with Laron dwarfism respond normally to serum growth factors (Cogan and Phillips, 2001).
Pertzelan et al. (1968) described a form of dwarfism in which the abnormality of pituitary hormones is limited to GH, but the level of GH as measured by the immunoassay method is high rather than low. In Israel, all cases (13 females, 7 males) of this type were in Oriental Jews. Laron (1974) listed a number of non-Jewish cases. Several of them were of Dutch or Arab extraction. Inheritance was clearly autosomal recessive. Similarly, Merimee et al. (1968) reported a 30-year-old man who had increased levels of plasma GH that were not suppressed by hyperglycemia and were further augmented by insulin-induced hypoglycemia and by arginine infusion. With respect to all metabolic indices examined, he showed attenuated responses to exogenous GH. Similarities to cases of isolated growth hormone deficiency (IGHD) type I (see 262400) were exaggerated hypoglycemic response to exogenous insulin and insulinopenia after glucose or arginine. Also, Saldanha and Toledo (1981) reported 2 brothers who had apparent severe IGHD but high serum GH levels. These were born to first-cousin parents of possible Italian extraction.
In an inbred population of Spanish extraction in the province of Loja in southern Ecuador, Rosenbloom et al. (1990) studied 20 patients (2 to 49 years of age) with the clinical features of Laron syndrome. Seventeen patients were members of 2 large pedigrees; among 13 affected sibships there were 19 affected and 24 unaffected female sibs and 1 affected and 21 unaffected male sibs. The height of the patients ranged from 6.7 to 10.0 standard deviation (SD) below the normal mean height for age in the United States. In addition to the previously described features, 15 patients had limited elbow extensibility, all had blue sclerae, affected adults had relatively short limbs, and all 4 affected women over 30 years of age had hip degeneration. Acrohypoplasia, defined as hand or foot length below the tenth percentile for height, was noted in 80% of the patients. A high-pitched voice was present in both children and adults. The timing of menarche was moderately to markedly delayed in 5 of 12 women more than 16 years old. Basal serum concentrations of GH were elevated in all affected children and normal to moderately elevated in the adults. The serum level of GHBP ranged from 1 to 30% of normal. Reporting further on this Ecuadorian form of Laron syndrome, Guevara-Aguirre et al. (1991) described 47 patients; approximately 60 cases had been reported worldwide before 1990, half of them from Israel. Guevara-Aguirre et al. (1991) emphasized the occurrence of markedly advanced osseous maturation for height and age; normal body proportions in childhood but childlike proportions in adults; disproportionately greater deviation of stature than head size, giving an appearance of large cranium and small facies; blue sclerae; and limited elbow extension. Unlike the other large group of patients reported from Israel, the Ecuadorian patients were of normal or superior intelligence. Although phenotypically identical, the Ecuadorian patients from Loja province had a markedly skewed sex ratio (19 females:2 males) while those from the El Oro province had a normal sex distribution (14 females:12 males).
Rosenbloom et al. (1999) reviewed the clinical, endocrine, and molecular findings of affected members of this kindred in great detail. They noted that the kindred was descended from 'conversos,' Spanish Jews who became Catholic during the Inquisition.
Schaefer et al. (1994) used computerized image analysis to perform facial morphometrics on patients with Laron syndrome from Ecuador. Morphometrics were compared for 49 patients, 70 unaffected relatives, and 14 unrelated persons. Patients with growth hormone receptor deficiency showed significant decreases in measures of vertical facial growth as compared to unaffected relatives and unrelated persons with short stature from other causes. The findings validated and quantified the clinical impression of foreshortened facies in Laron syndrome.
Buchanan et al. (1991) described anomalous findings in a family from northern India in which 3 sisters had the phenotype of Laron syndrome. All members of the family had high-affinity serum GHBP activity similar in size, circulating levels, and apparent affinity for GH to that of normal subjects. The parents were not known to be consanguineous. Buchanan et al. (1991) concluded that some novel biochemical defect must be responsible for GH-resistance and reduced production of IGF1 in this family.
