RARE DISEASE
Laron syndrome
Laron syndrome
Laron syndrome
Synonyms: Complete growth hormone insensitivity, GH receptor deficiency, Growth hormone receptor deficiency, Laron-type dwarfism, Primary GH insensitivity, Primary GH resistance, Primary growth hormone insensitivity, Primary growth hormone resistance, Short stature due to growth hormone resistance
Synonyms: Complete growth hormone insensitivity, GH receptor deficiency, Growth hormone receptor deficiency, Laron-type dwarfism, Primary GH insensitivity, Primary GH resistance, Primary growth hormone insensitivity, Primary growth hormone resistance, Short stature due to growth hormone resistance
Synonyms: Complete growth hormone insensitivity, GH receptor deficiency, Growth hormone receptor deficiency, Laron-type dwarfism, Primary GH insensitivity, Primary GH resistance, Primary growth hormone insensitivity, Primary growth hormone resistance, Short stature due to growth hormone resistance
Drug discovery
1
drug
With orphan designation
Overview
Laron syndrome is a rare autosomal recessive disorder caused by mutations in the growth hormone receptor (GHR) gene, leading to growth hormone insensitivity [1][6][12]. Characterized by severe postnatal short stature (−4 to −10 SD), distinctive facial features (protruding forehead, saddle nose), obesity, and hypoglycemia [1][6][7], it is associated with low insulin-like growth factor-1 (IGF-1) despite elevated growth hormone levels [1][6]. Notably, patients exhibit reduced risks of cancer and type 2 diabetes despite obesity [1][12], though lifespan remains unchanged [1][4]. Treatment involves recombinant IGF-1 (mecasermin) to improve growth and metabolic parameters [3][8][13].
Burden
Physical: Severe short stature (~4–4.5 feet in adults), delayed puberty, hypogenitalism, and dental abnormalities [1][6][7].
Metabolic: Lifelong risks of obesity, hypercholesterolemia, and hypoglycemia [1][6]; increased fracture risk due to osteopenia [6][12].
Psychosocial: Challenges related to dwarfism, delayed motor development, and social stigma [1][6]. Despite reduced cancer/diabetes incidence, mortality risk persists from cardiovascular complications [4][12].
Therapies
Recombinant IGF-1 (mecasermin): Daily subcutaneous injections to stimulate growth; improves height velocity, muscle mass, and metabolic markers [3][8][13].
Symptomatic management: Address hypoglycemia, hypercholesterolemia, and obesity through dietary interventions [6][12].
Limitations: High treatment burden (frequent injections), transient adverse effects (fluid retention, pain at injection site), and variable growth response [3][8][13].
Categories: rare endocrine diseases, rare genetic diseases
Research Papers
339 drug discovery papers about Laron syndrome, with 1 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
339 drug discovery papers about Laron syndrome, with 1 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-08 | The Laron Syndrome Mouse Model Reveals a Potential Contribution of Methylglyoxal-Derived Glycative Stress to IGF-1-Driven Prostate Cancer Progression
Individuals with Laron syndrome, a rare condition characterized by congenital insulin-like growth factor 1 (IGF-1) deficiency, display a remarkably low incidence of cancer, suggesting the existence of protective mechanisms linking reduced IGF-1 signaling to decreased cancer susceptibility. Consistent with this observation, IGF-1 is a recognized promoter of prostate cancer (PCa) progression, although the underlying mechanisms remain incompletely understood. Methylglyoxal (MG)-derived glycative stress, reflected by the accumulation of MG-derived hydroimidazolone 1 (MG-H1), has been implicated in PCa progression but has never been investigated in Laron syndrome. We found that liver tissues from Laron mice exhibited lower MG-H1 levels, suggesting reduced MG-derived glycative stress associated with low IGF-1 signaling. These findings prompted us to investigate whether MG-derived glycative stress contributes to IGF-1-driven PCa progression. Compared with the less aggressive LNCaP cells, PC3 cells displayed higher basal IGF-1 and MG-H1 levels, consistent with a potential association between IGF-1 and MG-derived glycative stress in PCa progression. Moreover, IGF-1 stimulation of LNCaP cells increased MG-H1 accumulation, proliferation, colony formation, invasiveness, and gene expression of matrix metalloproteinase (MMP)-1, MMP-7, MMP-9, receptor for advanced glycation end-products (RAGE), and Osteopontin (OPN), all of which were markedly attenuated by the MG scavenger aminoguanidine (AG). Collectively, these findings support a potential contribution of MG-derived glycative stress to IGF-1-driven PCa progression.
