European journal of medical genetics最新文献

{"title":"Clinical presentation and genetics of tricho-rhino-phalangeal syndrome (TRPS) type 1: A single-center case series of 15 patients and seven novel TRPS1 variants","authors":"Laura Krogh Herlin ,&nbsp;Morten Krogh Herlin ,&nbsp;Jenny Blechingberg ,&nbsp;Kirsten Rønholt ,&nbsp;Lise Graversen ,&nbsp;Sigrun A.J. Schmidt ,&nbsp;Mette Warming Jørgensen ,&nbsp;Michel Bach Hellfritzsch ,&nbsp;Jannie Dahl Hald ,&nbsp;Signe Sparre Beck-Nielsen ,&nbsp;Hans Gjørup ,&nbsp;Brian Nauheimer Andersen ,&nbsp;Pernille Axél Gregersen ,&nbsp;Mette Sommerlund","doi":"10.1016/j.ejmg.2024.104937","DOIUrl":"https://doi.org/10.1016/j.ejmg.2024.104937","url":null,"abstract":"<div><p>Tricho-rhino-phalangeal syndrome (TRPS) is a rare malformation syndrome characterized by distinctive facial, ectodermal, and skeletal features. TRPS is divided into TRPS type I/III caused by pathogenic variants in <em>TRPS1</em> and TRPS type II caused by contiguous gene deletions also spanning <em>EXT1</em> and <em>RAD21</em>. Due to its rarity, knowledge of the clinical course of TRPS remains limited.</p><p>Therefore, we collected and characterized a case series of 15 TRPS type I patients (median age at diagnosis 15 [interquartile range: 10–18] years, 11 females [73%]) seen at Aarhus University Hospital, Denmark, with a median follow-up period of 10 years. We estimated a minimum point prevalence of 0.5 in 100,000 (95% CI: 0.3–0.8 per 100,000) persons.</p><p>Common craniofacial features included fine and sparse hair with a high anterior hairline, eyebrows with lateral thinning and a thicker medial part, prominent ears, a bulbous nose tip with small nasal alae, a low-hanging, and often wide columella, and a long philtrum with a thin upper vermillion. Specific skeletal features included short stature and deviating and short fingers with cone-shaped epiphyses and shortened metacarpals on radiographs. The most significant morbidity of the cohort was joint complaints, which were reported by all patients, often already before the TRPS diagnosis was established.</p><p>We identified ten different <em>TRPS1</em> variants including both frameshift/nonsense, missense, and splice-site variants, including seven variants not previously reported in the literature. In accordance with previous literature, no genotype-phenotype correlation was identified.</p><p>The clinical trajectories were heterogeneous involving pediatrics, dermatology, orthopedic surgery, clinical genetics, and/or odontology, emphasizing that close multidisciplinary collaboration is essential for early diagnosis of TRPS and to ensure proper and timely patient care and counseling.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"69 ","pages":"Article 104937"},"PeriodicalIF":1.9,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000296/pdfft?md5=bd46259febf30bd57bbedec11df65999&pid=1-s2.0-S1769721224000296-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140351336","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":"Genotype-phenotype of autosomal dominant polycystic kidney disease in Malta","authors":"Natalie Ciantar ,&nbsp;Graziella Zahra ,&nbsp;Julian Delicata ,&nbsp;Fiona Sammut ,&nbsp;Jean Calleja-Agius ,&nbsp;Emanuel Farrugia ,&nbsp;Edith Said","doi":"10.1016/j.ejmg.2024.104934","DOIUrl":"10.1016/j.ejmg.2024.104934","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;p&gt;Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of multiple renal cysts causing kidney enlargement and end-stage renal disease (ESRD) in half the patients by 60 years of age. The aim of the study was to determine the genetic aetiology in Maltese patients clinically diagnosed with ADPKD and correlate the clinical features.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;p&gt;A total of 60 patients over 18 years of age clinically diagnosed with ADPKD were studied using a customized panel of genes that had sufficient evidence of disease diagnosis using next generation sequencing (NGS). The genes studied were &lt;em&gt;PKD1&lt;/em&gt;, &lt;em&gt;PKD2&lt;/em&gt;, &lt;em&gt;GANAB&lt;/em&gt;, &lt;em&gt;DNAJB11&lt;/em&gt;, &lt;em&gt;PKHD1&lt;/em&gt; and &lt;em&gt;DZIP1L&lt;/em&gt;. Selected variants were confirmed by bidirectional Sanger sequencing with specifically designed primers. Cases where no clinically significant variant was identified by the customized gene panel were then studied by Whole Exome Sequencing (WES). Microsatellite analysis was performed to determine the origin of an identified recurrent variant in the &lt;em&gt;PKD2&lt;/em&gt; gene. Clinical features were studied for statistical correlation with genetic results.