RARE DISEASE
SHOX-related short stature
SHOX-related short stature
SHOX-related short stature
Drug discovery
1
drug
With orphan designation
Overview
SHOX-related short stature is a genetic disorder caused by mutations or deletions in the SHOX gene, leading to impaired skeletal growth. It manifests as isolated short stature or with skeletal abnormalities (e.g., mesomelia, Madelung deformity) and overlaps with conditions like Leri-Weill dyschondrosteosis and Turner syndrome [1][4][19]. Diagnosis combines clinical evaluation, radiological signs (e.g., triangular radial epiphysis), and genetic testing. Treatment focuses on recombinant human growth hormone (rhGH) to improve adult height [3][13].
Burden
Psychosocial impact due to short stature; functional limitations from skeletal deformities [1][9].
Delayed diagnosis common due to subtle childhood features; ~12 cm mean adult height deficit without treatment [4][19].
Lifetime costs from rhGH therapy (~5–7 years) and orthopedic interventions [3][11].
Therapies
rhGH therapy: Standard dose 0.23 mg/kg/week, improving height by +0.8–1.14 SDS; most effective when initiated early [3][13][17].
Supportive care: Wrist splints, activity modification, and ergonomic tools for skeletal complications [1][11].
Genetic counseling and multidisciplinary management recommended [1][16].
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases
Research Papers
26 drug discovery papers about SHOX-related short stature, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
26 drug discovery papers about SHOX-related short stature, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2025-10-01 | SAT-213 Trial of Vosoritide for Treatment of Short Stature in Turner syndrome: Preliminary Data
Abstract Disclosure: R. Kanakatti Shankar: RKS has received research funding from BioMarin Pharmaceutical Inc., is a consultant for BioMarin, with fees paid to her institution.. N. Shafaei: None. A. Zhang: None. K. Pitner: None. N. Dham: None. A.N. Dauber: AD has received grant funding from BioMarin Pharmaceutical Inc., and is a consultant for BioMarin with fees paid to institution. Turner syndrome (TS) is a genetic condition associated with the absence of whole or part of the second sex chromosome in a phenotypic female. Haploinsufficiency of the SHOX gene on the pseudo autologous region of the sex chromosome is one of the mechanisms of short stature commonly seen in TS and is linked to increased FGFR3 signaling as well as direct effects on the C-type natriuretic peptide (CNP). Vosoritide is a modified recombinant CNP analog that is approved for treatment of short stature in achondroplasia and enhances endochondral bone growth by inhibiting the ERK1/2-MAPK pathway and FGFR3 signaling. Hence, we hypothesized that vosoritide may increase height gain in TS by promoting chondrocyte differentiation and growth. Pre-pubertal girls (ages 3-11 years) with karyotype-confirmed TS <- 2 SD for height are eligible for recruitment to a single center Phase II open label clinical trial of vosoritide if either naïve to growth hormone (GH) or with annualized growth velocity (AGV) of <50%ile for age and sex despite treatment with GH for more than a year. Subjects are excluded if they have chronic medical conditions affecting growth (e.g. untreated celiac disease, inflammatory bowel disease etc.), or hemodynamically severe congenital or acquired cardiovascular disease which places the subject at increased risk of an adverse cardiac outcome in the setting of hypotension. GH is discontinued prior to the screening visit and participants receive daily subcutaneous injections of vosoritide using the weight-based dosing band strategy (approved for achondroplasia). Dose is adjusted for weight at 6 months and followed for a total of 12 months on the trial. The primary outcomes are change in AGV and height SD from baseline (efficacy) and incidence of adverse events (AEs) (safety). We report on preliminary results of the ongoing trial: 4 subjects are enrolled, one failed screen and was excluded from participation; 3 have completed 6 months of treatment. One participant (age 6y) is GH naïve and increased AGV from 4.46cm/year at baseline to 10.5 cm/year at the 6 month visit on vosoritide (+6cm/y), with a height SD increase of +0.5 SD. Participants with prior GH exposure (ages 9 and 10y) increased AGV by +4.9 and +1.57 cm/y at 6 months with vosoritide, over the baseline AGV on GH treatment. Height SD increased by +0.38 and +0.22 respectively for these 2 participants. Vosoritide was well tolerated, with transient injection site erythema/swelling (Grade 1-2) and no subjects discontinued participation due to AEs. There were no episodes of hypotension or serious AEs related to treatment. Data from the 12-month visit are anticipated. Preliminary data are encouraging for safety and efficacy of vosoritide injections in both GH naïve and in previously GH-treated girls with TS to improve height gain in the short term. Longer term data and ongoing enrollment are anticipated to clarify the potential role of vosoritide in TS. Presentation: Saturday, July 12, 2025
