Idiopathic short stature in the genomic era: a focused narrative review of genotype-phenotype correlation, selective neuroimaging, IGF-1 biology, and growth hormone responsiveness

Abstract.

Idiopathic short stature (ISS) is a provisional clinical label rather than a final diagnosis. This narrative review (2000–2026) synthesizes how genomic findings intersect with neuroimaging, IGF-1 biology, and GH responsiveness. Diagnostic yield varies by modality: candidate-gene (4.7%), chromosomal microarray (16.3%), multigene panels (21.6%), and exome sequencing (33.3% overall; 15.1% isolated). These estimates decrease if variants of uncertain significance (VUS) are excluded. Recurrent genes include ACAN, NPR2, SHOX, IHH, FGFR3, IGF1R, and PAPPA2. Study comparisons are limited by heterogeneous definitions and neuroimaging selection bias. While major structural hypothalamic-pituitary lesions are uncommon in ISS, pituitary size overlaps significantly with both controls and GH deficiency. GH response is genotype-dependent; SHOX deficiency typically shows robust gains, while ACAN variants yield more modest, sustained responses. ISS should be managed as a heterogeneous working phenotype. A clinically effective approach integrates careful phenotyping, selective MRI, explicit separation of pathogenic findings from VUS, and genotype-informed counseling regarding prognosis and treatment response.

Highlights

● ISS is a heterogeneous phenotype rather than a single diagnostic entity.

● Genetic yield depends on testing modality and specific clinical phenotyping.

● Genotype predicts growth hormone responsiveness and improves counseling.

Introduction

Idiopathic short stature (ISS) remains a common referral label in pediatric endocrinology, but current evidence makes it increasingly difficult to regard ISS as a single diagnostic category. Rather, ISS describes a heterogeneous group of short children in whom routine evaluation has not yet identified a systemic, nutritional, endocrine, chromosomal, or syndromic cause. As genomic approaches become more widely available, a meaningful proportion of children initially classified as ISS are reclassified into biologically defined disorders, particularly disorders affecting the growth plate or selected components of the GH-IGF axis (1, 4).

The interpretive landscape changed further in 2026 with publication of a systematic review dedicated to diagnostic yield in short stature and the first international guideline specifically addressing genetic testing in children with short stature (2, 3). These papers are highly relevant because they show that diagnostic yield depends not only on the genetic platform used, but also on phenotype enrichment, variant interpretation, and the presence of clues such as dysmorphism, skeletal abnormalities, or developmental features (2, 3).

At the same time, these recent publications do not eliminate the need for a clinically oriented synthesis focused on children initially labeled as ISS. In everyday practice, clinicians must still decide how to interpret borderline IGF-1 results, whether pituitary MRI is warranted, how strongly to weigh a multigene or exome result, and what to tell families about likely response to GH therapy once a genotype is identified. These questions are related, but they are usually discussed separately.

A second challenge is that the term ISS has been applied inconsistently across studies. Cohorts vary in height thresholds, use of target-height deviation, inclusion or exclusion of children born small for gestational age, definitions of normal GH secretion, and the depth of clinical/radiologic exclusion before the term ISS is assigned. These differences likely influence both reported genetic yield and apparent GH responsiveness, and they complicate direct comparison between cohorts (2, 3, 5).

Accordingly, the purpose of the present article is not to duplicate the 2026 systematic review or guideline, but to complement them with a focused narrative synthesis centered on genotype-phenotype correlation in ISS-labeled children. The review integrates four clinically linked domains: genetic determinants, selective neuroimaging, IGF-1 biology, and genotype-dependent GH response.

What distinguishes the present review from existing narrative or systematic reviews is its deliberate integration across four clinical decision points that are usually examined in isolation: (i) the impact of cohort-definition heterogeneity on apparent genetic yield, (ii) the targeted, indication-driven use of pituitary/brain MRI with explicit attention to selection bias, (iii) the interpretation of IGF-1 in light of genotype and IGF bioavailability, and (iv) the genotype-informed prediction of GH response set within the differing regulatory frameworks of the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). Rather than re-cataloguing recurrent gene–phenotype associations, the review offers a phenotype-driven, clinically actionable synthesis intended to help pediatric endocrinologists move from the working label of ISS toward an individualized, mechanism-based management plan.

