Search Results (387)

Background/Objectives: X-linked hypophosphatemia (XLH), the most frequent heritable cause of hypophosphatemic rickets, is characterized by impaired linear growth and skeletal deformities, that can lead to disproportionate short stature. Linear growth depends on the coordinated regulation of systemic endocrine signals and local growth plate regulatory mechanisms controlling chondrocyte proliferation, differentiation, and apoptosis. This review critically discusses the molecular processes underlying growth impairment in XLH, with particular emphasis on growth plate dysfunction. Methods: A narrative review of experimental and clinical studies was conducted, focusing on growth plate biology, and on the pathophysiology of XLH. Particular attention was given to the role of systemic phosphate-regulating hormones, local paracrine factors, and intracellular signaling pathways, as well as the effects of current therapeutic strategies on linear growth. Results: Excess fibroblast growth factor 23 (FGF23) in XLH disrupts phosphate homeostasis and vitamin D metabolism, impairing skeletal mineralization and growth plate signaling. Beyond FGF23-related dysregulation, additional FGF23-independent mechanisms directly affect growth plate chondrocyte function and extracellular matrix composition, further contributing to growth plate disorganization. Current therapeutic approaches, including conventional phosphate and active vitamin D supplementation, FGF23 inhibition with human monoclonal antibody, and combination with recombinant human growth hormone, exert heterogeneous effects on linear growth through distinct biological mechanisms. Conclusions: Growth impairment in XLH reflects the combined impact of systemic endocrine dysregulation, and intrinsic growth plate dysfunctions. A better understanding of these mechanisms may facilitate the development of targeted therapeutic strategies, improving growth outcomes in individuals with XLH. Full article

Wheat ideotypes for dense indoor cultivation require compact architecture, maintained reproductive development, and sufficient biomass accumulation with high planting density and restricted rooting space. Milyang54 is an extremely short-stature winter wheat line developed as a candidate for space-efficient cultivation, but its response to indoor cultivation conditions differing in planting density and rooting space has not been characterized. In this study, Milyang54 and Jokyoung were grown with eight tray, pot, and spacing treatments in a speed-breeding greenhouse. These treatments were designed to generate contrasting planting densities and rooting-space conditions, ranging from low-density pot cultivation to high-density plug-tray and 1.5 cm spacing treatments. Agronomic and reproductive traits, shoot and root biomass, and root-to-shoot ratio were evaluated using a two-factor GLM with variety, cultivation treatment, and their interaction as fixed effects. Cultivation treatment significantly affected all measured traits, and significant variety × treatment interactions were detected for most traits. Across treatments, Milyang54 had a markedly lower mean plant height than Jokyoung (25.62 vs. 42.81 cm) but showed greater mean grain number per spike (11.03 vs. 7.51), shoot dry weight (25.85 vs. 21.58 g), and root dry weight (1.69 vs. 0.97 g). The grain-number advantage of Milyang54 was particularly evident in high-density and restricted-rooting-space tray treatments, including the 105-, 128-, and 162-cell trays. Root-to-shoot ratios varied among cultivation treatments, but a high ratio was not consistently associated with greater grain number. These results indicate that Milyang54 combines compact plant architecture with maintained reproductive performance and biomass accumulation under dense indoor cultivation conditions, suggesting its potential value as a compact wheat ideotype for controlled-environment agriculture. Full article

