GM1 gangliosidosis is a rare autosomal recessive hereditary disorder caused by mutations in the GLB1 gene. The deficient activity of the enzyme β-galactosidase leads to the pathological accumulation of GM1 ganglioside, primarily in the cells of the central nervous system and visceral organs, resulting in progressive neurodegeneration and systemic symptoms. The clinical presentation is highly heterogeneous and can include neurological deterioration, epilepsy, skeletal abnormalities, facial dysmorphism, organomegaly, and ophthalmological manifestations. This clinical polymorphism, along with the variable age of onset and the differing degrees of neurological and systemic involvement, is attributed to the specific mutations and their impact on the residual enzyme activity. Based on this, three types of GM1 gangliosidosis are distinguished: the infantile, juvenile, and late-onset forms. This article reviews current knowledge on the etiology, biochemical defects, pathogenesis, and clinical manifestations of GM1 gangliosidosis. It also analyzes novel potential therapeutic approaches for patients, with insights from animal model studies. While no effective cure for GM1 gangliosidosis currently exists, several strategies show significant promise. The most advanced therapeutic approaches include enzyme replacement therapy, substrate reduction therapy, chaperone therapy, hematopoietic stem cell transplantation, and gene therapy using adeno-associated viral vectors, some of which have already progressed to clinical trials.

To summarize the clinical and genetic characteristics of children with Silver-Russell syndrome (SRS) and improve the recognition of this disease. A retrospective analysis was conducted on the clinical manifestations and genetic testing results of 29 children with SRS diagnosed at the Children's Hospital Affiliated to Zhengzhou University between March 2016 and June 2025. The 29 children had included 18 boys and 11 girls, with the age ranging from 2 months to 16 years. Their primary clinical manifestations included postnatal growth retardation (100%), small for gestational age (SGA) (100%), characteristic facial features (90%), limb asymmetry (83%), feeding difficulties (76%), ulnar deviation of the fifth finger (69%), body mass index (BMI) of < -2 SD (62%), and abnormal bone age (55%), including 15 cases with delayed bone age for an average of 1.5 years and 1 case with advanced bone age for 2.5 years. Additional manifestations included abnormal sexual development in 11 cases (38%), dental malocclusion in 11 cases (38%), allergic diseases in 10 cases (34%), cardiac diseases in 9 cases (31%), skeletal abnormalities in 7 cases (24%), renal hypoplasia in 5 cases (17%), and abnormal cranial MRI findings in 5 cases (17%). Twenty children were treated with recombinant human growth hormone (rhGH) at a dose of 0.1 ~ 0.15 U/(kg.d). Among them, 7 cases achieved annual height increase of ≥ 10 cm, 11 cases achieved annual height increase of ≥ 5 ~ 9 cm, and 2 cases achieved annual height increase < 5 cm. Twenty three children exhibited hypomethylation of imprinted genes in the chromosome region of 11p15, 4 presented maternal uniparental disomy of chromosome 7 [UPD(7)mat], and 2 had harbored nonsense variants of the HMGA2 gene. SRS patients may present with diverse clinical manifestations including postnatal growth retardation, SGA, characteristic facial features, limb asymmetry, feeding difficulties, and ulnar deviation of the fifth finger. Most patients may exhibit abnormal methylation in the 11p15 region. rhGH therapy can improve the height of these patients.

To investigate the clinical manifestations and genetic etiology of a fetus with Neurodevelopmental disorders with deformed facial features and distal skeletal abnormalities (NEDDFSA). Clinical data of a NEDDFSA fetus diagnosed at the Affiliated Women and Children's Hospital Affiliated to Ningbo University in March 2025 was selected as the study subject. Whole-exome sequencing (WES) was carried out on the amniotic fluid and parental peripheral blood samples, and candidate variants was verified by Sanger sequencing. The pathogenicity of candidate variant was rated based on guidelines from the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: EC2023-094). At 30 weeks of gestation, the fetus was found to have microcephaly, short femur and intrauterine growth restriction. WES revealed that the fetus harbored a de novo heterozygous frameshift variant c.2633dup (p.Gly879ArgfsTer22) of the ZMIZ1 gene, which was rated as pathogenic (PM2_Supporting+PS2_Supporting+PVS1). Combined with 25 cases from the literature, the main manifestations of patients have included intellectual disability, growth retardation and cranio-limb skeletal dysplasia, albeit without clear genotype-phenotype correlation. The de novo variant c.2633dup (p.Gly879ArgfsTer22) of the ZMIZ1 gene probably underlay the NEDDFSA in this fetus. Genetic testing has enabled accurate prenatal diagnosis and provided evidence for genetic counseling and reproductive guidance of this family.