2026-06-15 | GH-resistant (Laron) mice: gene therapy with a liver-specific GH receptor causes unbalanced upregulation of female-biased and growth-related genes.
Growth hormone (GH) receptor (GHR) mutations give rise to GH-resistance (Laron syndrome). We previously treated GH-resistant Ghr-/- mice (Laron mice) with adeno-associated virus (AAV) delivering mouse (m)Ghr controlled by a constitutively active liver-specific promoter (HLP). A single injection of AAV-HLP-mGHR resulted in a significant but limited increase in body length and weight, consistent with studies of IGF-1 treatment in humans and mice. Here, we performed RNA-seq on male and female mouse livers comprising the following groups: GHR+/+ (wild-type), GHR-/- (Laron), AAV-HLP-mGHR-treated GHR-/- (treatment group), and AAV-HLP-Luc (Luciferase)-treated GHR-/- (control group). Only four genes showed significant differential expression in GHR -/- mouse liver following Luciferase vector treatment, indicating minimal effect of the AAV-HLP vector. AAV-HLP-mGHR stimulated significant expression changes in 448 genes compared to AAV-HLP-Luc control, substantially fewer than the 2781 genes whose expression was altered in GHR-/- compared to GHR+/+. AAV-HLP-mGHR treatment induced the GH-responsive IGF signaling genes Igf1 and Igfals ~16-fold compared to AAV-HLP-Luc control, but only to 40-45% of GHR+/+ liver levels. The treatment also upregulated a small subset of genes beyond GHR+/+ expression levels (p-adj < 0.05), including the proto-oncogenes Ascl1, Tmprss4, and others. Finally, genes dysregulated upon GHR loss and upregulated in livers of AAV-HLP-mGHR-treated mice were significantly enriched for sex-biased genes, consistent with the major role of GH and GHR in regulating liver sex differences. While gene replacement therapy is a potential therapy for Laron syndrome, an unregulated constitutively active promoter may drive unexpected and unbalanced changes in liver gene expression that will require monitoring.
2026-03-31 | Growth hormone: Synthesis and regulation.
Growth hormone (GH) plays an essential role in the regulation of postnatal growth and metabolism through both direct and GH-IGF-1 axis-mediated mechanisms. GH action involves a complex interplay of endocrine, paracrine and autocrine signals that affect multiple tissues and organs. This review addresses the molecular and physiological fundamentals of GH secretion and action, as well as the multiple factors that modulate it, including central and peripheral signals, metabolic variables, physiological and pharmacological states. The relevance of GH receptor signaling and intracellular pathways involved in tissue response is discussed, as well as the mechanisms of hormone resistance that may arise in different clinical contexts. GH secretion, which is pulsatile, is subject to strict regulation by the hypothalamic-pituitary system, involving GHRH, somatostatin and ghrelin, together with negative feedback from GH and IGF-1. In addition, factors such as sleep, nutrition, stress, age or sex contribute significantly to its physiological variability. The implications of the somatotropic axis in pathological conditions such as GH deficiency, acromegaly or GH insensitivity syndromes are also explored.
2026-03-30 | The IGF-1 senescence switch: a biphasic model for SASP-driven aging and precision senomodulation.
Insulin-like growth factor-1 (IGF-1) signaling plays a paradoxical role in aging, acting as both a mediator of tissue repair and a driver of chronic inflammation through the senescence-associated secretory phenotype (SASP). In this review, we propose a biphasic senescence switch model in which the temporal pattern of IGF-1 exposure, acute versus chronic, determines cellular fate. Transient IGF-1 signaling supports homeostasis and repair, whereas sustained activation promotes stable senescence via reactive oxygen species (ROS)-mediated DNA damage, p53/p21 pathway activation, and a potent pro-inflammatory SASP. Central to this process is IGF-binding protein-5 (IGFBP-5), which amplifies senescence in vascular and stromal cells by linking coagulation and inflammatory signals to p53-dependent arrest. The contrasting human conditions of IGF-1 deficiency (Laron syndrome) and excess (acromegaly) illustrate the lifespan and disease risks associated with dysregulated IGF-1 signaling. Emerging evidence highlights the role of extracellular vesicles in bypassing soluble IGFBP regulation, enabling paracrine propagation of senescence even under systemic IGF-1 modulation. Ultimately, we position the IGF-1/IGFBP axis as a prime target for precision senomodulation, advocating for combined strategies that temporally tune endocrine signaling with senolytic and senomorphic therapies to mitigate chronic inflammation, delay age-related dysfunction, and extend healthspan.
2026-03-25 | A cartilage-targeted IGF-1-antibody fusion protein as a new therapeutic approach for IGF-1 deficiency.