Introduction and Clinical Significance: Skeletal dysplasias comprise a genetically heterogeneous group of disorders with substantial phenotypic overlap, often complicating diagnosis. Clinical exome sequencing (CES) can facilitate molecular diagnosis in children with unexplained disproportionate short stature. Case Presentation: An 8-year-old boy presented with severe short stature (−3.24 SDS), brachydactyly, relative macrocephaly, broad nasal bridge, and mild calf hypertrophy. Endocrine evaluation confirmed growth hormone deficiency (GHD). Following negative SHOX testing, CES identified a heterozygous likely pathogenic IHH variant (c.446G>A; p.Arg149His), establishing the diagnosis of brachydactyly type A1 (BDA1). Recombinant human growth hormone (rhGH), initiated for GHD, resulted in improved growth velocity and height SDS. Transient unilateral prepubertal gynecomastia developed during treatment and resolved after temporary rhGH withdrawal, with no recurrence following reinitiation. Conclusions: This case highlights the diagnostic value of CES in children with disproportionate short stature after unrevealing targeted testing and illustrates that GHD may coexist with IHH-related skeletal dysplasia. An integrated genetic and endocrine evaluation can refine diagnosis, identify coexisting treatable endocrine disorders, and guide individualized management. Full article

Spondylocarpotarsal synostosis syndrome (SCT) is a rare autosomal recessive skeletal dysplasia caused by biallelic loss-of-function variants in FLNB, characterized by disproportionate short stature, progressive vertebral fusion, scoliosis, and carpal (typically capitate–hamate) synostosis, classically without rib anomalies. We performed a systematic literature search of PubMed/MEDLINE and Scopus, supplemented by citation searching, following the PRISMA 2020 statement, to identify all reports providing original, molecularly confirmed FLNB-related SCT patient data. Eleven eligible publications, spanning Taiwanese, Argentinian, Pakistani, Italian, German and Indian cohorts, were included in a qualitative synthesis together with a novel case. The novel patient, an adopted child of Indian origin, presented with severe disproportionate short stature, multisegmental vertebral fusion and posterior arch clefts extending from the cervical to the sacral spine, coccygeal dysgenesis, capitate–hamate fusion, and global developmental delay; targeted exome sequencing identified a novel homozygous frameshift FLNB variant. Integration of this case with the reviewed literature confirms disproportionate short stature, contiguous vertebral fusion, and carpal synostosis as near-universal core features, while tarsal fusion, hearing loss, and facial dysmorphism are variably present. The extent and multisegmental pattern of axial involvement in our patient appear more severe than in most previously reported cases, broadening the recognized phenotypic spectrum of FLNB-related SCT and reinforcing the need for structured, multidisciplinary long-term follow-up. Full article

Background/Objectives: Celiac disease (CD) is a chronic immune-mediated disorder associated with a broad spectrum of extraintestinal manifestations, including hematological abnormalities. Although anemia and micronutrient deficiencies are well recognized, neutrophil morphological abnormalities have not been systematically investigated in pediatric CD; this study aimed to evaluate peripheral blood smear findings in children with CD compared with healthy controls. Methods: This retrospective case–control study included 70 children with CD and 74 healthy controls; demographic characteristics, anthropometric measurements, hematological and biochemical parameters, and peripheral blood smear findings were analyzed and compared between groups. Results: Children with CD had significantly higher frequencies of underweight status (15.7% vs. 2.7%) and short stature (21.4% vs. 1.4%) than controls. Most hematological and biochemical parameters were comparable between groups, except for platelet counts and ferritin levels, which differed significantly. Pseudo-Pelger–Huët anomaly (PPHA) was identified in 87.1% of children with CD versus 8.1% of controls (p < 0.001), and neutrophil dysplasia was observed in 52.9% versus 1.4%, respectively (p < 0.001). After adjustment for age and sex, CD remained strongly associated with PPHA (adjusted OR 81.19, 95% CI 28.65–278.45), neutrophil dysplasia (adjusted OR 93.85, 95% CI 18.46–1724.96), and the combined presence of both abnormalities (adjusted OR 79.89, 95% CI 15.86–1461.89) (all p < 0.001). ROC analysis demonstrated excellent discrimination between CD and controls (AUC = 0.924; sensitivity = 90.0%; specificity = 91.9%). Within the CD cohort, PPHA and dysplasia were not associated with celiac antibody positivity, gluten-free diet adherence, vitamin D deficiency, or comorbid conditions. Conclusions: To our knowledge, this is the first study to systematically evaluate peripheral blood smear morphology in pediatric CD, demonstrating a remarkably high prevalence of PPHA and neutrophil dysplasia. These findings suggest that neutrophil morphological abnormalities may represent an underrecognized hematological manifestation of pediatric CD, potentially reflecting chronic immune-mediated alterations in granulopoiesis. Further prospective studies are needed to clarify their pathogenesis, clinical significance, and reversibility following long-term gluten-free diet treatment. Full article

