OBJECTIVE:To synthesize current evidence on genetic testing yield in children with short stature and to identify phenotypic and methodological factors influencing outcomes. The review served as a basis for the development of a consensus guideline on genetic evaluation of short stature. DESIGN:Systematic review. METHODS:Diagnostic yields were calculated by testing modality and clinical characteristics of study cohorts. Results were compared across time periods and recalculated excluding variants of uncertain significance (VUS). Phenotypic features associated with higher yields and the most frequently implicated genes were also analyzed. RESULTS:Out of 1163 records, 134 studies were included. The overall diagnostic yield was 4.7% for candidate gene testing (n = 78), 16.3% for chromosomal microarray (n = 8), 21.6% for gene panels (n = 14), and 33.3% for exome sequencing (ES) (n = 39). After exclusion of VUS, the reestimated yields were lower for all approaches. ES approaches yielded higher diagnostic rates in syndromic short stature (50.8%, n = 15) compared to isolated short stature (15.1%, n = 13). Among 45 studies evaluating predictive factors, facial dysmorphism (68.2%) and skeletal abnormalities (61.1%) were most strongly associated with increased diagnostic yield. Recurrently identified genes included PTPN11, NF1, COL2A1, ACAN, and FGFR3. CONCLUSIONS:Genetic testing substantially improves the diagnostic process in children with isolated and syndromic short stature. Diagnostic yield varies by testing modality and phenotype, with higher rates observed using comprehensive genomic methods and in individuals with dysmorphic or syndromic features. Frequently implicated genes highlight common biological pathways involved in growth regulation, underscoring the utility of genetic evaluation in this population.

Short stature may be caused by a multitude of conditions, including genetic and non-genetic causes. Over the last decade, advances in genetic sequencing technologies have revolutionized our understanding of the underlying physiology of growth and greatly increased our ability to identify genetic etiologies of short stature. The current guideline provides a general overview of the approach to the evaluation of a child with short stature, followed by recommendations identifying factors in the medical and family history, physical examination, radiographic, and laboratory work up which increase the likelihood of identifying a genetic etiology. An algorithm is proposed for the genetic workup of individuals with short stature based on their clinical presentation. The benefits and risks of genetic testing are discussed as well.

Background Hypochondroplasia is a skeletal dysplasia characterized by disproportionate short stature that is caused by gain-of-function variants in the fibroblast growth factor receptor 3 gene ( FGFR3 ), which negatively regulates endochondral bone growth. Current treatments are based on symptom management; there are no treatments targeting the signaling pathways that underlie hypochondroplasia. Vosoritide, a C-type natriuretic peptide analog that counteracts overactive FGFR3 signaling to stimulate endochondral bone growth, is approved for the treatment of achondroplasia in children. A phase 1/2 clinical trial demonstrated that vosoritide treatment for 1 year increased growth in children with hypochondroplasia and was well-tolerated. Objectives The objectives of CANOPY HCH-3 are to evaluate the efficacy and safety of vosoritide for the treatment of hypochondroplasia in children. Design CANOPY HCH-3 was a phase 3, randomized, double-blind, placebo-controlled, multicenter study. Methods and Analysis Children aged ≥3 to <18 years with confirmed hypochondroplasia who had ≥6 months of pre-treatment standing height from a prior observational study before randomization were enrolled. Participants were randomized to receive 52 weeks of daily treatment with vosoritide or placebo, followed by 2 weeks of safety follow-up. The primary endpoint is change from baseline in annualized growth velocity at week 52 versus placebo. Ethics CANOPY HCH-3 was conducted in accordance with the Council for International Organizations of Medical Sciences International Ethical Guidelines, the principles of the Declaration of Helsinki and of Good Clinical Practice, and applicable laws and regulations. Protocols were approved by relevant local health authorities, ethics committees, and institutions. Written informed consent from the participant, or parent or legal guardian, was obtained prior to any study-related procedures being performed. Discussion CANOPY HCH-3 will provide further evidence for the efficacy and safety of vosoritide in children with hypochondroplasia.

