Molecular Syndromology最新文献

{"title":"WDR81 Mutation in Two Siblings: A Case Report and Review of Literature.","authors":"Mehmet Kaan Öztürk, Sezin Canbek, Peren Perk Yücel","doi":"10.1159/000548770","DOIUrl":"10.1159/000548770","url":null,"abstract":"<p><strong>Introduction: </strong>The <i>WDR81</i> gene is critically involved in autophagy, endosomal trafficking, and neurodevelopment. Pathogenic variants in this gene are associated with autosomal recessive disorders, such as cerebellar ataxia, intellectual disability, and disequilibrium syndrome. Despite recent advances, the full phenotypic spectrum remains incompletely characterized.</p><p><strong>Case presentation: </strong>We report two female siblings carrying a homozygous missense variant in the <i>WDR81</i> gene. The elder sister (age 15) presented with developmental regression, optic atrophy, motor neuropathy, and pes equinovarus. The younger sister (age 6) exhibited astigmatism, gait disturbance, and mild intellectual disability. Both were born to apparently non-consanguineous parents. Genetic testing confirmed the variant in both patients, and their clinical findings were compared with previously reported cases in the literature.</p><p><strong>Conclusion: </strong>These cases expand the clinical spectrum of <i>WDR81</i>-related disorders. Our observations highlight the gene's central role in neurodevelopment and emphasize the need for further investigation into its diverse systemic effects.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":" ","pages":"387-399"},"PeriodicalIF":0.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12618044/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145543203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Highlighting the Impact of Structural Genome Variants in Medical Genetics.","authors":"Martin Poot","doi":"10.1159/000553595","DOIUrl":"10.1159/000553595","url":null,"abstract":"","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2026-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13427350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148654782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive Evaluation of Clinical, Developmental, Genetic, and Reproductive Characteristics of 133 Patients with Klinefelter Syndrome.","authors":"Gizem Ürel Demir, Serap Ketenci İşlek, Hasibe Nesligül Gönen, Gülen Eda Utine, Pelin Özlem Şimşek Kiper","doi":"10.1159/000553594","DOIUrl":"https://doi.org/10.1159/000553594","url":null,"abstract":"<p><strong>Introduction: </strong>Klinefelter syndrome, the most common sex chromosome aneuploidy and a major genetic cause of male infertility, is also associated with systemic comorbidities, congenital anomalies, neurodevelopmental impairments, dysmorphic features, and an increased risk of certain malignancies. While the classical form is 47,XXY, mosaicism and higher-grade sex chromosome aneuploidies are also observed. This study aimed to evaluate the clinical and genetic characteristics of patients diagnosed with Klinefelter syndrome over a 25-year period at a single tertiary center and to compare findings across different karyotype groups.</p><p><strong>Methods: </strong>A total of 133 patients diagnosed with Klinefelter syndrome between January 2000 and September 2025 were retrospectively reviewed. Patients were categorized into three groups: 47,XXY; mosaic karyotypes; and higher-grade sex chromosome aneuploidies. Demographic, clinical, and reproductive characteristics were analyzed, and intergroup statistical comparisons were performed.</p><p><strong>Results: </strong>The majority of patients had a 47,XXY karyotype (87.2%), followed by mosaic forms (6.8%) and higher-grade sex chromosome aneuploidies (6%). Infertility was the most common presenting complaint (62.4%). The predominant clinical findings were hypoplastic or atrophic testes (68.3%), tall stature (15.8%), and gynecomastia (15.8%). Patients with higher-grade sex chromosome aneuploidies were diagnosed at younger ages and exhibited significantly higher rates of congenital anomalies, dysmorphic features, and neurodevelopmental impairment compared with those with the 47,XXY karyotype.</p><p><strong>Conclusion: </strong>Because most individuals with Klinefelter syndrome are diagnosed in adulthood following infertility evaluation and often display subtle manifestations in childhood, early recognition is essential. Increasing awareness of Klinefelter syndrome is crucial to ensure timely detection and management of associated comorbidities, particularly endocrine disorders.