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;p&gt;Genetic diagnosis was reached in 49 (82%) of cases studied. Pathogenic/likely pathogenic variants &lt;em&gt;PKD1&lt;/em&gt; and &lt;em&gt;PKD2&lt;/em&gt; gene were found in 25 and in 23 cases respectively. The relative proportion of genetically diagnosed &lt;em&gt;PKD1&lt;/em&gt;:&lt;em&gt;PKD2&lt;/em&gt; cases was 42:38. A pathogenic variant in the &lt;em&gt;GANAB&lt;/em&gt; gene was identified in 1 (2%) case. A potentially significant heterozygous likely pathogenic variant was identified in &lt;em&gt;PKHD1&lt;/em&gt; in 1 (2%) case. Potentially significant variants of uncertain significance were seen in 4 (7%) cases of the study cohort. No variants in &lt;em&gt;DNAJB11&lt;/em&gt; and &lt;em&gt;DZIP1L&lt;/em&gt; were observed. Whole exome sequencing (WES) added the diagnostic yield by 10% over the gene panel analysis. Overall no clinically significant variant was detected in 6 (10%) cases of the study population by a customized gene panel and WES. One recurrent variant the &lt;em&gt;PKD2&lt;/em&gt; c.709+1G &gt; A was observed in 19 (32%) cases. Microsatellite analysis showed that all variant cases shared the same haplotype indicating that their families may have originated from a common ancestor and confirmed it to be a founder variant in the Maltese population.&lt;/p&gt;&lt;p&gt;The rate of decline in eGFR was steeper and progression to ESRD was earlier in cases with &lt;em&gt;PKD1&lt;/em&gt; variants when compared to cases with &lt;em&gt;PKD2&lt;/em&gt; variants. Cases segregating truncating variants in &lt;em&gt;PKD1&lt;/em&gt; showed a significantly earlier onset of ESRD and this was significantly worse in cases with frameshift variants. Overall extrarenal manifestations were commoner in cases segregating truncating variants in &lt;em&gt;PKD1&lt;/em&gt;.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;p&gt;This study helps to show that a customized gene panel is the first-line method of choice for stu","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"69 ","pages":"Article 104934"},"PeriodicalIF":1.9,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000260/pdfft?md5=70a251f2e08cf605b5c690f8ac0fe66b&pid=1-s2.0-S1769721224000260-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140305245","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":"Penetrance, variable expressivity and monogenic neurodevelopmental disorders","authors":"Servane de Masfrand ,&nbsp;Benjamin Cogné ,&nbsp;Mathilde Nizon ,&nbsp;Wallid Deb ,&nbsp;Alice Goldenberg ,&nbsp;François Lecoquierre ,&nbsp;Gaël Nicolas ,&nbsp;Marie Bournez ,&nbsp;Antonio Vitobello ,&nbsp;Frédéric Tran Mau-Them ,&nbsp;Gwenaël le Guyader ,&nbsp;Frédéric Bilan ,&nbsp;Peter Bauer ,&nbsp;Christiane Zweier ,&nbsp;Juliette Piard ,&nbsp;Laurent Pasquier ,&nbsp;Stéphane Bézieau ,&nbsp;Bénédicte Gerard ,&nbsp;Laurence Faivre ,&nbsp;Pascale Saugier-Veber ,&nbsp;Bertrand Isidor","doi":"10.1016/j.ejmg.2024.104932","DOIUrl":"10.1016/j.ejmg.2024.104932","url":null,"abstract":"<div><h3>Purpose</h3><p>Incomplete penetrance is observed for most monogenic diseases. However, for neurodevelopmental disorders, the interpretation of single and multi-nucleotide variants (SNV/MNVs) is usually based on the paradigm of complete penetrance.</p></div><div><h3>Method</h3><p>From 2020 to 2022, we proposed a collaboration study with the French molecular diagnosis for intellectual disability network. The aim was to recruit families for whom the index case, diagnosed with a neurodevelopmental disorder, was carrying a pathogenic or likely pathogenic variant for an OMIM morbid gene and inherited from an asymptomatic parent. Grandparents were analyzed when available for segregation study.</p></div><div><h3>Results</h3><p>We identified 12 patients affected by a monogenic neurodevelopmental disorder caused by likely pathogenic or pathogenic variant (SNV/MNV) inherited from an asymptomatic parent. These genes were usually associated with <em>de novo</em> variants. The patients carried different variants (1 splice-site variant, 4 nonsense and 7 frameshift) in 11 genes: <em>CAMTA1, MBD5, KMT2C, KMT2E, ZMIZ1, MN1, NDUFB11, CUL3, MED13, ARID2</em> and <em>RERE</em>. Grandparents have been tested in 6 families, and each time the variant was confirmed <em>de novo</em> in the healthy carrier parent.