Hypochondroplasia is a skeletal dysplasia caused by pathogenic variants in FGFR3 and characterized by disproportionate short stature and relative macrocephaly. Diagnostic uncertainty remains common, particularly in early childhood and in individuals with mild or atypical presentations, leading to delayed diagnosis, inconsistent management, and challenges in counselling and care planning. Individuals can be affected by medical complications and psychosocial consequences and have unmet needs for multidisciplinary care. To address these unmet needs, an international, multidisciplinary panel of experts and patient representatives convened to develop consensus-based diagnostic recommendations using a modified two-stage Delphi approach, with a predefined consensus threshold of 70% of respondents rating statements ≥70 (on a scale of 0 to 100). The panel integrated clinical, anthropometric, radiographic, neuroimaging and genetic criteria to define diagnostic categories that can be applied across diverse health-care settings globally. Major and minor diagnostic criteria are proposed, alongside guidance on the appropriate use of molecular testing, radiographic evaluation and brain magnetic resonance imaging. These recommendations provide a practical framework to help standardize timely and accurate diagnosis of hypochondroplasia in clinical practice and research.

IntroductionHypochondroplasia (HCH) is a disproportionate short-statured skeletal dysplasia condition caused by gain-of-function pathogenic variants in the fibroblast growth receptor 3 gene (FGFR3). Although HCH typically becomes clinically apparent after the first year of life, when height discrepancy compared with the general population becomes more pronounced, diagnosis is often delayed by several years. Early recognition of HCH is challenging because of wide phenotypic variability and subtle clinical and radiographic features, leading to delayed or missed diagnosis. Furthermore, wide variant heterogeneity and restrictive testing criteria can contribute to diagnostic delays. Early diagnosis may facilitate timely clinical management and psychosocial support. However, no standardized diagnostic criteria for HCH currently exist, nor are diagnostic pathways well described in the literature.MethodsIn October 2024, 14 experts across multiple specialties completed an online survey on current clinical practices for diagnosing HCH. A subset convened in person to discuss strategies to optimize clinical diagnostic pathways, which were subsequently refined by the collective group.ResultsAge-specific diagnostic opportunities were identified. Prenatally, sonographic features of HCH may be detectable from approximately 20 weeks' gestation. Postnatally, features suggestive of HCH include a sustained fall in length/height centiles over the first 2 years of life, relative macrocephaly, neonatal seizures, and specific radiographic and neuroimaging findings. Between ages 2-3 years, a characteristic growth pattern including limb shortening and body disproportion may become evident. Neurocognitive involvement including neurodevelopmental challenges may become apparent. HCH should be considered in the differential diagnosis of idiopathic or isolated short stature. Genetic testing panels that include FGFR3 and evaluation of short-statured parents can support diagnosis.ConclusionEarly diagnosis of HCH is achievable when age-specific key clinical and radiologic features are recognized and supported by molecular testing using appropriate diagnostic platforms. This work represents an important first step towards developing consensus-based diagnostic guidelines for HCH.

OBJECTIVE:Daily growth hormone (GH) injections restore normal growth and improve psychological outcomes in children with idiopathic short stature (ISS) but treatment burden is significant. The objective of this study is to demonstrate efficacy and safety of once-weekly somapacitan, a long-acting GH, in children with ISS. DESIGN:REAL8 (ClinicalTrials.gov: NCT05330325) is a global, randomized, open-labelled, active-comparator, phase 3 basket study including 4 non-GH deficiency indications comprising a 52-week main phase and 104-week extension. Here, we present 52-week results from the REAL8 ISS study. METHODS:Eighty-eight pre-pubertal, treatment-naive children with ISS at clinics in 20 countries were randomized 2:1 to somapacitan .24 mg/kg/week or daily GH 0.050 mg/kg/day, both administered subcutaneously. Eighty-five children completed the main 52-week treatment period. RESULTS:Observed mean height velocity, HV, (SD) at week 52 was 10.2 (1.7) and 10.6 (1.6) cm/year for somapacitan and daily GH groups, respectively (estimated treatment difference [ETD]: -0.3 cm/year [-1.00;0.42]95%CI, non-inferiority confirmed). Safety profiles were similar (somapacitan: 191 events in 47 (79.7%) participants, daily GH: 87 events in 22 (78.6%) participants) with most adverse events (AEs) mild and unlikely related to study product. Disease and treatment burden questionnaires presented favourable results. CONCLUSIONS:Similar efficacy and safety were confirmed for once-weekly somapacitan versus daily GH in treatment-naïve children with ISS, with favourable patient-reported outcome measures, setting the ground for future treatment for ISS with a once-weekly option. CLINICAL STUDY REGISTRATION:NCT05330325.

