Mapping cardiac innervation in the long QT syndrome type 1 transgenic mouse model using whole heart imaging.

Objective:To detect the molecular etiology of a proband with Waardenburg syndrome type type Ⅳ（WS4） and their family members, explore the possible pathogenic mechanism of SOX10 gene mutation, analyze its incomplete penetrance combined with clinical phenotypes, and dicuss the potential molecular pathogenesis. Methods:Clinical data of the proband and their family members were collected. Peripheral blood genomic DNA was extracted from the proband and family members, and all exons and flanking sequences were analyzed using a next-generation sequencing（NGS） -based deafness gene panel. Based on the high-throughput sequencing results, the mutation sites were verified and analyzed in the family members by Sanger sequencing. Results:The proband was diagnosed with typical Waardenburg syndrome type type IVC（WS4C）, presenting with sensorineural hearing loss, Hirschsprung's disease（HD） and heterochromia iridis. Sanger sequencing revealed a pathogenic heterozygote c.127C>T mutation in the SOX10 gene of the proband, resulting in a substitution of arginine（Arg） tat codon 43 with a stop codon. The same mutation site was also identified in the proband's father, aunt and sister. The proband's sister had hearing impairment and heterochromatic iridis, presenting with a Waardenburg syndrome type type Ⅱ（WS2） phenotype, while the proband's father was phenotypically normal, and the proband's aunt had deafness but no heterochromia iridis. Conclusion:The heterozygous c.127C>T mutation in SOX10 is the molecular pathological cause of WS4C in this proband. The clinical and genetic characteristics of this family illustrate the genetic heterogeneity and incomplete penetrance of WS4C.

We report a 39-year-old woman with lifelong visual impairment who presented in June 2024 with progressive visual deterioration in her right eye. Ophthalmologic evaluation revealed severe high myopia, vitreoretinal degeneration, phthisis bulbi of the left eye, and downward lens dislocation of the right eye. Neurological workup revealed bilaterally blurred optic discs, an elevated cerebrospinal fluid opening pressure of 31 cm H2O that normalized on repeat lumbar puncture, nonspecific white matter signal changes on MRI, and bilateral frontal polymicrogyria. Initial mild homocysteine elevation prompted consideration of homocystinuria; however, whole-exome sequencing identified a homozygous frameshift mutation in COL18A1 (c.2824_2831del, p.Gly942Argfs*142), confirming Knobloch syndrome type 1. This case illustrates an adult presentation of Knobloch syndrome with retinitis pigmentosa-like retinal changes and lens dislocation mimicking homocystinuria.

Repurposing osteoporosis medications for other diseases: a narrative review by the European Calcified Tissue Society (ECTS).

Evidence of heterogeneity in the opioid withdrawal syndrome: Spontaneous and precipitated withdrawal.

Carpal tunnel syndrome (CTS) is the most common neuropathy worldwide. Although multiple factors contribute to CTS, persistent median artery (PMA)-related CTS is relatively uncommon. To date, no literature has reported the ultrasonic features of different types of PMA-induced CTS. We report the clinical manifestations and ultrasonographic features of 3 patients with different types of CTS associated with PMA and review relevant literature. All 3 cases were diagnosed with PMA combined with CTS, specifically categorized as CTS with PMA thrombosis, CTS with PMA and median nerve bifidity, and CTS with PMA and high bifurcation of the median nerve. Different treatment measures were administered based on ultrasound diagnosis and clinical presentation, all with good prognoses. Ultrasound enables precise and rapid identification of various PMA-related types of CTS, effectively guiding clinicians in making the most patient-friendly treatment decisions.

Dual rare genetic variants: case report of a child with SBIDDS syndrome and citrullinemia type 1.

Background/Objectives: FAM111A is a trypsin-like serine protease that has emerged as a regulator of DNA replication, and is directly related to genome stability, protein homeostasis, antiviral defense and cancer progression. Pathogenic variants in FAM111A are correlated with genetic syndromes such as Kenny–Caffey syndrome type 2 (KCS2) and gracile bone dysplasia/osteocraniostenosis (GCLEB/OCS). This study focuses on the evolutionary, genetic, and structural analysis of FAM111A, in order to identify key regions and candidate pharmacological targets that are related to this enzyme’s function. Methods: The methodology of this in silico study includes separate analyses at the sequence, structural and functional levels. Initially, data mining was carried out using NCBI/Protein (2025), and then data filtering was performed in order to identify representative FAM111A sequences for several species. Sequence analysis was then executed through multiple alignments and phylogenetic analyses. Through this, conserved domains and motifs were identified. For structural analysis, human pathogenic mutations and protein structures were identified through searches in biological databases including PDB and ClinVar, and then all data were analyzed in order to identify candidate pharmacological targets related to FAM111A function. Results: Approximately 1850 FAM111A protein sequences were retrieved for several species, and after filtering processes a dataset of 85 representative sequences was generated. Evolutionary analysis indicates that FAM111A originated in early metazoans, with progressive domain specialization leading to mammal-restricted acquisition of regulatory elements, including the PIP-box PCNA (proliferating cell nuclear antigen) interacting peptide and UBL (ubiquitin-like) domains. The ubiquitin-like/DNA binding domain and catalytic serine protease domain (SPD) are the most conserved, containing seven highly conserved motifs. The structural analysis was based on two protein structures and 34 critical mutations that accumulate in two distinct regions. Finally, by combining the results, six pharmacological targets and 100 inhibitors are proposed. Conclusions: Advancing the structural and function characterization of FAM111A, coupled with pharmacological target identification and evolutionary insights, will be critical to validate this underexplored protease as a therapeutic genetic target in genetic disorders, cancer, and antiviral responses.