Growth hormone (GH) insensitivity syndrome (GHIS) is a childhood growth disorder characterized by an inability to generate insulin-like growth factor-1 (IGF-1) in response to GH. Consequently, GH therapy is ineffective in patients with GHIS. Patients are often treated with recombinant IGF-1 instead, which requires twice-daily injections and is associated with adverse effects including hypoglycemia. In the current study, we evaluated CV1623-1, a cartilage-targeted antibody-like IGF-1 fusion protein as a potential new treatment for GHIS and for other disorders of linear growth involving IGF-1 deficiency. Using Ghrhrlit mice as a model for IGF-1 deficiency, we found that CV1623-1 stimulated the growth plate at a lower dose and decreased dose frequency compared with IGF-1. Alternate-day injections of CV1623-1 significantly increased body weight, tail length, and tibial bone length. In addition, CV1623-1, unlike IGF-1, did not induce hypoglycemia. Taken together, our findings indicate that CV1623-1 represents a promising new drug candidate for GHIS with improved efficacy, longer duration of action, and reduced hypoglycemia compared with the current treatment, recombinant IGF-1. Preclinical studies and clinical trials would be required to further validate the safety and efficacy of CV1623-1, paving the way for its potential clinical application as a new treatment for GHIS.
2026-08-08 | The Laron Syndrome Mouse Model Reveals a Potential Contribution of Methylglyoxal-Derived Glycative Stress to IGF-1-Driven Prostate Cancer Progression
Individuals with Laron syndrome, a rare condition characterized by congenital insulin-like growth factor 1 (IGF-1) deficiency, display a remarkably low incidence of cancer, suggesting the existence of protective mechanisms linking reduced IGF-1 signaling to decreased cancer susceptibility. Consistent with this observation, IGF-1 is a recognized promoter of prostate cancer (PCa) progression, although the underlying mechanisms remain incompletely understood. Methylglyoxal (MG)-derived glycative stress, reflected by the accumulation of MG-derived hydroimidazolone 1 (MG-H1), has been implicated in PCa progression but has never been investigated in Laron syndrome. We found that liver tissues from Laron mice exhibited lower MG-H1 levels, suggesting reduced MG-derived glycative stress associated with low IGF-1 signaling. These findings prompted us to investigate whether MG-derived glycative stress contributes to IGF-1-driven PCa progression. Compared with the less aggressive LNCaP cells, PC3 cells displayed higher basal IGF-1 and MG-H1 levels, consistent with a potential association between IGF-1 and MG-derived glycative stress in PCa progression. Moreover, IGF-1 stimulation of LNCaP cells increased MG-H1 accumulation, proliferation, colony formation, invasiveness, and gene expression of matrix metalloproteinase (MMP)-1, MMP-7, MMP-9, receptor for advanced glycation end-products (RAGE), and Osteopontin (OPN), all of which were markedly attenuated by the MG scavenger aminoguanidine (AG). Collectively, these findings support a potential contribution of MG-derived glycative stress to IGF-1-driven PCa progression.
2026-06-15 | GH-resistant (Laron) mice: gene therapy with a liver-specific GH receptor causes unbalanced upregulation of female-biased and growth-related genes.
Growth hormone (GH) receptor (GHR) mutations give rise to GH-resistance (Laron syndrome). We previously treated GH-resistant Ghr-/- mice (Laron mice) with adeno-associated virus (AAV) delivering mouse (m)Ghr controlled by a constitutively active liver-specific promoter (HLP). A single injection of AAV-HLP-mGHR resulted in a significant but limited increase in body length and weight, consistent with studies of IGF-1 treatment in humans and mice. Here, we performed RNA-seq on male and female mouse livers comprising the following groups: GHR+/+ (wild-type), GHR-/- (Laron), AAV-HLP-mGHR-treated GHR-/- (treatment group), and AAV-HLP-Luc (Luciferase)-treated GHR-/- (control group). Only four genes showed significant differential expression in GHR -/- mouse liver following Luciferase vector treatment, indicating minimal effect of the AAV-HLP vector. AAV-HLP-mGHR stimulated significant expression changes in 448 genes compared to AAV-HLP-Luc control, substantially fewer than the 2781 genes whose expression was altered in GHR-/- compared to GHR+/+. AAV-HLP-mGHR treatment induced the GH-responsive IGF signaling genes Igf1 and Igfals ~16-fold compared to AAV-HLP-Luc control, but only to 40-45% of GHR+/+ liver levels. The treatment also upregulated a small subset of genes beyond GHR+/+ expression levels (p-adj < 0.05), including the proto-oncogenes Ascl1, Tmprss4, and others. Finally, genes dysregulated upon GHR loss and upregulated in livers of AAV-HLP-mGHR-treated mice were significantly enriched for sex-biased genes, consistent with the major role of GH and GHR in regulating liver sex differences. While gene replacement therapy is a potential therapy for Laron syndrome, an unregulated constitutively active promoter may drive unexpected and unbalanced changes in liver gene expression that will require monitoring.