BACKGROUND:Hypochondroplasia, a fibroblast growth factor receptor 3 (FGFR3)-related skeletal condition characterized by disproportionate short stature and a spectrum of clinical features, has no available targeted therapies. Vosoritide, a C-type natriuretic peptide analogue approved for the treatment of achondroplasia, is being investigated for hypochondroplasia. METHODS:In this phase 3, multicenter trial, children with hypochondroplasia who were 3 to less than 18 years of age were randomly assigned to receive once-daily subcutaneous injections of vosoritide or placebo for 52 weeks per weight-band dosing regimen. The primary end point was change from baseline in annualized growth velocity at week 52 versus placebo. Confirmatory statistical testing using hierarchical procedures to control for type I error at the one-sided 0.025 significance level (equivalent to the two-sided 0.05 level) was performed for the primary and six key secondary efficacy end points. The safety and side effect profile of vosoritide versus placebo was assessed. RESULTS:A total of 81 participants were randomly assigned to receive vosoritide (n=41) or placebo (n=40). At week 52, the least squares mean (LSM) change from baseline in annualized growth velocity was 1.95 cm/year with vosoritide versus -0.39 cm/year with placebo (LSM difference of 2.33 cm/year; 95% confidence interval, 1.85-2.82 cm/year; two-sided P<0.0001). Most participants in the vosoritide group (87.8%) and the placebo group (72.5%) experienced at least one adverse event (AE). There were no reports of grade 3 or higher AEs, AEs leading to treatment discontinuation, or deaths. CONCLUSIONS:One year of vosoritide treatment significantly increased linear growth in children with hypochondroplasia. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT06455059.).

CONTEXT:Classic congenital adrenal hyperplasia (CAH) is a rare genetic condition characterized by impaired cortisol and aldosterone synthesis. Historical management required glucocorticoid (GC) therapy to replace cortisol and, often, to suppress excess ACTH and adrenal androgens. However, supraphysiologic GC doses can lead to substantial complications. OBJECTIVE:This study aimed to characterize the clinical burden associated with CAH and quantify the degree to which CAH- and/or GC-related complications manifest. METHODS:Retrospective cohort analyses were conducted using administrative claims data from MarketScan® Research Databases (1/1/2020-12/31/2022) to quantify the burden of CAH- and/or GC-related complications among insured patients with CAH in the United States compared with a matched cohort. RESULTS:A total of 719 patients with CAH receiving GC therapy were matched 1:5 with 3595 individuals based on age, sex, payer, region, and enrollment duration. Patients with CAH had significantly higher rates of predominantly GC-related complications, including cardiovascular/circulatory diseases, type 2 diabetes, hypertension, hyperglycemia, metabolic complications, obesity, and osteoporosis (all P < .05). Patients with CAH demonstrated significantly higher rates and risks of nearly all CAH-related complications compared with matched controls (P < .05). Rates and risks of nearly all complications categorized as both CAH- and GC-related were significantly higher among patients with CAH (P < .05). Rates were consistently higher in adults than pediatric patients, underscoring the progressive and cumulative nature of CAH- and GC-related morbidity. CONCLUSION:Individuals with CAH experience higher rates and risks of CAH- and/or GC-related complications, highlighting the considerable burden associated with CAH and supraphysiologic GC treatment. Higher complication rates in adults emphasize the need for early and effective management of CAH. Novel non-GC therapies may enable GC dose reduction while maintaining androgen control, potentially mitigating these complications.

