Oligosaccharides ameliorate insulin resistance and hepatic metabolism by promoting the leptin/POMC axis to accelerate short stature growth and development.

Both genetic and environmental factors affect human stature, including overall height and familial short stature (FSS), and it is associated with various health outcomes. However, the study of genetic connections between stature and health conditions remains lacking in East Asian populations. Hence, we conducted parallel genome-wide association studies (GWAS) of body height and FSS in the Han Taiwanese population, aiming to elucidate the genetic influences of stature on health and facilitate the formulation of precision-health strategies. We analyzed large-scale GWAS data on adult height (120,301 Han Taiwanese) and FSS (FSS; 2,050 cases, 27,966 controls) to examine cross-trait genetic correlations across five East Asian biobanks, and applied phenome-wide association studies (PheWAS) and polygenic risk score (PRS) analyses to assess clinical outcomes using Cox proportional hazard models and Kaplan-Meier analyses. We identified 293 loci for height and five for FSS, with cross-biobank genetic correlations linking stature to body size, lung function, and cardiovascular/reproductive traits (atrial flutter/fibrillation [AF], menarche, and endometriosis). PheWAS showed that height PRS increased risks of AF and endometriosis, while FSS PRS had a protective effect against endometriosis. MR analyses showed that taller stature increased AF risk independently and endometriosis risk through menarche/weight, while shorter stature had a weak protective effect against endometriosis. Survival analyses showed the association of higher height PRS with greater AF risk and an earlier divergence of cumulative incidence curves. These time-to-event patterns were consistently replicated using meta-analysis-derived PRSs. The findings highlight stature-related genetic determinants, associated health outcomes, and polygenic risk scores as effective tools for early risk prediction and precision health strategies in East Asian populations.

Zinc finger MYND-type containing 11 (ZMYND11)-related neurodevelopmental disorder is an autosomal dominant condition caused by pathogenic variants in ZMYND11. Most previously reported patients harbor loss-of-function (LoF) variants, whereas missense variants are rare and their clinical and mechanistic characteristics remain insufficiently defined. Here we report a patient with a heterozygous ZMYND11 c.1798C>T, p.(Arg600Trp) variant identified through the Initiative on Rare and Undiagnosed Diseases program. Detailed clinical evaluation, developmental assessment and whole-exome sequencing were performed. In addition, a systematic review of previously published ZMYND11 cases was conducted to compare genotype-phenotype correlations between missense and LoF variants. The present patient showed global developmental delay, hypotonia, distinctive craniofacial features, microcephaly, short stature, cryptorchidism and right-sided inguinal hernia. Comparison with two previously reported individuals carrying the same c.1798C>T variant demonstrated consistent shared features, including microcephaly, broad nasal alae, short stature, cryptorchidism and nipple anomalies, findings that are not typically emphasized in LoF-associated cases. Aggregate analysis of reported 13 missense variants suggested higher frequencies of strabismus, hypotonia and severe intellectual disability compared with LoF variants, supporting the hypothesis that missense variants including c.1798C>T may define a partially distinct clinical subgroup. These findings expand the phenotypic spectrum associated with ZMYND11 missense variants and suggest variant-specific clinical patterns, particularly for c.1798C>T, which may reflect a mechanism different from simple haploinsufficiency.