</p></div><div><h3>Conclusion</h3><p>Incomplete penetrance for SNV and MNV in neurodevelopmental disorders might be more frequent than previously thought. This point is crucial to consider for interpretation of variants, family investigation, genetic counseling, and prenatal diagnosis. Molecular mechanisms underlying this incomplete penetrance still need to be identified.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"69 ","pages":"Article 104932"},"PeriodicalIF":1.9,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000247/pdfft?md5=fad69324e654d733a7e4fed05d79fbe8&pid=1-s2.0-S1769721224000247-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140059028","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":"Clinical manifestations and genetic mutation analysis of patients with mucopolysaccharidosis type VII in China","authors":"Xueying Su,&nbsp;Xiaoyuan Zhao,&nbsp;Xi Yin,&nbsp;Li Liu,&nbsp;Yonglan Huang,&nbsp;Chunhua zeng,&nbsp;Xiuzhen Li,&nbsp;Wen Zhang","doi":"10.1016/j.ejmg.2024.104933","DOIUrl":"10.1016/j.ejmg.2024.104933","url":null,"abstract":"<div><h3>Objective</h3><p>This study aimed to explore the clinical and genetic features of Chinese patients with mucopolysaccharidosis type VII (MPS VII), thereby improving early detection, disease management, and patient outcomes.</p></div><div><h3>Methods</h3><p>A retrospective review of medical records for five patients presenting with coarse facial features, rib protrusion, chest deformities, and scoliosis was conducted. Exome sequencing was employed to identify causative genetic mutations.</p></div><div><h3>Results</h3><p>The study comprised five patients (four males, one female) with disease onset at six months of age (range: 0–1.5 years). Common symptoms included coarse facial features, skeletal abnormalities, delayed motor and language development, and intellectual disability. Approximately 80% of the patients exhibited multiple skeletal dysplasias, enlarged adenoids or tonsils, and snoring; 60% had hernias; 40% reported hearing loss and hepatosplenomegaly. Less frequent manifestations were short stature, valvular heart disease, non-immune hydrops fetalis, and corneal opacity. All patients demonstrated elevated urine glycosaminoglycans levels and absent β-glucuronidase activity in leukocytes. Exome sequencing identified compound heterozygous mutations in the <em>GUSB</em> gene in all four tested patients, uncovering seven mutations in total, three of which were novel (c.189G &gt; A, c.869C &gt; T, and c.1745 T &gt; C). Furthermore, prenatal diagnosis through chorionic villus sampling in subsequent pregnancies of one patient's mother revealed both fetuses had normal β-glucuronidase activity and no disease-causing mutations in the <em>GUSB</em> gene.</p></div><div><h3>Conclusion</h3><p>The study's patients all presented with classic symptoms of MPS VII due to β-glucuronidase deficiency, with three new pathogenic mutations identified in the <em>GUSB</em> gene. Genetic counseling and prenatal testing were highlighted as crucial for disease prevention.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104933"},"PeriodicalIF":1.9,"publicationDate":"2024-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000259/pdfft?md5=0cba2714e37998ee5b99c7bc52c3512d&pid=1-s2.0-S1769721224000259-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140038980","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 systematic review of the assessment of the clinical utility of genomic sequencing: Implications of the lack of standard definitions and measures of clinical utility","authors":"Claudia Azuelos ,&nbsp;Marc-Antoine Marquis ,&nbsp;Anne-Marie Laberge","doi":"10.1016/j.ejmg.2024.104925","DOIUrl":"10.1016/j.ejmg.2024.104925","url":null,"abstract":"<div><h3>Purpose</h3><p>Exome sequencing (ES) and genome sequencing (GS) are diagnostic tests for rare genetic diseases. Studies report clinical utility of ES/GS. The goal of this systematic review is to establish how clinical utility is defined and measured in studies evaluating the impacts of ES/GS results for pediatric patients.</p></div><div><h3>Methods</h3><p>Relevant articles were identified in PubMed, Medline, Embase, and Web of Science. Eligible studies assessed clinical utility of ES/GS for pediatric patients published before 2021. Other relevant articles were added based on articles’ references. Articles were coded to assess definitions and measures of clinical utility.