RARE DISEASE
Growth hormone insensitivity syndrome
Growth hormone insensitivity syndrome
Growth hormone insensitivity syndrome
Synonyms: GHIS, Short stature due to a defect in growth hormone receptor or post-receptor pathway
Synonyms: GHIS, Short stature due to a defect in growth hormone receptor or post-receptor pathway
Synonyms: GHIS, Short stature due to a defect in growth hormone receptor or post-receptor pathway
Drug discovery
5
drugs
With orphan designations
Overview
Growth hormone insensitivity syndrome (GHIS) encompasses rare genetic disorders characterized by severe short stature despite normal/elevated GH levels, due to defects in GH receptor signaling or downstream pathways like IGF-1 production [1][6][17]. Key features include facial dysmorphism, delayed puberty, and metabolic complications [1][6]. Diagnosis relies on hormonal profiling (low IGF-1, high GH) and genetic testing [1][17]. Treatment primarily involves recombinant IGF-1 (mecasermin) [1][13].
Categories: rare endocrine diseases, rare genetic diseases
Research Papers
208 drug discovery papers about Growth hormone insensitivity syndrome, with 2 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
208 drug discovery papers about Growth hormone insensitivity syndrome, with 2 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-13 | Novel NPR2 heterozygous variant in a familial short stature and the therapeutic response to rhGH: a case report.
Natriuretic peptide receptor 2 (NPR2) expression in the hypertrophic zone of the growth plate is essential for endochondral ossification. Heterozygous variants in the NPR2 gene have been identified in 2-6 % of idiopathic short stature cases. Here, we present a large family with a novel heterozygous NPR2 variant, detailing endocrine features and long-term recombinant human growth hormone (rhGH) therapy outcomes. A total of 18 subjects among the family exhibited short stature. The proband was a 5.2-year-old boy presenting with proportionate short stature, delayed bone age, facial abnormalities, premature delivery, small for gestational age and hypospadias. Whole-exome sequencing revealed a novel heterozygous variant, c.553G>A variant, in the NPR2 gene, leading to the missense variant site in the extracellular ligand-binding domain of NPR2 protein. All the family members with NPR2 gene mutation demonstrated marked short stature, except for four subjects. Five other children who received rhGH therapy were also included in the results. The difference between bone age and chronological age in all six children ranged from -2.3 to 0 years. The average height SDS before rhGH treatment ranged from -4.01 to -1.20 (-2.59 ± 1.16). The treatment has lasted for 4.68 ± 2.68 years, and height SDS improved by 1.54 ± 0.78 after rhGH therapy. Our study confirms NPR2 variants as a cause of familial short stature (FSS), with variability in phenotypes, clinical features, and rhGH response, even within families. Early genetic testing might be crucial for offspring with FSS, as it allows for timely initiation of rhGH therapy.
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.
2026-05-01 | Growth hormone receptor blockade in cancer treatment.
Cancer remains as the most feared human disease and embodies deep psychological and physical suffering (1). It is one of the unsolved medical problems nowadays and constitutes a heavy burden not only for the individual and his family but also for health systems worldwide (2). In this context, cancer prevention and early diagnosis and treatment is of cardinal importance; hence, identification of cancer risk factors in the genesis of human cancer is an urgent necessity. Among these deleterious influences, obesity and aberrantly increased growth hormone receptor (GHR) signaling have been identified as two of the most relevant factors in the etiology of malignancy (3, 4). Considering the above premises, attempts at effectively and safely treating patients with cancer are within the noblest aims in medicine and science. At present, radical surgery, radio and chemotherapy, targeted therapy, and immunotherapy are the basis for dealing with this widespread issue (5). Nevertheless, and especially in several types of cancer, all efforts are ineffective (6). In consequence, strategies to discover new medicines aimed at safely and effectively treating individuals affected by cancer are needed. Similarly, adjuvant methods aimed at making more effective use of standard therapies are required. Contextually, a new experimental approach to dealing with melanoma, liver cancer, pancreatic cancer, and cholangiocarcinoma, some of the most lethal malignancies in humans, has been developed based on the previous discovery of a GHR antagonist used for acromegaly and its mode of action (7, 8). Development of new drugs for cancer treatment is partially based on observations in humans who have a distinct phenotype that combines obesity -the most epidemiologic risk factor in cancer etiology- along with absent growth hormone receptor (GHR) signaling (4, 9).