Goddard et al. (1995) broadened the phenotype of GHIS by demonstrating mutations in the GHR gene (600946.0006, 600946.0007, 600946.0008) in 4 of 14 children with idiopathic short stature selected on the basis of normal growth hormone secretion and low serum concentrations of GH-binding protein. Most children with idiopathic short stature respond to recombinant growth hormone treatment with increases in their growth rates (Hopwood et al., 1993). The report of Goddard et al. (1995) raised the question of whether mutations in the genes for IGF1 (147440), IGF-binding protein-3 (146732), or IGF1R may be involved in some cases of idiopathic short stature.
Woods et al. (1997) examined the phenotypic and biochemical features of 82 GHIS patients from 23 countries. There were 45 males and 37 females (mean age, 8.25 years; mean height, -6.09 SD score; and mean insulin-like growth factor binding protein-3 (IGFBP3; 146732) value, -7.99 SD score). Of these, 63 were GHBP negative and 19 were GHBP positive (greater than 10% binding). The mean heights of GHBP-negative and -positive subjects were -6.5 and -4.9 SD scores (P less than 0.001), respectively. Clinical and biochemical heterogeneity was seen in the wide range of height (-2.2 to -10.4 SD score) and IGFBP3 (-1.4 to -14.7 SD score) values, which were positively correlated (r(2) = 0.45; P less than 0.001). This contrasted with the lack of correlation between mean parental height SD score and height SD score (r(2) = 0.01). Fifteen different GHR mutations were identified in 27 patients. These mutations included 5 nonsense, 2 frameshift, 4 splice, and 4 missense. All patients except 1, a compound heterozygote, were homozygous. There was no relationship between mutation type or exon of the GHR gene involved and height or IGFBP3 SD score. Woods et al. (1997) concluded that GHIS is associated with wide variation in the severity of clinical and biochemical phenotypes. Since this variation cannot clearly be accounted for by defects in the GHR gene, they proposed that other genetic and/or environmental factors contribute to the GHIS phenotype.
Ayling et al. (1997) described a 'new' category of congenital GHIS inherited as an autosomal dominant and caused by a dominant-negative mutation of the growth hormone receptor. There was no evidence of the phenotype usually associated with congenital GHIS (midfacial hypoplasia, blue sclera, limited elbow extension, sparse hair in childhood, or truncal adiposity). The patients studied were a mother and daughter. Sequencing of all GHR coding exons revealed a G-to-C transversion at position -1 of the splice acceptor site of intron 8 (600946.0015). The abnormality was not detected in the maternal grandparents, indicating a de novo mutation in the proband's mother. A signal peptide and extracellular sequence of the GHR gene are encoded by exons 2 to 7 and the transmembrane domain by most of exon 8. The intracellular sequence is encoded by a small part of exon 8, together with exons 9 and 10. RT-PCR with primers located in exons 8 and 10 produced 2 bands of approximately 290 and 220 bp, suggesting that the mutation caused deletion of exon 9. This was confirmed by sequencing. The predicted consequence of the exon skipping was a frameshift resulting in a premature stop codon so that the cytoplasmic sequence of the mutant GHR would be reduced to only 7 amino acids. The GHR belongs to the cytokine superfamily of receptors that depend on JAK tyrosine kinases (see 147795) for activation of STATs (see 600555) and other signaling pathways. Association of JAK2 (147796) with the GHR requires a conserved proline-rich sequence encoded by exon 9, which is located in the cytoplasmic domain. Cotransfection of the mutant and wildtype GHR together with a reporter gene containing STAT5 (601511) binding sites showed that the mutant GHR was unable to activate STAT5. More importantly, the truncated receptor exerted a marked dominant-negative effect on GHR. Ayling et al. (1997) noted that ligand-induced dimerization of GHR is essential for signal transduction, and immunoprecipitation after cotransfecting cells with both forms of GHR showed that the wildtype and mutant forms heterodimerize. A specific cytoplasmic residue is necessary for internalization and degradation of the receptor, and this process is also dependent on ubiquitination of the cytoplasmic domain. Lacking these sequences, the mutant receptors would be expected to accumulate at the cell surface, reinforcing their dominant-negative effect. Overexpression of the mutant allele was also observed and appeared to contribute to the dominant-negative effect. Most previously identified mutations had been located in the extracellular hormone-binding domain of GHR, with consequent decrease in serum GH-binding protein (which is derived from this region of the receptor). The heterozygous mutations found by Goddard et al. (1995) as an apparent contributing factor to the problem in children with 'idiopathic' short stature and low GHBP were also located in the extracellular domain. An important implication of the study by Ayling et al. (1997) was that dominant GHR mutations should be sought in children who would not previously have been thought to have endocrinopathy, namely those with familial short stature and normal GHBP.
