Search Results (201)

Primary dystrophin deficiency, caused by X-chromosome mutations within the DMD gene, encompasses a continuous clinical spectrum of neurological, muscular, and cardiac disorders known as dystrophinopathies that exhibit profound phenotypic variability driven by specific mutation profiles and epigenetic factors. This comprehensive review analyzes the clinical and molecular characteristics of seven primary classifications: Duchenne muscular dystrophy (DMD), a severe childhood myopathy caused by a complete absence of the protein that leads to loss of ambulation and fatal cardiorespiratory failure in youth; Becker muscular dystrophy (BMD), a milder variant with partial protein deficiency that preserves walking capabilities into adulthood and prolongs life expectancy; pseudometabolic dystrophinopathic syndrome, featuring exercise intolerance, cramps, and recurrent rhabdomyolysis that mimics metabolic diseases; asymptomatic dystrophinopathy, representing the mild end of the spectrum identified incidentally through chronically elevated creatine kinase levels; brain dystrophin-related syndrome, where the disruption of distal isoforms like Dp140 and Dp71 results in neurodevelopmental and neuropsychiatric comorbidities such as ADHD, autism, and intellectual disability; X-linked dilated cardiomyopathy (XLDCM), a cardiac-selective condition causing severe heart failure and arrhythmias while sparing skeletal muscle function; and female dystrophin-related syndrome, distinguishing between familial carriers—who can manifest symptoms due to skewed X-chromosome inactivation—and rare sporadic females who develop an exceptional, severe, Duchenne-like phenotype due to cytogenetic accidents such as Turner syndrome or chromosomal translocations. Ultimately, advancements in molecular testing (NGS and WGS) have significantly optimized diagnostic precision, proving essential for implementing early cardioprotective care, accurate genetic counseling, and the development of future tissue-specific targeted gene therapies. The present study also discusses the psychosocial impact that the disease has on patients. Full article

Loss-of-function (LoF) variants in the PRPS1 gene, encoding the phosphoribosyl pyrophosphate (PRPP) synthetase 1 enzyme, cause rare neurometabolic disorders historically viewed as discrete entities: nonsyndromic deafness (DFNX1), Charcot–Marie–Tooth disease type X5 (CMTX5), and Arts syndrome. A major clinical challenge is the temporal dissociation between early auditory failure and subsequent neurodegeneration, causing fragmented diagnostics. We systematically quantified this diagnostic latency and reconceptualized the disease spectrum through a molecular lens. A PRISMA-compliant systematic review identified 19 patients with genetically confirmed PRPS1 LoF variants, including our index case (c.362C>G) presenting a 15-year diagnostic delay. Kaplan–Meier analysis revealed sensorineural hearing loss manifested acutely (median 0 years; 95% CI: 0–1). In contrast, neurological deficits demonstrated a prolonged latency (median 3 years; 95% CI: 1–8), followed by ophthalmological signs (median 11.5 years). The median symptomatic delay was 3 years (range up to 19). We posit that this temporal dissociation reflects differential tissue vulnerability to intracellular ATP/GTP and NAD+ depletion caused by the primary enzymatic defect. Ultimately, DFNX1, CMTX5, and Arts syndrome represent a continuous PRPS1-related neurometabolic spectrum. Because targeted metabolic interventions (such as S-adenosylmethionine or nicotinamide riboside) have limited efficacy on advanced structural nerve damage, recognizing this early diagnostic window to initiate biochemical rescue prior to irreversible axonal degeneration is critical. Full article

