OBJECTIVE: To explore the genetic etiology for a pregnant woman with a history of multiple adverse pregnancies and assess the phenotype-genotype correlation of 22q11.2 microduplication syndrome in her family. METHODS: Amniotic fluid sample was taken from a pregnant woman for whom non-invasive prenatal screening indicated chromosome 22 abnormalities in the fetus. Peripheral blood samples from the woman, her brother and parents were collected for high-throughput low-depth whole genome sequencing (CNV-seq). A pedigree traceability analysis of the results was conducted in conjunction with analysis of clinical manifestation. Relevant literature (from establishment to March 2025) was systematically searched. This study was approved by the Medical Ethics Committee of Mianyang Maternal and Child Health Care Hospital (Ethics No.: Lun Shen [2024]009). RESULTS: CNV-seq revealed that the fetus had harbored a 6.02 Mb duplication at 22q11.21q11.23. Karyotyping confirmed it as 46,X?dup(22)(q11.2). Pedigree verification demonstrated that the pregnant woman, her brother and mother had all carried the same duplication. Phenotypic analysis of the affected family members showed classic features of 22q11.2 microduplication syndrome, including hypernasal speech, low nasal bridge, congenital heart disease, and cognitive impairment. A total of 44 cases with full information (including three patients from this pedigree) were included in the analysis. The penetrance of 22q11.2 duplication was approximately 29.5% (13/44), and 52.3% (23/44) of the cases had inherited the variant from a phenotypically normal parent. CONCLUSION This study has identified the genetic basis for the woman's recurrent adverse pregnancies and phenotypic abnormalities in her family members. The scoliosis identified in her younger brother has not been previously reported, thereby may enrich the clinical phenotype of this syndrome. For fetuses identified with a 22q11.2 microduplication, detailed fetal imaging is recommended, and genetic counseling should be provided to the couples.
Humans ; Female ; Pregnancy ; Prenatal Diagnosis/methods* ; Chromosome Duplication/genetics* ; Male ; Pedigree ; DiGeorge Syndrome/diagnosis* ; Adult ; Chromosomes, Human, Pair 22/genetics* ; Abnormalities, Multiple

OBJECTIVE: To summarize the clinical and genetic characteristics of children with Silver-Russell syndrome (SRS) and improve the recognition of this disease. METHODS: 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. RESULTS: 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. CONCLUSION 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.
Humans ; Silver-Russell Syndrome/diagnosis* ; Male ; Female ; Child ; Child, Preschool ; Infant ; Adolescent ; Retrospective Studies

Humans ; Silver-Russell Syndrome/genetics* ; China ; Consensus

Patient 1, a 3-year-6-month-old male, presented with feeding difficulties and delayed motor development. He exhibited poor responsiveness at birth, weak crying, intellectual and motor delays, low immunity, recurrent respiratory infections, hypotonia of the limbs, and distinctive facial features (low-set ears, double chin, and high arched palate), as well as a single transverse palmar crease on the right hand. Genetic testing revealed a c.1096C>T heterozygous variant in the SMARCB1 gene. Patient 2, a 3-year-old male, presented with developmental delay and distinctive facial features. Genetic testing identified the same pathogenic mutation as in Patient 1. The two patients are unrelated, and clinical phenotyping and genetic testing confirmed both cases as Coffin-Siris syndrome type 3. Coffin-Siris syndrome is a rare genetic disorder, and early genetic testing can aid in diagnosis.
Child, Preschool ; Humans ; Male ; Abnormalities, Multiple/genetics* ; Chromosomal Proteins, Non-Histone/genetics* ; Ear/abnormalities* ; Face/abnormalities* ; Hand Deformities, Congenital/genetics* ; Intellectual Disability/genetics* ; Micrognathism/genetics* ; Mutation ; Neck/abnormalities*

OBJECTIVES: Verrucous epidermal nevus (VEN), seborrheic keratosis (SK), verruca plana (VP), verruca vulgaris (VV), and nevus sebaceous (NS) are common verrucous proliferative skin diseases with similar clinical appearances, often posing diagnostic challenges. Dermoscopy and reflectance confocal microscopy (RCM) can aid in their differentiation, yet their specific features under these tools have not been systematically described. This study aims to summarize and analyze the dermoscopic and RCM features of VEN, SK, VP, VV, and NS. METHODS: A total of 121 patients with histopathologically confirmed verrucous proliferative skin diseases were enrolled. Dermoscopy and RCM imaging was used to observe and analyze the microscopic features of these conditions. RESULTS: Under dermoscopy, the 5 diseases displayed distinct characteristics: VEN typically showed gyriform structures; SK was characterized by gyriform structures, comedo-like openings, and milia-like cysts; VP and VV featured dotted vessels and frogspawn-like structures; NS presented as brownish-yellow globules. RCM revealed shared features such as hyperkeratosis and acanthosis across all 5 diseases. Specific features included gyriform structures and elongated rete ridges in VEN; pseudocysts and gyriform structures in SK; evenly distributed ring-like structures in VP; vacuolated cells and papillomatous proliferation in VV; and frogspawn-like structures in NS. CONCLUSIONS These 5 verrucous proliferative skin conditions exhibit distinguishable features under both dermoscopy and RCM. The combination of these 2 noninvasive imaging modalities holds significant clinical value for the differential diagnosis of verrucous proliferative skin diseases.
Humans ; Dermoscopy/methods* ; Diagnosis, Differential ; Microscopy, Confocal/methods* ; Male ; Female ; Adult ; Middle Aged ; Adolescent ; Keratosis, Seborrheic/pathology* ; Young Adult ; Warts/diagnosis* ; Child ; Aged ; Skin Diseases/pathology* ; Nevus, Sebaceous of Jadassohn/diagnosis* ; Skin Neoplasms/diagnosis* ; Child, Preschool