Objectives

1. To summarize how heterogeneity in ISS definitions influences interpretation of genetic yield and treatment response.

2. To synthesize recurrent molecular diagnoses reported in children initially classified as ISS and to distinguish pathogenic or likely pathogenic findings from VUS.

3. To review the role and limitations of brain and pituitary MRI in ISS, with explicit attention to referral and indication bias.

4. To evaluate how genotype helps interpret IGF-1 patterns, growth phenotype, and expected response to GH therapy.

5. To integrate the above into a concise, phenotype-driven clinical decision pathway, while acknowledging that GH treatment indications and reimbursement differ between the US FDA, the European EMA, and the Japanese PMDA.

Methods

This article was designed as a focused narrative review rather than a systematic review. PubMed was searched for English-language publications from January 2000 through March 2026 using combinations of the terms idiopathic short stature, isolated short stature, genetics, exome, gene panel, chromosomal microarray, pituitary MRI, IGF-1, PAPPA2, SHOX, ACAN, NPR2, IHH, and growth hormone response. Systematic reviews and clinical practice guidelines were prioritized first, followed by pivotal original studies that were repeatedly cited in the field or that materially informed clinical decision-making.

Eligible articles included pediatric studies reporting one or more of the following domains in children classified as ISS or isolated short stature: (i) diagnostic yield of genetic testing; (ii) recurrent molecular diagnoses and phenotype correlations; (iii) pituitary or brain MRI findings; (iv) IGF-1 or GH-IGF pathway biology; and (v) GH response or adult/near-adult height outcomes. Studies based on mixed short stature populations were considered when data were interpretable for ISS-like or isolated short stature subgroups.

Because this was not a formal systematic review, no PRISMA flow diagram, registration record, or pooled meta-analysis was generated. Instead, evidence was synthesized descriptively and interpreted according to study design, phenotype definition, genetic platform, and clinical context. Formal risk-of-bias scoring was not applied; however, recurrent sources of bias, especially phenotype enrichment, MRI indication bias, and referral bias, were explicitly considered in the narrative interpretation.

A key methodological principle in the present review was the handling of VUS. Variants were considered diagnostic only when classified by the original investigators as pathogenic or likely pathogenic, or when the source clearly treated them as established disease-causing findings. VUS were not counted as solved cases and were not used to define genetic diagnostic yield. This approach is consistent with the 2026 systematic review, which showed that diagnostic yields decreased after exclusion of VUS, and with the 2026 international guideline, which distinguishes causal findings from unresolved variants (2, 3).

Gene names are italicized throughout the text and tables in accordance with standard nomenclature.

For terminological clarity, in this review the term “idiopathic short stature” (ISS) is used as the principal working label for short children in whom routine clinical, biochemical, and hormonal evaluation has not identified a defined cause. The term “isolated short stature” is used only in the narrower sense applied by the 2026 systematic review by Scalco et al., where it specifically denotes ISS-spectrum children without dysmorphic, syndromic, or skeletal features. “Non-GHD ISS” is reserved for instances in which the discussion turns specifically on the demonstration of preserved GH secretion. These terms are used consistently throughout the manuscript.

In addition, because the evidence base for GH responsiveness depends on differing levels of regulatory approval and reimbursement, the methods were extended to include a search for licensing decisions and pivotal trials registered with the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). Specifically, additional searches were performed for SHOX deficiency, ACAN-related short stature, FGFR3-related hypochondroplasia, and the broader ISS label using the terms “regulatory approval”, “label”, “FDA”, “EMA”, “PMDA”, and “phase 3”. Key clinical trials from Japan and other regions were considered as part of the evidence base. The aim was not to provide an exhaustive regulatory review but to ensure that the section on GH responsiveness reflects geographically variable evidence levels and indications.

