Abstract
Background:
Familial short stature (FSS) has traditionally been considered a benign growth pattern characterized by short stature clustering within families and has often been regarded as a normal variant of growth. However, recent advances in genomic technologies have demonstrated that a subset of children presenting with an FSS phenotype harbor identifiable monogenic variants, particularly in genes involved in growth plate development and skeletal growth. These findings challenge the traditional phenotype-based understanding of FSS and support an etiology-oriented diagnostic framework.
Objective:
To summarize current knowledge regarding the genetic architecture of FSS, review existing clinical risk stratification frameworks for genetic evaluation, and evaluate available evidence regarding treatment outcomes across different genetic etiologies.
Methods:
A literature search was performed in PubMed, Embase, and Web of Science from inception to May 2026, using keywords including “familial short stature,” “familial idiopathic short stature,” “genetic testing,” “ACAN,” “SHOX,” and “NPR2”. Relevant original studies and review articles addressing genotype–phenotype correlations, diagnostic yield of genetic testing, or responses to recombinant human growth hormone (rhGH) therapy were considered.
Results:
Emerging evidence indicates that monogenic variants can be identified in a subset of children with an FSS phenotype, especially among those with more severe short stature and autosomal dominant inheritance patterns. Variants affecting growth plate biology represent some of the most frequently reported genetic causes of FSS, with ACAN, SHOX, and NPR2 being the most frequently implicated genes. Existing clinical frameworks based on parental height patterns and inheritance characteristics may help stratify patients with FSS according to the likelihood of monogenic etiology and guide selection of individuals who may benefit from genetic testing. Available evidence suggests that rhGH therapy may improve growth outcomes in several monogenic forms of FSS, although treatment responses vary according to genetic etiology.
Conclusions:
FSS should be regarded as a heterogeneous clinical phenotype rather than a single diagnostic entity. Integration of existing clinical risk stratification approaches with molecular diagnosis may enable more precise identification of underlying genetic causes and facilitate individualized therapeutic decision-making. Future advances in FSS management will likely depend on precision medicine approaches linking phenotype, genotype, and treatment response.
1 Introduction
Familial short stature (FSS) is a clinical descriptive term referring to the recurrent occurrence of short stature within a family after exclusion of overt systemic, endocrine, nutritional, or chromosomal disorders (–).
Historically, FSS has been regarded as a normal variant of growth and has long been considered one of the most common explanations for childhood short stature encountered in pediatric endocrine practice (, ). Early longitudinal studies demonstrated that many children with FSS followed a growth trajectory consistent with their genetic background, leading to the traditional view of FSS as a benign constitutional growth pattern rather than a pathological condition.
In contemporary pediatric endocrinology, children with a short stature who remain undiagnosed after comprehensive clinical evaluation are classified as having idiopathic short stature (ISS) (). Among these individuals, those with a positive family history of short stature are often categorized as familial idiopathic short stature (FISS), a subtype formally recognized by the International Classification of Pediatric Endocrine Diagnoses (ICPED) (). Importantly, FSS and FISS are not synonymous concepts. FSS is a broad phenotypic description based primarily on clinical presentation and family history, whereas FISS is a diagnostic category established only after exclusion of all currently identifiable causes of growth failure ().
Recent advances in next-generation sequencing have fundamentally altered our understanding of the genetic basis of short stature. Human height is recognized as a highly heritable trait influenced by both common variants with small effects and rare variants with larger phenotypic consequences (). Increasing evidence indicates that a subset of children presenting with an FSS phenotype may harbor pathogenic monogenic variants, particularly in genes regulating growth plate development, extracellular matrix (ECM) composition, and endocrine signaling pathways (–).
Several studies have reported that the diagnostic yield of genetic testing is particularly high among children with familial aggregation of short stature, severe height deficits, or additional subtle skeletal abnormalities (–). Consequently, genetic evaluation is increasingly incorporated into the diagnostic assessment of children previously classified as ISS or FSS (, ). Beyond establishing a molecular diagnosis, genetic testing may provide information regarding prognosis, treatment responsiveness, recurrence risk, and family counseling (). However, clear clinical criteria for identifying which children with an FSS phenotype should undergo genetic testing remain incompletely established.
Therefore, the aim of this review is to summarize current evidence regarding the genetic architecture of FSS, review existing clinical risk stratification frameworks for genetic evaluation, and discuss available therapeutic evidence across different genetic subtypes. By integrating phenotype recognition, molecular diagnosis, and genotype-informed treatment considerations, this review provides a clinically oriented perspective on the transition of FSS from a descriptive auxological phenotype toward a genetically informed and clinically meaningful condition.
2 Genetic risk stratification of FSS
2.1 FSS as a clinical phenotype
FSS should primarily be regarded as a clinical phenotype rather than a specific etiological diagnosis. The presence of short stature in multiple family members may reflect the inheritance of numerous common height-associated variants with small effects, but it may also result from transmission of pathogenic variants with major effects on skeletal growth (, , ).
Recent genomic studies have demonstrated that a subset of children presenting with an FSS phenotype harbor identifiable monogenic variants (–, ). Importantly, many of these disorders follow autosomal dominant inheritance patterns and therefore produce family histories that closely resemble classical FSS. Consequently, the observation of short stature in multiple generations should not automatically be interpreted as evidence of benign constitutional inheritance.
The recognition of FSS as a heterogeneous phenotype has important clinical implications. Rather than representing a single diagnostic category, FSS may encompass polygenic short stature, monogenic growth plate disorders, mild skeletal dysplasias, and other inherited growth conditions that may be clinically difficult to distinguish during initial evaluation (, ).
2.2 Clinical risk stratification based on parental height patterns
To improve identification of patients most likely to benefit from genetic testing, Grigoletto et al. proposed a clinically applicable risk stratification framework that categorizes children with an FSS phenotype into autosomal dominant short stature (AD-SS) and constitutional familial short stature (C-FSS) based on parental height patterns (). Importantly, this framework was developed as a clinical risk assessment tool rather than a definitive etiological classification. It aims to estimate the likelihood of monogenic disease and guide prioritization of genetic evaluation (Figure 1).
Figure 1
AD-SS describes children with height SDS ≤−2.0 and at least one parent with height SDS ≤−2.0, suggesting a potential autosomal dominant inheritance pattern (). This group is considered at higher risk for monogenic causes and may represent a priority population for genetic evaluation.
In contrast, C-FSS refers to children whose height falls within the expected target height range based on parental stature, while both parents remain within the normal population range (>−2 SDS) (). In these cases, short stature is more likely to reflect polygenic inheritance rather than a highly penetrant monogenic disorder. Although children classified as C-FSS are generally considered less likely to harbor highly penetrant monogenic disorders, this classification does not exclude the possibility of an underlying genetic defect. Assortative mating between individuals with short stature, variable penetrance, and the coexistence of polygenic and monogenic determinants may result in families in which both parents are short despite the presence of an autosomal dominant pathogenic variant. Therefore, genetic testing may still be appropriate in selected C-FSS patients, particularly when severe short stature, disproportion, abnormal bone age patterns, skeletal abnormalities, or a strong multigenerational family history is present.
Although this classification does not establish a definitive diagnosis, it provides a practical framework for prioritizing genetic investigations in clinical practice and may improve the efficiency of genetic evaluation strategies ().
2.3 Clinical indicators suggesting monogenic etiology
Not all children with an FSS phenotype have the same likelihood of harboring monogenic variants. Several clinical features have been associated with a higher likelihood of identifying pathogenic variants.
The severity of height deficit represents an important predictor of monogenic disease. Studies have shown that the prevalence of pathogenic variants increases as stature becomes progressively shorter, particularly among children with height SDS below −3.0 (, –).
Family history may also provide important clues. The presence of multiple affected individuals across successive generations is suggestive of autosomal dominant inheritance and should raise suspicion for monogenic growth disorders (, ).
In addition, specific auxological and radiological findings may help identify children who warrant genetic evaluation. Disproportionate body segments, mesomelia, Madelung deformity, abnormal bone age patterns, brachydactyly, or subtle skeletal abnormalities have all been associated with pathogenic variants in genes such as SHOX, ACAN, and NPR2 (, –). Even when these abnormalities are mild, their presence may substantially increase the likelihood of establishing a molecular diagnosis.