ABSTRACTBackgroundThrombocytopenia‐absent radius (TAR) syndrome is a rare congenital disorder characterized by bilateral radial aplasia with preserved thumbs and early‐onset thrombocytopenia. While hematologic and skeletal abnormalities define the condition, its association with hematologic malignancies is extremely rare, with only a few reported cases of leukemia. Juvenile myelomonocytic leukemia (JMML) is an uncommon pediatric myelodysplastic/myeloproliferative neoplasm frequently linked to RAS pathway mutations. To our knowledge, JMML has not previously been reported in association with TAR syndrome.Case PresentationWe report the case of a male infant diagnosed with TAR syndrome based on clinical features and molecular confirmation of a homozygous RBM8A c.‐21G>A variant. The patient presented initially with persistent thrombocytopenia, skeletal deformities, and neonatal sepsis‐like manifestations. At 2 years of age, he developed pancytopenia and progressive splenomegaly. Bone marrow evaluation and molecular testing confirmed JMML harboring a pathogenic NF1 mutation. He underwent successful haploidentical hematopoietic stem cell transplantation (HSCT) from a sibling donor, following a conditioning regimen of melphalan, treosulfan, cyclophosphamide, and anti‐thymocyte globulin. The patient achieved full donor chimerism and hematologic remission with stable engraftment.ConclusionThis case represents, to our knowledge, one of the very few—if not the first—reported instances of successful HSCT for JMML in a patient with TAR syndrome. It underscores the importance of vigilant surveillance in TAR patients for potential malignant transformation and demonstrates the curative potential of HSCT in rare congenital‐hematologic overlap syndromes.

Fipronil-based insecticide induces developmental toxicity and skeletal deformities in zebrafish (Danio rerio).

The cartilage hair hypoplasia-anauxetic dysplasia (CHH-AD) spectrum represents a group of rare autosomal recessive skeletal dysplasias with significant phenotypic heterogeneity. These disorders are classified based on pathogenic variants in the RMRP, POP1, and NEPRO genes. Among these, anauxetic dysplasia type 3 (ANXD3), associated with NEPRO variants, manifests as severe skeletal dysplasia characterized by short stature, brachydactyly, skin laxity, and joint hypermobility, with distinct radiographic findings such as ovoid vertebrae, hypoplastic ilia, narrow acetabular angles, and irregular metaphyses. Unlike other CHH-AD subtypes, ANXD3 lacks immunological or gastrointestinal involvement. This study reports three new ANXD3 cases from a consanguineous Iranian family, carrying the homozygous pathogenic variant Chr3:113014014G>A; exon3; c.280C>T; p.Arg94Cys in the NEPRO gene. The clinical phenotypes expand the known spectrum of ANXD3, including unique features such as microcephaly, clubfoot, cataracts, urolithiasis, and hearing impairments, whi12-18ch suggest systemic involvement beyond skeletal abnormalities. Diagnostic whole-exome sequencing, supported by Sanger validation, confirmed the autosomal recessive inheritance pattern. A comparative analysis with previously reported ANXD3 cases revealed shared characteristics, including short stature, brachydactyly, and thoracolumbar kyphoscoliosis, while highlighting variability in head size, scalp hair, and systemic features. Microcephaly was observed in our patients, same as previously reported cases, underscoring the phenotypic variability of ANXD3. This study also emphasizes the importance of genetic counseling and early interventions for associated complications, such as orthopedic, renal, and ophthalmological management.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is an autosomal dominant condition that may co-occur with cardiac, renal, and skeletal abnormalities. It affects females causing utero-vaginal agenesis. Radiological assessment tools such as ultrasound and Magnetic Resonance Imaging (MRI) can be utilised for the confirmation of MRKH syndrome and for planning further management. Management of MRKH syndrome includes both non-surgical and surgical approaches, depending on the clinical presentation. The current report presents a case of a 21-year-old female who presented with a complaint of primary amenorrhoea and dyspareunia. Examination of the genitalia revealed normal external urethral meatus, labia majora and minora, and pubic hair development. Speculum examination confirmed the lack of a vaginal canal. Radiological findings were suggestive of uterine agenesis. Genetic analysis showed a 46,XX karyotype, thereby ruling out the chromosomal abnormalities. Based on the above findings and clinical evaluations, a final diagnosis of MRKH syndrome was confirmed. The patient declined surgical interventions at present and was managed non-surgically. In MRKH syndrome patients, counselling is crucial attributed to the associated physical abnormalities, related queries and mental stress.