Objective: The objective of this study was to analyze the clinical phenotypes and genetic variant characteristics of four unrelated Chinese children carrying pathogenic variants in the CTCF gene and to explore the genotype–phenotype heterogeneity of autosomal dominant intellectual disability type 21 (MRD21, OMIM 615,502). Methods: Four pediatric patients admitted to Beijing Children’s Hospital, Capital Medical University, from 2020 to 2024 were enrolled in this retrospective study. All patients underwent medical history collection, physical examination, laboratory tests and high-throughput sequencing. Identified variants were verified in the probands and parents via Sanger sequencing or CNV-seq. Results: Four distinct heterozygous CTCF variants were identified: a missense variant c.1117C>T (p.His373Tyr); an 8.92 Mb microdeletion at 16q21-q22.1 (arr[GRCh37] 16q21q22.1(58,986,875–67,907,636)×1), encompassing the entire CTCF gene; a frameshift deletion c.615_618delGAAA (p.Lys206Profs*15); and an intragenic deletion of exons 8–10. Parental testing confirmed that all identified variants were of de novo origin. The missense variant and the frameshift deletion have been reported previously in ClinVar (VCV000521287.19 and VCV001308122.2), but the two deletions were not found in public databases. Three patients presented with global developmental delay consistent with MRD21, with variable additional features including autistic-like behavior and facial dysmorphism. Notably, two of these patients showed somatic overgrowth with height and weight above the 97th percentile, contrasting with the short stature classically emphasized in MRD21. The fourth patient was a preterm infant with neonatal chylothorax, cardiopulmonary failure, and multiple congenital cardiovascular malformations; developmental assessment at a corrected age of 11 months showed only mild lags. Conclusions: This study expands the spectrum of pathogenic CTCF variants in the Chinese population and underscores the marked phenotypic heterogeneity of CTCF-related disorders, ranging from benign developmental outcomes with complete catch-up to severe neonatal multisystem involvement. In neonates presenting with unexplained chylothorax and multisystem abnormalities, especially when accompanied by features suggestive of a neurodevelopmental syndrome, CTCF should be considered in the differential diagnosis. Given this heterogeneity, a broad genomic approach rather than targeted CTCF screening is recommended in patients with complex presentations. Full article