</p></div><div><h3>Results</h3><p>Of 1346 articles, 83 articles met eligibility criteria. Clinical utility was not clearly defined in 19% of studies and 92% did not use an explicit measure of clinical utility. When present, definitions of clinical utility diverged from recommended definitions and varied greatly, from narrow (diagnostic yield of ES/GS) to broad (including decisions about withdrawal of care/palliative care and/or impacts on other family members).</p></div><div><h3>Conclusion</h3><p>Clinical utility is used to guide policy and practice decisions about test use. The lack of a standard definition of clinical utility of ES/GS may lead to under- or overestimations of clinical utility, complicating policymaking and raising ethical issues.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104925"},"PeriodicalIF":1.9,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S176972122400017X/pdfft?md5=9b5e70319407f11c453377cf08fa49d2&pid=1-s2.0-S176972122400017X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140021257","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":"Disclosure of genetic risk to family members: A qualitative study on healthcare professionals' perceived roles and responsibilities","authors":"Álvaro Mendes ,&nbsp;Milena Paneque ,&nbsp;Jorge Sequeiros","doi":"10.1016/j.ejmg.2024.104931","DOIUrl":"10.1016/j.ejmg.2024.104931","url":null,"abstract":"<div><p>This paper presents the perspectives of healthcare professionals regarding their roles and responsibilities in supporting patients with the disclosure of genetic risk to their families. The study involved eight focus groups and two individual interviews with 34 healthcare professionals working in medical genetics services across Portugal. The data were analyzed thematically, resulting in three primary themes: i) informing patients about the risk to relatives; ii) ensuring patient confidentiality; and iii) encouraging family communication. Participants believed it is their responsibility to inform patients about the genetic risk to their relatives, with patients bearing a moral responsibility to convey this information. They explained that the principles of medical confidentiality of the patient take precedence over any direct responsibility to patients' relatives. Treating personal and familial genetic information separately was perceived as challenging to implement and potentially problematic. While most participants reported encouraging patients to inform their relatives, the extent to which they facilitate this communication varies and is also constrained by lack of resources and concerns about complying with legal requirements. Some participants called for clearer national guidelines. These results contribute for ongoing discussions regarding the scope of practice and the roles and responsibilities of healthcare professionals in appropriately cascading pertinent information to at-risk relatives.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104931"},"PeriodicalIF":1.9,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000235/pdfft?md5=a0069856e1eccc704d967b55fa8d5d73&pid=1-s2.0-S1769721224000235-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140021258","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":"Prenatal onset GAPO syndrome with a novel ANTXR1 variant in an Indian child: Expansion of the phenotype & literature review","authors":"Surya Balakrishnan ,&nbsp;Iravathy Goud ,&nbsp;Madhavi Latha Teegala","doi":"10.1016/j.ejmg.2024.104929","DOIUrl":"10.1016/j.ejmg.2024.104929","url":null,"abstract":"<div><p>GAPO syndrome is a rare genetic condition caused by bi-allelic variants in <em>ANTXR1</em> gene &amp; is an abbreviation for its core features - growth retardation, alopecia, pseudo-anodontia &amp; optic atrophy. Certain additional features involving various other systems have been reported over the years &amp; contribute to the expanding spectrum of this evolving phenotype. We report GAPO syndrome in a 3.75 year old Indian female child, who presented with some unique features such as sagittal craniosynostosis with scaphocephaly &amp; bilateral choroid plexus cysts, alongside the core phenotype. We also report a novel frameshift variant in our patient &amp; offer first evidence for the prenatal onset of some features.