Pulmonary interstitial fibrosis is a common and difficult disease of respiratory system, which belongs to the category of interstitial lung disease. At present, the global incidence rate is about 0. 09–1. 30/10000, and it is increasing year by year. There is no effective treatment in modern medicine. Lung transplantation is often performed after the complete loss of lung function. The operation cost is high and the medical burden is heavy. Traditional Chinese medicine has rich experience and unique advantages in treating this disease. On the basis of inheriting the predecessors, Professor Liu Huawei created the theory of five elements Zang Fu Qi machine gasification (referred to as “five elements gasification theory”), which has achieved good clinical effect. Guided by this theory, this paper systematically expounds the TCM syndrome differentiation and treatment rules of pulmonary interstitial fibrosis. Through the analysis of the etiology, pathogenesis and syndrome evolution law of the disease, the basic pathogenesis of the disease is the deficiency of lung qi (Yin), the loss of Qi, phlegm dampness and blood stasis, and the imbalance of Qi mechanism, which belongs to the syndrome of excess due to deficiency, deficiency due to excess, and the mixture of deficiency and excess. On this basis, the six syndrome types of qi deficiency and phlegm stagnation, upper excess and lower deficiency, Qi deficiency and blood obstruction, lung stomach qi inversion, lung kidney yin deficiency, spleen kidney yang deficiency were summarized, and the basic treatment method of “strengthening vital energy to replenish lung and spleen, promoting gasification to expel phlegm and blood stasis” was established, and the representative prescriptions were given respectively. For the early asymptomatic patients, the idea of disease differentiation and treatment was put forward, which was mainly composed of Maiwei Buzhong Yiqi Decoction and Qianjin Weigan decoction. In order to provide new ideas and methods for TCM clinical diagnosis and treatment of pulmonary interstitial fibrosis, this paper preliminarily constructed the syndrome differentiation and treatment system of pulmonary interstitial fibrosis under the guidance of the five element theory of gasification.

Sanfilippo syndrome type A with acute metabolic acidosis: a case report of the first documented SGSH c.571G > A homozygous mutation.

A preterm male neonate born at 28 + 2weeks gestation, with a birth weight of 1520g (large for gestational age) and antenatal polyhydramnios, presented with prematurity, early-onset sepsis, and septic shock. Between days 4 and 9 of life, the neonate developed marked polyuria, hyponatremia, and compensated metabolic acidosis with normal to transiently elevated serum potassium levels, initially obscuring the diagnosis of a tubular disorder. Subsequently, the biochemical profile evolved to hypokalemia, metabolic alkalosis, and hypercalciuria, consistent with Bartter syndrome. The clinical course improved with fluid resuscitation, targeted electrolyte correction, and supportive care including respiratory, inotropic support and antibiotic therapy. Whole exome sequencing identified a novel frameshift variant, chrX:54837417delT (c.701delT; p.Leu234TrpfsTer12), in exon 4 of the MAGED2 gene. The neonate was discharged in stable condition on day 47 of life (weight 1775g). This report highlights the diagnostic challenges of neonatal polyuria and salt-wasting syndromes in the setting of prematurity and sepsis and underscores the value of genetic confirmation for prognosis and counseling.

Telomere recapping via gene therapy as a beneficial strategy for cardio-renal syndrome type 4.

Recent advances in epilepsy genetics have revolutionized the diagnosis and management of patients. This study was conducted to evaluate the clinical significance of molecular diagnosis in Egyptian patients with pediatric-onset drug-resistant epilepsy (DRE). All patients lacked electro-clinic-radiological concordant lesions and therefore were not candidates for surgical intervention. More than 70% of cases had variable degrees of cognitive impairment, and about 25% had different forms of movement disorders. Exome sequencing was able to unravel potential genetic defects in 40 patients across 31 genes. The study identified 15 novel variants, including those in MYCBP2 and BAZ2B, which were recently linked to genetic epilepsy. Genetic diagnosis refined classification and guided therapy in several patients, particularly those with ion channelopathies, progressive myoclonic epilepsy, infantile convulsions, choreoathetosis syndrome, and glucose transporter Type 1 deficiency. Our findings underscore the importance of genetic testing for patients with DRE, improving clinical classifications beyond electroclinical assessments and supporting better outcomes.