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.
2026-07-13 | Novel NPR2 heterozygous variant in a familial short stature and the therapeutic response to rhGH: a case report.
Natriuretic peptide receptor 2 (NPR2) expression in the hypertrophic zone of the growth plate is essential for endochondral ossification. Heterozygous variants in the NPR2 gene have been identified in 2-6 % of idiopathic short stature cases. Here, we present a large family with a novel heterozygous NPR2 variant, detailing endocrine features and long-term recombinant human growth hormone (rhGH) therapy outcomes. A total of 18 subjects among the family exhibited short stature. The proband was a 5.2-year-old boy presenting with proportionate short stature, delayed bone age, facial abnormalities, premature delivery, small for gestational age and hypospadias. Whole-exome sequencing revealed a novel heterozygous variant, c.553G>A variant, in the NPR2 gene, leading to the missense variant site in the extracellular ligand-binding domain of NPR2 protein. All the family members with NPR2 gene mutation demonstrated marked short stature, except for four subjects. Five other children who received rhGH therapy were also included in the results. The difference between bone age and chronological age in all six children ranged from -2.3 to 0 years. The average height SDS before rhGH treatment ranged from -4.01 to -1.20 (-2.59 ± 1.16). The treatment has lasted for 4.68 ± 2.68 years, and height SDS improved by 1.54 ± 0.78 after rhGH therapy. Our study confirms NPR2 variants as a cause of familial short stature (FSS), with variability in phenotypes, clinical features, and rhGH response, even within families. Early genetic testing might be crucial for offspring with FSS, as it allows for timely initiation of rhGH therapy.
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.
2026-05-01 | Growth hormone receptor blockade in cancer treatment.
Cancer remains as the most feared human disease and embodies deep psychological and physical suffering (1). It is one of the unsolved medical problems nowadays and constitutes a heavy burden not only for the individual and his family but also for health systems worldwide (2). In this context, cancer prevention and early diagnosis and treatment is of cardinal importance; hence, identification of cancer risk factors in the genesis of human cancer is an urgent necessity. Among these deleterious influences, obesity and aberrantly increased growth hormone receptor (GHR) signaling have been identified as two of the most relevant factors in the etiology of malignancy (3, 4). Considering the above premises, attempts at effectively and safely treating patients with cancer are within the noblest aims in medicine and science. At present, radical surgery, radio and chemotherapy, targeted therapy, and immunotherapy are the basis for dealing with this widespread issue (5). Nevertheless, and especially in several types of cancer, all efforts are ineffective (6). In consequence, strategies to discover new medicines aimed at safely and effectively treating individuals affected by cancer are needed. Similarly, adjuvant methods aimed at making more effective use of standard therapies are required. Contextually, a new experimental approach to dealing with melanoma, liver cancer, pancreatic cancer, and cholangiocarcinoma, some of the most lethal malignancies in humans, has been developed based on the previous discovery of a GHR antagonist used for acromegaly and its mode of action (7, 8). Development of new drugs for cancer treatment is partially based on observations in humans who have a distinct phenotype that combines obesity -the most epidemiologic risk factor in cancer etiology- along with absent growth hormone receptor (GHR) signaling (4, 9).
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
5 orphan drug designations for Growth hormone insensitivity syndrome, including 2 approved therapies.
5 orphan drug designations for Growth hormone insensitivity syndrome, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Mecasermin rinfabate [IPLEX] | proteins | EMA | 2006-06-20 | — | [INACTIVE] Insmed Europe Limited |
Mecasermin | proteins | EMA | 2005-08-26 | — | Ipsen Pharma |
Mecasermin rinfabate [Iplex] | proteins | EMA | 2003-07-09 | — | [INACTIVE] Insmed Europe Limited |
mecasermin rinfabate [Iplex] | proteins | FDA | 2002-05-17 | 2005-12-12 | Insmed, Inc. |
Mecasermin [Increlex] | proteins | FDA | 1995-12-12 | 2005-08-30 | Eton Pharmaceuticals, Inc. |
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