Skeletal muscle in spinal muscular atrophy: Critical insights from pathogenesis to therapeutic strategies.

Structural and functional insights into Vitamin D receptor mutations: An in-silico investigation of polymorphism-induced resistance.

Phosphoglucomutase 3 deficiency (PGM3 deficiency) is a rare congenital disorder of glycosylation classically associated with severe immunodeficiency, skeletal abnormalities, and neurodevelopmental impairment. However, emerging evidence suggests that PGM3 deficiency may also present with attenuated or milder clinical phenotypes. In this study, we describe patients with a novel PGM3 variant exhibiting a less severe immunological and clinical presentation, thereby expanding the known phenotypic spectrum of PGM3 deficiency. Demographic-data and Wechsler Intelligence Scale for Children profiles were evaluated alongside laboratory data, including complete blood cell counts, lymphocyte subsets, serum immunoglobulin levels, vaccine antibody titers, and lymphocyte cytokine profiles. Whole exome sequencing was conducted, and phospho-flow assays were utilized for the analysis of p-STATs. Five patients with a mild form of PGM3 deficiency were described, exhibiting a Hyper-IgE Syndrome phenotype without severe skeletal dysplasia or dysmorphism, with the exception of one patient displaying very mild skeletal dysplasia and three patients exhibiting mild to moderate intellectual disability. All patients demonstrated an increase in Natural Killer T cells and a decrease in B cells, alongside an increase in activated CD4 + T cells (CD45RO+), a decrease in naïve CD4 + and CD8 + T cells (CD45RA+ CCR7+), and an increase in TEMRA CD8 + T cells (CD45RA+CCR7–). Functional analysis of all patients revealed impaired PGM3 function, as evidenced by decreased surface expression of gp130 and p-STAT3. Defective glycosylation in PGM3 deficiency leads to reduced gp130 expression and attenuated gp130-dependent STAT3 phosphorylation. The resulting cellular features partially overlap with those observed in STAT3 loss-of-function and gp130 deficiency, supporting a shared signaling mechanism while remaining clinically distinct.

Placental calcium (Ca2+) transport is essential for foetal bone mineralisation and development, as well as for Ca2+ homoeostasis. Rare mutations in transient receptor potential vanilloid (TRPV) 6 of the infant cause insufficient maternal-foetal Ca2+ transport through the placenta. Although there is a limited number of cases, phenotype analyses of these patients show skeletal deformities and hyperparathyroidism. In this study, we identified a case with a homozygous mutation in the TRPV6 channel that leads to the deletion of the Ca2+ pore. The neonate was born with skeletal abnormalities, increased umbilical cord PTH levels (75 pmol/L) and normal total Ca2+ level (2.06 mmol/L). Skeletal abnormalities improved during the first months of life. 45Ca2+ uptake assays demonstrated loss-of-function, and biotinylation assays demonstrated failure of the channel to reach the cell surface. These findings indicate that the TRPV6-p.Arg492* mutation affects maternal-foetal Ca2+ transport and explains the observed phenotype.

Fibrous dysplasia/McCune-Albright Syndrome (FD/MAS) is a rare skeletal disorder associated with significant pain and symptom burden. Pain in FD/MAS has been predominantly attributed to bone fracturing or fibrous tissue changes within the skeletal system. However, recent evidence indicates that factors beyond skeletal disease burden may contribute to pain in FD/MAS, including central nervous system alterations. Further, the type of pain experienced by patients (eg, constant, flare, radiating, and local) has yet to be fully characterized, limiting the development of individualized treatment approaches. In this pilot study, we examined the associations between bone lesions detected using sodium fluoride F18 [18F-NaF] PET/CT scans and self-reported pain in 14 patients with FD/MAS. All participants completed body pain maps and questionnaires regarding pain and symptom burden. Bone turnover markers (eg, osteocalcin, alkaline phosphatase, and N-terminal telopeptidase [NTx]) were also evaluated in relation to pain. Contrary to the previously described characterization of FD/MAS pain as persistent background pain with occasional flares, only 38% of the current sample described pain as "persistent pain with pain attacks." Patients also described pain as "persistent with slight fluctuations" (31%), "pain attacks with pain between them" (23%), and "pain attacks without pain between them" (8%). Patients reported pain across multiple body sites. Neither background pain nor flare pain were reliably associated with skeletal burden scores or bone lesions in our sample. The presence of bone lesions in FD/MAS may not provide sufficient evidence to predict pain. Other factors, including the size or number of bone lesions, as well as other skeletal abnormalities, may also contribute to the pain experience. Future phenotyping efforts in FD/MAS are needed to better understand peripheral and central nervous system contributions that may lead to improved therapeutic strategies.