Soft tennis is a racket sport involving frequent overhead motions that is popular in Asia, especially among high school students in Japan. In other overhead sports, such as baseball and tennis, lower kinetic chain elements, such as hip range of motion (ROM), have been implicated in the development of shoulder pain. However, their specific involvement has not been fully clarified. In this observational cross-sectional study, we evaluated 160 elite male high school soft tennis players. Collected data included participant characteristics, history of shoulder pain, and passive shoulder and hip ROM. Three logistic regression models were constructed: Model 1 (height + shoulder ROM), Model 2 (height + hip ROM), and Model 3 (height + shoulder and hip ROM). Model performance was assessed using the Akaike Information Criterion (AIC), the Bayesian Information Criterion (BIC), and the area under the curve (AUC). Model 3 demonstrated the best overall fit (AIC: 185.1, BIC: 197.4, AUC: 0.73); however, the improvement over Model 1 was marginal in practical terms. Glenohumeral internal rotation deficit (GIRD) and height were significantly associated with shoulder pain, whereas hip ROM variables were not. GIRD and shorter stature were associated with shoulder pain in elite male high school soft tennis players. Hip ROM was not directly associated with shoulder pain. This study is the first to investigate shoulder pain-related factors in elite adolescent soft tennis players by systematically comparing shoulder ROM-only, hip ROM-only, and combined models, demonstrating greater explanatory performance for models incorporating shoulder ROM.

To describe clinical and laboratory characteristics, emphasizing the evolution of patients with hepatic glycogen storage diseases (GSDs) followed in Brazilian reference centers. Multicenter, retrospective study involving 13 centers, using RedCap platform. 132 patients were included: 63 (47.8%) GSD type I (56 Ia, 7 Ib), 13 (9.8%) with type III (12 IIIa, 1 IIIb), 1 (0.8%) type IV, 6 (4.5%) type VI, and 49 (37.1%) with type IX (28 IXa, 7 IXb, and 14 IXc). Type I patients presented earlier (4 months) and had more episodes of hypoglycemia at clinical presentation (p < 0.001). Anthropometric data at admission revealed impaired growth, with a tendency toward short stature across the groups (median -2.06, -1.89, and -1.96 among type I, III, and IX respectively). The median body mass index (BMI) z-scores at admission for all three types were above +1. Only patients with type IX demonstrated significant improvement in height (p = 0.007) and BMI (p = 0.020) z-scores during follow-up. Regarding laboratory tests, significant decreases were observed in total cholesterol, triglycerides, venous lactate and aminotransferases in patients with types I and IX. Hepatic GSDs are heterogeneous diseases. There is a significant height impairment with a troublesome trend to overweight and obesity, especially in type I. Although there is improvement in aminotransferases, cholesterol, and triglycerides with follow-up, adherence to treatment remains a challenge.

Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive disorder characterized by spondyloepiphyseal dysplasia, progressive nephropathy, immunodeficiency, and distinctive ectodermal features. We report two affected siblings born to consanguineous parents. The first case is a 4-year-old girl presenting with severe disproportionate short stature, lumbar lordosis, facial dysmorphism, coarse hair, hyperpigmented macules, and persistent lymphopenia, with normal renal function. The second case is her 3-year-old brother, who presented with growth retardation, facial dysmorphism, thoracic kyphosis, lumbar lordosis, steroid-resistant nephrotic syndrome, secondary hypothyroidism, and marked T-cell deficiency. An older sibling had previously died from chronic kidney disease, and molecular testing in the family confirmed a SMARCAL1 mutation. These observations illustrate the phenotypic variability and severity of SIOD and emphasize the importance of early diagnosis, monitoring of immunological and renal functions, and multidisciplinary management to improve outcomes.

CSS is a clinically and genetically heterogeneous syndrome. Patients may present with highly variable features, and typical signs of the syndrome may not be observed in all cases. This study expands the clinical spectrum of this rare syndrome and contributes to its genetic spectrum with the identification of new variants. •Coffin-Siris syndrome (CSS) is a clinically and genetically heterogeneous neurodevelopmental disorder most commonly caused by variants in SWI/SNF (BAF) complex genes (e.g., ARID1B, SMARCA4) and characterized by dysmorphic features, developmental delay, hypertrichosis, and fifth-digit/nail anomalies. •Endocrine and growth-related manifestations can occur in CSS, but their frequency and phenotypic range vary across cohorts and require individualized clinical follow-up. •This case series of eight genetically confirmed CSS patients (7 ARID1B, 1 SMARCA4) expands the phenotypic spectrum by detailing dysmorphic findings together with endocrine features including pathological short stature with delayed bone age, hypothyroidism, transient hypercalcemia, cryptorchidism, and recurrent fractures. •We identified eight pathogenic/likely pathogenic variants, including two novel variants, and highlight that fifth digit/nail involvement may be subtle (mild terminal fifth phalanx hypoplasia and minor fifth nail changes) rather than overt.