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13472637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148763367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A <i>HECW2</i> Missense Variant with a Coexisting 15q25.2-q25.3 Deletion: A Dual Molecular Diagnosis Case Report.","authors":"Javid Taghiyev, Alper Gezdirici, Tuna Eren Esen","doi":"10.1159/000553561","DOIUrl":"https://doi.org/10.1159/000553561","url":null,"abstract":"<p><strong>Introduction: </strong>Dual molecular diagnoses are increasingly recognized with expanded genomic testing, and may result in blended phenotypes when two independent pathogenic findings contribute to the clinical presentation.</p><p><strong>Case presentation: </strong>A 3-year-old female patient presented with seizures beginning at 8 months of age (generalized tonic-clonic), severe global developmental delay/intellectual disability, generalized hypotonia, absent meaningful speech, and microcephaly (head circumference 44.1 cm, <3rd percentile). Craniofacial features included midface retrusion/hypoplasia, thick eyebrows, bilateral epicanthal folds, upslanting palpebral fissures, large ears, a wide mouth, a full lower lip, and a low posterior hairline. Electroencephalography showed age-inappropriate background activity with frequent high-amplitude bifrontal spike-slow wave discharges that often generalized and occasionally displayed a hypsarrhythmia-like pattern. Cranial magnetic resonance imaging was reported as showing a mega cisterna magna variation.</p><p><strong>Conclusion: </strong>Exome sequencing (ES) identified a heterozygous missense variant in <i>HECW2,</i> NM_001348768.2:c.4485G>T p.(Arg1495Ser). Copy-number variant (CNV) analysis of the ES data detected an approximately 2.6 megabase (Mb) heterozygous deletion on chromosome 15, subsequently confirmed by chromosomal microarray analysis as a 2.79 Mb 15q25.2-q25.3 deletion and classified as pathogenic according to American College of Medical Genetics and Genomics/Clinical Genome Resource (ACMG/ClinGen) technical standards. Both alterations were de novo. This case represents a rare dual molecular diagnosis involving a <i>HECW2</i> missense variant and a 15q25.2-q25.3 deletion, supporting a potential blended phenotype and expanding the molecular and phenotypic spectrum of <i>HECW2</i>-related neurodevelopmental disorder.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13472634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148762541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>THUMPD1</i>-Related Neurodevelopmental Disorder: A Novel Homozygous Loss-of-Function Variant with an Unusual Skeletal Phenotype - A Case Report.","authors":"Serife Ozturk Yilmaz, Mehmet Kocabey, Huseyin Bahadir Senol, Semra Gursoy, Ayse Semra Hız, Ahmet Okay Çağlayan, Ozlem Giray Bozkaya","doi":"10.1159/000553495","DOIUrl":"https://doi.org/10.1159/000553495","url":null,"abstract":"<p><strong>Introduction: </strong>Genes involved in tRNA modification are critical contributors to a broad range of human neurodevelopmental disorders, reflecting the essential role of RNA modifications in brain development and function. The <i>THUMPD1</i> gene plays a key role in tRNA modification, and biallelic loss-of-function variants in this gene are known to cause Neurodevelopmental Disorder with Speech Delay and Variable Ocular Anomalies (NEDSOA), an autosomal-recessive condition.</p><p><strong>Case presentation: </strong>We report two sisters harboring a novel homozygous frameshift variant in <i>THUMPD1</i>(NM_017736.5):c.311del;p.(Gly104ValfsTer9), who presented with global developmental delay, severe speech impairment, and ocular anomalies. One affected individual also exhibited severe unilateral skeletal abnormalities on the left hand, including aplasia of the middle and distal phalanges of the fourth finger and the middle phalanx of the fifth finger. To our knowledge, this skeletal feature has not previously been reported in a patient with <i>THUMPD1</i>-related neurodevelopmental disorder.</p><p><strong>Conclusion: </strong>Although this skeletal anomaly contributes to the clinical description of the present family, the presence of the finding in only 1 of the 2 affected siblings, both of whom carry the same homozygous variant, limits the strength of the genotype-phenotype association. Therefore, a definitive causal relationship between the <i>THUMPD1</i> variant and the skeletal phenotype cannot be established, and confirmation in additional individuals will be required.