Idiopathic short stature (ISS) refers to a heterogeneous group of growth disorders with an undefined aetiology, defined as a height more than two standard deviations (SDs) below the mean for age, sex, and ethnicity. Children diagnosed with ISS typically present with normal birth length, weight, and body proportions. Clinical evaluation reveals no evidence of systemic, endocrine, nutritional, chromosomal, or genetic abnormalities (1). Diagnosing ISS requires the exclusion of identifiable causes and presents certain clinical challenges. Epidemiological studies have found that approximately 60–80% of children with a height ≤ -2 SDs meet the criteria for ISS (2). The underlying mechanisms of ISS are multifactorial and involve dysregulation of the growth hormone–insulin-like growth factor (GH–IGF) axis, dysfunction of growth plate chondrocytes, and alterations in genetic regulatory networks (3–6).

Clinically, ISS reduces final adult height, impairs psychosocial well-being, and increases long-term cardiovascular risk (7, 8). Currently, recombinant human growth hormone (rhGH) is the only United States of America’s (USA’s) Food and Drug Administration (FDA)-approved treatment for children with ISS (9). Although rhGH has been shown to improve final height in many patients, treatment responses vary markedly. Adverse events include increased intracranial pressure, slipped capital femoral epiphysis, and scoliosis, which require long-term safety monitoring (10–12). Despite these advancements in understanding and treatment, there remains a notable absence of comprehensive macroscopic analyses detailing the evolution of ISS research. Although the existing literature is rich in specific clinical and molecular studies, it has not systematically mapped the intellectual landscape of the field. ISS-related research has steadily increased over the past three decades; however, no systematic analysis of the field’s development and current landscape exists.

Bibliometrics, an interdisciplinary method that integrates statistics and informatics, allows for the quantitative analysis of scientific literature. By examining the distribution of nations, institutions, authors, keywords, and references, bibliometric analysis tracks academic development, identifies research hotspots, and assesses scholarly influence (13–15). The Web of Science (WOS), a comprehensive academic database, includes high-impact journals in multiple disciplines. Therefore, the primary limitation of this study is the absence of a holistic, quantitative overview of research trends and the intellectual structure within the field of ISS. In this study, we conducted a bibliometric analysis of ISS-related publications indexed in the WOS from 1 January, 1993 to 31 December, 2024. Using network visualisation tools, we systematically reviewed the past 32 years of ISS research, highlighting key developmental trends and current research dynamics. Our objective was to guide researchers, particularly new entrants to the field, by mapping influential authors and references, identifying suitable journals, and highlighting emerging directions in ISS research. This study presents the first comprehensive bibliometric mapping of the ISS research landscape, offering new insights into its growth, collaborative networks, thematic shifts, and impact over more than three decades.

Compared with Google Scholar and Scopus, the Web of Science Core Collection (WoSCC) provides higher-quality journal indexing and more comprehensive citation data (16, 17). Concurrently, PubMed provides extensive coverage of biomedical and clinical research literatures with specialized precision filtering for publication types. This combined infrastructure enables efficient and accurate retrieval of clinical trial progress related to ISS. Therefore, we conducted comprehensive searches of WoSCC and PubMed for publications dated 1 January 1993 to 31 December 2024. Only English-language records were included.