Van Maldergem Syndrome (VMS) is a rare autosomal recessive disorder caused by pathogenic variants in the atypical cadherin genes DCHS1 or FAT4 and is marked by craniofacial, skeletal, and neurodevelopmental abnormalities. Although DCHS1-FAT4 binding is mediated by their respective extracellular domains, the in vivo function of the DCHS1 intracellular domain (ICD) is poorly defined. To test its function, we generated mice in which the DCHS1 ICD was deleted and replaced with a V5 epitope tag (Dchs1ΔICD-V5). Homozygous Dchs1ΔICD-V5/ΔICD-V5 mice are viable but exhibit VMS-like craniofacial flattening with enlarged fontanelles and reduced palatine/maxillary structures, along with airway cartilage abnormalities including reduced mineralization and decreased tracheal circularity. In periventricular regions, wild-type DCHS1 expression shows polarized localization, whereas mice with the ICD deletion exhibit altered cell polarization within the subventricular zone, concomitant with changes in neural cellular distribution. Neonatal brains display reduced pYAP1: YAP1 ratios and increased Ki67+ proliferation with greater Ki67-neuronal co-localization within the periventricular zone. Together, these data identify the DCHS1 ICD as a critical effector for DCHS1 signaling and a regulator of polarity-dependent growth, with associated changes in Hippo pathway activity during craniofacial and neural morphogenesis. Additionally, our data establish Dchs1ΔICD-V5/ΔICD-V5 mice as a model that recapitulates core features of VMS, thereby allowing new mechanistic discoveries into its pathogenesis.

Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of Polycomb Repressive Complex 2, catalyses H3K27 trimethylation and directs lineage development programs, yet its function in early multipotent progenitors remains incompletely understood. ISL1 marks cardiopharyngeal and neural crest progenitors that contribute to second heart field derivatives and to craniofacial and limb morphogenesis. Here, Isl1-cre lineage tracing showed that lineage derivatives populated the cardiopharyngeal region and the posteromedial hindlimb bud during mid-gestation, and contributed extensively to the developing right ventricle, outflow tract, and hindlimb. Loss of Ezh2 in Isl1-expressing progenitors resulted in a high incidence of congenital heart defects, dominated by incomplete atrial and ventricular septation and outflow tract malformations, including double outlet right ventricle and persistent truncus arteriosus. These defects were accompanied by ventricular wall thickening at birth. In parallel, Ezh2 mutants exhibited hindlimb skeletal abnormalities, including pelvic and tarsal malformations with impaired ossification. These abnormalities were associated with cyanosis and perinatal demise. Together, these findings identify a requirement for EZH2 in Isl1-lineage contribution to heart and hindlimb development.

Background/Objectives: Coffin-Lowry syndrome (CLS) is a rare X-linked disease caused by pathogenic variants in the RPS6KA3 gene. It is generally characterized by syndromic intellectual disability and distinctive facial features, skeletal abnormalities, stimulus-induced drop attacks in males, and variable manifestations in females. Methods: We report clinical and genetic findings in a series of 10 cases, eight males and two females, evaluated at the Regional Centre of Medical Genetics Dolj-Emergency Clinical County Hospital Craiova. Results: Genetic testing identified 10 de novo variants in the RPS6KA3 gene consisting of six missense mutations, one nonsense variant, one frameshift, and two variants in non-coding or intronic regions. Case management requires multidisciplinary coordination and is limited to resources mostly available in reference centers. Conclusions: CLS highlights the importance of molecular diagnosis in rare genetic disorders, particularly when clinical features are subtle or atypical. These findings have practical implications for clinical management, suggesting the need for comprehensive genetic screening and individualized care approaches.