Background/Objectives: Achondroplasia is the most common genetic skeletal dysplasia associated with disproportionate short stature and is primarily caused by gain-of-function variants in the fibroblast growth factor receptor 3 (FGFR3) gene. Constitutive FGFR3 activation disrupts growth plate homeostasis and endochondral ossification through complex alterations in chondrocyte proliferation, differentiation, hypertrophy, extracellular matrix organization, and intracellular signaling. The increasing understanding of these mechanisms has enabled the transition from exclusively supportive management toward disease-modifying and precision-based therapeutic strategies. This narrative review aimed to critically synthesize current evidence on the genetic basis, molecular pathogenesis, growth plate abnormalities, and current and emerging targeted therapies in achondroplasia. Methods: A narrative literature review was conducted using PubMed/MEDLINE, Scopus, and Web of Science Core Collection, with Google Scholar used as a supplementary source, together with manual screening of the reference lists of relevant original studies, clinical trials, reviews, consensus documents, and clinical guidelines. The principal literature search covered publications from January 2010 to March 2026, while selected seminal primary studies published before 2010 were included when necessary to document the original identification of pathogenic FGFR3 variants and foundational mechanisms of FGFR3-mediated growth plate regulation. Particular emphasis was placed on FGFR3 variants, receptor activation mechanisms, growth plate dysfunction, intracellular signaling pathways, vosoritide, C-type natriuretic peptide-based therapies, FGFR3 inhibitors, ligand–receptor blockade, drug repurposing, Wnt/β-catenin modulation, and gene-based therapeutic approaches. Results: Achondroplasia is characterized by marked molecular homogeneity, with the recurrent p.Gly380Arg substitution accounting for most cases. Mutant FGFR3 displays sustained activity through partial ligand independence, enhanced receptor dimerization and kinase activation, increased receptor stability, and reduced degradation. Excessive signaling through MAPK/ERK, STAT, PI3K/AKT, IHH/PTHrP, and related pathways impairs chondrocyte proliferation and hypertrophic differentiation, alters extracellular matrix turnover, disrupts primary cilium function, and reduces longitudinal bone growth. Vosoritide provides clinical proof that pharmacological modulation of FGFR3-related signaling can improve growth velocity. Additional therapeutic strategies under clinical or preclinical investigation include long-acting CNP analogues, selective FGFR inhibitors, decoy receptors, RNA aptamers, repurposed drugs, Wnt/DKK1 pathway modulation, and gene- or enhancer-targeted interventions. Conclusions: Achondroplasia is increasingly understood as a disorder of dysregulated growth plate signaling rather than solely a condition of reduced stature. Although vosoritide has established the feasibility of disease-modifying treatment, substantial uncertainty remains regarding final adult height, skeletal proportionality, cranio-spinal development, orthopedic outcomes, and long-term safety. Future progress will depend on mechanistically informed therapeutic combinations, improved biomarkers, advanced cellular and animal models, and long-term clinical and real-world evidence. Full article

Background/Objectives: Achondroplasia is the most common skeletal dysplasia and the leading genetic cause of disproportionate short stature. Although its biological basis involves gain-of-function variants in the FGFR3 gene, achondroplasia is a lifelong multisystem disorder associated with neurological, respiratory, orthopedic, otolaryngological, cardiovascular, oral, functional, and psychosocial complications. This narrative review aims to synthesize the evidence on developmental and adaptive functioning, age-specific healthcare needs, multidisciplinary service delivery, transition to adult care, psychosocial well-being, caregiver burden, and patient- and family-centered outcomes in achondroplasia across the lifespan. Methods: A narrative literature review was conducted using PubMed/MEDLINE, Scopus, Web of Science Core Collection, and CINAHL, with Google Scholar used as a supplementary source. Studies published between January 2010 and July 2026 were considered, together with earlier clinically relevant reports. Evidence addressing prenatal and postnatal diagnosis, age-specific manifestations, neurological and respiratory complications, orthopedic and otolaryngological care, cardiometabolic risk, growth monitoring, multidisciplinary management, transition to adult services, disease-modifying therapy, quality of life, and caregiver burden was evaluated. Results: The clinical priorities of achondroplasia change substantially across the lifespan. Infancy is characterized by an increased risk of foramen magnum stenosis, cervicomedullary compression, hypotonia, and sleep-disordered breathing, whereas orthopedic deformities, chronic pain, reduced mobility, spinal stenosis, hearing impairment, obesity, and cardiovascular risk become increasingly relevant during later childhood, adolescence, and adulthood. Early diagnosis, condition-specific imaging, neurological and respiratory surveillance, growth monitoring, and coordinated specialist care are essential for preventing severe complications. Vosoritide has introduced a disease-modifying therapeutic option, but it does not replace comprehensive clinical surveillance, rehabilitation, orthopedic care, psychosocial support, or shared decision-making. Functional limitations, environmental barriers, treatment burden, and caregiver stress contribute substantially to reduced quality of life. Conclusions: Achondroplasia should be managed as a lifelong multisystem condition rather than solely as a disorder of short stature. Standardized surveillance, multidisciplinary coordination, planned transition to adult care, and patient- and family-centered management are essential for improving function, autonomy, long-term health outcomes, and quality of life. Full article