Evidence Synthesis

1. Heterogeneity of ISS definitions remains a major source of between-study variation

Across the literature, ISS is not a uniform construct. Some cohorts required only height below –2 SDS after exclusion of chronic disease and overt endocrine deficiency, whereas others additionally required a normal birth size, normal body proportions, target-height deviation, or specific GH stimulation cutoffs. Studies also differed in how aggressively they excluded subtle skeletal dysplasia, dysmorphic features, and neurodevelopmental abnormalities before assigning the label ISS (2, 3, 5).

This heterogeneity matters clinically. A cohort enriched for severe short stature, mild disproportion, or familial clustering is expected to yield more monogenic diagnoses than a cohort of proportionate short children with otherwise typical examination findings. Likewise, differences in GH stimulation thresholds and prior exclusion pathways affect which children remain in the non-GHD ISS category, thereby influencing both neuroimaging comparisons and observed GH responsiveness.

2. Current genetic yield data require careful phenotype-specific interpretation

The most comprehensive current estimate comes from the 2026 systematic review by Scalco et al., which included 134 studies. The overall diagnostic yield was 4.7% for candidate-gene testing, 16.3% for chromosomal microarray, 21.6% for gene panels, and 33.3% for exome sequencing; however, exome yield in isolated short stature was only 15.1%, compared with substantially higher yields in syndromic short stature and skeletal dysplasia (2). Importantly, yields fell further after VUS were excluded (2).

These results underscore why broad summary statements such as a 15–25% genetic yield in ISS can be misleading if phenotype, platform, and variant-classification criteria are not specified. Multigene panel studies focused on children clinically classified as ISS do support a clinically meaningful diagnostic rate. For example, Andrade et al. identified pathogenic or likely pathogenic variants in 16.7% of a 102-child ISS cohort using a targeted multigene panel, with many diagnoses involving growth-plate genes (5).

Recurrent genes across ISS-spectrum cohorts include ACAN, NPR2, SHOX, IHH, FGFR3, and selected GH-IGF pathway genes (5,6,7,8,9,10, 21). Nevertheless, direct comparisons between older candidate-gene studies and newer next-generation sequencing cohorts are limited by changes in sequencing depth, copy-number detection, phenotype enrichment, and ACMG-based variant interpretation. Some older studies were published before current variant-classification frameworks were uniformly adopted, and some cohorts reported VUS alongside pathogenic findings. For that reason, diagnostic yield should be interpreted as platform- and cohort-specific rather than as a single universal estimate for all children labeled ISS (2, 3).

3. Recurrent genotypes explain distinct biologic mechanisms and IGF-1 patterns

Among growth-plate disorders, heterozygous ACAN variants are now recognized as a major cause of short stature that may present with variable proportionality and without obvious dysmorphism, meaning that affected children may initially appear to have classic ISS (6). NPR2 variants similarly explain a subset of children with apparently proportionate short stature, with or without mild skeletal signs (7). Pathogenic variants in IHH may also mimic ISS clinically because skeletal abnormalities can be subtle and only recognized retrospectively (8). Hidden hypochondroplasia due to FGFR3 variants appears uncommon in unselected ISS cohorts, but it remains an important differential diagnosis because it changes both counseling and classification (21).

In the GH-IGF pathway, variants in IGF1 and IGF1R help explain children with short stature who do not have classic GH deficiency but nonetheless show altered growth signaling (10). PAPPA2 deficiency is especially instructive because it demonstrates that total IGF-1 may be normal or elevated while growth remains poor due to impaired liberation of bioactive IGF from its binding proteins (9). Accordingly, the interpretation of IGF-1 in ISS cannot be entirely phenotype-blind; discordant biochemical patterns may be mechanistically informative once genotype is considered.

4. Neuroimaging findings in ISS must be interpreted in light of strong selection bias

In routine practice, MRI is not performed in all children with non-GHD ISS. Rather, imaging is more likely in children with severe short stature, low or borderline GH secretion, other pituitary hormone abnormalities, headaches, neurologic symptoms, visual concerns, or other red flags. Therefore, comparisons between MRI-defined GHD cohorts and ISS cohorts are inherently selected and should not be interpreted as if they represent unselected ISS populations.