Collectively, these observations support a phenotype-guided approach in which genetic testing is prioritized for children with severe short stature, dominant familial inheritance patterns, or additional clinical indicators suggestive of specific genetic disorders (, ).
2.4 Clinical implications of risk stratification
The primary goal of risk stratification is not merely to identify genetic variants but to improve clinical management. Establishing a molecular diagnosis may provide information regarding disease mechanisms, expected growth trajectories, treatment responsiveness, and recurrence risk within affected families ().
Increasing evidence suggests that molecular diagnosis may also influence therapeutic decision-making. For example, children with variants in ACAN, SHOX, or NPR2 may show variable but potentially favorable responses to recombinant human growth hormone (rhGH) therapy, whereas treatment outcomes may differ substantially across other genetic etiologies (, , –). Identification of the underlying genetic cause therefore has potential implications for patient selection, treatment timing, and long-term follow-up.
Ultimately, integrating clinical phenotyping with molecular testing represents an important step toward precision medicine in pediatric growth disorders. Such an approach allows clinicians to move beyond descriptive classifications and establish management strategies tailored to the biological basis of individual growth impairment (, , ).
3 Genetic architecture of FSS
3.1 Polygenic and monogenic contributions to FSS
Human height is one of the most heritable quantitative traits, with genetic factors accounting for approximately 80% of the observed variation in adult stature (). Recent large-scale genomic studies have demonstrated that height determination exists on a continuous spectrum, ranging from the cumulative effects of thousands of common variants with small individual effects to rare pathogenic variants with large phenotypic consequences ().
Traditionally, FSS has been regarded as a polygenic trait resulting from the inheritance of multiple height-lowering alleles across generations (). Genome-wide association studies (GWAS) have identified thousands of loci associated with human height, supporting the concept that many individuals with mild FSS represent the lower end of the normal distribution of polygenic growth potential (, , ).
However, the rapid implementation of next-generation sequencing has fundamentally altered this view. Increasing evidence indicates that a considerable proportion of selected children with an FSS phenotype may harbor identifiable monogenic variants. In a landmark cohort study, Plachy et al. reported that pathogenic monogenic variants were detected in approximately 38% of children with FSS, particularly among those with more severe height deficits and autosomal dominant inheritance patterns (). These findings suggest that FSS should no longer be viewed as a purely polygenic condition but rather as a heterogeneous clinical entity encompassing both polygenic and monogenic growth disorders ().
Current evidence indicates that genetic causes of FSS involve several biological pathways, including growth plate development, GH–IGF-1 signaling, intracellular signaling cascades, and ECM organization (, ). Understanding these mechanisms provides the foundation for genetic diagnosis and precision management (Table 1).
Table 1
| Pathway | Gene | Typical phenotype | Reported cases | rhGH-treated cases | Reference |
|---|---|---|---|---|---|
| Growth plate genes | ACAN | • Advanced bone age (variable, may be absent or only mildly advanced in some patients) • Mild brachydactyly • Early growth cessation | 91 | 61 | (, , , , , , –, –) |
| SHOX | • Increased sitting-height/height ratio • Madelung deformity or subtle wrist changes • Short limbs or mesomelic disproportion | 23 | 5 | (, , , , –) | |
| NPR2 | • Mild skeletal abnormalities(subtle hand X-ray changes) • Occasionally disproportionate body segments • No consistent bone age advance | 39 | 32 | (, , , , , –) | |
| FGFR3 | • Mild skeletal dysplasia features • disproportionate short stature • subtle radiographic abnormalities | 6 | 0 | (, , , , ) | |
| GH–IGF1 axis genes | GHSR | • Moderate obesity (elevated BMI) • Relatively low GH peak • Possible family history of short stature with obesity | 5 | 3 | (, , , ) |
| IGF1R | • Intrauterine growth restriction • Persistent postnatal growth impairment | 1 | 0 | (, , –) | |
| GH1 | • Isolated growth hormone deficiency • Proportionate short stature | / | / | (, ) | |
| GHRHR | • Isolated growth hormone deficiency; • Proportionate short stature • Autosomal recessive inheritance | / | / | (, ) | |
| GHR | • GH insensitivity • Low IGF-1 • Severe postnatal growth failure | / | / | (, ) | |
| STAT5B | • GH insensitivity; • Variable immune abnormalities | / | / | (, , ) | |
| IGF1 | • Primary IGF-1 deficiency • Severe prenatal and postnatal growth | / | / | (, ) | |
| RAS/MAPK pathway genes | PTPN11 | • Subtle facial features (hypertelorism, low-set ears) • Possible congenital heart disease | 3 | 0 | (–, ) |
| NF1 | • Skin abnormalities • Mild learning difficulties | 2 | 0 | (–, ) | |
| SOS1 | • Noonan-like phenotype | 2 | 0 | (–, ) | |
| RAF1 | • Noonan-like phenotype | / | / | (, ) | |
| KRAS | • Noonan-like phenotype | / | / | (, ) | |
| SHOC2 | • Noonan-like phenotype | / | / | (, ) | |
| ECM and collagen genes | COL2A1 | • Mild spondyloepiphyseal dysplasia • Joint laxity or early osteoarthritis • Possible myopia | 14 | 5 | (, , –) |
| COL11A1 | • Skeletal abnormalities • Auditory system abnormalities | 10 | 4 | (, , –) | |
| COL11A2 | • Bone fragility or blue sclera • Dentinogenesis imperfecta (mild) | 4 | 3 | (, –) | |
| COL9A1 | • Multiple epiphyseal dysplasia • Early-onset osteoarthritis | / | / | (, , , ) | |
| COL9A2 | • Multiple epiphyseal dysplasia; • Early-onset osteoarthritis | / | / | (, , , ) | |
| COL9A3 | • Multiple epiphyseal dysplasia • Early-onset osteoarthritis | / | / | (, , , ) | |
| COL10A1 | • Schmid metaphyseal chondrodysplasia • Bowed legs • Waddling gait | / | / | (, , ) | |
| Other emerging genes | TRHR | • Insufficient data | 2 | 0 | (, ) |
| MBTPS2 | • Insufficient data | 2 | 0 | (, ) | |
| IGFALS | • Insufficient data | 2 | 0 | (, ) | |
| HMGA2 | • Insufficient data | 2 | 0 | (, ) | |
| OTX2 | • Insufficient data | 1 | 0 | () | |
| MATN3 | • Insufficient data | 1 | 0 | () | |
| FLNB | • Insufficient data | 1 | 0 | () | |
| SALL4 | • Insufficient data | 1 | 0 | () | |
| Total | / | / | 212 | 113 | / |
Monogenic causes of familial short stature and their characteristic phenotypes.
“/” denotes the absence of reported FSS-specific cases.Bold values indicate the total number of reported cases and rhGH-treated cases among the listed monogenic causes of familial short stature.
3.2 Growth plate genes: the major contributors of monogenic FSS
Growth plate dysfunction has emerged as the predominant mechanism underlying monogenic FSS (, ). The growth plate is a highly organized cartilage structure responsible for longitudinal bone growth, and disruption of chondrocyte proliferation, differentiation, or ECM formation may result in impaired linear growth.
Among currently identified monogenic causes, pathogenic variants in the ACAN gene represent the most frequently reported genetic defect associated with FSS (, ). ACAN encodes aggrecan, a major proteoglycan component of the ECM within growth plate cartilage. Aggrecan provides structural support and hydration to cartilage tissue and is essential for normal endochondral ossification (, –). Several studies have demonstrated that ACAN variants are enriched in FSS cohorts. Furthermore, the prevalence of ACAN variants increases with increasing severity of parental short stature, suggesting a strong genotype–phenotype correlation (, , ). Advanced bone age is traditionally considered a characteristic feature of ACAN-related short stature (). Nevertheless, subsequent studies have demonstrated considerable phenotypic variability, with some patients exhibiting normal or even delayed bone age (, ). Therefore, the absence of advanced bone age should not exclude ACAN testing when clinical suspicion is high. Expanding evidence from large cohort studies has further characterized the phenotypic spectrum of ACAN-related short stature, demonstrating considerable variability in bone age patterns, skeletal manifestations, and treatment responses (–).