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104929"},"PeriodicalIF":1.9,"publicationDate":"2024-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000211/pdfft?md5=ee69e08cc83df9db80ab76f456f3332a&pid=1-s2.0-S1769721224000211-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139995944","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":"Two siblings with PEX11B-related peroxisome biogenesis disorder","authors":"Somayeh Khoddam ,&nbsp;Neda Kamal ,&nbsp;Amirmasoud Shiri ,&nbsp;Hossein Jafari Khamirani ,&nbsp;Jamal Manoochehri ,&nbsp;Mehdi Dianatpour ,&nbsp;Seyed Mohammad Bagher Tabei ,&nbsp;Seyed Alireza Dastgheib","doi":"10.1016/j.ejmg.2024.104928","DOIUrl":"10.1016/j.ejmg.2024.104928","url":null,"abstract":"<div><p>The <em>PEX11β</em> gene contains four exons and encodes peroxisomal membrane protein 11β, which is involved in peroxisome proliferation and division. Pathogenic variants in this gene result in a rare genetic disorder with autosomal recessive inheritance called peroxisome biogenesis disorder 14B (MIM: 614920). Here, we report two affected siblings with a novel variant (NM_003846: c.11G &gt; A, p. Trp4Ter) in the <em>PEX11β</em> gene that was identified by whole exome sequencing and confirmed by Sanger sequencing. The proband is a 22-year-old Iranian female who was born to consanguineous parents. The homozygous variant (NM_003846: c.11G &gt; A, p. Trp4Ter) in the <em>PEX11β</em> gene was identified in the proband, who presented with cataracts, strabismus, nystagmus, intellectual disability, developmental delay, speech disorders, dry skin, and behavioral problems. Her younger affected brother, who had the same homozygous variant, suffered from similar but slightly milder symptoms. This paper reports the seventh family in the world with novel pathogenic variants in the <em>PEX11β</em> gene as the cause of peroxisome biogenesis disorder 14B. Additionally, the phenotypes of the previously reported patients are reviewed. Some of the phenotypes, such as bilateral congenital cataracts and intellectual disability, were present in all patients. However, other observed symptoms in previous cases, such as abnormal gait, myopia, abnormal muscle strength, hearing loss, gastrointestinal problems, skeletal disorders, and seizures, were not observed in the patients of this study. Further studies on this disorder could be valuable in determining the precise phenotype characteristics of this disease.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104928"},"PeriodicalIF":1.9,"publicationDate":"2024-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S176972122400020X/pdfft?md5=5871df2da6abe02184bff13c62a15a90&pid=1-s2.0-S176972122400020X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139995945","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":"Ligamentous laxity in children with achondroplasia: Prevalence, joint involvement, and implications for early intervention strategies","authors":"Domenico Marco Romeo ,&nbsp;Virginia Pironi ,&nbsp;Chiara Velli ,&nbsp;Elisabetta Sforza ,&nbsp;Donato Rigante ,&nbsp;Valentina Giorgio ,&nbsp;Chiara Leoni ,&nbsp;Cristina De Rose ,&nbsp;Eliza Maria Kuczynska ,&nbsp;Domenico Limongelli ,&nbsp;Roberta Ruiz ,&nbsp;Cristiana Agazzi ,&nbsp;Eugenio Mercuri ,&nbsp;Giuseppe Zampino ,&nbsp;Roberta Onesimo","doi":"10.1016/j.ejmg.2024.104930","DOIUrl":"10.1016/j.ejmg.2024.104930","url":null,"abstract":"<div><p>Achondroplasia (ACH), the most common form of skeletal dysplasia, is characterized by severe disproportionate short stature, rhizomelia, exaggerated lumbar lordosis, brachydactyly, macrocephaly with frontal bossing and midface hypoplasia.</p><p>Ligamentous laxity has been reported as a striking feature of ACH, but its prevalence and characteristics have not been systematically evaluated yet. There is growing evidence that ligamentous laxity can be associated with chronic musculoskeletal problems and may affect motor development leading to abnormal developmental trajectories.</p><p>This study aimed to assess the prevalence of ligamentous laxity in children with ACH through standardized tools, the Beighton scale and its modified version for preschool-age children.</p><p>A total of 33 children (mean age 6.4 ± 3.2 years; age range 1–12.5 years) diagnosed with ACH by the demonstration of a pathogenic variant in the <em>FGFR3</em> gene and 33 age- and sex-matched healthy controls were included in the study. Both ligamentous laxity assessment and neurological examinations were performed; medical history was also collected from caregivers.</p><p>Children with ACH showed a 2 times higher risk of ligamentous laxity than the group without skeletal dysplasia (OR = 2.2; 95% CI = 1.0 to 4.7), with 55% of children meeting the diagnostic criteria for hypermobility. No significant difference in ligamentous laxity was observed between males and females.