With the aid of a continuous blood withdrawal pump, Keret et al. (1988) studied the 24-hour secretory pattern of GH in 3 Laron syndrome patients. Secretion of GH was exaggerated but the diurnal secretory profile, as expressed by the number of pulses and the sleep-related maximal pulse, was preserved. The decline in GH secretion that is characteristic of advancing age in normal subjects seemed to occur in Laron syndrome as well. An exaggerated rate of production of GH was thought to be the result of a lack of negative feedback because of IGF1 deficiency.
A functionally abnormal, although immunoreactive, GH molecule was postulated at first to be the cause of Laron syndrome. The demonstration of deficient sulfation factor (somatomedin or IGF1, 147440; IGF2, 147440) generation (Daughaday et al., 1969) suggested that the mutation could involve that substance. By a special receptor assay, Jacobs et al. (1976) concluded that the GHR is defective. This explains the clinical hyposomatotropism, failure to generate IGF and abnormal regulation of fasting GH levels. Plasma GH in Laron syndrome reacts normally with a variety of antisera and also binds normally to GH receptors. In Laron syndrome IGF1 is low and exogenous GH does not cause IGF1 to increase or restore normal growth. In vitro fibroblasts from patients with Laron syndrome respond normally to serum growth factors. The somatomedins, or insulin-like growth factors IGF1 and IGF2, are a family of small peptides that circulate bound to larger carrier proteins. They resemble proinsulin in amino acid sequence and tertiary structure but have limited cross-reactivity with insulin in binding to receptor sites. Circulating somatomedin inhibitors have been demonstrated. Insulin and nutritional status, as well as GH, influence IGF production by the liver. Dietary protein is especially important in the effect. Much of both intrauterine and postnatal growth is probably IGF-dependent.
Circulating GH appears to be immunochemically and biochemically normal in Laron syndrome. Furthermore, endogenous GH of affected persons binds normally in radioreceptor assays. Hepatic unresponsiveness with resulting low levels of circulating IGF1 is the fundamental problem. Golde et al. (1980) showed that the normal in vitro responsiveness of circulating erythropoietic stem cells to exogenous GH was lacking in Laron syndrome, thus suggesting that the biologic defect is indeed peripheral unresponsiveness to GH. In liver tissue from 2 patients with Laron syndrome subjects, aged 4 and 26 years, Eshet et al. (1984) found no specific binding of radiolabelled GH. On the other hand, liver tissue from 6 healthy subjects (kidney transplantation donors) showed a mean specific binding of 14% (range, 7.9 to 24%).
Daughaday and Trivedi (1987) found that serum GHBP is absent in Laron syndrome. This and other evidence points to the identity or close relationship of the cellular receptor and the serum binding protein. The latter may originate through alternative splicing of mRNA or partial degradation resulting in a smaller unanchored protein.
Pintor et al. (1989) described a Sardinian child who appeared to have Laron-type syndrome, but the serum level of IGF1 was within normal limits, as determined by assay of unextracted serum. Laron and Silbergeld (1989) questioned the reliability of IGF1 measurements in unextracted serum, because of the interference of IGF1-binding proteins in the assay. Pintor et al. (1990) restudied their patient and studied a second Sardinian child with the same disorder and found that after extraction of the plasma with acid, IGF1 was indeed low. Aguirre et al. (1990) found that high-affinity GHBP is diminished in the serum of persons heterozygous for GHR mutations.