2023-05-31 | Integration of nurse-led virtual reviews with growth hormone device-linked patient adherence information: a mixed methods feasibility study
Introduction Easypod-connect™ for childhood growth disorders is a unique connected system that enables transmission of injection adherence information for recombinant human growth hormone (r-hGH). Although this system has the potential to facilitate greater adherence, observational studies have shown declining adherence over prolonged periods when used without additional support. Supplemental nurse practitioner support has been envisaged but not investigated; in this study, we have undertaken feasibility analysis of nurse-led virtual reviews (NVR) in combination with easypod-connect™ in a single centre using quantitative and qualitative analyses. Aims We aimed to test feasibility by assessing compliance with NVR, height standard deviation score (SDS) gain, adherence improvement and patient opinions. Methods Patients using easypod™ r-hGH were recruited prospectively to a 12-month study with two telephone NVR appointments in addition to standard of care in-person hospital outpatient visits. A subset was recruited for a semi-structured interview for qualitative thematic analysis. Results Forty-three patients of median (range) age 10.7 (6.7, 15.2) were recruited for a period of 1.1 (0.7, 1.8) years. Thirty-three (76.7%) patients were fully compliant with NVR integration with easypod-connect™, establishing feasibility. Median (inter-quartile range, IQR) height SDS improved from -1.85 (-2.44, -1.37) to -1.48 (-2.14, -1.07) (p<0.001) while adherence remained similar in the majority from study start [96.5 (88.8, 100.0)] to end [99.0 (94.0, 100.0)]. Qualitative analysis identified themes supporting patient benefit: practicalities of appointments, perceived purpose and significance of virtual reviews, and the importance of optimising growth. Four patients complained of injection pain, of whom two switched to an alternative r-hGH device. Conclusion Our study has demonstrated the feasibility of nurse-led virtual review integration with easypod-connect™ in a mixed methods study, laying the foundation for research in larger groups over longer periods. Nurse practitioner supported application of easypod-connect™ offers the potential for improved growth outcomes in all r-hGH devices providing adherence information.
2022-05-06 | Investigating the Impact of the TUITEK® Patient Support Programme, Designed to Support Caregivers of Children Prescribed Recombinant Human Growth Hormone Treatment in Taiwan
Purpose Poor adherence to recombinant human growth hormone (r-hGH) treatment presents a significant barrier to achieving optimal growth outcomes. It is important to identify and address the treatment adherence-related needs of children prescribed r-hGH treatment, and develop new approaches to improve adherence. We aimed to measure the impact of the TUITEK ® patient support programme, a multi-component personalized service intervention, on caregivers’ knowledge, beliefs, and perceptions of short stature and adherence to its treatment. Patients and Methods The evaluation of the TUITEK ® patient support programme was conducted among 31 caregivers of children with short stature and receiving r-hGH treatment via the easypod™ auto-injector device in Taiwan. Caregivers within the ‘high risk’ category for knowledge, beliefs and perception factors influencing adherence to r-hGH treatment (disease and treatment coherence, emotional burden, self-administration, and treatment-related anxiety) were identified via the TUITEK ® personalization questionnaire and followed up with bi-weekly telephone calls by a nurse practitioner over a 3-month period. A Wilcoxon signed-rank test was used to compare changes in questionnaire-based scoring patterns between baseline and follow-up. Results Between baseline and follow-up, the percentage of caregivers scoring as ‘high risk’ for emotional burden reduced by 37%; there was an improvement in confidence of self-administration by 57% and the percentage of caregivers scoring as ‘high risk’ for treatment-related anxiety reduced by 52%. At follow-up, all caregivers classified as ‘high risk’ within the disease and treatment coherence item at baseline moved into the ‘low risk’ category. Statistically significant changes in questionnaire scores between baseline and follow-up for disease and treatment understanding, emotional burden, self-administration, and treatment-related anxiety were also observed. Conclusion These findings indicate that the TUITEK ® patient support programme can positively address disease and treatment-related barriers amongst caregivers regarding optimal adherence of their children to r-hGH treatment, which has the potential to positively impact on adherence levels and patient clinical health outcomes.