Abstract In the artificial seed production of Japanese eels, Anguilla japonica , the frequent occurrence of glass eels with jaw abnormalities has become a serious problem. To gain fundamental insights into this issue, we evaluated the effects of lower jaw abnormalities on survival during the glass eel stage and revealed that these abnormalities are lethal. Bone staining of glass eels and cartilage staining of leptocephali larvae showed that the abnormality was caused by mandibular dislocation in both stages. Focusing on the jaw opening angle (OA), we examined the relationship between OA and the occurrence of mandibular dislocation during the glass eel stage using logistic regression and receiver operating characteristic (ROC) analyses. The results indicated that the probability of mandibular dislocation increases when OA exceeds 69.3°. Therefore, individuals with an OA of 70° or greater were defined as having mandibular dislocation, and their appearance timing and body size were investigated. As a result, individuals with an OA of 70° or greater appeared when the total length reached approximately 35 mm, and their occurrence increased with age. These findings provide important insights into the mechanisms underlying mandibular dislocation and may contribute to its prevention in artificial eel seed production.

To the Editors: Rising maternal syphilis infections have led to a surge in congenital syphilis (CS), which causes severe and permanent health issues leading to substantial social and economic burdens compared with adult infection.1,2 However, the immunopathogenesis of CS, especially the role of neonatal immunity, remains unclear. Here, we report a case of a preterm infant with CS following incomplete maternal treatment, providing a unique opportunity to observe fetal–neonatal immune responses to active Treponema pallidum infection. A female neonate was born at 27 weeks gestation (1024 g). Maternal syphilis screening at 8 weeks gestation was negative. However, seroconversion was confirmed at 26 weeks and 5 days following fetal ascites detection: rapid plasma reagin (56 units) and T. pallidum hemagglutination assay titers (259, cutoff index). Maternal amoxicillin treatment was initiated, but spontaneous delivery occurred 2 days later. At birth, she presented respiratory failure, hepatosplenomegaly, ascites, skeletal abnormalities, anemia and thrombocytopenia. Serological tests confirmed CS diagnosis (rapid plasma reagin: 76.8, T. pallidum hemagglutination assay: 28.7, cutoff index; fluorescent treponemal antibody-absorption immunoglobulin [Ig]M, 1:1,280). Administration of intravenous penicillin G improved CS symptoms. After surgical ligation for patent ductus arteriosus and initiation of home oxygen therapy for bronchopulmonary dysplasia, she was discharged from the hospital on day 114. Time course analysis of peripheral blood lymphocyte subsets revealed a polarization of T helper (Th)2 cells at birth, followed by gradual increase in Th1 cells, T follicular helper cells, memory B cells and regulatory T cells (Fig. 1A). Cytokine profiling revealed elevated interleukin (IL)-12, IL-8, IL-10 and IL-21 levels; however, pro-inflammatory or Th1 cytokines were not elevated: IL-1β, IL-2, IL-6, tumor necrosis factor-alpha and interferon-gamma (Fig. 1B).FIGURE 1.: Temporal progression of the peripheral immunophenotype. A: Immune cell analyses in peripheral blood on days of life 0, 3, 7 and 11 using a LSRFortessa flow cytometer (Becton Dickinson, Franklin Lakes, NJ) and FlowJo software (version 10.6.2; Becton Dickinson). The proportions of Th1 cells (CCR6−CXCR3+), Th2 cells (CCR6−CXCR3−) within memory Th cells (CD4+CD45RO+); Treg cells (CD127dimCD25+) within Th cells (CD4+); Tfh cells (CD45RO+CXCR5+) within Th cells (CD4+) and memory B cells (CD19+CD27+IgD+) within B cells (CD19+) were assessed. B: Cytokine profiles in peripheral blood were evaluated on days of life 0, 1, 7 and 11 using a BD Cytometric Bead Array (Becton Dickinson). Tfh indicates T follicular helper; Treg, regulatory T cells.At primary infection sites in adult syphilis, pro-inflammatory cytokines, Th1-mediated immunity and humoral responses, which are all critical for bacterial clearance, are induced.3 As observed in the present case, infants with CS present with systemic infection at birth, resembling that of adult secondary syphilis.1,2 However, despite detectable humoral immune responses, pro-inflammatory cytokine production and Th1-mediated immunity were markedly reduced at birth, with T-cell differentiation skewed toward a Th2 phenotype. Th2 polarization and attenuated pro-inflammatory cytokine production and Th1-mediated immunity indicated developmentally distinct characteristics of the neonatal immunoregulatory immune system, which are essential for fetal–maternal tolerance.4 A previous report suggested that preterm infants with CS exhibit pro-inflammatory cytokine production and Th1 responses at birth, indicating that they possess pathogen clearance mechanisms similar to those in adults5; however, the infant was born to a mother who had completed syphilis treatment. Therefore, the reported immune profile may not represent the immune status during active T. pallidum infection and likely differs from that observed in our case, where maternal treatment was incomplete. Accordingly, the Th1 response in our case gradually developed following the initiation of antimicrobial treatment. These findings suggest that developmentally distinct features of the neonatal immune system contribute to impaired clearance of T. pallidum, leading to the severity of CS symptoms. Study limitations include the single-case design. Future research with larger cohorts is necessary to further elucidate the immunopathogenic features of CS.