Although the classic finding in Laron syndrome is absence of GHBP in the serum, Woods et al. (1996) described a homozygous point mutation within the intracellular domain of the growth hormone receptor resulting in Laron syndrome with elevated GHBP (600946.0014). The findings predicted that the mutant protein would not be anchored in the cell membrane and would be measurable in the serum as GHBP, thus explaining the phenotype of severe GH resistance combined with elevated circulating GHBP.
Guevara-Aguirre et al. (2011) monitored for 22 years Ecuadorian individuals who carried mutations in the GHR gene that led to severe GHR and IGF1 deficiencies. Guevara-Aguirre et al. (2011) combined this information with surveys to identify the cause and age of death for individuals in this community who died before this period. The individuals with GHR deficiency exhibited only 1 nonlethal malignancy and no cases of diabetes, in contrast to a prevalence of 17% for cancer and 5% for diabetes in control subjects. A possible explanation for the very low incidence of cancer was suggested by in vitro studies: serum from subjects with GHR deficiency reduced DNA breaks but increased apoptosis in human mammary epithelial cells treated with hydrogen peroxide. Serum from GHR-deficient subjects also caused reduced expression of RAS (e.g., 190020), protein kinase A (PKA; see 188830), and mTOR (601231) and upregulation of SOD2 (147460) in treated cells, changes that promote cellular protection and life span extension in model organisms. Guevara-Aguirre et al. (2011) also observed reduced insulin concentrations (1.4 microU/ml vs 4.4 microU/ml in unaffected relatives) and a very low HOMA-IR (homeostatic model assessment-insulin resistance) index (0.34 vs 0.96 in unaffected relatives) in individuals with GHR deficiency, indicating higher insulin sensitivity, which Guevara-Aguirre et al. (2011) postulated could explain the absence of diabetes in these subjects. The results provided evidence for a role of evolutionarily conserved pathways in the control of aging and disease burden in humans.
Autosomal recessive and autosomal dominant modes of inheritance have been reported in different families. Guevara-Aguirre et al. (1991) observed a distorted sex ratio (19F:2M) among affected cases from the Loja province of Ecuador.
Amselem et al. (1989) used denaturing gradient gel electrophoresis and sequencing of specific GHR fragments to characterize specific intragenic DNA markers in 35 control subjects of Mediterranean descent for use in linkage studies. In the 2 Mediterranean families in which the parents were consanguineous and some of the children had Laron syndrome, the disease trait and the DNA polymorphisms on chromosome 5p13-p12 were inherited together.
See growth hormone receptor (600946) for a description of mutations in the GHR gene in Laron syndrome.
Berg et al. (1993) reported that 10 GHR mutations had been reported in Laron syndrome to that time; one was a recurrent mutation, R43X (600946.0003), occurring in a CpG dinucleotide hotspot.
Francke and Berg (1993) reviewed genetic heterogeneity in Laron syndrome.
Laron syndrome is characterized by (1) clinical signs of GH deficiency (short stature, decreased growth velocity and delayed bone age) despite normal or increased plasma GH levels; (2) low IGF1 levels that are unresponsive to exogenous GH; and often by (3) low GHBP levels.
Geffner et al. (1987) found that whereas tissues from patients with Laron syndrome are resistant to the actions of either endogenous or exogenous GH, erythroid progenitor cells and permanently transformed T-cell lines from 2 patients with Laron syndrome responded in vitro to exogenous IGF1. Responsiveness of insulin was also normal or near normal. The response to IGF in vitro suggested that patients may respond to this agent in vivo. By acute administration of exogenous IGF1, Laron et al. (1988) demonstrated a rapid onset of hypoglycemia associated with a reduction in plasma insulin; thus, the lack of growth hormone receptors in Laron syndrome does not apply to IGF1 receptors and to postreceptor pathways. One would expect that long-term treatment with IGF1 might be beneficial. In an 11-day infusion of recombinant IGF1 in a 9-year-old boy with Laron syndrome, Walker et al. (1991) found metabolic responses like those of GH. They observed the reduction in fasting blood glucose levels expected with IGF1 and undoubtedly related to its insulin-like effect on target cells. Laron et al. (1992) found an impressive response to biosynthetic IGF1 administered subcutaneously once daily for 3 to 10 months in 5 children aged 3.3 to 14.5 years. There was stimulation of rapid linear growth, a striking increase in head circumference, an increase in body weight, and a reduction in subcutaneous fat.