For WoSCC, we used the Topic field (TS, including title, abstract, author keywords, and Keywords Plus), with limits applied for document type, language, and year. The exact Advanced Search query was TS = (“idiopathic short stature” OR “idiopathic dwarfism” OR “idiopathic dwarf”) AND DT = (Article OR Review) AND LA=(English) AND PY = (1993-2024). This search retrieved 1, 567 records, which were exported with cited references in plain-text format for analysis. For clinical progress assessment, PubMed was searched using the Title/Abstract field tag with publication-type, language, and date restrictions. The exact query was: (“idiopathic short stature”[Title/Abstract] OR “idiopathic dwarfism”[Title/Abstract] OR “idiopathic dwarf”[Title/Abstract]) AND (Clinical Trial [Publication Type] OR Randomized Controlled Trial [Publication Type]) AND (“1993/01/01”[Date - Publication]: “2024/12/31”[Date - Publication]) AND English [Language]. Data cleaning and deduplication were conducted through a two-phase protocol. In Phase 1, we retained only Article and Review publications (DT field) while excluding non-research publication types (Editorials, Letters, Meeting Abstracts, etc.). Language (LA = English) and publication year (PY = 1993-2024) filters were systematically applied. In Phase 2, duplicate removal via composite matching of DOI, title, and author-publication year combinations; geopolitical unification adhering to ISO 3166–1 standards (e.g., “Peoples R China” and “Taiwan” were grouped under “China”; “United States of America” was standardized as “USA”; and “England, “ “Scotland, “ “Wales, “ and “Northern Ireland” were merged into “UK.”).

To reduce lexical fragmentation, synonym/thesaurus files in CiteSpace 6.1.R6, VOSviewer 1.6.20, and the bibliometrix R package (18, 19) were used to merge duplicate or variant terms (e.g., “GH” and “growth hormone”), correct spelling inconsistencies, and remove non-informative keywords. Reference metadata were imported into these tools to identify core countries, institutions, authors, journals, keywords, and influential references. Title and abstract screening were conducted independently by two reviewers; disagreements were resolved through discussion, and unresolved conflicts were adjudicated by a third reviewer.

In this study, we systematically mapped the developmental trajectory and current status of ISS research from 1993 to 2024 through a multidimensional bibliometric analysis, which included annual publication trends, national and institutional collaboration networks, influential authors and journals, keyword evolution, and frequently cited references. Annual publications have steadily increased over the past three decades, particularly since 2010. Despite a slight decline since 2021, the overall publication volume remained high, indicating that ISS has become a prominent research topic in paediatric endocrinology and has received increasing global attention. This sustained growth highlights the persistent clinical challenge posed by ISS and the ongoing scientific efforts to unravel its complexities.

Collaboration network analysis revealed that nations, such as the USA, Germany, and the UK held central positions in ISS research, with the USA exhibiting high centrality, highlighting its academic leadership. Research contributions from Asian nations, including China, Japan, and South Korea, have increased in recent years, promoting diversity and international collaboration. The top three most productive institutions were Leiden University (Netherlands), University of Gothenburg (Sweden), and Oregon Health & Science University (USA). By contrast, institutions, such as the University Children’s Hospital Zürich, University of Tübingen, and Hospital Universitario La Paz demonstrated high centrality, reflecting their pivotal roles within the ISS research network. Author collaboration and co-citation analyses reveal the emergence of a relatively stable core academic community in ISS research. These highly productive and frequently cited scholars have driven both fundamental research advances and therapeutic innovation, while directly influencing clinical practice through consensus guidelines and standardized protocols. This dual impact reflects a maturation phase in ISS research, characterized by robust academic collaboration and cumulative knowledge integration.

Keyword-density and burst analyses reveal the dynamic evolution of ISS research themes. Early work focused primarily on GH secretory mechanisms and clinical phenotypes, laying the groundwork for disease understanding and initial therapeutic approaches. Subsequently, attention shifted to evaluating the efficacy and long-term safety of rhGH, thereby facilitating its widespread clinical adoption. In recent years, research has progressively expanded to encompass genetic diagnosis and putative genetic mechanisms, aligning with the broader shift in medicine towards precision and individualized treatment. Human height exemplifies a polygenic trait where additive effects of multiple variants create continuous, genetically determined phenotypic variation (38). Within ISS research, molecular genetics has thus assumed increasing prominence. Pathogenic variants in genes such as FGFR3, SHOX, and GHR have been associated with ISS (39–41). Genetic testing now enables clinicians not only to establish an aetiological diagnosis but also to identify comorbidities and refine treatment plans (5, 42). Databases (e.g., GWAS Catalog, Deciphering Developmental Disorders) continually expand ISS-related variant collections, while clinical data reciprocally enrich these resources, creating a translational research-practice cycle. For example, pathogenic FGFR3 variants induce constitutively upregulated signaling that suppresses proliferation and differentiation in growth-plate chondrocytes, leading to short stature; genetically confirmed cases demonstrate indications for vosoritide therapy (39). Conversely, GHR mutations or STAT5B deficiency predict a suboptimal response to rhGH, necessitating therapeutic reassessment. These findings support expanding genetic testing in clinical care to enable precision and individualized interventions. However, implementation challenges persist. Rigorous cost-effectiveness analyses are needed to justify diagnostic and therapeutic expenditures, while regional and familial disparities in affordability limit access. Translating genetic discoveries into clinical decisions (e.g., GH regimen selection and dose adjustment) will require further large-scale studies. Notably, the recent emergence of “Guideline” in burst analysis reflects influential international consensus statements (9, 22) that standardize etiological classification, treatment pathways, and monitoring protocols, advancing global practice harmonization.