The SHOX gene is located within the pseudoautosomal region of the X and Y chromosomes and plays a critical role in growth plate development (). SHOX functions as a transcription factor regulating chondrocyte proliferation and differentiation. Haploinsufficiency of SHOX leads to a broad phenotypic spectrum ranging from isolated short stature to Leri–Weill dyschondrosteosis and Langer mesomelic dysplasia (, , ). Body disproportion remains one of the most important clinical clues for identifying SHOX deficiency. Increased sitting-height-to-height ratio and abnormal extremity-to-trunk ratio have been proposed as useful screening markers in children with FSS (–).
The NPR2 gene encodes natriuretic peptide receptor-B (NPR-B), the primary receptor for C-type natriuretic peptide (CNP) (). Activation of the CNP/NPR-B signaling pathway stimulates cyclic guanosine monophosphate (cGMP) production and promotes chondrocyte proliferation while antagonizing FGFR3-mediated growth inhibition (). Recent studies have demonstrated that heterozygous NPR2 variants are relatively common among children with FSS, with reported detection rates ranging from 5.7% to 13.6% (, ). Long-term observational studies further suggest that NPR2-related short stature exhibits substantial phenotypic heterogeneity but generally favorable responses to growth hormone treatment (). Functional studies have suggested that NPR2 variants may influence chondrocyte differentiation through additional signaling pathways, including JAK2-STAT5 signaling ().
The FGFR3 gene encodes fibroblast growth factor receptor 3, a key negative regulator of growth plate activity. Activation of FGFR3 signaling inhibits chondrocyte proliferation and differentiation through downstream pathways such as MAPK signaling, thereby restricting endochondral bone growth. Pathogenic FGFR3 variants are classically associated with skeletal dysplasias, including achondroplasia and hypochondroplasia (). However, milder variants may occasionally present with relatively isolated short stature and mimic an FSS phenotype (). Therefore, FGFR3-related disorders should be considered in children with disproportionate short stature, subtle skeletal abnormalities, or atypical features suggestive of growth plate dysfunction.
Collectively, ACAN, SHOX, and NPR2, and other growth plate-related genes such as FGFR3 represent important genetic contributors to monogenic short stature, although their phenotypic spectrum extends beyond classic FSS.
3.3 GH–IGF-1 axis-related genes
The GH–IGF-1 axis is a critical endocrine pathway regulating childhood growth. Although growth plate defects represent the predominant genetic mechanism underlying monogenic FSS, variants affecting GH secretion, receptor signaling, or IGF-1 action may occasionally present with familial clustering of short stature and overlap phenotypically with FSS and should be considered during genetic evaluation ().
Genetic abnormalities involving the GH–IGF-1 axis can impair growth through defects in hormone production, receptor activation, or downstream signaling. Defects affecting GH secretion include pathogenic variants in GH1, GHRHR, and GHSR, which may impair GH synthesis, hypothalamic regulation, or ghrelin-mediated stimulation of GH release, respectively, resulting in reduced activation of the GH–IGF-1 axis (–). Although these disorders are generally classified as isolated growth hormone deficiency (IGHD) rather than FSS, milder forms may present with an FSS phenotype and are clinically relevant because affected individuals may benefit from rhGH therapy.
Abnormalities in GH signaling and IGF-1 action represent additional mechanisms of growth impairment. Pathogenic variants in GHR, encoding the growth hormone receptor, cause GH insensitivity syndrome through impaired GH signaling and reduced IGF-1 production (). Similarly, defects in downstream signaling components such as STAT5B may result in impaired GH signaling, short stature, and variable immune abnormalities (, ). Variants affecting IGF1 or IGF1R may directly impair IGF-1 production or cellular responsiveness to IGF-1, respectively, leading to growth impairment in affected individuals (–).
Although GH–IGF-1 axis-related disorders are less frequently identified than growth plate defects in FSS cohorts, their recognition remains clinically important because molecular diagnosis may influence endocrine evaluation, treatment selection, and interpretation of response to rhGH therapy.
3.4 RAS/MAPK signaling pathway genes
The RAS/MAPK signaling pathway is a highly conserved intracellular cascade that regulates cell proliferation, differentiation, and developmental processes. Abnormal activation or dysregulation of this pathway can affect skeletal growth and contribute to short stature, particularly in individuals with RASopathies (, ).
Pathogenic variants in genes involved in the RAS/MAPK pathway, including PTPN11, SOS1, RAF1, KRAS, and SHOC2, are primarily associated with Noonan syndrome and related disorders (, ). Although many affected individuals exhibit characteristic syndromic features, some individuals may have mild or atypical presentations dominated by growth impairment, potentially leading to misclassification as FSS.
Among these genes, PTPN11 is one of the most frequently implicated genes in Noonan syndrome and plays an important role in regulating intracellular growth signaling. Other pathway genes, including SHOC2 and KRAS, have been associated with variable phenotypic presentations ranging from typical RASopathies to milder growth abnormalities ().
Therefore, children with an FSS phenotype accompanied by dysmorphic features, developmental abnormalities, cardiac manifestations, or other syndromic clues should undergo careful clinical reassessment and consideration of molecular testing. Identification of RAS/MAPK pathway variants not only clarifies diagnosis but also provides important information regarding prognosis, surveillance, and genetic counseling.
3.5 ECM and collagen genes
The ECM provides structural support for growth plate cartilage and is essential for normal endochondral ossification. Genetic defects affecting ECM components may disrupt cartilage organization and longitudinal bone growth, resulting in a broad spectrum of skeletal phenotypes ranging from mild short stature to recognizable skeletal dysplasias ().
Several collagen genes involved in cartilage development have been associated with short stature phenotypes that may overlap with FSS. Variants in COL2A1, COL11A1, and COL11A2 are well-established causes of type II collagenopathies and can present with variable degrees of skeletal involvement, including disproportionate or proportionate short stature (–). In addition, defects in other cartilage-related collagen genes, including COL9A1, COL9A2, COL9A3, and COL10A1, have been associated with growth plate abnormalities and skeletal dysplasia phenotypes that may overlap with short stature presentations (–). However, these conditions usually belong to the skeletal dysplasia spectrum rather than representing classic FISS. Careful clinical evaluation for subtle skeletal features is therefore required.
Therefore, ECM and skeletal development-related genes represent an important but less common category of genetic causes in children presenting with an FSS phenotype. Recognition of these disorders is particularly relevant in patients with disproportion, abnormal radiographic findings, advanced bone age, or other subtle skeletal manifestations, in whom genetic evaluation may clarify diagnosis and guide clinical management.
3.6 From genetic architecture to precision diagnosis
The expanding understanding of FSS genetics has shifted the diagnostic paradigm from a phenotype-based classification toward a molecularly informed approach. FSS should be considered a genetically heterogeneous phenotype encompassing both polygenic growth variation and monogenic growth disorders (, ).
Genetic testing should be prioritized in children with clinical features suggestive of monogenic disease, including severe short stature, autosomal dominant inheritance, body disproportion, abnormal bone age, skeletal abnormalities, or additional syndromic features (–, ). Identification of pathogenic variants can refine diagnosis, improve genetic counseling, provide prognostic information, and influence therapeutic decision-making.
The increasing availability of next-generation sequencing has further expanded the feasibility of molecular diagnosis. Recent studies have demonstrated meaningful diagnostic yields of exome sequencing in children with short stature, particularly among those with additional clinical abnormalities or unexplained growth impairment (, ).
Therefore, integrating auxological characteristics, family history, and genomic information represents an essential step toward precision diagnosis in FSS. Future strategies should focus on developing risk stratification models to identify individuals most likely to benefit from genetic testing and individualized growth management (, , ).