Within these limits, available studies suggest that major structural hypothalamic-pituitary lesions are uncommon in children labeled as ISS. Early MRI studies in short stature cohorts found that clinically significant structural abnormalities clustered more strongly with GHD than with GH-sufficient groups (11, 12). Volumetric work showed that pituitary size in ISS generally lies closer to controls than to isolated GHD, but with substantial overlap that prevents pituitary volume from serving as a stand-alone discriminator (13). More recent work similarly found that pituitary volume cannot reliably distinguish GH deficiency from ISS and is at best a supportive, not definitive, marker (15) (Table 1).

Table 1. Why MRI comparisons between ISS and GHD must be interpreted cautiously.

A related issue is the frequency of incidental findings. In an endocrine MRI cohort, Brener et al. reported incidental findings in nearly one quarter of cases, including cysts, white-matter lesions, Chiari I malformation, and rare tumors requiring intervention (14). Marin et al. subsequently highlighted that many follow-up MRIs in pediatric endocrinology may not change management, reinforcing a more selective and indication-driven imaging strategy (16). Thus, MRI retains value in children with red flags, but it should not be framed as a routine comparator capable of cleanly separating ISS from GHD.

5. GH response is meaningfully influenced by genotype

At the group level, GH treatment can improve height in ISS, but average response masks important heterogeneity. In a large prospective observational study, GH-treated children with ISS achieved a mean near-adult height gain of about 1.1 SDS, with overall safety similar to that observed in idiopathic GHD; however, this cohort was genetically unselected and therefore combines biologically diverse disorders under one clinical label (20).

Genotype-specific data provide more clinically actionable expectations. SHOX deficiency remains the clearest example of a robust GH-responsive subgroup. Multicenter trial data demonstrated substantial gains to final height, and real-world follow-up showed similar near-adult height benefit without new safety concerns (17, 18). In contrast, children with pathogenic ACAN variants appear to have a more modest but still clinically meaningful response that is sustained over several years, particularly when therapy is initiated before puberty (19) (Tables 2 and 3 ).

Table 2. Genetic yield in short stature/ISS and the main factors affecting interpretation.

Table 3. Genotype-informed expectations for GH treatment response.

Importantly, the evidence base for GH therapy is not uniform across regulatory regions, and any synthesis of GH responsiveness in ISS-spectrum disorders must acknowledge this heterogeneity (22). The US Food and Drug Administration (FDA) has approved recombinant human GH for the broad indication of idiopathic short stature since 2003, alongside specific genetic indications including SHOX deficiency, Noonan syndrome, Prader–Willi syndrome, Turner syndrome, and children born small for gestational age (SGA) without catch-up growth (22). The European Medicines Agency (EMA), by contrast, has consistently declined a generic ISS label, instead approving GH for defined genetic or auxological subgroups such as Turner syndrome, SGA, SHOX deficiency, Prader–Willi syndrome, and chronic renal insufficiency (22). In Japan, the PMDA recognizes GH for SGA short stature, Turner syndrome, chronic renal insufficiency, Prader–Willi syndrome, and, most recently, SHOX deficiency, with the latter approval supported by a Japanese randomized phase 3 trial that demonstrated increased annualized height velocity and a favorable safety profile in children with genetically confirmed SHOX deficiency (23). These regulatory differences carry direct clinical consequences: identical molecular diagnoses may meet or fail reimbursement criteria depending on country, and clinicians must therefore interpret published response data within the context of the local label.

Beyond the well-established response in SHOX deficiency, GH treatment data are now also available for other monogenic ISS-spectrum disorders, although the level of evidence remains lower. Real-world cohort data in children with pathogenic ACAN variants demonstrate a height-SDS gain of approximately 0.8–1.0 SDS over three years, predominantly achieved in prepubertal children before advanced skeletal maturation (19). In FGFR3-related hypochondroplasia, small cohort studies have shown a measurable but attenuated first-year height-velocity increase and, when treatment is continued, a near-adult height gain that is consistently smaller than that observed in SHOX deficiency or genetically unselected ISS (24, 25); concerns about disproportionate growth and bone-age advancement also remain, so this indication is still considered investigational rather than standard of care. Limited case-level data in IHH-related and NPR2-related short stature suggest short-term height-velocity benefit broadly comparable to that of genetically unselected ISS, but adult-height data are still scarce (8). Across all these genotypes, response magnitude appears to be greater in children treated earlier, at younger bone age, and at GH doses adjusted toward the upper end of the labelled range used for non-GHD indications (22). PAPPA2 deficiency and other defects of IGF bioavailability or signalling remain an important caveat: in these children, conventional GH treatment may show only partial benefit, and the available mechanistic and small-series data have generated interest in IGF-1-based or combined approaches rather than GH monotherapy (9). The cumulative implication is that genotype refines, but does not yet replace, the conventional auxological criteria used to predict GH response.