The consensus guidelines published by Cohen et al. (2008) (1) and Grimberg et al. (2016) (9) have been extensively cited and offer standardised definitions, diagnostic pathways, and treatment strategies, providing a globally recognised framework for clinical management. In 1995, Goddard et al. (31) advanced the genetic understanding of ISS by identifying GH receptor gene mutations associated with GH insensitivity. Additional frequently cited studies have addressed GH dosing, long-term safety, and adverse events associated with rhGH therapy (32–34), reflecting ongoing efforts to balance therapeutic efficacy and patient safety. Despite these advances, the management of ISS remains challenging. Currently, rhGH is the most widely used treatment for ISS. Since its approval by the USA FDA in 2003, rhGH has been adopted in countries including China, Australia, and New Zealand. Multiple studies have confirmed its effectiveness in improving final height in children, with outcomes showing a dose-dependent response (10, 11, 33). However, concerns regarding their long-term safety persist. Some studies have documented elevated fasting insulin levels and increased insulin resistance in patients with ISS receiving rhGH (43). The 2012 French SAGhE study identified a higher mortality risk due to bone tumours or intracranial haemorrhage in adults previously treated with rhGH in childhood, with risk correlating to dosage (36). The 2020 SAGhE study, which included 24, 232 children, found increased all-cause mortality associated with specific underlying diagnoses. However, no overall increase in mortality was observed in patients with ISS. Nevertheless, the elevated risk of cerebrovascular mortality in patients treated with rhGH is consistent with previous findings (12). Additionally, the clinical applications of long-acting PEGylated rhGH are continuously expanding; however, its long-term efficacy and safety require further investigation. In 2023, Wit emphasised the need for strengthened post-marketing surveillance of PEGylated rhGH and advocated a cautious approach that balances therapeutic innovation with safety monitoring (44).

In addition to rhGH therapy, GnRH analogues (GnRHas) and aromatase inhibitors have frequently been used in combination therapies to delay skeletal maturation and extend the period of linear growth. During puberty, accelerated bone age in patients with ISS can limit growth potential, particularly in those receiving rhGH monotherapy. GnRHa suppresses the hypothalamic–pituitary–gonadal axis, delaying puberty. GnRHa alone has demonstrated limited effectiveness in increasing the final height (45). However, when administered early in puberty alongside rhGH therapy, this combination is associated with improved adult height outcomes (46, 47). A temporary reduction in growth velocity may occur; however, long-term outcomes for adult height are favourable. Clinical studies have shown that GnRHas are generally well tolerated, with minimal adverse effects and normal resumption of pubertal development following treatment cessation (48). Aromatase inhibitors, typically prescribed for boys with advanced bone age, inhibit the conversion of androgens to estrogens, thereby delaying epiphyseal fusion and supporting continued linear growth. The efficacy of aromatase inhibitors has been confirmed in multiple studies, particularly when used in combination with rhGH (49–51). Nevertheless, clinicians should remain vigilant regarding potential adverse effects, including hyperandrogenism, neuropsychological symptoms such as drowsiness and memory loss, low high-density lipoprotein levels, arthralgia, hyperinsulinemia, and hyperuricemia. Most adverse effects resolve within 3 months of discontinuing treatment. The impact of aromatase inhibitors on reproductive function in children remains unclear and requires further investigation (52).