4 Treatment and future therapeutic perspectives
4.1 Principles of rhGH therapy in FSS
At present, no specific international guidelines exist for the management of FSS. In clinical practice, therapeutic decisions are largely extrapolated from recommendations for ISS, particularly when patients fulfill regulatory criteria for rhGH treatment.
Historically, FSS was considered a benign growth variant with limited therapeutic implications. However, increasing recognition of monogenic growth disorders within the FSS spectrum has demonstrated substantial heterogeneity in treatment responsiveness.
The response to rhGH therapy is influenced by multiple factors, including age at treatment initiation, baseline height SDS, pubertal status, treatment duration, bone age, and underlying genetic etiology. Earlier initiation and longer treatment duration are generally associated with greater height gain across different causes of short stature, reflecting the preservation of residual growth potential rather than an ACAN-specific phenomenon.
Therefore, genetic diagnosis may provide additional information beyond confirming etiology, helping clinicians predict treatment responsiveness, optimize timing of intervention, and establish individualized management strategies ().
4.2 Genotype-specific responses to rhGH therapy
4.2.1 ACAN-related FSS
ACAN-related FSS represents the monogenic FSS subtype with the largest body of clinical evidence regarding rhGH treatment response (, ).
Published studies have reported improvements in height SDS ranging from +0.1 to +1.9 after rhGH treatment (, , , , , , –). Treatment response appears to be influenced by several factors. In ACAN-related patients, however, treatment timing may be particularly critical because accelerated skeletal maturation may reduce the duration of effective growth-promoting therapy.
Our exploratory analysis of published individual-level data suggested a numerical difference in short-term height SDS improvement according to skeletal maturation status (Table 2), with higher values observed in patients with advanced bone age. However, this finding should not be interpreted as evidence that advanced bone age predicts better rhGH responsiveness, given the limited sample size and substantial heterogeneity in treatment duration, age at initiation, and genetic background.
Table 2
| Gene | N (with outcome) | Age at GH initiation (years), median (IQR) | Baseline height SDS, median (IQR) | ΔHeight SDS, median (IQR) | Key observations |
|---|---|---|---|---|---|
| ACAN | 61 | 6.4(4.1–9.5) | –3.2(–3.8 to–2.7) | +0.6(+0.2 to+1.0) | Better outcomes with earlier treatment; advanced bone age may limit response |
| SHOX | 5 | 6.0(4.0–7.5) | −3.2(−3.6 to−2.8) | +0.7(+0.4 to+0.9) | Approved indication; consistent growth improvement |
| NPR2 | 32 | 7.5(4.6–11.7) | −3.1(−3.7 to−2.6) | +0.9(+0.4 to+1.6) | Generally favorable response; possible genotype-specific differences |
Summary of rhGH treatment outcomes in major monogenic forms of familial short stature.
N indicates the number of patients with available pre- and post-treatment height SDS data used to calculate median ΔSDS.
For ACAN, 61 patients received rhGH in the literature; for NPR2, 23 patients received rhGH. Data were extracted from published cases (see Supplementary Tables S1-S4 for individual patient data).
Unlike many other genetic causes of short stature, ACAN-related FSS is often, although not invariably, associated with advanced skeletal maturation, which represents an important therapeutic challenge by reducing the remaining period of linear growth (). However, skeletal maturation abnormalities are variable, and some individuals may present with normal or only mildly advanced bone age, reflecting the intrinsic growth plate dysfunction caused by aggrecan deficiency rather than accelerated skeletal maturation alone.
Because advanced bone age may accelerate epiphyseal fusion, adjunctive approaches aimed at delaying skeletal maturation have been considered in selected ACAN-related patients. Gonadotropin-releasing hormone analogs (GnRHa) have been explored as an adjunctive approach to suppress pubertal progression and potentially prolong the growth period, although current evidence remains limited and is primarily based on small observational studies ().
In addition, aromatase inhibitors (AIs), including anastrozole and letrozole, have been investigated as adjunctive therapies with rhGH to delay epiphyseal maturation and prolong the period of linear growth, particularly in pubertal boys with limited growth potential (). However, evidence supporting AI use specifically in ACAN-related short stature is currently lacking, and available data mainly derive from boys with idiopathic short stature or GH deficiency (, ).
Recent real-world data further confirm the effectiveness of rhGH in ACAN-deficient children and support early molecular diagnosis to maximize treatment opportunities ().
4.2.2 SHOX-related FSS
SHOX deficiency is currently the only monogenic form of FSS for which rhGH therapy has received regulatory approval. The FDA approved rhGH treatment for SHOX deficiency in 2006 based on randomized clinical trials demonstrating significant improvements in height velocity and adult height outcomes (, ). Although SHOX defects account for approximately 2%–15% of children with short stature in unselected ISS cohorts (), the prevalence in strictly defined FSS cohorts may be lower or remains to be fully determined, and only a limited number of studies have specifically reported treatment outcomes in patients meeting strict criteria for FSS (, ).
Available evidence suggests that rhGH treatment is highly effective in SHOX-related FSS, with reported gains in height SDS ranging from +0.4 to +1.94 (, –). Interestingly, genotype may influence treatment response. Preliminary observations indicate that patients carrying coding-region variants may exhibit greater growth responses than those with enhancer-region deletions, although larger studies are needed to confirm this finding.
Overall, SHOX deficiency currently represents one of the strongest examples of successful genotype-guided therapy in pediatric growth disorders.
4.2.3 NPR2-related FSS
The NPR2 gene encodes natriuretic peptide receptor-B (NPR-B), a key component of the CNP signaling pathway involved in growth plate regulation. Heterozygous NPR2 variants represent one of the most frequently identified monogenic causes of FSS (, ).
To date, approximately 80% of reported NPR2-related FSS patients have received rhGH therapy (). Across published cohorts, the mean improvement in height SDS is approximately +1.0, indicating a generally favorable therapeutic response (, , , , , –).
Interestingly, genotype-specific differences may exist. Recent observations suggest that patients carrying truncating variants may achieve greater height gains than those with missense variants, although this finding requires confirmation in larger cohorts ().
The multicenter real-world study by Renes et al. confirmed sustained growth acceleration during long-term rhGH therapy in children with NPR2 haploinsufficiency, supporting rhGH as an effective treatment option for this subgroup ().
Taken together, current evidence indicates that ACAN-, SHOX-, and NPR2-related FSS represent the monogenic FSS subtypes with the strongest evidence supporting rhGH efficacy (Table 3). However, the majority of available evidence remains derived from observational studies, and genotype-specific treatment algorithms have not yet been established.
Table 3
| Skeletal maturation category | N | Age at GH initiation (y) median(IQR) | ΔHeight SDS | 1st-year ΔHeight SDS | ΔHeight SDS/year | |||
|---|---|---|---|---|---|---|---|---|
| Median(IQR) | Range | Median(IQR) | Range | Median(IQR) | Range | |||
| Advanced bone age | 26 | 6.45 (4.35-11.6) | 0.55 (0.23-0.82) | −0.71 to 1.90 | 0.80 (0.40-0.80) | 0.22 to 1.80 | 0.53(0.26–0.90) | 0.09 to 1.74 |
| Normal or delayed bone age | 17 | 7.9 (6-11.8) | 0.40 (0.08-0.80) | −0.30 to 1.85 | 0.25 (0.03-0.60) | -0.03 to 1.30 | 0.38 (0.02–0.60) | 0 to 1.85 |
Exploratory comparison of rhGH treatment outcomes according to skeletal maturation status in children with ACAN-related short stature.
N denotes the number of patients with available data for the corresponding outcome. ΔHeight SDS represents the change in height SDS from baseline to the last follow-up. First-year growth response data were available from a limited number of studies (advanced bone age: n=5; normal/delayed bone age: n=7). Annualized ΔHeight SDS was calculated among patients treated for ≥1 year (advanced bone age: n=11; normal/delayed bone age: n=11). No formal statistical comparison was performed due to heterogeneity among published studies and limited sample size. Individual patient-level data are provided in Supplementary Table S2.
4.3 Emerging precision therapies
The expanding understanding of the molecular mechanisms underlying FSS has stimulated interest in targeted therapies that directly address disease-specific pathways rather than relying solely on growth hormone stimulation.