ABSTRACT Individuals urbanize when the net benefits of urban living exceed those of rural conditions. Body mass index (BMI), height, and weight are measures of welfare that reflect the balance between caloric intake and the physiological demands of labor and environmental conditions. Using 19th- and early 20th-century US prison records, this study illustrates that urban residents had lower BMIs, shorter stature, and lower body weight than rural residents. Urban nutritional outcomes varied by race: both white and black urban residents had lower BMIs, shorter stature, and lower weight relative to their rural counterparts. Net nutrition variation was greater among urban males compared to females, indicating that urbanization affected male net nutrition more than female nutritional status.

Rationale:Lamb-Shaffer syndrome (LAMSHF) is a rare neurodevelopmental disorder caused by pathogenic variants in the SRY-related high-mobility group box 5 (SOX5) gene. Clinical features are heterogeneous, and novel variants continue to be reported, expanding the genotypic and phenotypic spectrum of the disease.Patient concerns:A 15-year-old male presented with short stature, mild intellectual disability, epilepsy, and multiple congenital anomalies, including facial dysmorphism and right thumb syndactyly.Diagnoses:Whole-exome sequencing identified a novel heterozygous variant in the SOX5 gene, c.1160G>A (p.Ser387Asn), located at 12p12.1. Although initially classified as a variant of uncertain significance according to ACMG criteria, its strong correlation with the clinical phenotype supported the diagnosis of LAMSHF.Interventions:The patient has been maintained on levetiracetam for epilepsy management and is receiving dental care for maxillofacial deformities. A multidisciplinary rehabilitation approach is recommended.Outcomes:Seizures are well-controlled with no recurrence. The patient demonstrates stable cognitive and functional status under current supportive care.Lessons:This case reports a novel SOX5 variant associated with LAMSHF and highlights the importance of genetic confirmation in patients with unexplained neurodevelopmental features to guide appropriate management and avoid unnecessary interventions.

SUMMARY For the past thirty years, the daily recombinant human growth hormone (rhGH) therapy such as Somatropin has been demonstrated to be safe and effective and has been widely used for pediatric growth hormone deficiency (pGHD) and other growth failure conditions in children. More recently, several long-acting recombinant human growth hormone (LAGH) have also been developed or are close to regulatory approval to decrease the inconvenience of daily injections and increase treatment adherence through once weekly administration (Grillo et al., 2023). Somatrogon is an example of one such LAGH which was approved by FDA for pGHD indication in June 2023. A randomized Phase 3 study was conducted and demonstrated non-inferiority (NI) of Somatrogon compared to daily Somatropin for pGHD patients. It is of interest to study Somatrogon in other conditions involving growth failure in children. These include Small for Gestational Age (SGA), Idiopathic Short Stature (ISS) and Turner Syndrome (TS). All these conditions result in growth failure, albeit because of different etiologies. We propose a single study which utilizes a master protocol design that promotes efficiencies for the Sponsor, investigators, study participants, and regulatory agencies and a novel application of the meta-analysis across the multiple indications. This single master protocol approach provides the framework by which we are able to evaluate a common intervention across multiple indications in parallel, which is an innovative and efficient alternative to the standard series of clinical trials that typically investigate one intervention in a disease in a single study. The study design and statistical methodologies are described. Simulations are also presented to compare study power under different scenarios.