Backeljauw et al. (1996) treated 8 children with GH insensitivity syndrome, 5 with GH receptor deficiency (Laron syndrome) and 3 with growth-attenuating antibodies to GH with recombinant IGF1 for 24 months (one was treated for 36 months). During the first year of treatment, height velocity improved in each patient, but declined by one-third during the second year. The third year height velocity of the 1 patient so treated was approximately the same as that in the second year. The increased HV was accompanied by weight gain. IGF1-related hypoglycemia occurred infrequently and only early in treatment. No adverse changes in biochemical profiles were observed. Bone age did not advance more rapidly than chronological age. The growth of the spleen and kidneys was rapid in the first year of therapy. In the second year, spleen growth slowed to a normal rate in most patients. Kidney growth, however, remained relatively rapid. Backeljauw et al. (1996) concluded that IGF1 stimulates statural growth for at least 2 years and that this peptide has the capacity to act through endocrine mechanisms. However, the stimulation of growth by IGF1 treatment over years needs to be documented, and patients need to be monitored for side effects.
Backeljauw et al. (2001) presented the results of prolonged treatment (6.5 to 7.5 years) of the 8 children treated by Backeljauw et al. (1996) with recombinant human IGF1. Height velocity remained slightly below that achieved during the first and second years of treatment during the subsequent years. No major adverse changes in biochemical profile were observed. IGF1-related hypoglycemia occurred early in treatment with the younger patients, but this problem abated as treatment was continued. The authors concluded that IGF1 therapy is effective in promoting statural growth in GH insensitivity syndrome patients, but that the growth response is neither as intense nor as well-sustained as the growth response to GH among children with GH deficiency.
Guevara-Aguirre et al. (1997) reported 1-year results of a double-blind, placebo-controlled trial of recombinant human IGF1 replacement in 16 children from the Ecuadorian Laron syndrome population. The report extended observations of IGF1 efficacy at 2 dosage levels, over 2 years, compared biochemical responses and their relationship to growth effects, and compared treatment effects of IGF1 in Laron syndrome to GH in idiopathic GH deficiency. Comparable growth responses to the 2 dosage levels and the biochemical changes indicated a plateau effect at or below 80 micrograms/kg body weight twice daily. The greater increase in percent mean body weight for height with treatment of Laron syndrome than with treatment of idiopathic GH deficiency may reflect comparable effects on lean body mass without the lipolytic effects of GH in the Laron syndrome subjects. The difference in growth response between IGF1-treated Laron syndrome and GH-treated GH deficiency groups is consistent with the hypothesis that 20% or more of GH-influenced growth is due to the direct effects of GH on bone. Comparable changes in bone height age suggested similar long-term effects of replacement therapy in the 2 conditions.
Mauras et al. (2000) investigated the in vivo effects of 8 weeks of therapy with recombinant human IGF1 in a cohort of 10 adult Ecuadorian subjects with profound IGF1 deficiency due to homozygous mutation in the GHR gene (GAA180GAG; 600946.0005). There was no change in weight during these studies, but a significant change in body composition was observed, with a decrease in percent fat mass and an increase in lean body mass. These were accompanied by increased rates of protein turnover, decreased protein oxidation, and increased rates of whole body protein synthesis, as measured by leucine tracer methods. There were significant decreases in insulin concentrations and a reciprocal increase in glucose production rates during IGF1 therapy, while glucose concentrations remained constant, suggesting a significant insulin-like action of IGF1. The authors concluded that, similar to GH treatment of adults with GH deficiency, IGF1 may be beneficial as long-term replacement therapy for the adult patient with Laron syndrome.