4.3.1 CNP analogs
The CNP pathway has emerged as one of the most promising therapeutic targets in skeletal growth disorders.
Activation of NPR-B signaling stimulates chondrocyte proliferation and ECM synthesis while antagonizing FGFR3-mediated growth inhibition. Because NPR2 and FGFR3 play critical roles in several forms of monogenic short stature, pharmacological enhancement of CNP signaling has attracted considerable attention (, ).
Vosoritide, a long-acting CNP analog, has demonstrated efficacy in promoting linear growth in children with achondroplasia in randomized clinical trials (). Long-term extension studies have further shown sustained increases in growth velocity with continued treatment and with continued monitoring of safety outcomes (, ).
Although currently approved only for achondroplasia, its mechanism of action suggests potential applicability to selected forms of FSS involving abnormalities of the NPR2/CNP/FGFR3 axis. Future clinical studies are needed to evaluate its role in genetically defined FSS populations. Emerging evidence also suggests that CNP can mediate skeletal growth even in the absence of growth hormone, raising the possibility that CNP analogs might benefit selected patients with FSS who do not respond optimally to rhGH ().
4.3.2 RNA-based therapeutic strategies
Recent advances in RNA therapeutics and extracellular vesicle-based delivery systems have opened new possibilities for mechanism-based treatment strategies ().
In a landmark preclinical study, Yuan et al. developed engineered exosomes capable of delivering growth plate-targeted siRNA and growth hormone molecules. In animal models of ISS, silencing of the long non-coding RNA ISSRL significantly enhanced growth plate activity and promoted longitudinal bone growth ().
Although these approaches remain experimental, they represent an important proof of concept for future precision therapies capable of correcting disease mechanisms at the molecular level.
4.3.3 Gene-based therapies
Rapid advances in genome editing technologies, including CRISPR-Cas systems and gene replacement approaches, have generated interest in potential future therapies for monogenic growth disorders (, ).
Although clinical application remains distant, disorders caused by haploinsufficiency of genes such as ACAN, SHOX, and NPR2 may theoretically become candidates for future gene-targeted approaches. Continued progress in gene-editing safety and delivery systems will be essential before such approaches can enter clinical practice.
4.4 Future perspectives for precision management
The management of FSS is undergoing a transition from phenotype-based treatment toward genotype-guided precision medicine.
Historically, treatment decisions were based primarily on auxological criteria, including height SDS, growth velocity, and predicted adult height. However, accumulating evidence demonstrates that identical phenotypes may arise from markedly different molecular mechanisms, each associated with distinct prognostic and therapeutic implications.
Future clinical management is therefore likely to involve three integrated components: early clinical risk stratification, identifying patients at increased likelihood of monogenic disease; comprehensive genomic testing, enabling precise molecular diagnosis; mechanism-based therapy, including rhGH, CNP analogs, RNA therapeutics, and future gene-targeted interventions.
Under this framework, the traditional concept of FSS as a benign familial growth variant is being replaced by a biologically informed model linking phenotype, genotype, and treatment response (). Such an approach has the potential to improve diagnostic accuracy, optimize therapeutic outcomes, and ultimately establish precision growth medicine as the standard of care for children with FSS.
5 Limitations and future directions
Despite the significant progress summarized in this review, several limitations should be acknowledged. First, most of the included studies originated from tertiary referral centers, which may introduce selection bias and overestimate the true prevalence of monogenic variants in the general FSS population. Second, the majority of evidence on treatment responses comes from observational studies or small cohorts; large, prospective randomized controlled trials comparing rhGH responses across different genetic etiologies are still lacking. Third, the clinical utility of polygenic risk scores (PRS) in differentiating benign C-FSS from monogenic AD-SS remains unexplored. Fourth, data on non-European populations are limited, and the generalizability of current findings to diverse ethnic groups requires further validation.
Looking forward, several key questions warrant investigation. (1) Can PRS be integrated with clinical parameters to improve the pretest probability of finding a monogenic variant? (2) What are the long-term safety and efficacy profiles of CNP analogs and RNA-based therapies in children with FSS, particularly regarding growth plate-specific delivery and off-target effects? (3) How should the clinical definition of FSS be updated to incorporate molecular findings, and what are the implications for diagnostic coding and clinical management? Addressing these questions will be essential for translating current genetic knowledge into tangible improvements in patient care.
6 Conclusion
FSS should no longer be considered a single clinical entity or merely a benign familial growth variant. Emerging evidence demonstrates that FSS represents a biologically heterogeneous spectrum encompassing both polygenic inheritance and a substantial proportion of monogenic growth disorders.
Recent advances in genomic medicine have fundamentally reshaped the understanding of FSS by revealing the important contribution of pathogenic variants in growth plate genes, GH–IGF-1 axis genes, RAS/MAPK signaling genes, and extracellular matrix-related genes. Among these, defects involving ACAN, SHOX, and NPR2 appear to account for a significant proportion of genetically diagnosed cases.
The existing clinical risk stratification framework provides a practical approach for identifying patients most likely to benefit from genetic testing. Furthermore, accumulating evidence indicates that treatment response varies according to genetic etiology, highlighting the importance of integrating molecular diagnosis into therapeutic decision-making.
As precision medicine continues to evolve, future management of FSS will increasingly depend on the combination of clinical phenotyping, genomic testing, and mechanism-based therapies. This transition from phenotype-based classification to genotype-guided management has the potential to improve diagnostic accuracy, optimize therapeutic outcomes, and establish a new paradigm for the care of children with FSS.
Statements
Author contributions
CZ: Writing – review & editing, Writing – original draft, Visualization, Conceptualization. NW: Writing – review & editing. MG: Writing – review & editing. MY: Writing – review & editing. LM: Writing – review & editing. YX: Writing – review & editing.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This research was supported by the National Natural Science Foundation of China (No.81700706), and Beijing Huaxia Charity Foundation (No.01).
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declared that generative AI was not used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fendo.2026.1890896/full#supplementary-material
References
1
TannerMJ. Human Growth. Oxford; New York: Pergamon Press (1960).
2
LaceyKAParkinJM. The normal short child. Community study of children in Newcastle upon Tyne. Arch Dis Child. (1974) 49:417–24. doi: 10.1136/adc.49.6.417
3
VimpaniGVVimpaniAFPocockSJFarquharJW. Differences in physical characteristics, perinatal histories, and social backgrounds between children with growth hormone deficiency and constitutional short stature. Arch Dis Child. (1981) 56:922–8. doi: 10.1136/adc.56.12.922
4
Consortium Icped. International Classification of Pediatric Endocrine Diagnoses. 1C.1 Familial Idiopathic Short Stature. Available online at: http://www.icped.org (Accessed January 12, 2026).