These data support a precision-counseling approach. The question is no longer whether children with ISS respond as a group, but which biological subgroups respond best, which respond partially, and which require more guarded expectations because the primary lesion lies in growth-plate architecture or GH-IGF bioavailability rather than GH secretion alone.

The narrative summaries previously placed within this section that paraphrased Tables 1–3 and Fig. 1 have been condensed and consolidated into the corresponding figure and table legends (below), where they now serve as self-explanatory captions for readers who consult the tables in isolation. This avoids repetition between the body of the manuscript and the captions and addresses the related editorial comments.

Fig. 1.

Idiopathic short stature in the genomic era: integrating genomics, imaging, and genotype-driven growth outcomes. This figure provides a comprehensive, clinically oriented overview of idiopathic short stature (ISS) as a heterogeneous and evolving phenotype rather than a definitive diagnosis. It highlights how advances in genomic testing significantly improve diagnostic yield, particularly with exome sequencing, while emphasizing the importance of phenotype-driven evaluation. The diagram integrates key biological pathways, including growth plate regulation (ACAN, NPR2, SHOX, IHH, FGFR3) and the GH–IGF axis (IGF1R, PAPPA2), illustrating the mechanistic diversity underlying ISS. The unique contribution of this figure, compared with previously published conceptual diagrams, is that it integrates three layers within a single schematic: (i) the genetic and biochemical heterogeneity of ISS; (ii) the phenotype-driven decision points (auxology, selective MRI, IGF-1 interpretation, and genetic testing) that move a child away from a generic ISS label; and (iii) the genotype-informed GH-response expectations and the differing FDA, EMA, and PMDA regulatory contexts that shape what can be offered in clinical practice. Together with the new five-step pathway summarised in Fig. 2, Figure 1 is intended to function as an at-a-glance mechanistic and clinical reference rather than as a mechanistic illustration alone.

6. From phenotype to plan: a clinically oriented decision pathway

To make the integrated evidence directly usable at the bedside, we propose a five-step phenotype-driven pathway that translates the present synthesis into routine practice. Step 1 (auxological re-evaluation): confirm the ISS label by re-measuring height, sitting height, arm span, body proportions, mid-parental target height, and growth velocity, and by re-examining for subtle dysmorphic, neurodevelopmental, or skeletal clues that may reclassify the child out of ISS at the outset (3, 5). Step 2 (biochemical core panel): repeat IGF-1 and IGFBP-3 measurement using validated, age- and pubertal-stage-specific reference intervals, and verify exclusion of GH deficiency, hypothyroidism, coeliac disease, renal disease, and Turner syndrome when sex-appropriate (1, 10). Step 3 (selective neuroimaging): reserve pituitary/brain MRI for children with clear red flags – severe short stature with very low IGF-1, multiple pituitary hormone deficiencies, headache or visual symptoms, or polyuria/polydipsia – rather than as a generic adjunct in well-phenotyped ISS, in light of the high incidental-finding rate and limited discriminative value of pituitary morphometry (11,12,13,14,15,16). Step 4 (phenotype-driven genetic testing): start with a chromosomal microarray when developmental or syndromic features are present, prioritise a targeted multigene growth-plate/GH–IGF panel when the phenotype is dominated by familial short stature or mild skeletal clues, and proceed to exome sequencing for unresolved cases or for clearly broader phenotypes; report only pathogenic or likely pathogenic variants as diagnostic and keep VUS clearly separated (2, 3, 5). Step 5 (genotype-informed therapy and counselling): use the genetic result to refine prognosis and treatment expectations, with robust gains anticipated in SHOX deficiency (17, 18, 23), more modest sustained gains in ACAN-related short stature (19), attenuated and still-investigational responses in FGFR3-related hypochondroplasia (24, 25), and an explicit acknowledgement that GH-monotherapy expectations should be tempered in PAPPA2 deficiency and other IGF-bioavailability defects (9). Throughout, decisions should be framed within the locally applicable FDA, EMA, or PMDA approval and reimbursement criteria (22, 23). This five-step pathway is presented schematically in Fig. 2 to complement, rather than duplicate, the mechanistic content of Fig. 1.