Background/Objectives: The therapeutic window for growth hormone (GH) therapy in late-pubertal males with advanced bone age (BA ≥ 15 years) is generally considered closed. Yet, open knee physes may indicate residual growth potential. This single-arm retrospective study evaluated the efficacy and safety of letrozole combined with GH in Chinese males with short stature, advanced BA (15 –< 18 years), and open knee physes. Methods: We included 139 male adolescents stratified by baseline BA: 15 ≤ BA < 16 (n = 24), 16 ≤ BA < 17 (n = 31), and 17 ≤ BA < 18 (n = 84). All received subcutaneous GH (0.05–0.07 mg/kg/day) and oral letrozole (2.5 mg/day). The primary outcome was the change in final adult height (FAH) from baseline predicted adult height (PAH). Longitudinal changes in height velocity and height SDS-BA were also assessed. Results: Among 75 patients who reached FAH, combination therapy was associated with a mean gain of 6.58 ± 3.46 cm over baseline PAH (p < 0.001). The gain was inversely correlated with baseline BA; the largest gain occurred in the 15 ≤ BA < 16 subgroup (10.04 ± 4.66 cm), significantly exceeding gains in the 16 ≤ BA < 17 (6.30 ± 3.01 cm) and 17 ≤ BA < 18 (5.70 ± 2.52 cm) subgroups (p < 0.001). In the youngest subgroup, FAH exceeded mid-parental height. The safety profile was acceptable; acne was the most common adverse event (46.76%), and no severe metabolic or endocrine disorders were observed. Conclusions: Letrozole plus GH therapy may be associated with improved FAH in late-pubertal males with advanced BA and open knee physes, with gains varying by baseline skeletal maturity and being numerically greatest in those with BA 15 –< 16 years. Knee epiphyseal status may be a useful consideration when individualizing therapy in this population. Full article

Background: Pathogenic variants in ZNF292 cause intellectual disability type 64 (MIM#619188), characterized by intellectual impairment ranging from mild to severe, speech delay, and autism spectrum disorder. However, reports of ZNF292-related neurodevelopmental disorders remain scarce, and most published studies are based on multi-center cohorts. Methods: We performed whole-exome sequencing in eight unrelated individuals presenting with unexplained neurodevelopmental disorders, including global developmental delay and/or intellectual disability. Detailed clinical characterization, neuroimaging, and developmental assessments were conducted. Results: Seven de novo variants in ZNF292 were identified, including two nonsense and five frameshift variants, namely, c.4189C>T (p.Arg1397Ter), c.6343C>T (p.Arg2115Ter), c.1533del (p.Ile511Metfs*11), c.3094dup (p.Ser1032Phefs*18), c.3997_3998del (p.Thr1333Glnfs*8), c.6028_6031del (p.Ala2010Ter) and c.6160_6161del (p.Glu2054Lysfs*14). Among these, c.1533del (p.Ile511Metfs11), c.3094dup (p.Ser1032Phefs18) and c.3997_3998del (p.Thr1333Glnfs*8) are reported here for the first time. All variants were classified as pathogenic. All individuals exhibited global developmental delay, intellectual disability, and short stature. The majority presented with language impairment, motor delays, autism spectrum features, and dysmorphic facial features, while brain magnetic resonance imaging revealed nonspecific abnormalities such as ventriculomegaly. Conclusions: This study contributes additional cases to the expanding phenotypic and mutational spectrum of ZNF292-related neurodevelopmental disorder. Growth retardation was observed in all eight individuals, but given the limitations of a single-center referral cohort, this observation should be interpreted with caution and requires validation in larger studies. Full article