Multiple endocrine neoplasia syndrome type 1 (MEN 1, Wermer syndrome) is a group of heterogeneous inherited diseases, caused by hyperplasia or neoplastic transformation of several endocrine glands. MEN 1 syndrome is characterized by variable combinations of endocrine disorders. Cancer awareness in patient with diagnosed and genetically confirmed multiple endocrine neoplasia type 1 syndrome relatives plays an important role.This case demonstrates a non-classical manifestation of the disease with neuroendocrine tumor of the pancreas, accompanied by hiperinsulinemic hypoglycemia, and the subsequent detection of primary hyperparathyroidism.

Autoimmune Polyendocrine Syndrome Type 1 (APS-1) is a rare monogenic disorder caused by mutations in the autoimmune regulator (AIRE) gene. Although AIRE is essential for central immune tolerance, how distinct APS-1-associated mutations differentially affect medullary thymic epithelial cell (mTEC) biology remains incompletely understood. Here, we investigated the molecular and functional consequences of three Aire/AIRE variants using complementary murine mTEC models. To define transcriptional effects, we performed single-cell RNA sequencing (scRNA-seq) on mTECs carrying a heterozygous genomic Aire c.735delG mutation generated by CRISPR-Cas9. This analysis revealed reduced transcriptional heterogeneity, decreased expression of tissue-restricted antigens (TRAs) mRNAs (including Col4a3, Col7a1, and Neto2), and downregulation of key mTEC lineage markers (Epcam, Cldn4, Krt14). Mutant cells also displayed altered expression of mRNAs involved in chemokine-mediated migration (Ccl25, Cxcl16), extracellular matrix and cell adhesion (Fn1, Lama5, Col4a1, Nectin1, Cdh1), and actin cytoskeleton organization (Gsn, Rac1, Wasl, Actn1), indicating broad disruption of pathways governing mTEC identity and cell-cell interactions. Guided by these findings, we assessed mutation-specific functional outcomes using a CRISPR-derived Aire functional knockout and lentiviral expression of the human AIRE missense variants p.G229W and p.C313Y in wild-type mTECs. Functional assays revealed mutation-dependent alterations in mTEC morphology, thymocyte migration, and adhesion, with the p.C313Y variant exerting the strongest effects. Together, these data demonstrate that heterozygous and missense AIRE mutations exert distinct yet convergent effects on mTEC transcriptional programs and cellular behavior, providing mechanistic insight into AIRE-dependent immune tolerance failure in APS-1.

Autoimmune polyendocrine syndrome type-1 (APS-1) is a rare, yet severe multiorgan autoimmune disease caused by mutations in the Autoimmune Regulator (AIRE) gene. Classical APS-1 arises from biallelic recessive AIRE mutations, whereas dominant negative mutations cause a milder, non-classical phenotype with variable clinical presentation. Due to its rarity, long-term, population-based data are limited, underscoring the need for extended follow-up to guide lifelong care and research. To characterize the clinical profiles of APS-1 and explore associations between disease manifestations, autoantibody profiles, and AIRE mutations over an extended follow-up (1996-2025). All known Norwegian patients with APS-1. We analysed longitudinal clinical and laboratory data of 71 APS-1 patients (49 classical, 22 non-classical) from the Norwegian Registry of Organ-specific Autoimmune Diseases. Data included clinical progression, autoantibody and cytokine profiles, and AIRE genotypes. Additionally, we compared age at diagnosis of primary adrenal insufficiency (PAI) in patients with and without (n=999) APS-1. In classical APS-1, the most frequent clinical manifestations were chronic mucocutaneous candidiasis, enamel hypoplasia, and PAI, while for non-classical APS-1 vitiligo, hypothyroidism, and PAI were most common. A broad pro-inflammatory cytokine signature was observed in classical APS-1, along with increased levels of the soluble form of the IFN-α/β receptor. APS-1 should be considered in patients diagnosed with PAI before age 20, and AIRE sequencing is recommended for diagnostic confirmation. The presence of IFN-ω autoantibodies, a pro-inflammatory cytokine profile, and increased soluble IFN receptor levels further support the role of dysregulated interferon responses in APS-1 pathogenesis.