INTRODUCTION:Vosoritide is a C-type natriuretic peptide analog approved for treatment of children with achondroplasia with established safety and efficacy. We report slipped capital femoral epiphysis (SCFE) as a treatment-emergent serious adverse event in two prospective clinical trials of vosoritide for individuals with genetic forms of short stature. CASE REPORT:We report 5 participants from two investigator-initiated, single center, phase II, prospective, open label clinical trials of vosoritide (NCT04219007 Basket trial including patients with RASopathies, Aggrecan mutations (ACAN) and NPR2 deficiency and NCT05849389 in girls with Turner syndrome) who developed SCFE. In the basket trial, SCFE was observed in 2/12 participants with ACAN mutations, 1/11 with RASopathy but not in the 7 participants with NPR2 mutations or 24 with hypochondroplasia. In the Turner syndrome trial, 2/5 participants receiving vosoritide developed SCFE. All 5 participants who developed SCFE had received >12 months of treatment and presented with the rare valgus type of SCFE. CONCLUSION:Vosoritide treatment may be associated with a higher risk of SCFE in some individuals with genetic forms of short stature such as Turner syndrome and Aggrecan mutations. The causal mechanisms and contributory factors to the predisposition for valgus deformities noted with vosoritide therapy in children with these genetic conditions warrant further study.

INTRODUCTION:Collagen X biomarker (CXM) is a by-product of type X collagen that is deposited in the hypertrophic zones of growth plates and released during endochondral ossification. Prior studies have shown a correlation between annualized height velocity (AHV) and CXM values as well as between change in CXM in relation to change in AHV over time. We aim to test these correlations in children undergoing growth hormone (GH) therapy, and to evaluate whether short-term changes in CXM at 4 weeks post treatment initiation predict first year growth response to treatment. METHODS:We conducted a prospective noninterventional study of GH-naïve patients, >3 years old who were about to start GH therapy (any formulation under any indication). We collected historical heights from 6 to 18 months prior to enrollment, along with anthropometrics, CXM (measured by ELISA in serum) and IGF-1 values at enrollment, 4, 12, and 52 weeks post GH start. Normality of dependent variable (AHV or change in AHV) was tested using the Shapiro-Wilk normality test and a visual inspection of histograms. Linear regression models were used to assess each relationship. Due to a limited sample size, interactions were not assessed. RESULTS:A total of 28 patients (9 females, 12 with GH deficiency, 5 with idiopathic short stature [ISS], 3 SGA, 3 SHOX, 2 Turner syndrome, 3 other) were enrolled and followed for the duration of the study. Mean age was 9.12 years with height Z score of -2.28 at baseline. AHV increased from 4.85 cm/y at baseline to 8.69 cm/y after treatment, and CXM increased from 19.11 ng/mL to 25.04 ng/mL after 52 weeks. Baseline CXM at enrollment was associated with baseline AHV (slope = 0.117; 95% CI 0.044-0.019; p = 0.002). However, the same was not true when looking at CXM values at 52 weeks in relation to the treatment AHV (slope = 0.024; 95% CI (-0.046 - 0.094); p = 0.52). Change in CXM from baseline to 4 (slope = 0.017; 95% CI -0.168 - 0.201); p = 0.86) or 52 weeks (slope = 0.03; (-0.081 - 0.148); p = 0.57) was also not predictive of change in AHV over 52 weeks despite adjusting for sex and age. CONCLUSION:Our study confirms prior findings of CXM correlating with baseline AHV. However, that correlation was not significant during the 1 year of GH therapy. This is possibly due to multiple cofounders including differences in GH dosing, underlying diagnoses, and inability to confirm universal adherence to therapy, with some subjects having prolonged pauses in therapy for different reasons. Short-term change in CXM did not accurately predict growth response. Future prospective studies of a larger scale would be needed to investigate the role of CXM as a surrogate for GH therapy response.