5
PaparellaRBeiABernabeiITaraniFNicetaMPucarelliIet al. Idiopathic short stature in the genomic era: Integrating auxology, endocrinology, and emerging genetic insights. Children (Basel). (2025) 12(7):855. doi: 10.3390/children12070855
6
BicknellLSHirschhornJNSavarirayanR. The genetic basis of human height. Nat Rev Genet. (2025) 26(9):604–19. doi: 10.1038/s41576-025-00834-1
7
DauberA. Genetic testing for the child with short stature-has the time come to change our diagnostic paradigm? J Clin Endocrinol Metab. (2019) 104:2766–9. doi: 10.1210/jc.2019-00019
8
PlachyLPetruzelkovaLDusatkovaPMaratovaKZemkovaDElblovaLet al. Analysis of children with familial short stature: Who should be indicated for genetic testing? Endocr Connect. (2023) 12(10):e230238. doi: 10.1530/ec-23-0238
9
PlachyLDusatkovaPAmaratungaSANeumanVSumnikZLeblJet al. Monogenic causes of familial short stature. Front Endocrinol (Lausanne). (2024) 15:1506323. doi: 10.3389/fendo.2024.1506323
10
PlachyLStrakovaVElblovaLObermannovaBKolouskovaSSnajderovaMet al. High prevalence of growth plate gene variants in children with familial short stature treated with GH. J Clin Endocrinol Metab. (2019) 104:4273–81. doi: 10.1210/jc.2018-02288
11
ZhouEHauserBRJeeYH. Genetic evaluation in children with short stature. Curr Opin Pediatr. (2021) 33:458–63. doi: 10.1097/mop.0000000000001033
12
ZhaoQZhangMLiYZhangCZhangYShaoQet al. Molecular diagnosis is an important indicator for response to growth hormone therapy in children with short stature. Clin Chim Acta. (2024) 554:117779. doi: 10.1016/j.cca.2024.117779
13
LinYJChengCFWangCHLiangWMTangCHTsaiLPet al. Genetic architecture associated with familial short stature. J Clin Endocrinol Metab. (2020) 105(6):1801–13. doi: 10.1210/clinem/dgaa131
14
GrigolettoVOcchipintiAAPellegrinMCSirchiaFBarbiETorneseG. Definition and prevalence of familial short stature. Ital J Pediatr. (2021) 47:56. doi: 10.1186/s13052-021-01018-3
15
HuXGuiBSuJLiHLiNYuTet al. Novel pathogenic ACAN variants in non-syndromic short stature patients. Clin Chim Acta. (2017) 469:126–9. doi: 10.1016/j.cca.2017.04.004
16
AndradeNLMCellinLPRezendeRCVasquesGAJorgeAAL. Idiopathic short stature: What to expect from genomic investigations. (2023) 4:1–17. doi: 10.3390/endocrines4010001
17
Adanur SaglamKBekfilaviogluSYıldız BoyrazACimbekEAOzdenATurkyilmazAet al. Genetic heterogeneity in pediatric short stature: Insights from whole exome sequencing and snp- array analyses in a Turkish cohort. Eur J Pediatr. (2025) 184:680. doi: 10.1007/s00431-025-06529-3
18
GuazzarottiLMozzatoCZolettoSBoarettoFRigonCCassinaM. Optimising diagnosis in children with short stature: An integrated clinical and NGS approach. Endocr Connect. (2025) 14(9):e250229. doi: 10.1530/ec-25-0229
19
BinderG. Short stature due to SHOX deficiency: Genotype, phenotype, and therapy. Horm Res Paediatr. (2011) 75:81–9. doi: 10.1159/000324105
20
GkourogianniAAndrewMTyzinskiLCrockerMDouglasJDunbarNet al. Clinical characterization of patients with autosomal dominant short stature due to aggrecan mutations. J Clin Endocrinol Metab. (2017) 102:460–9. doi: 10.1210/jc.2016-3313
21
HuangHJinJXiangRWangX. Case report: A novel heterozygous frameshift mutation of ACAN in a Chinese family with short stature and advanced bone age. Front Genet. (2023) 14:1101695. doi: 10.3389/fgene.2023.1101695
22
PlachyLDusatkovaPMaratovaKPetruzelkovaLZemkovaDElblovaLet al. NPR2 variants are frequent among children with familiar short stature and respond well to growth hormone therapy. J Clin Endocrinol Metab. (2020) 105(3):e746–52. doi: 10.1210/clinem/dgaa037
23
RenesJSReedijkAMJLosekootMKantSGVan Der SteenMVan Der KaayDCMet al. Clinical characteristics of pathogenic ACAN variants and 3-year response to growth hormone treatment: Real-world data. Horm Res Paediatr. (2024) 97:456–69. doi: 10.1159/000535651
24
RenesJSReedijkAMJHokken-KoelegaACSHendriksYMCBakkerBBootAMet al. Clinical characteristics and response to growth hormone treatment in 27 children with heterozygous NPR2 variants: Real-world data. J Clin Endocrinol Metab. (2025) 111:e166–74. doi: 10.1210/clinem/dgaf309
25
DauberAJorgeAALNilssonODekkersOMArgenteJNetchineIet al. International guideline on genetic testing of children with short stature. Eur J Endocrinol. (2026) 194:R17–r36. doi: 10.1093/ejendo/lvag013
26
CohenLERogolAD. Children with idiopathic short stature: An expanding role for genetic investigation in their medical evaluation. Endocr Pract. (2024) 30:679–86. doi: 10.1016/j.eprac.2024.04.009
27
NilssonOGuoMHDunbarNPopovicJFlynnDJacobsenCet al. Short stature, accelerated bone maturation, and early growth cessation due to heterozygous aggrecan mutations. J Clin Endocrinol Metab. (2014) 99:E1510–1518. doi: 10.1210/jc.2014-1332
28
QuintosJBGuoMHDauberA. Idiopathic short stature due to novel heterozygous mutation of the aggrecan gene. J Pediatr Endocrinol Metab. (2015) 28:927–32. doi: 10.1515/jpem-2014-0450
29
Sentchordi-MontanéLAza-CarmonaMBenito-SanzSBarreda-BonisACSánchez-GarreCPrieto-MatosPet al. Heterozygous aggrecan variants are associated with short stature and brachydactyly: Description of 16 probands and a review of the literature. Clin Endocrinol (Oxf). (2018) 88:820–9. doi: 10.1111/cen.13581
30
StavberLHovnikTKotnikPLovrečićLKovačJTesovnikTet al. High frequency of pathogenic ACAN variants including an intragenic deletion in selected individuals with short stature. Eur J Endocrinol. (2020) 182:243–53. doi: 10.1530/eje-19-0771
31
LinLLiMLuoJLiPZhouSYangYet al. A high proportion of novel ACAN mutations and their prevalence in a large cohort of Chinese short stature children. J Clin Endocrinol Metab. (2021) 106:e2711–9. doi: 10.1210/clinem/dgab088
32
DengSHouLXiaDLiXPengXXiaoXet al. Description of the molecular and phenotypic spectrum in Chinese patients with aggrecan deficiency: Novel ACAN heterozygous variants in eight Chinese children and a review of the literature. Front Endocrinol (Lausanne). (2022) 13:1015954. doi: 10.3389/fendo.2022.1015954
33
WuSWangCCaoQZhuZLiuQGuXet al. The spectrum of ACAN gene mutations in a selected Chinese cohort of short stature: Genotype-phenotype correlation. Front Genet. (2022) 13:891040. doi: 10.3389/fgene.2022.891040
34
TatsiCGkourogianniAMohnikeKDearmentDWitchelSAndradeACet al. Aggrecan mutations in nonfamilial short stature and short stature without accelerated skeletal maturation. J Endocr Soc. (2017) 1:1006–11. doi: 10.1210/js.2017-00229
35
TriguiMPallares-RuizNGenevièveDAmourouxCEdouardTSigaudySet al. Expanding the molecular spectrum of aggrecanopathies: Exploring 24 patients with ACAN significant variants. Eur J Hum Genet. (2025) 33:1647–54. doi: 10.1038/s41431-025-01943-5
36
PattaniNPageABarberJLDel Rey JimenezJCAlstersSAlbaneseAet al. ACAN-related disorder, antenatal presentation and phenotypic variability: A case series. J Med Genet. (2026) 63(7):456–62. doi: 10.1136/jmg-2025-111354
37
SosinATkachukTFurtakAJaneczkoMStożekKKsiążekTet al. Aggrecanopathy as an underrecognized cause of idiopathic short stature: The importance of early genetic confirmation for timely diagnosis and management-case reports and literature review. Diseases. (2026) 14(4):127. doi: 10.3390/diseases14040127