Maternal uniparental disomy of chromosome 15 [UPD(15)mat] and imprinting defects account for about 30% of cases of Prader–Willi syndrome (PWS). Mosaic UPD(15)mat is rare and may escape routine testing. We describe a 45-year-old male patient in whom persistent clinical suspicion of PWS was not genetically confirmed by repeated methylation-based analyses. Clinical manifestations included neonatal hypotonia with low birth weight, early hyperphagia, severe obesity, short stature, growth hormone deficiency, type 2 diabetes mellitus, dyslipidemia, and MASLD/MASH with compensated cirrhosis. He presented with very mild neurodevelopmental impairment. Following the detection of proteinuria and microalbuminuria from age 22 years, focal segmental glomerulosclerosis was diagnosed upon renal biopsy. A family history of cerebrovascular events was recorded. Combined SNP-array and MS-MLPA analyses across tissues established a diagnosis of PWS due to mosaic UPD(15)mat. The mosaic fraction, estimated by SNP-array, was approximately 10% in peripheral blood and 40% in buccal cells; MS-MLPA detected abnormal methylation only in buccal cells, explaining the previous negative blood-based results. Exome sequencing identified the paternally inherited pathogenic NOTCH3 variant NM_000435.2:c.3016C>T, p.(Arg1006Cys). Subsequent brain MRI showed chronic vascular-type leukoencephalopathy consistent with CADASIL, despite the absence of overt ischemic events in the proband. Collectively, these investigations established a dual molecular diagnosis of PWS due to mosaic UPD(15)mat and NOTCH3-related CADASIL. This report highlights the pivotal role of clinical genetics in assessing the precise diagnosis in rare diseases. With respect to PWS, it demonstrates that mosaicism can lead to a missed diagnosis when the genetic investigation is limited to peripheral blood. In addition, following the diagnosis of CADASIL, and based on the available evidence linking NOTCH3 to renal physiology and disease, we discuss whether NOTCH3-related renal microangiopathy may have contributed to the renal phenotype. However, given the patient’s multiple renal risk factors, FSGS was considered most likely multifactorial, and a causal association with CADASIL cannot be established from this single case. Full article

Short stature is a common pediatric endocrine–metabolic disorder characterized by impaired linear growth and increased risks of adverse health outcomes. Although previous reviews have summarized associations between gut microbiota and childhood health, few have focused on the mechanistic links among microbial composition, microbial-derived metabolites, endocrine regulation, and skeletal growth in short stature. This review provides an integrated framework exploring the potential interactions among gut microbiota composition, microbial-derived metabolites, endocrine regulation, and skeletal development in short stature. We summarize the clinical characteristics and epidemiological features of major short stature subtypes and discuss emerging evidence demonstrating the involvement of gut microbiota alterations and metabolite dysregulation in growth regulation. Particular attention is given to the bidirectional interactions between the gut microbiota and the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis, as well as the potential role of the gut–liver–bone axis in skeletal growth. Furthermore, this review integrates evidence from metabolomics studies, experimental animal models, and microbiota-targeted interventions to provide mechanistic insights into microbiota-mediated growth regulation. Dietary factors, physical activity, sleep, antibiotic exposure, probiotic interventions, and current clinical treatments are also discussed from the perspective of microbiota modulation. Despite increasing interest in microbiota-based strategies, clinical translation remains limited by insufficient functional validation, unclear causal relationships, and a lack of well-designed intervention trials. Future integration of functional microbiology, multi-omics approaches, and human-based validation platforms may facilitate the development of microbiome-based precision interventions for improving growth outcomes in children with short stature, particularly those with ISS. Full article