CONTEXT:Insulin-like growth factor-1 (IGF-1) and C-type natriuretic peptide (CNP) promote endochondral bone growth. We previously reported that vosoritide, a CNP analogue, increases annualized growth velocity (AGV) and height SD in prepubertal children with hypochondroplasia (HCH). OBJECTIVE:We hypothesized that IGF-1 and CNP will be inversely associated at baseline and will respond differentially during a single-arm, unblinded, standardized 12-month phase 2 clinical trial of vosoritide in prepubertal patients aged 3 to 11 years with HCH and height less than -2.25 SD. Participants were followed for a baseline 6-month observation period and then received a dose of 15 μg/kg/day of vosoritide subcutaneous daily injections for 12 months. Anthropometrics, IGF-1, and NTproCNP were measured every 6 months. Longitudinal changes in IGF-1 and NTproCNP as well as the correlations between these 2 analytes and changes in height SD and AGV were analyzed. RESULTS:Baseline IGF-1 values are reduced in children with HCH and increased throughout the study, but IGF-1 SD did not change significantly. NTproCNP was raised at baseline and declined throughout the study, with NTproCNP SD significantly lower at months 6 and 12 on treatment. Change in height SD or AGV were not correlated to IGF-1 or NTproCNP SD at 12 months. The change in IGF-1 concentrations at 12 months was positively correlated with the change in NTproCNP plasma concentrations (ρ = 0.57; P = .024). CONCLUSION:In children with HCH, IGF-1 levels are reduced and NTproCNP levels are elevated at baseline. A correlation between changes in these levels during treatment suggests a possible interaction between IGF-1 and CNP signaling.

INTRODUCTION:Short stature resulting from genetic conditions is associated with various emotional, physical, and social challenges resulting in significantly lower health-related quality of life. There are minimal qualitative data available on this topic. METHODS:We performed a cross-sectional, remote, qualitative interview study targeting children receiving vosoritide for >2 years as part of a clinical trial and their caregivers. Interviews assessed participants' daily experiences of short stature and the impact of vosoritide on HRQoL. Principles of thematic analysis with features from grounded theory-guided coding and analysis of interviews. RESULTS:Twenty-one caregivers and 14 child participants from 20 families were interviewed. Child participants were ages 8 to 15 years (M=10.2). Four conditions were represented in the sample (12 hypochondroplasia, 4 NPR2 mutation, 2 ACAN mutation, 2 Noonan syndrome). At baseline, short stature had significant impacts on physical, social, and daily activities domains. After starting vosoritide, changes were most reported for impacts on daily activities by both caregiver (74%) and child (100%) participants. Most reported were "improved ability to reach things" (12 caregivers and 14 children) and "being more independent/needing less assistance" (9 caregivers and 5 children). CONCLUSION:Genetic short stature significantly impacts health-related quality of life, as reported by both children and their caregivers. Both children and caregivers noted emotional, physical, and social impacts as well as impacts on daily activities. Vosoritide treatment was associated with meaningful improvements in physical impacts and impacts on daily activities.