Heart failure (HF) with reduced ejection fraction is a systemic disorder that extends beyond cardiac dysfunction and involves peripheral organs, particularly skeletal muscle. Exercise intolerance and fatigue are the hallmark manifestations of HF that strongly predict morbidity and mortality. Accumulating evidence suggests that intrinsic skeletal muscle abnormalities are key contributors to exercise intolerance in HF. In HF, skeletal muscle undergoes metabolic remodeling characterized by shifts in fiber type composition, mitochondrial dysfunction, and increased oxidative stress. Mitochondrial dysfunction, characterized by decreased mitochondrial density, impaired biogenesis, and reduced respiratory capacity, further compromises skeletal muscle performance. These alterations impair adenosine triphosphate (ATP) generation via oxidative phosphorylation, forcing reliance on less efficient anaerobic glycolysis. The resulting metabolic shift exacerbates early lactate accumulation, muscle fatigue, and diminished exercise capacity. In parallel, an increase in oxidative and carbonyl stress, along with a decrease in antioxidant defenses as well as derangements in pathways that remove toxic lipid peroxidation, heightens oxidative and carbonyl stress perpetuating injury and establishing a vicious cycle of progressive muscle dysfunction. Thus, metabolic remodeling in skeletal muscle represents a central determinant of exercise intolerance in HF. While exercise training remains the most effective strategy to restore skeletal muscle health and exercise tolerance, emerging therapies offer novel avenues for intervention. Future research should focus on elucidating the molecular mechanisms underlying skeletal muscle dysfunction and developing therapies that restore metabolic integrity and functional capacity in HF.

Focal dermal hypoplasia is an X-linked dominant genetic disorder predominantly affecting females, caused by loss-of-function variants in the PORCN gene, characterized by ectodermal, skeletal, craniofacial and ocular structural abnormalities. We report three cases with de novo novel variants, and performed a comprehensive review of the clinical features of this disorder focusing on Asian patients, and identified significant differences compared with previous literature focusing on Caucasian patients. Cleft lip and palate is a frequently reported feature in Asian patients, but not in Caucasians. This improves the understanding of this rare disease in particular ethnic-specific differences.

STT3A encodes the catalytic subunit of the oligosaccharyltransferase A (OST-A) complex and is classically linked to severe autosomal-recessive congenital disorder of glycosylation (CDG). To define the distinct autosomal-dominant disorder, we reviewed all published cases and integrated three previously unpublished individuals from the CDG natural history study. Across 21 individuals, abnormal transferrin glycosylation was present in nearly all individuals (20/21), and subtle facial dysmorphism was common (18/21). Neurodevelopmental involvement was frequent, including motor delay (13/21), learning difficulties (13/21), speech delay (12/21), and intellectual disability (10/21). Musculoskeletal manifestations were also common, including skeletal abnormalities (12/21), short stature (11/21), muscle cramps (8/21), and early-onset osteoarthritis in adults (6/21). Less frequent features included congenital heart defects (5/21) and coagulation factor deficiency (5/21). Importantly, the newly reported individuals expand dominant STT3A-CDG with previously unreported features, including anorectal malformation, morbid obesity, and clinically significant bleeding diathesis with von Willebrand factor and factor VIII deficiency. Biochemical signatures ranged from classic type I transferrin patterns to subtle or atypical abnormalities, emphasizing that near-normal transferrin testing does not exclude the diagnosis. Variants clustered in conserved catalytic regions, with recurrent p.Arg405 across de novo, inherited, and mosaic cases supporting a mutational hotspot and likely dominant-negative mechanism.