38
ChenYWuSGuW. Research progress of short stature and advanced bone age, early-onset osteoarthritis and osteochondritis dissecans (SSOAOD) caused by acan gene mutation. (2026) 17:1809260. doi: 10.3389/fendo.2026.1809260
39
GürsoySHazanFAykutANalbantoğluÖKorkmazHADemirKet al. Detection of SHOX gene variations in patients with skeletal abnormalities with or without short stature. J Clin Res Pediatr Endocrinol. (2020) 12:358–65. doi: 10.4274/jcrpe.galenos.2020.2019.0001
40
LiuLLiJLiJHuHLiuJTangP. Novel heterozygous mutation in the SHOX gene leading to familial idiopathic short stature: A case report and literature review. Med (Baltimore). (2023) 102:e35471. doi: 10.1097/md.0000000000035471
41
HodaxJKDivallSA. Update on methods to enhance growth. Curr Opin Endocrinol Diabetes Obes. (2020) 27:82–6. doi: 10.1097/med.0000000000000513
42
Gao-Hui ZhuMin Zhu. Clinical applications of body proportion in children. Chin J Pract Pediatr. (2022) 37:579–83. doi: 10.19538/j.ek2022080604
43
Hui LiHua-Hong WuYa-Qin ZhangXin-Na Zong. Growth charts of sitting-height/leg length ratio and sitting-height/height ratio for Chinese children and adolescents aged 0-18 years. (2023) 18:298–302. doi: 10.3969/j.issn.1673-5501.2023.04.010
44
YuanKChenJChenQChenHZhuJFangYet al. NPR2 gene variants in familial short stature: A single-center study. J Pediatr Endocrinol Metab. (2022) 35:185–90. doi: 10.1515/jpem-2021-0332
45
WeiSHeMZhangCLiYZhangMHouXet al. Identification of NPR2 gene mutations affecting chondrocyte differentiation in short stature through JAK2-STAT5. Orphanet J Rare Dis. (2025) 20:392. doi: 10.1186/s13023-025-03936-5
46
ZhangXJiangSZhangRGuoSShengQWangKet al. Review of published 467 achondroplasia patients: Clinical and mutational spectrum. Orphanet J Rare Dis. (2024) 19:29. doi: 10.1186/s13023-024-03031-1
47
KantSGCervenkovaIBalekLTrantirekLSantenGWDe VriesMCet al. A novel variant of FGFR3 causes proportionate short stature. Eur J Endocrinol. (2015) 172:763–70. doi: 10.1530/eje-14-0945
48
MastromauroCChiarelliF. Novel insights into the genetic causes of short stature in children. touchREV Endocrinol. (2022) 18:49–57. doi: 10.17925/ee.2022.18.1.49
49
AlatzoglouKSDattaniMT. Genetic causes and treatment of isolated growth hormone deficiency-an update. Nat Rev Endocrinol. (2010) 6:562–76. doi: 10.1038/nrendo.2010.147
50
GoddardADCovelloRLuohSMClacksonTAttieKMGesundheitNet al. Mutations of the growth hormone receptor in children with idiopathic short stature. The Growth Hormone Insensitivity Study Group. N Engl J Med. (1995) 333:1093–8. doi: 10.1056/nejm199510263331701
51
PantelJLegendreMCabrolSHilalLHajajiYMorissetSet al. Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature. J Clin Invest. (2006) 116:760–8. doi: 10.1172/jci25303
52
KlammtJNeumannDGeversEFAndrewSFSchwartzIDRockstrohDet al. Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation. Nat Commun. (2018) 9:2105. doi: 10.1038/s41467-018-04521-0
53
KofoedEMHwaVLittleBWoodsKABuckwayCKTsubakiJet al. Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med. (2003) 349:1139–47. doi: 10.1056/NEJMoa022926
54
KawashimaYHakunoFOkadaSHotsuboTKinoshitaTFujimotoMet al. Familial short stature is associated with a novel dominant-negative heterozygous insulin-like growth factor 1 receptor (IGF1R) mutation. Clin Endocrinol (Oxf). (2014) 81:312–4. doi: 10.1111/cen.12317
55
FangPSchwartzIDJohnsonBDDerrMARobertsCTJr.HwaVet al. Familial short stature caused by haploinsufficiency of the insulin-like growth factor i receptor due to nonsense-mediated messenger ribonucleic acid decay. J Clin Endocrinol Metab. (2009) 94:1740–7. doi: 10.1210/jc.2008-1903
56
WalenkampMJLosekootMWitJM. Molecular IGF-1 and IGF-1 receptor defects: from genetics to clinical management. Endocr Dev. (2013) 24:128–37. doi: 10.1159/000342841
57
TartagliaMAokiYGelbBD. The molecular genetics of RASopathies: An update on novel disease genes and new disorders. Am J Med Genet C Semin Med Genet. (2022) 190:425–39. doi: 10.1002/ajmg.c.32012
58
ChenMMiaoHLiangHKeXYangHGongFet al. Clinical characteristics of short-stature patients with collagen gene mutation and the therapeutic response to rhGH. Front Endocrinol (Lausanne). (2022) 13:820001. doi: 10.3389/fendo.2022.820001
59
JeeYH. Letter to the editor from Jee: "Familial short stature-a novel phenotype of growth plate collagenopathies. J Clin Endocrinol Metab. (2022) 107:e436–7. doi: 10.1210/clinem/dgab664
60
BaoPJiangLLiuGLiYChenXWangM. Two cases of autosomal dominant familial short stature associated with COL11A2 gene variant and the therapeutic response to recombinant human growth hormone. Transl Pediatr. (2025) 14:618–27. doi: 10.21037/tp-2024-551
61
Czarny-RatajczakMLohinivaJRogalaPKozlowskiKPeräläMCarterLet al. A mutation in COL9A1 causes multiple epiphyseal dysplasia: further evidence for locus heterogeneity. Am J Hum Genet. (2001) 69:969–80. doi: 10.1086/324023
62
YangJZhangJLuQTianHWangKLiuZet al. The p.W651fsX666 mutation on COL10A1 results in impaired trimerization of normal collagen X to induce Schmid type metaphyseal chondrodysplasia. Hum Mol Genet. (2025) 34:1265–85. doi: 10.1093/hmg/ddaf071
63
JacksonGCMittaz-CrettolLTaylorJAMortierGRSprangerJZabelBet al. Pseudoachondroplasia and multiple epiphyseal dysplasia: a 7-year comprehensive analysis of the known disease genes identify novel and recurrent mutations and provides an accurate assessment of their relative contribution. Hum Mutat. (2012) 33:144–57. doi: 10.1002/humu.21611
64
BonafeLCormier-DaireVHallCLachmanRMortierGMundlosSet al. Nosology and classification of genetic skeletal disorders: 2015 revision. Am J Med Genet A. (2015) 167a:2869–92. doi: 10.1002/ajmg.a.37365
65
ScalcoRCSchoonesJWGaletakiDSantillan-VasconezAMKimGJCellinLPet al. Diagnostic yield of genetic testing in children with short stature: a systematic review. Eur J Endocrinol. (2026) 194:S15–s24. doi: 10.1093/ejendo/lvag011
66
Martinez De LapiscinaIZürcherMZinggTJannerMSanerCBoettcherCet al. Exome findings in children with short stature evaluated by growth hormone stimulation testing. Eur J Endocrinol. (2026) 194:285–97. doi: 10.1093/ejendo/lvag038
67
RankeMB. Towards a consensus on the definition of idiopathic short stature. Horm Res. (1996) 45:64–6. doi: 10.1159/000184851
68
CohenPRogolADDealCLSaengerPReiterEORossJLet al. Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. J Clin Endocrinol Metab. (2008) 93:4210–7. doi: 10.1210/jc.2008-0509
69
WitJMClaytonPERogolADSavageMOSaengerPHCohenP. Idiopathic short stature: definition, epidemiology, and diagnostic evaluation. Growth Hormone IGF Res. (2008) 18:89–110. doi: 10.1016/j.ghir.2007.11.004
70
PoyrazogluSDarendelilerFBasFBundakRSakaNDarcanSet al. Target height estimation in children with idiopathic short stature who are referred to the growth clinic. Horm Res. (2009) 72:178–83. doi: 10.1159/000232494
71
SisleySTrujilloMVKhouryJBackeljauwP. Low incidence of pathology detection and high cost of screening in the evaluation of asymptomatic short children. J Pediatr. (2013) 163:1045–51. doi: 10.1016/j.jpeds.2013.04.002
72