Background: The incidence of early-onset colorectal cancer (EOCRC) is rising, yet the relative contribution of metabolic, inflammatory, and laboratory abnormalities remains incompletely defined. Objectives: We compared these associations between EOCRC and late-onset colorectal cancer (LOCRC) while addressing the possibility that some laboratory abnormalities may reflect occult cancer rather than antecedent risk. Methods: We conducted a matched case–control study using the TriNetX US Network. Adults diagnosed with CRC between 2010 and 2023 were identified as EOCRC (18–49 years) or LOCRC (50–75 years). Patients with prior malignancy, inflammatory bowel disease, hereditary or familial CRC risk, or prior colectomy were excluded. Three separate analyses were performed. First, a direct EOCRC-versus-LOCRC comparison evaluated gastrointestinal symptoms during the 6 months preceding diagnosis. Second, EOCRC and LOCRC were each compared with their respective matched cancer-free controls to assess clinical, metabolic, and laboratory features during the 24 months preceding diagnosis. When multiple laboratory values were available, the most recent value preceding the index date was used. Conditional logistic regression estimated adjusted odds ratios with 95% confidence intervals, with Bonferroni correction applied for multiple comparisons. Results: The direct matched EOCRC-versus-LOCRC comparison included 7752 patients with CRC, comprising 2584 with EOCRC and 5168 with LOCRC. EOCRC more frequently presented with rectal bleeding, abdominal pain, diarrhea, iron-deficiency anemia, and weight loss. Rectal tumors were more common in EOCRC, whereas proximal tumors were more common in LOCRC. In separate control-based analyses, 3217 patients with EOCRC and 12,112 patients with LOCRC were compared with 6434 and 24,336 matched cancer-free controls, respectively. The strongest independent features associated with EOCRC were severe obesity (aOR 2.61), microcytosis (aOR 2.29), low ferritin (aOR 2.11), and elevated C-reactive protein (aOR 1.87). Similar but generally attenuated associations were observed in LOCRC. In adjusted EOCRC-versus-LOCRC analyses, obesity (aOR 1.38), metabolic syndrome (aOR 1.41), and MASH (aOR 1.22) remained more closely associated with EOCRC. Conclusions: EOCRC is associated with a distinct clinical–metabolic phenotype, with more pronounced metabolic, inflammatory, and hematologic abnormalities than LOCRC. These findings should be interpreted as hypothesis-generating prediagnostic associations, not as validated predictors or causal risk factors. Full article

Background: Small intestine bacterial overgrowth (SIBO) is associated with steatohepatitis (SH) in subjects with metabolic-associated steatotic liver disease (MASLD). The impact of ileocecal valve (ICV) incontinence, a major cause of SIBO in patients with MASLD, remains unknown because of the unmet need for a non-X-ray-dependent diagnosis. Methods: Exploiting water as contrast medium and colonic irrigation via a hydro-colon machine (Clean Colon Srl, Monza, Italy), we developed a new abdominal ultrasound (US) procedure for diagnosing and grading ICV incontinence. In a pilot, observational, feasibility and safety study, we correlated a new ICV incontinence parameter with irritable bowel syndrome (IBS, ROMA IV criteria), serum transaminases (AST, ALT), platelet counts, FIB-4, US liver steatosis and stiffness (LS, measured by Shear Wave and Transient Elastography, SWE and TE). Results: We prospectively studied 32 consecutive subjects with IBS who underwent a pre-colonoscopy colon cleansing after informed consent: 19 males (59%), body mass index (BMI) 26.6 ± 2.6 kg/m², age 57 ± 19 years, 16 (50%) with US liver steatosis. The half-hour (27 min, range 20–35 min) procedure was safe and well tolerated except in two males with prostate hypertrophy. ICV incontinence was graded (after 2500–3000 mL irrigation) according to cecum/right-colon distention with/without (immediate or delayed) reflux into terminal ileum (TI): 0 = cecum distension without TI reflux; 1 = cecum distension with TI reflux; 2 = absence of cecum distension with TI reflux. Cecum/right-colon distention (grade 0 or 1) was perceived by the patients whereas the right colon irrigation with complete ICV incontinence (grade 2) was symptomless. ICV continence associated with LS (p ≤ 0.0001). A histologic diagnosis of non-alcoholic steatohepatitis was confirmed in a 35-year-old obese male with SIBO and LS > 8 kPa (8.7/8.5 kPa by SWE/TE):steatosis (grade S3) with hepatocyte ballooning, lobular inflammation (grade 6/8) without fibrosis (stage 0/4, F0). Conclusions: The new US-based approach provides a feasible, easy-to-perform, mini-invasive tool for the diagnosis and grading of ICV incontinence. Preliminary results prompt prospective studies investigating the impact of ICV incontinence as a possible co-factor of steatohepatitis in patients with MASLD. Full article