Objective:To investigate the impact of Waardenburg syndrome（WS） -associated Sox10 p.S100Rfs*9 mutation on inner ear function and its mechanism in noise-induced hearing impairment. Methods:A mice model carrying the Sox10 p.S100Rfs*9 mutation was established using CRISPR-Cas9 gene editing technology. Auditory phenotypes were assessed under baseline conditions and after noise exposure（96 dB SPL, 2 hours）. Auditory brainstem response（ABR） tests were performed to evaluate hearing function, combined with immunofluorescence staining of cochlear basilar membrane whole-mounts to observe hair cells and ribbon synapses. Transcriptome sequencing was conducted to analyze molecular mechanisms. Results:Sox10 p.S100Rfs*9 heterozygous mice exhibited normal hearing thresholds with characteristic ventral pigmentation abnormalities under baseline conditions. Following noise exposure, mutant mice showed significantly higher ABR thresholds at 24 000 Hz compared to wild-type controls（[60.00±6.12]vs[48.13±4.28]dB SPL, P<0.000 1）, and a significant reduction in ribbon synapses（CtBP2-positive puncta） in the basal turn（[55.0±2.3]vs[64.8±3.3]per inner hair cell, P=0.006 6）, while hair cell morphology and number remained intact. Transcriptome analysis revealed altered expression of genes involved in immune regulation, membrane structures, ion channels, and neuroactive ligand-receptor interactions. Conclusion:The Sox10 p.S100Rfs*9 mutation does not alter baseline hearing function but significantly increases inner ear susceptibility to noise damage, primarily manifested as enhanced ribbon synapse vulnerability, especially in high-frequency regions. This gene-environment interaction reveals that Sox10 haploinsufficiency may compromise noise tolerance by affecting synaptic stability and inner ear protective mechanisms. These findings provide new perspectives on the phenotypic heterogeneity in WS patients and theoretical basis for individualized noise protection strategies for patients carrying SOX10 mutations.
Animals ; SOXE Transcription Factors/genetics* ; Waardenburg Syndrome/physiopathology* ; Mice ; Hearing Loss, Noise-Induced/genetics* ; Evoked Potentials, Auditory, Brain Stem ; Mutation ; Noise ; Disease Models, Animal ; Ear, Inner/physiopathology*

Objective:To investigate the molecular characteristics and clinical heterogeneity of Usher syndrome（USH） -related gene variants in patients with hereditary hearing loss in southwest China, providing a basis for early diagnosis and clinical management. Methods:Thirteen patients from twelve families with hearing loss who attended the Affiliated Children's Hospital of Kunming Medical University between January 2017 and March 2021 were enrolled. All patients were identified as carrying USH-related gene variants through next-generation sequencing. Sanger sequencing was performed for all patients and their parents to validate the pathogenic variants. Comprehensive clinical evaluations, including medical history collection, otologic and ophthalmologic examinations, and vestibular function assessments, were conducted. Results:Among the 13 patients, 4 were diagnosed with USH type 1 and 2 with USH type 2. A total of 19 pathogenic or likely pathogenic variants were detected in USH-related genes, including MYO7A,CDH23,USH1C, and USH2A. The causative gene was MYO7A in 3 probands, CDH23 in 5, USH1C in 3, and USH2Ain 2. All patients exhibited an autosomal recessive inheritance pattern. Vestibular dysfunction was observed in 4 patients, and retinitis pigmentosa（RP） in 3 patients. Based on the genotype-phenotype correlation, 6 patients were initially diagnosed with USH, while 7 were classified as having non-syndromic hearing loss（NSHL）. Conclusion:This study revealed the clinical heterogeneity of USH-related gene variants in patients with hereditary deafness in southwest China. Although the clinical manifestations of USH are complex and there are overlapping characteristics between different subtypes, genetic testing provides an important basis for early diagnosis and precise clinical management. Especially for those with typical hearing loss, early genetic diagnosis can provide a window of time for early detection and intervention of retinitis pigmentosa.
Humans ; Usher Syndromes/genetics* ; Myosin VIIa ; Phenotype ; Male ; Female ; Myosins/genetics* ; Mutation ; Cadherins/genetics* ; Child ; Extracellular Matrix Proteins/genetics* ; Adolescent ; Pedigree ; High-Throughput Nucleotide Sequencing ; Cadherin Related Proteins ; Cytoskeletal Proteins ; Cell Cycle Proteins