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13472639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148761245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond the Spectrum: A Case Report of Phelan-McDermid Syndrome and the Atypical Teratoid/Rhabdoid Tumor Co-Occurrence.","authors":"Dilsu Dicle Erkan, Merve Soğukpınar, Gülen Eda Utine, Ali Varan, Pelin Özlem Şimşek-Kiper","doi":"10.1159/000553440","DOIUrl":"https://doi.org/10.1159/000553440","url":null,"abstract":"<p><strong>Introduction: </strong>Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder most often caused by terminal 22q13.3 deletions involving <i>SHANK3</i>. Although primarily associated with developmental delay, hypotonia, and autism spectrum disorder-like features, rare reports have described atypical teratoid/rhabdoid tumor (AT/RT) in PMS, suggesting a potential oncogenic link.</p><p><strong>Case presentation: </strong>We report the clinical, molecular, and treatment features of a child with PMS and AT/RT and review previously published cases. The proband presented with global developmental delay, absent speech, hypotonia, joint laxity, and characteristic dysmorphic features. Chromosomal microarray revealed a ∼2.26 Mb terminal deletion at 22q13.32q13.33, encompassing 31 OMIM-listed genes including <i>SHANK3</i>. At 6 months of age, he was diagnosed with AT/RT and treated with multimodal chemotherapy and craniospinal radiotherapy, achieving remission. Literature review identified additional PMS patients with AT/RT, supporting a role for 22q instability in tumorigenesis.</p><p><strong>Conclusion: </strong>This case highlights a rare but clinically significant association between PMS and AT/RT. Awareness of this potential link and careful radiotherapy planning are warranted to optimize outcomes in affected individuals.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13472638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148765145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early Pubertal Progression and Increased 11-Oxygenated Androgens in a Girl with Wiedemann-Steiner Syndrome and a <i>KMT2A</i> Variant: A Case Report.","authors":"Erina Suzuki, Kentaro Sawano, Yoko Kuroki, Sumito Dateki, Keisuke Nagasaki, Maki Fukami","doi":"10.1159/000553259","DOIUrl":"https://doi.org/10.1159/000553259","url":null,"abstract":"<p><strong>Introduction: </strong>The factors that determine the tempo of pubertal progression are not fully understood. Although a few patients with <i>KMT2A</i> variants were noted to have precocious puberty, in addition to various clinical features of Wiedemann-Steiner syndrome (WSS), the hormonal data of these individuals were unreported. Recently, high blood levels of 11-ketotestosterone, a potent 11-oxygenated androgen, were observed in a girl with WSS.</p><p><strong>Case presentation: </strong>We encountered a Japanese girl who experienced menarche at 9 years and 4 months of age. She showed pubertal levels of LH and estradiol and advanced bone age and was treated with a gonadotropin-releasing hormone analog. She exhibited hirsutism, craniofacial features, and mild intellectual disability but no other clinical features of WSS. Exome sequencing identified a hitherto unreported de novo variant at the splice acceptor site of <i>KMT2A</i> exon 5 (c.3335-1G>A). Her blood levels of 11-oxygenated androgens, androstenedione, and dehydroepiandrosterone were markedly elevated, while those of estrogen and testosterone were within normal ranges.</p><p><strong>Conclusion: </strong>The present case implies possible roles of KMT2A in the hypothalamic-pituitary-gonadal axis or in adrenal steroidogenesis. The results of this study, together with previous findings, imply that overproduction of 11-oxygenated androgens contributes to advanced bone age and hypertrichosis in patients with WSS. Our data merit further validation.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13472632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148763613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Duodenal Duplication Cyst in Cardiofaciocutaneous Syndrome: A Possible Expansion of the Gastrointestinal Phenotype of RASopathies - A Case Report.","authors":"Adnan Deniz, Özlem Akgün Doğan, Burak Tander","doi":"10.1159/000553336","DOIUrl":"10.1159/000553336","url":null,"abstract":"<p><strong>Introduction: </strong>Cardiofaciocutaneous (CFC) syndrome is a rare RASopathy caused predominantly by germline <i>BRAF</i> variants; functional gastrointestinal symptoms are common, but structural gastrointestinal malformations are exceptional.</p><p><strong>Case presentation: </strong>We report a 10-month-old male with a de novo <i>BRAF</i> (NM_004333.6):c.1914T>A, p.(Asp638Glu) pathogenic variant who presented neonatally with a duodenal duplication cyst causing partial pyloric obstruction and underwent surgical excision at 3.5 months. To our knowledge, no previous duodenal duplication cyst has been reported in CFC syndrome or in any other RASopathy in the indexed literature.