WangSRJacobsenCMCarmichaelHEdmundABRobinsonJWOlneyRCet al. Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature. Hum Mutat. (2015) 36:474–81. doi: 10.1002/humu.22773
73
CrippaMGiangiobbeSVillaRBestettiIDe FilippisTFattiLet al. A balanced reciprocal translocation t(10;15)(q22.3;q26.1) interrupting ACAN gene in a family with proportionate short stature. J Endocrinol Invest. (2018) 41:929–36. doi: 10.1007/s40618-017-0819-3
74
ZengTLiaoLLiNWangJPengJGuoYet al. Familial short stature caused by ACAN gene mutation: a familial case report. J Clin Pediatr. (2018) 36:463–6. doi: 10.3969/j.issn.1000-3606.2018.06.015
75
XuDSunCZhouZWuBYangLChangZet al. Novel aggrecan variant, p. Gln2364Pro, causes severe familial nonsyndromic adult short stature and poor growth hormone response in Chinese children. BMC Med Genet. (2018) 19:79. doi: 10.1186/s12881-018-0591-z
76
ZhaoLZhuYYuanKLiangLWangC. Efficacy of recombinant human growth hormone therapy in familial short stature with ACAN gene variants and review of literature. J Clin Pediatr. (2021) 39:59–64. doi: 10.3969/j.issn.1000-3606.2021.01.015
77
WitJM. Should skeletal maturation be manipulated for extra height gain? Front Endocrinol (Lausanne). (2021) 12:812196. doi: 10.3389/fendo.2021.812196
78
LiangHMiaoHPanHYangHGongFDuanLet al. Growth-promoting therapies may be useful in short stature patients with nonspecific skeletal abnormalities caused by ACAN heterozygous mutations: six Chinese cases and literature review. Endocr Pract. (2020) 26:1255–68. doi: 10.4158/ep-2019-0518
79
HeroMNorjavaaraEDunkelL. Inhibition of estrogen biosynthesis with a potent aromatase inhibitor increases predicted adult height in boys with idiopathic short stature: a randomized controlled trial. J Clin Endocrinol Metab. (2005) 90:6396–402. doi: 10.1210/jc.2005-1392
80
MaurasNGonzalez De PijemLHsiangHYDesrosiersPRapaportRSchwartzIDet al. Anastrozole increases predicted adult height of short adolescent males treated with growth hormone: a randomized, placebo-controlled, multicenter trial for one to three years. J Clin Endocrinol Metab. (2008) 93:823–31. doi: 10.1210/jc.2007-1559
81
BlumWFCroweBJQuigleyCAJungHCaoDRossJLet al. Growth hormone is effective in treatment of short stature associated with short stature homeobox-containing gene deficiency: two-year results of a randomized, controlled, multicenter trial. J Clin Endocrinol Metab. (2007) 92:219–28. doi: 10.1210/jc.2006-1409
82
BlumWFRossJLZimmermannAGQuigleyCAChildCJKalifaGet al. GH treatment to final height produces similar height gains in patients with SHOX deficiency and Turner syndrome: results of a multicenter trial. J Clin Endocrinol Metab. (2013) 98:E1383–1392. doi: 10.1210/jc.2013-1222
83
DonzeSHMeijerCRKantSGZandwijkenGRVan Der HoutAHVan SpaendonkRMet al. The growth response to GH treatment is greater in patients with SHOX enhancer deletions compared to SHOX defects. Eur J Endocrinol. (2015) 173:611–21. doi: 10.1530/eje-15-0451
84
LucchettiLPronteraPMencarelliASallicandroEMencarelliACofiniMet al. Report of a novel SHOX missense variant in a boy with short stature and his mother with Leri-Weill dyschondrosteosis. Front Endocrinol (Lausanne). (2018) 9:163. doi: 10.3389/fendo.2018.00163
85
UngureanuMCHriscaACabaLTeodoriuLBilhaSPredaCet al. SHOX deletion and idiopathic short stature: what does the clinician need to know? Case series report. Diagnostics (Basel). (2022) 13(1):105. doi: 10.3390/diagnostics13010105
86
VasquesGAAmanoNDockoAJFunariMFQuedasEPNishiMYet al. Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature in patients initially classified as idiopathic short stature. J Clin Endocrinol Metab. (2013) 98:E1636–1644. doi: 10.1210/jc.2013-2142
87
VasquesGAHisado-OlivaAFunariMFLerarioAMQuedasEPSolbergPet al. Long-term response to growth hormone therapy in a patient with short stature caused by a novel heterozygous mutation in NPR2. J Pediatr Endocrinol Metab. (2017) 30:111–6. doi: 10.1515/jpem-2016-0280
88
JacobMMenonSBottiCMarshallI. Heterozygous NPR2 mutation in two family members with short stature and skeletal dysplasia. Case Rep Endocrinol. (2018) 2018:7658496. doi: 10.1155/2018/7658496
89
WeiSLiRHeDZhangCZhangMLiYet al. Identification and functional analysis of NPR2 truncating mutations in two Chinese families with short stature. BMC Pediatr. (2025) 25:130. doi: 10.1186/s12887-025-05478-y
90
AllenDBMerchantNMillerBSBackeljauwPF. Evolution and future of growth plate therapeutics. Horm Res Paediatr. (2021) 94:319–32. doi: 10.1159/000520812
91
SemlerOCormier-DaireVLauschEBoberMBCarrollRSousaSBet al. Vosoritide therapy in children with achondroplasia: early experience and practical considerations for clinical practice. Adv Ther. (2024) 41:198–214. doi: 10.1007/s12325-023-02705-9
92
AlfarajGAAlfarajHAAdelMAlgadeebRB. Efficacy and safety of vosoritide in children with achondroplasia: a systematic review and meta-analysis. Eur J Pediatr. (2026) 185(5):185. doi: 10.1007/s00431-026-06970-y
93
SavarirayanRHechtJTJayaramKIngoleSDeeAHoover-FongJ. Evaluating the impact of vosoritide on complications of achondroplasia. Genet Med. (2026) 28:102584. doi: 10.1016/j.gim.2026.102584
94
PapadimitriouDT. C-type natriuretic peptide as mediator of growth in the absence of growth hormone: unraveling the mystery of the growth without GH syndrome. Hormones (Athens). (2026) 25:319–21. doi: 10.1007/s42000-025-00742-3
95
KulkarniJAWitzigmannDThomsonSBChenSLeavittBRCullisPRet al. The current landscape of nucleic acid therapeutics. Nat Nanotechnol. (2021) 16:630–43. doi: 10.1038/s41565-021-00898-0
96
YuanJWangYHuangYLiSZhangXWuZet al. Investigating novel therapeutic approaches for idiopathic short stature: targeting siRNA and growth hormone delivery to the growth plate using exosome nanoparticles. Adv Sci (Weinh). (2024) 11:e2309559. doi: 10.1002/advs.202309559
97
DoudnaJA. The promise and challenge of therapeutic genome editing. Nature. (2020) 578:229–36. doi: 10.1038/s41586-020-1978-5
98
DunbarCEHighKAJoungJKKohnDBOzawaKSadelainM. Gene therapy comes of age. Science. (2018) 359(6372):eaan4672. doi: 10.1126/science.aan4672
99
MamadaMYorifujiTKurokawaKKawaiMMomoiTNakahataT. Prevalence of mutations in the FGFR3 gene in individuals with idiopathic short stature. Clin Pediatr Endocrinol. (2006) 15:61–4. doi: 10.1297/cpe.15.61
Summary
Keywords
familial short stature, genetic diagnosis, growth plate disorders, monogenic short stature, precision medicine, recombinant human growth hormone
Citation
Zhang C, Wu N, Gong M, Yang M, Meng L and Xin Y (2026) Familial short stature: genetic architecture, risk stratification, and precision management. Front. Endocrinol. 17:1890896. doi: 10.3389/fendo.2026.1890896
Received
25 May 2026
Revised
20 July 2026
Accepted
28 July 2026
Published
25 August 2026
Volume
17 - 2026
Edited by
Lukas Plachy, University Hospital in Motol, Czechia
Reviewed by
Gulcin Arslan, Izmir City Hospital, Türkiye
Shenali Anne Amaratunga, University Hospital in Motol, Czechia
Updates
Copyright
© 2026 Zhang, Wu, Gong, Yang, Meng and Xin.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Na Wu, 3441535223@qq.com
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.