2026-03-31 | Growth hormone: Synthesis and regulation.
Growth hormone (GH) plays an essential role in the regulation of postnatal growth and metabolism through both direct and GH-IGF-1 axis-mediated mechanisms. GH action involves a complex interplay of endocrine, paracrine and autocrine signals that affect multiple tissues and organs. This review addresses the molecular and physiological fundamentals of GH secretion and action, as well as the multiple factors that modulate it, including central and peripheral signals, metabolic variables, physiological and pharmacological states. The relevance of GH receptor signaling and intracellular pathways involved in tissue response is discussed, as well as the mechanisms of hormone resistance that may arise in different clinical contexts. GH secretion, which is pulsatile, is subject to strict regulation by the hypothalamic-pituitary system, involving GHRH, somatostatin and ghrelin, together with negative feedback from GH and IGF-1. In addition, factors such as sleep, nutrition, stress, age or sex contribute significantly to its physiological variability. The implications of the somatotropic axis in pathological conditions such as GH deficiency, acromegaly or GH insensitivity syndromes are also explored.
2026-03-30 | The IGF-1 senescence switch: a biphasic model for SASP-driven aging and precision senomodulation.
Insulin-like growth factor-1 (IGF-1) signaling plays a paradoxical role in aging, acting as both a mediator of tissue repair and a driver of chronic inflammation through the senescence-associated secretory phenotype (SASP). In this review, we propose a biphasic senescence switch model in which the temporal pattern of IGF-1 exposure, acute versus chronic, determines cellular fate. Transient IGF-1 signaling supports homeostasis and repair, whereas sustained activation promotes stable senescence via reactive oxygen species (ROS)-mediated DNA damage, p53/p21 pathway activation, and a potent pro-inflammatory SASP. Central to this process is IGF-binding protein-5 (IGFBP-5), which amplifies senescence in vascular and stromal cells by linking coagulation and inflammatory signals to p53-dependent arrest. The contrasting human conditions of IGF-1 deficiency (Laron syndrome) and excess (acromegaly) illustrate the lifespan and disease risks associated with dysregulated IGF-1 signaling. Emerging evidence highlights the role of extracellular vesicles in bypassing soluble IGFBP regulation, enabling paracrine propagation of senescence even under systemic IGF-1 modulation. Ultimately, we position the IGF-1/IGFBP axis as a prime target for precision senomodulation, advocating for combined strategies that temporally tune endocrine signaling with senolytic and senomorphic therapies to mitigate chronic inflammation, delay age-related dysfunction, and extend healthspan.
2026-03-25 | A cartilage-targeted IGF-1-antibody fusion protein as a new therapeutic approach for IGF-1 deficiency.
Growth hormone (GH) insensitivity syndrome (GHIS) is a childhood growth disorder characterized by an inability to generate insulin-like growth factor-1 (IGF-1) in response to GH. Consequently, GH therapy is ineffective in patients with GHIS. Patients are often treated with recombinant IGF-1 instead, which requires twice-daily injections and is associated with adverse effects including hypoglycemia. In the current study, we evaluated CV1623-1, a cartilage-targeted antibody-like IGF-1 fusion protein as a potential new treatment for GHIS and for other disorders of linear growth involving IGF-1 deficiency. Using Ghrhrlit mice as a model for IGF-1 deficiency, we found that CV1623-1 stimulated the growth plate at a lower dose and decreased dose frequency compared with IGF-1. Alternate-day injections of CV1623-1 significantly increased body weight, tail length, and tibial bone length. In addition, CV1623-1, unlike IGF-1, did not induce hypoglycemia. Taken together, our findings indicate that CV1623-1 represents a promising new drug candidate for GHIS with improved efficacy, longer duration of action, and reduced hypoglycemia compared with the current treatment, recombinant IGF-1. Preclinical studies and clinical trials would be required to further validate the safety and efficacy of CV1623-1, paving the way for its potential clinical application as a new treatment for GHIS.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
1 orphan drug designation for Laron syndrome.
1 orphan drug designation for Laron syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Recombinant human insulin-like growth factor 1 | proteins | FDA | 1995-06-07 | — | Pharmacia & Upjohn |
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