</p><p><strong>Conclusion: </strong>RAS/MAPK signalling regulates foregut recanalisation, raising the possibility of a mechanistic link, although causality cannot be established from a single observation. This hypothesis-generating case may expand the reported gastrointestinal phenotype of RASopathies; structural imaging may be considered in CFC patients with obstructive vomiting disproportionate to expected functional feeding difficulties.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13466564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148727618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blended Hereditary Neuropathy Phenotype Caused by Biallelic <i>PRX</i> and <i>SCN9A</i> Variants: A Case Report.","authors":"Yunus E Dogan, Mehmet Canpolat, Fırat Ozcelik, Selcan Ozturk, Michael D Weiss, Munis Dundar","doi":"10.1159/000553320","DOIUrl":"10.1159/000553320","url":null,"abstract":"<p><strong>Introduction: </strong>Inherited neuropathies are genetically heterogeneous, and with the increasing use of next-generation sequencing, multilocus pathogenic variants are now being recognized more frequently, particularly in populations with high consanguinity. We report the first known coexistence of <i>PRX-</i> and <i>SCN9A</i>-related disorders in the same patient.</p><p><strong>Case presentation: </strong>A 17-month-old girl presented with walking difficulties, profound insensitivity to pain, self-mutilation, finger tissue loss, and chronic ulcerations. Physical examination revealed dentition abnormality, distal phalanx loss, bilateral genu recurvatum, and reflex loss. Imaging revealed osteomyelitis and chronic fractures, while electrophysiology revealed severe demyelinating neuropathy. Genetic testing identified homozygous pathogenic variants in the <i>PRX</i> NM_181882.3:c.1390C>T p.(Arg464Ter) and <i>SCN9A</i> NM_002977.3:c.3143_3154delinsA p.(Ile1048LysfsTer13) genes, which were confirmed by Sanger sequencing.</p><p><strong>Conclusion: </strong>Coexisting autosomal recessive disorders can produce blended phenotypes beyond classical disease expectations. In populations where consanguineous marriages are common, multilocus pathogenic variants should be considered, and comprehensive genomic testing is recommended.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13461198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148714171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Homozygous GALNT3 Deletion in Hyperphosphatemic Familial Tumoral Calcinosis Presenting with Subcutaneous Calcifications and Raynaud's Phenomenon in an Adult Patient: A Case Report.","authors":"Mehmet Akif Baltaci, Hande Nur Cesur Baltaci, Cem Ozisler, Sule Altıner, Melih Pamukcu, Ertugrul Cagri Bolek","doi":"10.1159/000553258","DOIUrl":"10.1159/000553258","url":null,"abstract":"<p><strong>Introduction: </strong>Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare autosomal recessive disorder caused by pathogenic variants in the <i>GALNT3</i>, <i>FGF23</i>, or <i>KL</i> genes, leading to ectopic calcifications. It typically presents in childhood or adolescence with periarticular calcified masses; however, adult-onset cases are exceedingly rare.</p><p><strong>Case presentation: </strong>We report a 54-year-old woman with a 5-year history of inflammatory bone pain, Raynaud's phenomenon, and distal extremity calcifications. Laboratory evaluation revealed hyperphosphatemia, suppressed parathyroid hormone, elevated 1,25-dihydroxyvitamin D level, and increased tubular phosphate reabsorption, suggesting <i>FGF23</i> deficiency or resistance. Genetic analysis identified a novel homozygous deletion of exons 8 and 9 in <i>GALNT3</i>. This variant was classified as likely pathogenic per ACMG criteria. The patient was treated with calcium-free phosphate binders, corticosteroids, NSAIDs, and dietary phosphate restriction, resulting in partial symptomatic improvement.</p><p><strong>Conclusion: </strong>This case represents one of the oldest patients with a genetically confirmed HFTC diagnosis and expands its known phenotypic spectrum. Multidisciplinary evaluation, including genetic counseling and screening of family members, is essential. Awareness of atypical presentations and consideration of genetic testing in patients with unexplained soft-tissue calcifications can facilitate timely diagnosis and management.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13451027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148698024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}