Background: DNA Ligase 4 (LIG4) catalyzes the final ligation step during V(D)J recombination. Biallelic pathogenic variants in LIG4 cause severe combined immunodeficiency (SCID), a life-threatening immunodeficiency characterized by the lack of mature T and B cells. Case Presentation: An 18-year-old male exhibited widespread verrucous and keratotic cutaneous lesions across the face, neck, and extremities. The proband manifested early-onset short stature, chronic malnutrition, recurrent pulmonary infections with bronchiectasis, chronic diarrhea, and bilateral tenosynovitis. Immunophenotyping revealed persistent panhypogammaglobulinemia, absent B cells, reduced T and natural killer (NK) cells, and nearly undetectable naïve T cells. Both α-HPV and β-HPV were detected in the cutaneous lesions. Compound heterozygous LIG4 variants (hg19, NM206937.2, c.833G > T; p.Arg278Leu inherited from the mother; c.833G > A; p.Arg278 His inherited from the father) were identified. Conclusions: This study reports a proband with LIG4 syndrome presenting with rare phenotypes of multiple viral warts and combined lymphopenia of T, B, and NK cells. This proband harbors compound heterozygous variants at the same codon (c.833G), which not only confirm the clinical diagnosis but also enrich the known phenotypic spectrum of LIG4 syndrome. Full article

Background: Pathogenic variants in genes that cause skeletal dysplasias may, instead of producing classic findings, present in children with a phenotype whose hip radiographs resemble bilateral Legg-Calvé-Perthes disease (LCPD). Objectives: This study aims to investigate the efficacy of genetic diagnosis in children with waddling gait or joint pain and radiological evidence of hip dysplasia mimicking bilateral LCPD. Methods: Forty children with bilateral femoral head dysplasia from 36 families were included in the study. Exome sequencing was performed, and all identified variants were confirmed within the families by Sanger sequencing. Results: Twelve pathogenic or likely pathogenic variants were identified: six in COL2A1, two in COL9A1, and one each in RPL13, EIF2AK3, DNAJC21, and ARSK; six are novel. The diagnostic yield was 33.3% (12/36) in 12 families. Additionally, variants of uncertain significance (VUS), proposed as causative, were detected in five families (5/36:13.9%): two in COL11A1 and one each in COL9A3, COL11A2, and ARSK. Based on bilateral epiphyseal dysplasia of the femoral head, it was observed that seven families may be compatible with mild spondyloepiphyseal dysplasia and six families may have Stickler syndrome. Notably, among these, three children carrying closely localized pathogenic/likely pathogenic variants in COL2A1 shared a novel phenotype characterized by short stature and bilateral irregular femoral heads. In four families, EIF2AK3, DNAJC21, and ARSK were also responsible for the ultra-rare disorders Wolcott-Rallison syndrome, bone marrow failure syndrome 3, and mucopolysaccharidosis 10, respectively. Conclusions: This study, for the first time, investigated the frequency of associated genes in a pediatric cohort with bilateral hip dysplasia resembling LCPD, providing important information for pathogenesis and differential diagnosis. Full article

Background/Objectives: Individual responses to recombinant human growth hormone (rhGH) therapy in children with idiopathic short stature (ISS) vary substantially, limiting pretreatment decision-making. This study aimed to develop and externally validate an interpretable machine learning model for predicting suboptimal 12-month growth response to rhGH therapy. Methods: In this retrospective dual-center study, 901 children from Center 1 were used for model development and internal testing, and 51 children from Center 2 formed an independent external validation cohort. Routinely collected baseline demographic, laboratory, hormonal, radiographic, and family-history variables were used to develop multiple machine learning models. A soft-voting ensemble classifier was constructed and interpreted using SHapley Additive exPlanations (SHAP). The primary outcome was suboptimal growth response, defined as failure to achieve a height gain of at least 0.5 standard deviation score after 12 months of treatment. Results: The optimized ensemble model showed strong discrimination in the internal test set, with an area under the receiver operating characteristic curve of 0.927, and maintained robust performance in the external validation cohort, with an AUC of 0.897. SHAP analysis identified luteinizing hormone, body mass index, TW3 RUS bone age, and insulin-like growth factor 1 as the leading contributors to predicted suboptimal-response risk. Conclusions: An interpretable ensemble machine learning model based on routinely available pretreatment data can predict suboptimal short-term rhGH response in children with ISS and may support individualized risk stratification in pediatric endocrine practice. Clinical trial registration was not required because this was a retrospective analysis. Full article