2021-07-01 | Non-GH Agents and Novel Therapeutics in the Management of Short Stature
Short stature is one of the most common reasons for referral to pediatric endocrinologists. The vast majority of short children do not have growth hormone (GH) deficiency or another pathologic process that is interfering with normal growth. While GH has been approved in the US for several etiologies of non-GH deficient short stature, its high cost and need for daily injections represent barriers for many families. Alternative agents for the management of short stature include the use of gonadotropin releasing hormone analogs (GnRHas) to delay puberty, and aromatase inhibitors (AIs) in boys to postpone epiphyseal fusion. The results of studies employing GnRHas as either monotherapy or combined with GH are mixed, and there is a dearth of rigorously designed clinical trials that have followed patients to adult height. While AIs have been found to result in modest increases in adult height in some studies, important questions about their long-term safety exist. The C-type natriuretic peptide analog vosoritide is an experimental agent that is emerging as a potential treatment for a few specific conditions including achondroplasia, although its efficacy in attenuating disproportionality is as yet unproven. While each of these therapeutic strategies holds promise, none are currently considered standard of care and several important questions remain. These include the impact of these interventions on quality of life as well as long-term outcomes.
2020-04-03 | Identifying therapeutic drug targets for rare and common forms of short stature
Abstract While GWAS of common diseases has delivered thousands of novel genetic findings, prioritizing genes for translation to therapeutics has been challenging. Here, we propose an approach to resolve that issue by identifying genes that have both gain of function (GoF) and loss of function (LoF) mutations associated with opposing effects on phenotype (Bidirectional Effect Selected Targets, BEST). Bidirectionality is a desirable feature of the best targets because it implies both a causal role on the phenotype in one direction and that modulating the target activity might be safe and therapeutically beneficial in the other. We used height, a highly heritable trait and a model of complex diseases, to test our approach. Using 34,231 individuals with exome sequence data and height, we identified five genes ( IGF1R, NPPC, NPR2, FGFR3 , and SHOX ) with evidence for bidirectional effects on stature. Rare protein-altering variants significantly increased risk for idiopathic short stature (ISS) (OR=2.75, p= 3.99×10 −8 ). These genes are key members of the only two pathways successfully targeted for short stature: Growth Hormone/Insulin-like growth factor 1 axis and C-type Natriuretic peptide (CNP) for Achondroplasia, a monogenic form of dwarfism. We assayed a subset of NPR2 mutations and identified those with elevated (GoF) and diminished (LoF) activity and found that a polygenic score for height modulates the penetrance of pathogenic variants. We also demonstrated that adding exogenous CNP (encoded by NPPC ) rescues the NPR2 haploinsufficiency molecular phenotype in a CRISPR-engineered cell line, thus validating its potential therapeutic treatment for inherited forms of short stature. Finally, we found that these BEST targets increase the probability of success in clinical trials above and beyond targets with other genetic evidence. Our results show the value of looking for bidirectional effects to identify and validate drug targets.
proteins
2025-10-01 | SAT-213 Trial of Vosoritide for Treatment of Short Stature in Turner syndrome: Preliminary Data
Abstract Disclosure: R. Kanakatti Shankar: RKS has received research funding from BioMarin Pharmaceutical Inc., is a consultant for BioMarin, with fees paid to her institution.. N. Shafaei: None. A. Zhang: None. K. Pitner: None. N. Dham: None. A.N. Dauber: AD has received grant funding from BioMarin Pharmaceutical Inc., and is a consultant for BioMarin with fees paid to institution. Turner syndrome (TS) is a genetic condition associated with the absence of whole or part of the second sex chromosome in a phenotypic female. Haploinsufficiency of the SHOX gene on the pseudo autologous region of the sex chromosome is one of the mechanisms of short stature commonly seen in TS and is linked to increased FGFR3 signaling as well as direct effects on the C-type natriuretic peptide (CNP). Vosoritide is a modified recombinant CNP analog that is approved for treatment of short stature in achondroplasia and enhances endochondral bone growth by inhibiting the ERK1/2-MAPK pathway and FGFR3 signaling. Hence, we hypothesized