This study aimed to investigate the relationship between Osteoporosis (OP) and Complex Regional Pain Syndrome type 1 (CRPS-1), in the hypothesis that OP can influence the epidemiological and clinical features of CRPS-1. From March 2013 to May 2024, consecutive patients newly diagnosed with CRPS-1 were recruited. Demographic and clinical variables were collected in a standardised fashion. Univariate analyses and multivariate linear regression models were used to investigate the sample. We enrolled 425 patients, mostly females (70.1%), more than half (52.2%) with a fracture as the inciting event. A previous OP diagnosis was found in 113 patients (26.6%). Variables significantly associated with OP were female gender, hand localisation, fracture as the inciting event, and a more severe CRPS-1. A fracture in patients with OP seems to trigger CRPS-1 mainly in women in the first decade after menopause, while in males and in older women a weaker association was observed. Multivariate analysis showed a correlation between OP and a more severe CRPS-1 (p = 0.014). A higher incidence of OP was observed more frequently in women with CRPS-1 in the first decade after menopause. This result could be driven by the proinflammatory cytokines increase observed in the early menopause, inducing both a faster systemic bone loss and an "inflammatory milieu" acting as a predisposing factor for CRPS-1 onset and a more severe disease.

To apply dominant clinical syndrome for systematizing CVJ lesions and formation of surgical strategies. A retrospective analysis and systematization of patient groups with surgical CVJ lesions were conducted in 2 neurosurgical hospitals. The study included 181 patients with one of the five main CVJ lesions. Inclusion criteria were CVJ diseases and lesions: trauma - 76 (42%), developmental anomalies - 19 (10%), inflammatory and genetic diseases - 9 (5%), extradural tumors - 27 (15%), intradural tumors - 50 (28%). Systematization of material was based on the principle of dominant clinical syndrome. Two types of dominant clinical syndrome were distinguished: compression and instability. The specialized scales were used: the White & Panjabi criteria for trauma and anomalies, the Spinal Instability Neoplastic Score (SINS) for CVJ tumors, the Ranawat scale for rheumatoid arthritis, and the Kang scale for assessing compression of medulla oblongata and spinal cord. We distinguished 2 groups depending on dominant clinical syndrome: group 1 with compression (97 (54%) patients) and group 2 with instability (84 (46%) patients). Group I included 97 patients with trauma (n= 10, 10.3%), anomalies (n=16, 16.5%), inflammatory and genetic storage diseases (n=8, 8.2%), extradural tumors (n=13, 13.4%), intradural tumors (n=50, 51.6%). In this group, decompression was performed at the first stage. After eliminating compression of medulla oblongata and upper spinal cord, bone fixation was performed in 26 (34%) patients. Group II included 84 patients with trauma (n=66, 78.5%), anomalies (n=3, 3.5%), inflammatory and genetic storage diseases (n=1, 1.2%), extradural tumors (n=14, 16.8%). All patients underwent various fusion procedures. Of these, 17 (20.2%) patients underwent concomitant fusion and resection for extradural tumors, rheumatoid arthritis, and late sequelae of trauma. Anatomical, biomechanical, and clinical similarities allow for classification of surgical CVJ lesions based on dominant clinical syndrome. Identification of dominant clinical syndrome allows for appropriate surgical strategies, sequence of surgical stages and their timing.

Wedge-Shaped Lamellar Cataract in Stickler Syndrome Type I.

Introduction: Ehlers–Danlos syndrome (EDS) comprises a group of clinically and genetically heterogeneous connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and increased tissue fragility. As collagen is present in every organ system, EDS affects multiple body systems, and although its subtypes share overlapping features, each also exhibits distinctive clinical characteristics. Methods: We report 11 EDS patients from eight unrelated families. Whole-exome sequencing, clinical exome sequencing, and Sanger sequencing were performed for genetic diagnosis. Results: Six EDS subtypes were identified: cardiac-valvular EDS, dermatosparaxis EDS, musculocontractural EDS type 1, combined osteogenesis imperfecta/EDS type 2, brittle cornea syndrome type 2, and kyphoscoliotic EDS types 1 and 2. All patients exhibited joint hypermobility and skin hyperextensibility. Eight different variants were detected, including two novel variants; five were classified as pathogenic, two as likely pathogenic, and one as a variant of uncertain significance. Molecular diagnoses influenced clinical management by enabling subtype-specific surveillance, such as cardiologic monitoring in cardiac-valvular EDS, early ophthalmologic intervention in brittle cornea syndrome, avoidance of invasive procedures in dermatosparaxis EDS, implementation of fracture-preventive measures in patients with combined osteogenesis imperfecta/EDS, and improved surgical risk management across all EDS subtypes. Conclusion: This study expands the clinical and molecular spectrum of EDS by identifying two novel pathogenic variants and revealing previously unreported clinical findings. The results emphasize intrafamilial variability and the need to consider possible dual diagnoses, particularly in consanguineous families. Detailed phenotyping combined with comprehensive molecular testing improves subtype delineation and guides patient-specific surveillance and management strategies.