Background: Chung–Jansen syndrome (CHUJANS) is a rare autosomal dominant genetic condition caused by pathogenic variants in the PHIP gene, which encodes a protein involved in neurodevelopmental processes and IGF-1 signalling. The phenotype is characterised by variable degrees of intellectual disability, early-onset obesity or overweight, distinctive facial dysmorphisms, and behavioural disturbances. We here present a case of Chung–Jansen syndrome with a detailed endocrine work-up, highlighting the metabolic component of this syndrome. Case Presentation: We describe the case of a 21-year-old woman referred to our centre for evaluation of oligomenorrhea in the context of severe obesity (BMI 50.4 kg/m²), short stature (151 cm, <3rd percentile), and moderate-to-severe intellectual disability (full-scale IQ 38). Physical examination revealed dysmorphic features, including a round face, upslanting palpebral fissures, prominent zygomatic bones, anteverted nares, a prominent chin, and bilateral brachydactyly type E1. Laboratory investigations documented subclinical primary hypothyroidism of autoimmune origin, impaired glucose tolerance with associated hyperinsulinism, and polyendocrine metabolic ovarian syndrome (PMOS, previously known as PCOS). Exome analysis by next-generation sequencing (NGS) identified a heterozygous c.328C>T [p.(Arg110Cys)] variant in the PHIP gene, already reported in literature and classified as likely pathogenic (ACMG class 4). Segregation analysis in the mother (father was not available for the test) did not reveal the variant, suggesting a de novo origin in the patient. Concurrently, the same analysis revealed a variant of uncertain significance in the ANKRD17 gene, while array-CGH detected a maternally inherited microdeletion of uncertain significance on chromosome X (Xp11.23). Conclusions: This case confirms the association between the PHIP p.(Arg110Cys) variant and the phenotype of Chung–Jansen syndrome, providing a detailed characterisation of the endocrine and psychiatric comorbidities. Indeed, our report expands the knowledge on the endocrine phenotype providing further suggestion for personalised patient management. It underscores the importance of NGS in the diagnostic workup of syndromic obesity with intellectual disability, especially in the presence of negative family history and prior inconclusive genetic testing. This case suggests the inclusion of comprehensive endocrine evaluations in future studies on patients with Chung–Jansen syndrome, in order to support endocrine work-up and facilitate early identification and appropriate management of potentially treatable alterations. Full article

Alzheimer’s disease (AD) and metabolic syndrome often occur together, sharing characteristics such as insulin resistance, dyslipidemia, and chronic inflammation. Metabolic dysfunction frequently precedes cognitive decline, indicating that early intervention might alter the disease’s progression. We investigated whether the GLP-1 receptor agonist semaglutide (SMGL) influences metabolic impairment and AD pathology in an AD mouse model. Male and female 5xFAD and wild-type (WT) mice on regular (RD) or high-fat diets (HFD) were administered SMGL for 13 weeks. SMGL-treated groups exhibited significant, context-dependent effects. In metabolically challenged 5xFAD HFD mice, treatment led to reduced body weight, improved glucose tolerance, normalized cholesterol levels, and a restored balance of adiponectin and leptin. These improvements were associated with reduced Aβ40 and Aβ42 levels, restored GLP-1 receptor expression, increased synaptophysin and βIII-tubulin levels, and enhanced spatial memory. SMGL also decreased Iba1 and CD68 immunoreactivity in the hippocampus and cortex, reduced macrophage infiltration, and lowered CD36 expression in visceral adipose tissue (VAT), indicating coordinated anti-inflammatory effects. WT RD mice showed minimal metabolic responses and a modest decline in Y-maze performance, suggesting that excessive GLP-1 receptor activation may disrupt neuronal homeostasis when metabolic status is normal. SMGL acts as a context-specific metabolic and neuroprotective agent, offering the greatest benefits under conditions of metabolic dysfunction. These findings in a preclinical model suggest that targeting early metabolic disturbances provides a testable hypothesis for attenuating AD-related neurodegeneration, though further translational studies are required. Full article

Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism caused by ATP7B mutations, characterized by hepatic copper accumulation and multisystem involvement. Several rare inherited and acquired conditions can closely mimic WD, posing diagnostic challenges and the risk of inappropriate therapy. By examining neuroimaging patterns and distinguishing between diagnostic criteria, this narrative review provides a comprehensive synthesis of WD-mimicking disorders, emphasizing their molecular mechanisms, clinical phenotypes, and biochemical features. WD-mimicking disorders encompass ATP7A-related neurodegenerations (Menkes disease, occipital horn syndrome, X-linked distal hereditary motor neuropathy), MEDNIK syndrome, Huppke–Brendel syndrome, aceruloplasminemia, congenital disorders of glycosylation, primary familial intrahepatic cholestasis type 3, and acquired copper deficiency syndromes. Mechanisms include systemic copper deficiency, impaired intracellular trafficking, defective ceruloplasmin biosynthesis, secondary hepatic copper accumulation, and abnormal glycosylation. Clinical features range from neurodevelopmental delay, movement disorders, and hepatic dysfunction to dermatologic, hematologic, and connective-tissue abnormalities. Biochemical profiles may overlap with WD, particularly low serum ceruloplasmin and total copper, altered urinary copper excretion, and elevated hepatic copper in some disorders. Neuroimaging and genetic testing provide critical discriminative value. Management is largely supportive, with disease-specific therapies available in selected conditions, such as subcutaneous copper in Menkes disease or monosaccharide supplementation in certain congenital disorders of glycosylation subtypes. Accurate differentiation between WD and WD-mimicking disorders requires careful integration of clinical, biochemical, imaging, and molecular data. Recognition of distinctive features and understanding underlying pathophysiology are essential to avoid misdiagnosis and inappropriate anti-copper therapy, optimize management, and improve patient outcomes. Full article

Bartter syndrome (BS) represents a group of rare, autosomal recessive renal tubular disorders characterized by hypokalemic hypochloremic metabolic alkalosis, secondary hyperaldosteronism, and normal to low blood pressure. The underlying pathophysiology is primarily driven by defects in critical ion transport proteins or channels localized within the thick ascending limb of the loop of Henle, leading to impaired salt reabsorption. Recent advances in molecular genetics have refined the classification of Bartter syndrome. Current evidence supports SLC12A1, KCNJ1, CLCNKB, BSND, and MAGED2 as the core disease genes within the contemporary BS spectrum, with MAGED2 causing a distinct X-linked transient antenatal form. In contrast, gain-of-function CASR variants, historically labeled “type V Bartter syndrome”, are now more appropriately described as CaSR-associated Bartter-like phenotypes within the broader spectrum of disorders of calcium homeostasis. Despite significant progress, two primary research limitations remain. First, fully elucidating genotype–phenotype correlations and overcoming diagnostic complexities continues to be highly challenging due to substantial phenotypic overlap and genetic heterogeneity. Compounding these diagnostic hurdles is the equally critical challenge of understanding mutation-driven pathogenic mechanisms to develop viable clinical interventions. This review systematically summarizes the current molecular genetic landscape of BS to address these gaps. We highlight the relationships between specific genetic variants and clinical manifestations, delve into molecular pathophysiology including protein misfolding and trafficking defects, and explore emerging therapeutic approaches such as molecular chaperones. By integrating genetic and clinical data, this work aims to provide a comprehensive framework to facilitate precise diagnosis and individualized treatment strategies, ultimately advancing precision medicine in the management of Bartter syndrome. Full article