that vosoritide may increase height gain in TS by promoting chondrocyte differentiation and growth. Pre-pubertal girls (ages 3-11 years) with karyotype-confirmed TS <- 2 SD for height are eligible for recruitment to a single center Phase II open label clinical trial of vosoritide if either naïve to growth hormone (GH) or with annualized growth velocity (AGV) of <50%ile for age and sex despite treatment with GH for more than a year. Subjects are excluded if they have chronic medical conditions affecting growth (e.g. untreated celiac disease, inflammatory bowel disease etc.), or hemodynamically severe congenital or acquired cardiovascular disease which places the subject at increased risk of an adverse cardiac outcome in the setting of hypotension. GH is discontinued prior to the screening visit and participants receive daily subcutaneous injections of vosoritide using the weight-based dosing band strategy (approved for achondroplasia). Dose is adjusted for weight at 6 months and followed for a total of 12 months on the trial. The primary outcomes are change in AGV and height SD from baseline (efficacy) and incidence of adverse events (AEs) (safety). We report on preliminary results of the ongoing trial: 4 subjects are enrolled, one failed screen and was excluded from participation; 3 have completed 6 months of treatment. One participant (age 6y) is GH naïve and increased AGV from 4.46cm/year at baseline to 10.5 cm/year at the 6 month visit on vosoritide (+6cm/y), with a height SD increase of +0.5 SD. Participants with prior GH exposure (ages 9 and 10y) increased AGV by +4.9 and +1.57 cm/y at 6 months with vosoritide, over the baseline AGV on GH treatment. Height SD increased by +0.38 and +0.22 respectively for these 2 participants. Vosoritide was well tolerated, with transient injection site erythema/swelling (Grade 1-2) and no subjects discontinued participation due to AEs. There were no episodes of hypotension or serious AEs related to treatment. Data from the 12-month visit are anticipated. Preliminary data are encouraging for safety and efficacy of vosoritide injections in both GH naïve and in previously GH-treated girls with TS to improve height gain in the short term. Longer term data and ongoing enrollment are anticipated to clarify the potential role of vosoritide in TS. Presentation: Saturday, July 12, 2025
2023-05-31 | Integration of nurse-led virtual reviews with growth hormone device-linked patient adherence information: a mixed methods feasibility study
Introduction Easypod-connect™ for childhood growth disorders is a unique connected system that enables transmission of injection adherence information for recombinant human growth hormone (r-hGH). Although this system has the potential to facilitate greater adherence, observational studies have shown declining adherence over prolonged periods when used without additional support. Supplemental nurse practitioner support has been envisaged but not investigated; in this study, we have undertaken feasibility analysis of nurse-led virtual reviews (NVR) in combination with easypod-connect™ in a single centre using quantitative and qualitative analyses. Aims We aimed to test feasibility by assessing compliance with NVR, height standard deviation score (SDS) gain, adherence improvement and patient opinions. Methods Patients using easypod™ r-hGH were recruited prospectively to a 12-month study with two telephone NVR appointments in addition to standard of care in-person hospital outpatient visits. A subset was recruited for a semi-structured interview for qualitative thematic analysis. Results Forty-three patients of median (range) age 10.7 (6.7, 15.2) were recruited for a period of 1.1 (0.7, 1.8) years. Thirty-three (76.7%) patients were fully compliant with NVR integration with easypod-connect™, establishing feasibility. Median (inter-quartile range, IQR) height SDS improved from -1.85 (-2.44, -1.37) to -1.48 (-2.14, -1.07) (p<0.001) while adherence remained similar in the majority from study start [96.5 (88.8, 100.0)] to end [99.0 (94.0, 100.0)]. Qualitative analysis identified themes supporting patient benefit: practicalities of appointments, perceived purpose and significance of virtual reviews, and the importance of optimising growth. Four patients complained of injection pain, of whom two switched to an alternative r-hGH device. Conclusion Our study has demonstrated the feasibility of nurse-led virtual review integration with easypod-connect™ in a mixed methods study, laying the foundation for research in larger groups over longer periods. Nurse practitioner supported application of easypod-connect™ offers the potential for improved growth outcomes in all r-hGH devices providing adherence information.