Fig. 2.

Proposed five-step phenotype-driven clinical decision pathway for the child labelled with idiopathic short stature (ISS). Figure 2 (proposed; to be supplied as a schematic) translates the present synthesis into a sequential, phenotype-driven decision pathway intended for use at the bedside. Step 1: auxological re-evaluation (height, sitting height, arm span, body proportions, target height, growth velocity, search for subtle dysmorphic, skeletal, or neurodevelopmental clues). Step 2: biochemical core panel (IGF-1 and IGFBP-3 with age- and pubertal-stage-specific reference intervals; verify exclusion of GH deficiency, hypothyroidism, coeliac disease, renal disease, and Turner syndrome when sex-appropriate). Step 3: selective pituitary/brain MRI, reserved for red flags (severe short stature with very low IGF-1, multiple pituitary hormone deficiencies, headache or visual symptoms, polyuria/polydipsia) rather than as a generic adjunct. Step 4: phenotype-driven genetic testing (chromosomal microarray for syndromic/developmental features; targeted multigene growth-plate / GH–IGF panel for familial short stature or mild skeletal clues; exome sequencing for unresolved or broader phenotypes), with pathogenic and likely pathogenic variants reported separately from VUS. Step 5: genotype-informed therapy and counselling, with response expectations stratified by genotype (robust gain in SHOX deficiency; modest sustained gain in ACAN-related short stature; attenuated and still-investigational response in FGFR3-related hypochondroplasia; tempered expectations in PAPPA2 and other IGF-bioavailability defects), and framed within the locally applicable FDA, EMA, or PMDA approval and reimbursement criteria. The authors will provide a graphical version of this five-step pathway as Fig. 2 at acceptance.

Discussion

The present review is intended to complement, not replicate, those papers by integrating genetics, MRI, IGF-1 biology, and GH responsiveness within the narrower clinical context of children initially labeled as ISS (2, 3).

A central conclusion is that ISS should be treated as a working phenotype rather than a stable diagnosis. The term remains clinically useful as a temporary descriptor, but the evidence increasingly supports ongoing reclassification of many such children into growth-plate disorders, GH-IGF pathway disorders, or broader syndromic entities once phenotyping and molecular testing are extended (1, 4, 5).

The heterogeneity of ISS definitions is not a minor methodological issue; it is one of the main reasons why the literature appears inconsistent. Studies differ in height threshold, growth-velocity requirements, GH stimulation criteria, treatment eligibility, skeletal screening, and whether children born small for gestational age are retained or excluded. Therefore, two studies may both claim to investigate ISS while actually sampling clinically different populations (2, 3, 5).

This has direct consequences for interpreting diagnostic yield. The overall exome yield reported in mixed short stature cohorts should not be extrapolated directly to typical isolated ISS. The 2026 systematic review shows that the yield in isolated short stature is substantially lower than in syndromic cases or skeletal dysplasia, which means that the pretest phenotype remains crucial even in the genomic era (2).

The handling of VUS is equally important. VUS should not be treated as solved diagnoses, and this revision now states that they were not counted as diagnostic findings in the narrative synthesis. This distinction is necessary because yield estimates may otherwise be inflated and because uncertain variants do not provide the same clinical confidence for prognosis, family counseling, or treatment planning. The recent systematic review and guideline both support a cautious separation of VUS from pathogenic or likely pathogenic variants (2, 3).