Background/Objectives: X-linked Alport syndrome (XLAS) arises from pathogenic variants in COL4A5. Truncating variants are generally classified as severe, but whether clinically meaningful heterogeneity exists within this group remains unclear. This study aimed to establish a novel Col4a5 knock-in mouse model based on a clinical variant and to determine whether truncating mutation position influences disease severity. Methods: A de novo COL4A5 frameshift variant, c.2440delG, was identified in a patient with severe early-onset XLAS. A Col4a5-G814fs knock-in mouse was generated by CRISPR/Cas9 on the C57BL/6J inbred mouse strain background and compared with the established Col4a5-G5X nonsense model using survival analysis, serial functional measurements, kidney histopathology, transmission electron microscopy, and RNA sequencing. Results: The Col4a5-G814fs knock-in mouse was successfully generated and showed loss of glomerular α5(IV) collagen chain expression. Compared with G5X mice, G814fs mice exhibited shorter survival (median 141 vs. 161.5 days, p = 0.0004), earlier onset of proteinuria, and more severe kidney functional decline. By 16 weeks, G814fs mice also showed more severe glomerular basement membrane abnormalities and more extensive glomerulosclerosis. RNA sequencing revealed a shared inflammatory gene signature in both models, together with selective upregulation of genes related to the PPAR signaling pathway and fatty acid metabolism in G814fs kidneys. Conclusions: This study reports a novel de novo COL4A5 frameshift variant and establishes the first Col4a5-G814fs knock-in mouse model. Direct comparison with the G5X model shows that distinct truncating COL4A5 mutations can be associated with substantially different disease severity, providing a useful platform for future mechanistic and therapeutic studies in XLAS. Full article

X. fastidiosa subsp. pauca (Xfp) is the etiological agent of “Olive Quick Decline Syndrome” (OQDS). Cellina di Nardò (Olea europaea L., Oleaceae), one of the major Salento cultivars, is highly susceptible to Xfp, usually showing acute symptoms after infection. NuovOlivo^® a plant-derived formulation made with vegetal oils and water infusion from multi botanical species has been reported as effective against OQDS in plants affected by Xfp. A non-targeted ¹H NMR (Nuclear Magnetic Resonance) fingerprinting approach, with unsupervised and supervised analysis, was applied to observe the possible changes in the metabolic profile in leaf samples of cultivars Cellina di Nardò naturally affected by Xfp treated with NuovOlivo^® compared to untreated plants. The major differences were observed for the content of quinic acid, malate, mannitol, glucose, oleuropein, and aldehyde derivatives in treated compared to untreated samples. The resulting data indicated a season-dependent plant response to both disease and treatment. Moreover, the overall differences observed between the two investigated years, suggest a general decrease in the differences for the discriminating metabolites over time. The protocol NuovOlivo^® was demonstrated to promote changes in the metabolic profile of olive leaves, suggesting a possible role of this treatment, integrated with good agricultural practices, against Xfp and OQDS. Full article