Clinical progress analysis indicate that recent ISS research has increasingly shifted from a single therapeutic strategy toward more individualized and precision-based interventions, exploring combination therapies and refined approaches tailored to specific patient characteristics. Currently, rhGH remains the standard treatment for ISS; however, in recent years, combination regimens involving rhGH with GnRHa or aromatase inhibitors have gained growing attention in pubertal patients. These strategies aim to extend the growth period and improve adult height outcomes. Nevertheless, the long-term safety and efficacy of such combination therapies require further investigation and validation. Meanwhile, with the growing clinical adoption of genomic medicine, personalized treatment strategies based on genetic characteristics are showing growing potential. For example, Mecasermin may be considered for patients with GHR mutations and low IGF-1 levels, whereas Vosoritide may benefit children with FGFR3 mutations. This emerging trend reflects a paradigm shift in ISS treatment—from the traditional “one-size-fits-all” rhGH therapy to a more stratified and precise therapeutic model guided by genetic and biomarker profiles.

Overall, despite substantial advances in ISS research, current studies remain largely focused on genetic mechanisms and growth outcomes, with comparatively limited attention to children’s psychosocial health, cognitive development, and long-term metabolic outcomes (53, 54). Furthermore, the clinical evidence base predominantly derives from high-income countries, potentially limiting external validity for resource-limited settings. Based on developments over the past 32 years, ISS research is likely to diversify further over the next 5–10 years. Beyond existing genetic paradigms, future research is expected to prioritize psychosocial and cognitive outcomes alongside metabolic profiling. At the same time, systematic functional studies of clinically identified pathogenic gene variants will be essential to deepen our understanding of ISS pathogenesis. The integration of multi-omics approaches—including transcriptomics, proteomics, and metabolomics—holds great promise for elucidating the underlying mechanisms of ISS, thereby advancing precision diagnostics and enabling stratified treatment strategies. As clinical indications for long-acting growth hormone continue to expand, related clinical trials in pediatric ISS populations are expected to increase. Meanwhile, more emphasis should be placed on real-world implementation studies of newly developed clinical guidelines, evaluating their actual adoption, implementation quality, and cost-effectiveness to determine their clinical feasibility and health-economic value. Notably, advancements in artificial intelligence have the potential to revolutionize care delivery through automated bone-age imaging analysis, multimodal treatment optimization, and predictive modeling of adult height—collectively enhancing diagnostic accuracy and therapeutic decision-making.

This study has several limitations. First, although the literature search covered publications up to December 2024, data extraction was completed at an earlier date, which may have excluded the most recent studies and thus limited the assessment of current research trends. Second, bibliometric analyses rely primarily on quantitative indicators, such as publication and citation counts, without sufficiently accounting for study quality, methodological rigor, or scientific value; as a result, the academic impact of frequently cited articles may be overstated. Third, only English-language publications were included, which may have introduced language bias and underestimated contributions from non-English-speaking countries. Finally, the WoSCC was chosen as the primary database for bibliometric analysis due to its broad coverage and reliability, with PubMed additionally consulted for clinical research content; however, relevant studies indexed exclusively in other databases, such as Scopus or Embase, may still have been missed. This database selection ensured consistency and reproducibility but inevitably limited the comprehensiveness of the included literature.

In conclusion, A comprehensive bibliometric analysis mapped the literature on ISS from 1993 to 2024, presenting a systematic overview of the field’s developmental trajectory and current research priorities. Nations, institutions, and researchers based in North America and Europe occupy central positions in the progression of ISS-related work. Research emphasis included the identification of pathogenic genes, assessment of treatment-related risks, and standardisation of diagnostic and therapeutic protocols. Overall, the findings offer a structured reference for outlining knowledge frameworks and academic contributions. New investigators can access essential insights by locating foundational literature, recognising influential contributors, and identifying appropriate journals to inform their submission strategies and future research directions.