Basal Cell Nevus Syndrome (BCNS) is a rare autosomal dominant disorder characterized by a range of abnormalities, most notably multiple basal cell carcinomas (BCCs), odontogenic keratocysts, and palmar and/or plantar pits. BCC is the most common form of skin cancer globally. It is typically locally invasive and very rarely metastasizes, with distal metastases occurring in only 0.00028% to 0.55% of cases.

We present a case of a 68-year-old Filipino woman who was diagnosed with BCNS. She presented with multiple black nodules and plaques on her face and neck, histopathologically confirmed as BCCs. In addition, the presence of palmoplantar pits and calcification of the falx cerebri met three of the six major criteria for BCNS. Computed tomography (CT) and bone scans, revealed multiple bone metastases in the cranium, spine, sternum, and ribs. No previous cases of metastasis in a BCNS patient have been reported in the Philippines, making this the first documented case.

OBJECTIVE: To explore the pathogenic mechanism of a child with Waardenburg syndrome type 4C due to a c.661_664dup (p.P222Lfs*60) variant of SOX10 gene through in vitro experiments. METHODS: A child diagnosed at the Handan First Hospital was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples were collected from the child and his parents. Following extraction of genomic DNA, trio-whole exome sequencing was carried out. Pathogenicity of candidate variant was determined by bioinformatic analysis and reference to the guidelines from the American College of Medical Genetics and Genomics (ACMG). Candidate variant was verified by Sanger sequencing. Expression plasmids of wild-type SOX10 and the c.661_664dup (p.P222Lfs*60) variant were constructed and transiently transfected into 293T cells to determine the expression at the RNA and protein levels. The 293T cells transiently transfected with the wild-type/mutant SOX10 were treated with 10 ug/mL cycloheximide (CHX) for 0, 4, 8, 24 h, respectively, and the degradation rate of target protein was detected by Western blotting assay. This study has been approved by the Ethics Committee of Handan First Hospital (Ethics No. HDYY-LW-25053). RESULTS: The child was found to harbor a heterozygous c.661_664dup (p.P222Lfs*60) variant of the SOX10 gene, which was unreported previously. The variant did not significantly alter the expression of SOX10 at the mRNA level but the protein level. After the CHX treatment, the degradation of mutant SOX10 protein had slowed down. CONCLUSION The mutant SOX10 may affect the expression of downstream genes by affecting the degradation rate of its protein product.
Humans ; HEK293 Cells ; Mutation ; SOXE Transcription Factors/metabolism* ; Waardenburg Syndrome/genetics* ; Child

OBJECTIVE: To explore the genetic etiology of a Chinese pedigree with recurrent Joubert syndrome with negative results by whole-exome sequencing in the prior proband. METHODS: Chinese pedigree which opted elective abortion at the Women and Children's Hospital Affiliated to Chongqing Medical University in December 2024 was selected as the study subject. Whole-genome sequencing was carried out on fetal tissue after termination of pregnancy. Candidate variants were validated by Sanger sequencing and interpreted, while non-coding variant was analyzed using in silico prediction tools. RNA sequencing and cDNA sequencing were conducted on fetal brain tissue. This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.2024YL045-02). RESULTS: Both the fetus and the affected child were found to harbor compound heterozygous variants of the CEP290 gene, namely c.7341dup (p.Leu2448fs*8) (pathogenic, maternally inherited) and c.1523-408G>A (likely pathogenic, paternally inherited). Both in silico analysis and fetal brain RNA sequencing confirmed aberrant RNA splicing caused by the intronic variant. CONCLUSION This case has highlighted the value of combining whole-genome sequencing with RNA functional validation. Above results not only enriched the spectrum of CEP290 gene mutations but also underscored its diagnostic value in resolving complex prenatal cases, providing critical clues for the prenatal diagnosis and recurrence risk assessment in genetic counseling.
Female ; Humans ; Pregnancy ; Abnormalities, Multiple/genetics* ; Antigens, Neoplasm/genetics* ; Cell Cycle Proteins/genetics* ; Cerebellum/abnormalities* ; Cytoskeletal Proteins/genetics* ; Eye Abnormalities/genetics* ; Introns/genetics* ; Kidney Diseases, Cystic/diagnosis* ; Pedigree ; Retina/abnormalities* ; Sequence Analysis, RNA/methods* ; Whole Genome Sequencing/methods* ; Child