Using estimated volumetric values, Benbassat et al. (2003) evaluated bone mineral density (BMD) by DEXA in 12 Laron syndrome patients and compared the findings with 10 osteopenic subjects without developmental abnormalities and 10 healthy control subjects matched for sex and age to the Laron syndrome patients. Although areal BMD was significantly lower in the Laron syndrome and osteopenic subjects compared with controls (P less than 0.02) at both the lumbar spine and femoral neck, BMAD was low (P less than 0.01) in the osteopenic group only. It has been speculated that the low BMD found in Laron syndrome patients using conventional DEXA densitometry may be an artifact of reduced bone size. The authors concluded that DEXA does not seem to be a reliable measure of osteoporosis in patients with Laron syndrome.
The GHR defects known to cause Laron syndrome are as a rule heterogeneous and include gene deletion, recurring CpG dinucleotide substitutions, and other point mutations (Phillips, 1992). Interestingly, in an inbred Ecuadorian population of Spanish extraction, despite homozygosity for a single-nucleotide substitution in exon 6 of GHR that activates a cryptic donor splice site, a skewed sex ratio (19 females:2 males) was observed (Guevara-Aguirre et al., 1991).
Baumbach et al. (1997) characterized the GHR mutation that is responsible for GH insensitivity in a Bahamian genetic isolate. Sequencing identified homozygosity for a C-to-T transition in the third position of codon 236 (GGC to GGT). RT-PCR amplification of cDNA from lymphocytes showed that the 236C-T mutation generated a new splice donor site 63-bp 5-prime to the normal exon 7 splice site. The predicted protein product lacked 21 amino acids, including those defining the WS-like motif of the GHR extracellular domain. The high frequency of Laron syndrome in this isolated island population was proposed to result from the introduction of the mutation that perturbs splicing by a settler early in the 300-year history of English settlement.
The cDNAs for GHR have been cloned from a variety of primates, including humans, rabbits, and rats. The extracellular domain of GHR (residues 1-246) corresponds to the extracellular domain of various cytokine receptors, including erythropoietin, granulocyte colony-stimulating factor and interleukins 2-4 and 6-7. In addition, GHR shares approximately 30% sequence identity with the prolactin receptor, with the highest conservation occurring in the extracellular domain adjacent to the GHR transmembrane domain (Phillips, 1992).
Although GHRs in many species bind human growth hormone as well as their own, human GHR binds only primate growth hormone. Arg43 in human GHR interacts with asp171 of human GH. Nonprimates have a his in the position equivalent to residue 171 of primate GH and a leu in position 43 of primate GHR. To determine whether arg43 accounts for the species specificity of human GHR, point mutations that change leu43 to arg were introduced into the cDNAs encoding the bovine GHR or the rat GH-binding protein and these mutants or their wildtype counterparts were expressed in mouse L cells (Souza et al., 1995). The findings in binding studies and in expression systems indicated that incompatibility of arg43 in human GHR with his171 in nonprimate GH is the major determinant of species specificity. The findings of Behncken et al. (1997) agreed with those of Souza et al. (1995).
By segregation data, Eicher and Lee (1991) positioned the GHR locus relative to previously mapped genes on mouse chromosome 15. Just as the GHR locus in humans is the site of the mutation in Laron dwarfism, the locus in the mouse may be the site of the autosomal recessive mutation 'miniature' (mn), which is characterized by severe growth failure and early death and has been mapped to chromosome 15.
To create a mammalian model of Laron syndrome, Zhou et al. (1997) generated mice bearing a disrupted GHR/binding protein gene (GHR; 600946) through a homologous gene targeting approach. Homozygous GHR knockout mice showed severe postnatal growth retardation, proportionate dwarfism, absence of the growth hormone receptor and GH binding protein, greatly decreased serum IGF1, and elevated serum GH concentrations. These characteristics represent the phenotype typical of individuals with Laron syndrome. Animals heterozygous for the defect showed only minimal growth impairment but had an intermediate biochemical phenotype, with decreased GHR and GH binding protein expression and slightly diminished IGF1 levels. These findings indicated that the Laron mouse is a suitable model for human Laron syndrome, and should prove useful for the elucidation of many aspects of GHR/BP function that cannot be obtained in humans.
Laron (1990) gave an account of the discovery of the form of dwarfism that bears his name.
Laron (2004) reviewed the diagnosis, follow-up, and treatment of a cohort of patients over 40 years.
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