INTRODUCTION:Idiopathic short stature (ISS) refers to children whose height falls substantially below the mean for sex and age relative to a reference population, despite the absence of an identifiable endocrine, genetic, syndromic, or systemic disorder. Clinical management remains challenging because no dedicated ICD-11 code exists and no universally accepted diagnostic criteria have been established. This has led to variability in how the condition is classified, inconsistency in access to testing, and uncertainty around eligibility for growth-promoting therapies. To address these inconsistencies and support broader global alignment in the recognition and management of ISS, an international consensus initiative was undertaken. METHODS:A Steering Committee of 10 internationally recognized experts with extensive clinical and academic expertise in ISS supported the development of a structured modified Delphi process. An Expert Panel of 22 key opinion leaders participated in a three‑round survey conducted between November 2025 and February 2026. Panelists evaluated draft statements related to ISS definition, diagnostic criteria, burden of disease, and decision to treat. Consensus thresholds were predefined at 70%, and statements were refined between rounds, as needed. RESULTS:A total of 44 statements achieved consensus, with final agreement levels ranging from 77% to 100%. The statements establish a standardized clinical definition of ISS, propose evidence-based diagnostic criteria applicable across diverse healthcare settings, describe the impact of ISS on patients and caregivers, and suggest when to consider growth-promoting treatment for patients with ISS. For example, consensus was reached on the definition of ISS (a condition in which an individual has a height more than a standard deviation score of 2 below the mean for sex, age, and population, corresponding to below the 2.3 percentile, without identifiable underlying pathology) and on key elements of diagnostic evaluation (include the child's medical, developmental, and medication background, including prenatal and perinatal course, chronic illnesses or infections, and neurodevelopmental milestones, alongside family history and environmental exposures; perform a physical examination to identify clinical signs of underlying pathology, including assessment of body proportions, dysmorphic body features, head circumference, body mass index, and pubertal development). Key areas requiring future research were also highlighted. CONCLUSION:This international consensus offers the first globally derived, ISS‑focused guidance developed using a formal Delphi methodology for identifying and managing children and adolescents with ISS. Adoption of these recommendations may reduce regional variability, improve diagnostic clarity, and ultimately enhance outcomes for individuals affected by ISS.

CONTEXT:Genetic defects in many biological pathways, including activation of the Ras-MAPK pathway, cause short stature. Vosoritide, a C-type natriuretic peptide analog that inhibits this pathway, has been approved for use in achondroplasia. OBJECTIVE:To determine whether vosoritide improves growth in children with disorders of the Ras-MAPK pathway, including RASopathies, ACAN, and NPR2 deficiency. DESIGN:Prospective Phase 2 basket trial. SETTING:Academic medical center. PARTICIPANTS:Thirty prepubertal children aged 3 to 11 years with a RASopathy, ACAN or NPR2 deficiency and height ≤ -2.25 SD. INTERVENTION:Six-month observation period followed by 12-month treatment with vosoritide subcutaneously 15 µg/kg/day. MAIN OUTCOME MEASURES:Co-primary outcomes included incidence of adverse events, change in annualized growth velocity (AGV), and height standard deviation scores. RESULTS:The AGV increased from 4.53 ± 1.61 cm/year to 8.09 ± 1.58 cm/year with treatment (P < .0001). This corresponded to a 4.0 SD (95%CI 3.08-4.91) increase in age and sex-adjusted AGV Z-score (P < .0001). The increase in AGV was seen in all genetic subgroups. There was a height increase of 0.65 SD (95%CI 0.53-0.77) in the treatment vs observation period (P < .0001).Short-term safety was reassuring, with mild injection site reactions being the most common adverse events. However, with longer use, 5 subjects discontinued medication due to adverse events, including 3 slipped capital femoral epiphyses and 4 cases of genu valgum. CONCLUSION:Vosoritide led to marked increases in growth velocity in children with RASopathies, ACAN, and NPR2 deficiency, raising the possibility that vosoritide could be an effective precision medicine for all growth disorders affecting the MAPK pathway.

BACKGROUND:Growth hormone (GH) is a treatment option in some countries for children with idiopathic short stature (ISS) given to enable them to attain height within the expected range. Currently, it is not often utilised in clinical practice. A literature review was conducted to summarise the efficacy, safety, and outcomes associated with GH treatment in children with ISS. SUMMARY:Guidelines for the diagnosis and treatment of ISS may benefit from revision to accommodate recent findings on genetic factors that influence height. Clinical trials and observational studies designed to investigate the effect of GH treatment on children with ISS have shown that it is effective in enabling them to attain height within the normal range. In some instances, height improvements are reported up to adult height. The safety of GH treatment in this patient population has also been investigated and no new safety concerns have been observed. In analyses that were designed to investigate the effect of GH on quality of life, improvements in psychosocial scores were observed, either by the patient, parent, or the treating physician. KEY MESSAGE:GH treatment is effective in improving height outcomes and quality of life in children with ISS, with an acceptable safety profile.