</p><p>Joint involvement analysis revealed characteristic patterns, with knee hypermobility observed in 67% of patients, while rare was elbow hypermobility. Longitudinal assessments indicated a decreasing trend in ligamentous laxity scores over time, suggesting a potential decrease in hypermobility issues during adulthood.</p><p>The findings of this study provide valuable insights into the prevalence and characteristics of ligamentous laxity in ACH. Implementation of standardized ligamentous laxity assessments might guide patients’ follow-up and facilitate early interventions, helping to prevent pain and improve outcomes and quality of life for such patients. Further prospective studies are needed to explore the natural history of ligamentous laxity in ACH and investigate the potential impact of emerging pharmacological treatments upon hypermobility.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104930"},"PeriodicalIF":1.9,"publicationDate":"2024-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000223/pdfft?md5=9c0212b9351488775dadcf08870fae66&pid=1-s2.0-S1769721224000223-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140012380","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":"Long-term clinical evaluation of patients with alpha-mannosidosis – A multicenter study","authors":"Engin Köse ,&nbsp;Çiğdem Seher Kasapkara ,&nbsp;Aslı İnci ,&nbsp;Yılmaz Yıldız ,&nbsp;İlknur Sürücü Kara ,&nbsp;Ayça Burcu Kahraman ,&nbsp;Leyla Tümer ,&nbsp;Ali Dursun ,&nbsp;Fatma Tuba Eminoğlu","doi":"10.1016/j.ejmg.2024.104927","DOIUrl":"10.1016/j.ejmg.2024.104927","url":null,"abstract":"<div><h3>Background</h3><p>Alpha mannosidosis is an autosomal recessive lysosomal storage disorder caused by biallelic pathogenic variants in the <em>MAN2B1</em> gene. It manifests with clinical features, including intellectual disability, hearing impairment, coarse facial appearance, skeletal anomalies, immunodeficiency, central nervous system involvement, psychiatric comorbidities, corneal opacity, and hepatosplenomegaly.</p><p>This multicenter study assesses the long-term outcomes of individuals diagnosed with alpha-mannosidosis, examining demographic, clinical, laboratory, and molecular characteristics.</p></div><div><h3>Method</h3><p>Sixteen patients diagnosed with alpha-mannosidosis who presented to four pediatric metabolic units were included in the study. The patients' medical records were analyzed and data on demographics, clinical presentation and laboratory findings were recorded.</p></div><div><h3>Results</h3><p>Of the 16 patients (6 females, 10 males) with alpha mannosidosis included in the study, the mean age at the time of diagnosis was 79.4 ± 56.1 (16–208) months, and the mean diagnosis delay time was 57.9 ± 51.9 (4–181) months.</p><p>Hearing loss was the primary manifestation found in seven out of 16 patients (43.8%), followed by speech delay in 37.8%. On clinical follow-up, 87.5% of patients experienced recurrent infections, mainly in the upper respiratory tract, with 12 requiring the use of a hearing aid. Hepatomegaly was found in six out of 13 patients who received abdominal ultrasonography; two out of 12 patients who underwent echocardiography were found to have mitral valve prolapse (16.6%).</p><p>Upon neurological evaluation, five patients displayed no neurological manifestation. Delayed language development was observed in nine (56.3%) patients, intellectual disability in eight (50%) patients, and hypertonicity was identified in one (6.3%) patient with the severe form of the disease.</p><p>Homozygous c.2477C&gt;A (p.Ser826Ter) and homozygous c.967G&gt;A (p.Glu323Lys) novel variants were detected in four patients and one patient, respectively. The most common variant observed in the study was c.2477C&gt;A (p.Ser826Ter).</p></div><div><h3>Conclusion</h3><p>The present study identified two novel <em>MAN2B1</em> variants. An evaluation of the long-term outcome of alpha-mannosidosis, in which the early initiation of enzyme replacement therapy (ERT) may lead to a better clinical outcome, can permit a better analysis of the effect of ERT on the natural progression of the disease.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104927"},"PeriodicalIF":1.9,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000193/pdfft?md5=e070835ad551252ae75c0c87c59ce9e2&pid=1-s2.0-S1769721224000193-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139926805","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}