Background and Clinical Significance: Over the last two decades, glucagon-like peptide-1 (GLP-1) receptor agonists have dramatically improved the management of type 2 diabetes mellitus and obesity. Currently, little is known about the use of semaglutide (a second-generation GLP-1 receptor agonist) in patients with X chromosome abnormalities. Herein, we describe the therapeutic use of semaglutide in a woman with a partial deletion of the X chromosome long arm (partial Xq deletion) and comorbid obesity. We also conducted a narrative mini-review on overweight, obesity and common metabolic derangements in patients with partial Xq deletions and Turner syndrome. Case Presentation: A 65-year-old Italian woman with a partial Xq deletion, class 1 obesity, insulin resistance, prediabetes, hypercholesterolemia and metabolic dysfunction-associated steatotic liver disease (MASLD) was referred to our Institution for persistent difficulty in managing excess body weight despite regular adherence to different structured physical activity programs and hypocaloric diets. Therefore, we prescribed a combination therapy based on low-dose metformin (500 mg/day) and once-weekly subcutaneous semaglutide (as an adjunct to lifestyle intervention). At 5 months after initiation of the combination therapy, blood tests showed metabolic improvements, including improvement of prediabetes (0.3-percentage-point reduction in glycated hemoglobin [HbA1c] values) and normalization of markers of insulin sensitivity and insulin resistance (QUICKI, HOMA-IR and TyG index). At 8 months, the patient showed substantial weight loss, which amounted to 13.8 kg (percent total body weight loss: 20.95%), and was accompanied by a notable reduction in waist circumference (−14.1 cm). Moreover, body mass index (BMI)-based weight status improved from class 1 obesity to overweight: BMI value of 25.1 kg/m² at 8 months vs. 31.8 kg/m² at baseline (near-normalization of BMI values). Bioelectrical impedance analysis (BIA) revealed that the patient’s overall weight loss consisted of 74.6% fat mass (FM) loss (−10.3 kg) and 25.4% fat-free mass (FFM) loss (−3.5 kg). Despite the expected FFM reduction in absolute terms, percent FFM increased at 8 months (+9.6%). This increase in percent FFM was accompanied by a reduction in percent FM at 8 months (−9.6%), indicating an overall improvement in body composition. Normalization of percent FM and FFM values (28.6% and 71.4%, respectively) was also achieved at 8 months. These body composition changes are in line with those observed in clinical trials investigating the use of semaglutide in patients with overweight or obesity. At 6 months, an abdominal ultrasound also showed the disappearance of the sonographic characteristics suggestive of mild-to-moderate hepatic steatosis. Low-dose metformin (500 mg/day) and subcutaneous semaglutide (up to a weekly dose of 1.7 mg) were well tolerated by the patient. Conclusions: To the best of our knowledge, this is the first case documenting the effective use of once-weekly subcutaneous semaglutide plus low-dose metformin combination therapy for the treatment of obesity and prediabetes in a woman with a partial Xq deletion. Large prospective cohort studies are warranted to better investigate the safety and efficacy profile of semaglutide (alone or in combination with metformin) in patients with numerical and structural X chromosome abnormalities, comorbid overweight/obesity and related metabolic disorders. Full article

Tryptophan (TRP) is a proteinogenic and nutritionally essential amino acid involved in the formation of numerous bioactive substances. A crucial role in the TRP molecule is played by indole, a bicyclic ring formed by benzene and pyrrole, which confers hydrophobic and antioxidant properties and the ability to act as a ligand for aryl hydrocarbon and pregnane X receptors. The first parts of the article examine sources, nutritional requirements, and three pathways of TRP catabolism. Physiologically, ~5% of dietary TRP is catabolized through the pathway forming serotonin and melatonin in the brain and enterochromaffin cells of the gut, ~85% through the pathway resulting in the formation of nicotinamide nucleotides and kynurenine and its derivatives in the liver and immune cells, and ~10% in gut microbiota to indole derivatives. Alterations of individual TRP catabolism pathways in aging, alcoholism, inflammatory bowel disease, metabolic syndrome, renal insufficiency, liver cirrhosis, cancer, and nervous diseases, e.g., depression, Alzheimer’s and Parkinson’s diseases, multiple sclerosis, and schizophrenia, are examined in the central section. The final sections are devoted to the benefits and adverse effects of TRP supplementation, the therapeutic use of various TRP metabolites, and the pharmacological targeting of enzymes, transporters, and receptors involved in TRP catabolism. It is concluded that all pathways of TRP catabolism are altered across a broad spectrum of human illnesses, and further investigation is needed to understand their role in disease pathogenesis better. The goal for clinical research is to explore options for TRP-targeted therapies and their integration into new therapeutic strategies. Full article

Background/Objectives: Obstructive sleep apnea (OSA) is often accompanied by metabolic syndrome (MetS), forming a high-risk phenotype with elevated cardiometabolic burden. The contribution of lifestyle behaviors—particularly eating mechanics and psychological eating cues—to disease severity remains unclear. This study examined independent associations of dietary behaviors and physical activity (PA) with OSA severity, sleep quality, and metabolic health. Methods: Forty-four OSA patients (mean age 38.3 ± 9.1 years; 89% male) underwent attended polysomnography, dual-energy X-ray absorptiometry, and metabolic profiling. Validated questionnaires assessed dietary behaviors, PA, and sleep quality. Hierarchical logistic regression identified predictors of MetS, severe OSA, and poor sleep quality. Results: The prevalence of MetS was 45%. Compared with those with OSA alone, participants with MetS demonstrated significantly greater central adiposity and more severe nocturnal hypoxemia, despite similar apnea–hypopnea indexes. In multivariable models, MetS was independently associated with higher body mass index (adjusted odds ratio [aOR] = 1.64; p = 0.008) and reward eating (aOR = 3.34; p = 0.041), whereas higher total PA was associated with reduced odds (aOR = 0.96; p = 0.026). Poor subjective sleep quality was significantly associated with younger age (aOR = 0.91; p = 0.037). For severe OSA, slow chewing was associated with significantly reduced odds (aOR = 0.24; p = 0.038), while emotional eating was associated with increased odds (aOR = 2.40; p = 0.048). Conclusions: This hypothesis-generating study identifies a high-risk OSA phenotype marked by metabolic dysfunction and hypoxemia. Eating speed (a proxy for mindful eating), emotional and reward-driven eating, and PA independently shape metabolic and respiratory outcomes. These findings support incorporating behavioral nutrition into multidisciplinary OSA management. Full article