Differences between panels, exome sequencing, and chromosomal microarray should also be interpreted in context rather than as a simple ranking of technologies. Panels may be efficient when the phenotype strongly suggests a growth-plate disorder, whereas exome sequencing becomes more attractive when the phenotype is broader, when multiple mechanisms are plausible, or when panel results are negative. Microarray remains relevant when the child has developmental issues, congenital anomalies, or other features raising concern for copy-number change. In other words, the best test is phenotype dependent, which is precisely why current guidelines emphasize a phenotype-driven algorithm (3).

The neuroimaging component of the original manuscript was also revised to reduce repetition and to acknowledge selection bias more explicitly. The key point is that MRI findings in ISS are not wrong, but they are easily overinterpreted if one forgets who actually gets imaged. In practice, many children with otherwise typical ISS never undergo MRI; those who do are often already enriched for endocrine or neurologic concern. This biases comparisons with GHD cohorts and limits generalizability (11,12,13,14,15,16).

The integration of genotype with IGF-1 interpretation remains clinically important. Disorders such as PAPPA2 deficiency remind us that total IGF-1 concentration does not always reflect IGF bioavailability at the growth plate (9). Likewise, children with IGF1 or IGF1R pathway abnormalities may fall outside classic endocrine categories even though their growth disorder is mechanistically linked to altered GH-IGF signaling (10).

The genotype-dependent GH response section remains one of the strengths of the review. The literature supports a clear distinction between strongly GH-responsive subgroups, such as SHOX deficiency, and more moderately responsive subgroups, such as ACAN-associated short stature (17,18,19). For the broader ISS category, GH is effective on average, but response dispersion is wide because the label pools children with very different mechanisms of growth failure (20).

An additional consideration that has been strengthened in this revision is that the evidence base for GH treatment in ISS-spectrum disorders is not geographically uniform (22). The US FDA approves GH for a generic ISS indication and for SHOX deficiency, whereas the EMA does not recognize a generic ISS label and limits approvals to defined genetic or auxological subgroups; the Japanese PMDA has approved SHOX deficiency on the basis of a Japanese randomized phase 3 trial demonstrating significant height-velocity gain and acceptable safety (23). For other monogenic causes, the strength of evidence is necessarily different: real-world ACAN cohort data show a sustained modest response (19), small FGFR3-related hypochondroplasia studies suggest an attenuated and still-investigational response with concerns about disproportionate growth (24, 25), and PAPPA2 and related IGF-bioavailability defects illustrate that GH-monotherapy expectations must be tempered (9). Reframing the GH section in this way clarifies that genotype, evidence level, and regional regulatory framework jointly determine what can be promised to families at the point of care.

This review has limitations. It is a narrative synthesis and is therefore not exhaustive. It also depends on the quality and phenotype definitions of the cited studies, many of which are observational and subject to referral bias. Nevertheless, by explicitly acknowledging recent high-level evidence, by separating pathogenic findings from VUS, and by reframing MRI and treatment data in their correct clinical context, the revised manuscript now offers a more balanced and clinically relevant contribution.

Conclusion

Children initially classified as ISS do not represent a single biologic entity. The most useful contemporary view is to regard ISS as a temporary clinical phenotype that should be progressively refined through careful auxology, targeted examination for subtle skeletal or syndromic clues, selective neuroimaging when red flags are present, and phenotype-driven genetic testing.

Current evidence suggests that genetic diagnostic yield is clinically meaningful but highly dependent on cohort definition, testing modality, and variant interpretation. Pathogenic or likely pathogenic variants in growth-plate genes, especially ACAN, NPR2, SHOX, and IHH, account for a substantial proportion of reclassified cases, while GH-IGF pathway disorders such as PAPPA2 deficiency help explain biochemical discordance.

Brain and pituitary MRI should not be used routinely to contrast ISS with GHD without acknowledging strong indication bias. Finally, genotype adds practical value by refining prognosis and by providing more individualized expectations for GH response, with particularly favorable data for SHOX deficiency and more moderate but sustained benefit for ACAN-related short stature.

Conflict of interests

The authors have nothing to declare.