2022-05-06 | Investigating the Impact of the TUITEK® Patient Support Programme, Designed to Support Caregivers of Children Prescribed Recombinant Human Growth Hormone Treatment in Taiwan
Purpose Poor adherence to recombinant human growth hormone (r-hGH) treatment presents a significant barrier to achieving optimal growth outcomes. It is important to identify and address the treatment adherence-related needs of children prescribed r-hGH treatment, and develop new approaches to improve adherence. We aimed to measure the impact of the TUITEK ® patient support programme, a multi-component personalized service intervention, on caregivers’ knowledge, beliefs, and perceptions of short stature and adherence to its treatment. Patients and Methods The evaluation of the TUITEK ® patient support programme was conducted among 31 caregivers of children with short stature and receiving r-hGH treatment via the easypod™ auto-injector device in Taiwan. Caregivers within the ‘high risk’ category for knowledge, beliefs and perception factors influencing adherence to r-hGH treatment (disease and treatment coherence, emotional burden, self-administration, and treatment-related anxiety) were identified via the TUITEK ® personalization questionnaire and followed up with bi-weekly telephone calls by a nurse practitioner over a 3-month period. A Wilcoxon signed-rank test was used to compare changes in questionnaire-based scoring patterns between baseline and follow-up. Results Between baseline and follow-up, the percentage of caregivers scoring as ‘high risk’ for emotional burden reduced by 37%; there was an improvement in confidence of self-administration by 57% and the percentage of caregivers scoring as ‘high risk’ for treatment-related anxiety reduced by 52%. At follow-up, all caregivers classified as ‘high risk’ within the disease and treatment coherence item at baseline moved into the ‘low risk’ category. Statistically significant changes in questionnaire scores between baseline and follow-up for disease and treatment understanding, emotional burden, self-administration, and treatment-related anxiety were also observed. Conclusion These findings indicate that the TUITEK ® patient support programme can positively address disease and treatment-related barriers amongst caregivers regarding optimal adherence of their children to r-hGH treatment, which has the potential to positively impact on adherence levels and patient clinical health outcomes.
2021-07-01 | Non-GH Agents and Novel Therapeutics in the Management of Short Stature
Short stature is one of the most common reasons for referral to pediatric endocrinologists. The vast majority of short children do not have growth hormone (GH) deficiency or another pathologic process that is interfering with normal growth. While GH has been approved in the US for several etiologies of non-GH deficient short stature, its high cost and need for daily injections represent barriers for many families. Alternative agents for the management of short stature include the use of gonadotropin releasing hormone analogs (GnRHas) to delay puberty, and aromatase inhibitors (AIs) in boys to postpone epiphyseal fusion. The results of studies employing GnRHas as either monotherapy or combined with GH are mixed, and there is a dearth of rigorously designed clinical trials that have followed patients to adult height. While AIs have been found to result in modest increases in adult height in some studies, important questions about their long-term safety exist. The C-type natriuretic peptide analog vosoritide is an experimental agent that is emerging as a potential treatment for a few specific conditions including achondroplasia, although its efficacy in attenuating disproportionality is as yet unproven. While each of these therapeutic strategies holds promise, none are currently considered standard of care and several important questions remain. These include the impact of these interventions on quality of life as well as long-term outcomes.
2020-04-03 | Identifying therapeutic drug targets for rare and common forms of short stature
Abstract While GWAS of common diseases has delivered thousands of novel genetic findings, prioritizing genes for translation to therapeutics has been challenging. Here, we propose an approach to resolve that issue by identifying genes that have both gain of function (GoF) and loss of function (LoF) mutations associated with opposing effects on phenotype (Bidirectional Effect Selected Targets, BEST). Bidirectionality is a desirable feature of the best targets because it implies both a causal role on the phenotype in one direction and that modulating the target activity might be safe and therapeutically beneficial in the other. We used height, a highly heritable trait and a model of complex diseases, to test our approach. Using 34,231 individuals with exome sequence data and height, we identified five genes ( IGF1R, NPPC, NPR2, FGFR3 , and SHOX ) with evidence for bidirectional effects on stature. Rare protein-altering variants significantly increased risk for idiopathic short stature (ISS) (OR=2.75, p= 3.99×10 −8 ). These genes are key members of the only two pathways successfully targeted for short stature: Growth Hormone/Insulin-like growth factor 1 axis and C-type Natriuretic peptide (CNP) for Achondroplasia, a monogenic form of dwarfism. We assayed a subset of NPR2 mutations and identified those with elevated (GoF) and diminished (LoF) activity and found that a polygenic score for height modulates the penetrance of pathogenic variants. We also demonstrated that adding exogenous CNP (encoded by NPPC ) rescues the NPR2 haploinsufficiency molecular phenotype in a CRISPR-engineered cell line, thus validating its potential therapeutic treatment for inherited forms of short stature. Finally, we found that these BEST targets increase the probability of success in clinical trials above and beyond targets with other genetic evidence. Our results show the value of looking for bidirectional effects to identify and validate drug targets.
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 SHOX-related short stature, including 1 approved therapy.
1 orphan drug designation for SHOX-related short stature, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Somatropin [Humatrope] | proteins | FDA | Approved | Eli Lilly and Company |
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