Short stature in children born small for gestational age (SGA) is treated with daily injections of recombinant growth hormone (GH), a significant treatment burden. The objective of this study is to demonstrate the efficacy and safety of once-weekly somapacitan, a long-acting GH, in short children born SGA. REAL8 (NCT05330325) is a multinational, multicenter, randomized, open-labeled, active comparator, phase 3 basket study including four non-GH deficiency indications comprising a 52-week main phase and 104-week extension. Here, we present 52-week results from the SGA sub-study. 142 prepubertal, treatment-naïve children born SGA in 78 sites across 26 countries were randomized 2:1:1 to somapacitan .24 mg/kg/week or daily GH 0.035 or 0.067 mg/kg/day, all administered subcutaneously. 140 completed the main 52-week treatment period. The primary endpoint, estimated mean height velocity at week 52, was 11.0 cm/year for somapacitan vs. 9.4 cm/year [ETD = 1.6(0.91, 2.23)95%CI] and 11.1 cm/year [ETD = -0.1(-0.75, 0.60)95%CI] for daily GH 0.035 and 0.067 mg/kg/day, respectively. Noninferiority was confirmed for somapacitan compared to both daily GH groups. Superiority was demonstrated for somapacitan versus daily GH 0.035 mg/kg/day. Safety profiles were similar between treatment groups. As expected, somapacitan reduced disease burden at week 52, as for daily GH 0.067 mg/kg/day, while somapacitan was associated with reduced treatment burden. Somapacitan provides similar efficacy, safety, and tolerability as daily GH in short children born SGA after 52 weeks of treatment. Somapacitan may be an attractive alternative to daily GH in this population, reducing treatment burden to improve adherence and treatment outcomes.

Crouzon syndrome (CS) is a rare genetic condition characterised by craniofacial malformations due to mutations in the FGFR2 gene. This study aimed to evaluate the contributing factors for Angle's Class III malocclusion in patients with CS through cephalometric analysis. Six patients with confirmed CS diagnosis were included in the study. Cephalometric measurements were performed using CT scans and compared to established norms. Pathogenic variants in the FGFR2 gene were identified in all patients. Phenotypic and cephalometric characteristics were assessed in each patient. Results showed consistent craniofacial abnormalities, including midface retrusion, mandibular prognathism, and malocclusion. Cephalometric analysis revealed specific patterns indicating growth deficiency at the posterior base of the skull, maxillary retroposition, and an anterior accommodation of the mandibular condyles in the glenoid fossa. These findings provide valuable insights into the underlying factors contributing to Angle's Class III malocclusion in patients with Crouzon syndrome.

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Introduction: Turner syndrome (TS) is a genetic disorder caused by the complete or partial absence of one of the X chromosomes. Its clinical features include short stature, gonadal dysgenesis, primary amenorrhea, and infertility. The condition presents significant phenotypic variability, especially in cases involving chromosomal mosaicism and structural abnormalities. Case Presentation: A 21-year-old female patient from Tapauá, Amazonas, Brazil, was evaluated due to irregular bleeding followed by secondary amenorrhea. Cytogenetic analysis of peripheral blood lymphocytes was performed using conventional G-banding, followed by fluorescence in situ hybridization (FISH) for molecular characterization. Cytogenetic analysis revealed two cell lines: one with monosomy X (45,X) and another with 46 chromosomes including a ring X chromosome. The final karyotype was mos45,X[170]/46,X,r(X)(p11.22q13.23)[30]. The presence of a ring X chromosome was confirmed by FISH. Conclusion: This case illustrates the relevance of combining classical and molecular cytogenetic techniques to identify structural X chromosome abnormalities. Such analysis is essential for accurate diagnosis, understanding genotype–phenotype correlations, and guiding clinical management and genetic counseling in patients with TS.

L-fucose supplementation in a patient with global hypofucosylation and a mono-allelic variant in SLC35C1: Clinical improvement and assessment of biomarkers.

Heterozygous loss of OSR2 can cause radioulnar synostosis with ancillary skeletal manifestations.

Glycogen storage disease type IX: Long-term follow-up of 52 patients from three European countries.

A systems perspective on rare diseases: integrating human phenotype ontology with the Anukta framework of Ayurveda.

Growth patterns: Pathology vs. Normal variation.

In search of Vitruvian man.