Juvenile idiopathic arthritis (JIA) is the most prevalent chronic rheumatologic condition in childhood, with an incidence that continues to rise worldwide. Despite substantial progress in therapeutic strategies over the past two decades, JIA remains a major health concern. Beyond joint inflammation and musculoskeletal impairment, accumulating evidence indicates that JIA is associated with metabolic disturbances and altered body composition, which may predispose affected children to an elevated cardiovascular risk in the long term. The objective of this review is to synthesize current knowledge on these metabolic and anthropometric alterations and to evaluate the role of non-invasive diagnostic methods in detecting early cardiovascular changes. A narrative review of the literature was conducted using PubMed and Scopus databases, focusing on studies assessing lipid metabolism, insulin resistance, adiposity, and cardiovascular markers in pediatric patients with JIA. Special attention was given to non-invasive diagnostic approaches, including bioelectrical impedance analysis (BIA), dual-energy X-ray absorptiometry (DXA), skinfold thickness, transient elastography, carotid intima–media thickness (cIMT), as well as selected biochemical markers. Evidence suggests that children with JIA frequently present with dyslipidemia, increased insulin resistance, and abnormal body fat distribution compared with their healthy peers. Non-invasive assessment methods, particularly DXA and cIMT, have demonstrated sensitivity in detecting subclinical metabolic and vascular changes. These alterations resemble early features of metabolic syndrome and are thought to contribute to premature cardiovascular morbidity in this population. Incorporating non-invasive cardiovascular risk assessment into routine rheumatology practice may improve early detection of metabolic and vascular complications in JIA, support timely preventive interventions, and ultimately enhance long-term outcomes for affected children. Most available evidence is derived from cross-sectional studies, highlighting the need for longitudinal investigations to better define long-term cardiometabolic risk in JIA. Full article

Background: The immunoglobulin superfamily member 1 (IGSF1) gene encodes for a transmembrane glycoprotein involved in crucial processes such as growth, metabolism, and reproductive function. Loss-of-Function (LOF) mutations in the IGSF1 gene have been reported to cause the X-linked IGSF1 deficiency syndrome, a rare genetic condition that primarily affects males, characterized by hypothyroidism, macroorchidism, delayed puberty, obesity, and infertility. Case Report: In this study, we identified a novel hemizygous nonsense IGSF1 variant c.1989G>A (p.Trp663Ter) in a male patient who initially presented with growth impairment and growth hormone deficiency (GHD), with a positive family history on the maternal lineage. Notably, the proband does not present with macroorchidism, a feature typically associated with IGSF1 deficiency. The variant was also found in his heterozygous sister, who presented with isolated growth hormone deficiency, and in his mother, who displayed hypertension and thyroid dysfunction but no significant growth impairment. Discussion: This phenotypic variability suggests a differential expression of IGSF1-related symptoms depending on zygosity and sex within the same family, probably explained by X-chromosome inactivation (XCI) in females, which can lead to varying degrees of functional IGSF1 expression in different tissues. Conclusions: This case highlights the intrafamilial phenotypic variability associated with IGSF1 mutations, illustrating differences between male and female carriers and highlighting the importance of genetic testing in patients with similar clinical presentations. Full article