European journal of medical genetics最新文献

{"title":"Lessons learned from the RE(ACT) conference on medical devices for rare diseases","authors":"Anneliene H. Jonker ,&nbsp;Tim Buckinx ,&nbsp;Lucia Pannese ,&nbsp;Paulien Klap ,&nbsp;José-Alain Sahel ,&nbsp;Marc Dooms","doi":"10.1016/j.ejmg.2024.104976","DOIUrl":"10.1016/j.ejmg.2024.104976","url":null,"abstract":"<div><div>The field of rare disease therapeutics has witnessed significant growth in recent years, highlighting the need for diverse therapeutic approaches to cater to the unique needs of individuals with rare diseases. Rare disease therapies encompass a broad spectrum of interventions, including orphan medicinal products, orphan medical devices, rehabilitative therapies, and digital therapeutics, with the lines between these categories blurring. This paper covers the session of the RE (ACT)-IRDiRC Conference 2023 and delves into the landscape of orphan medical device research and development, shedding light on the challenges and opportunities in this burgeoning field. It provides a short overview of the different international legislations in the field. In addition, it highlights several exemplary orphan medical devices. The first example is an exoskeleton for boys with Duchenne Muscular Dystrophy, enabling them to maintain arm functionality and independence. Another example presented was an EEG device linked to an app detecting seizures in rare epilepsy conditions, which alerts caregivers to seizures in real-time but also facilitates objective seizure reporting for clinicians, aiding in diagnosis and treatment optimization. It also showcases the role of gamification and enabling technologies in addressing rare diseases, by showing a game designed for children with cystic fibrosis, and a telemedicine system for rehabilitation therapy. Both solutions aim to improve patients' understanding of their conditions and enhance their self-management. In conclusion, this paper underscores the critical need for patient-centric orphan and pediatric medical devices to provide therapeutic options for individuals with rare diseases. It highlights the impact of existing devices on enhancing the quality of life for rare disease patients and emphasizes the necessity for greater incentives and support for research and development in this field.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"72 ","pages":"Article 104976"},"PeriodicalIF":1.6,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142389040","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 germline Pregnane X Receptor (PXR) variant predisposing to Hodgkin lymphoma in two siblings","authors":"Khusan Khodzhaev ,&nbsp;Tugce Sudutan ,&nbsp;Yucel Erbilgin ,&nbsp;Merve Saritas ,&nbsp;Gulcin Yegen ,&nbsp;Ceyhun Bozkurt ,&nbsp;Muge Sayitoglu ,&nbsp;Rejin Kebudi","doi":"10.1016/j.ejmg.2024.104975","DOIUrl":"10.1016/j.ejmg.2024.104975","url":null,"abstract":"<div><div>Hodgkin's lymphoma (HL) is the most common cancer in adolescents and young adults. A family history of HL increases the risk of developing HL in other family members. Identification of genetic predisposition variants in HL is important for understanding disease aetiology, prognosis, and response to treatment. Aberrant activation of the NF-κB pathway is a hallmark feature of HL, contributing to the survival and proliferation of the malignant cells' characteristic of HL.</div><div>The family with multiple consanguineous marriages with siblings of diagnosed HL was examined by whole-exome sequencing. We found a germline homozygous variation in the PXR ligand binding domain (NM_003889.3:c.811G&gt;A, p.(Asp271Asn)), which was classified as pathogenic by prediction tools and segregated in HL cases. Increased <em>PXR</em> expression was found in homozygous variant carriers compared to heterozygous carriers by quantitative real time PCR (qRT-PCR) and immunofluorescence staining of patients' formalin-fixed paraffin-embedded tissues showed upregulation of PXR, particularly in Hodgkin Reed/Sternberg (HRS) cells.</div><div>Patients with homozygous <em>PXR</em> variant showed significantly high expression compared to <em>PXR</em> wild-type HL, heterozygous and controls (p = 0.0001, p = 0.0004 and p = 0.0001, respectively). <em>PXR</em> homozygous HRS cells had significantly higher PXR expression compared to <em>PXR</em> wild-type HRS cells (p &lt; 0.0001, 3.27-fold change). Albeit PXR's prominent expression in cytoplasm of HRS cells, homozygous <em>PXR</em> HRS cells showed increased PXR expression in nucleus (p &lt; 0.001).</div><div>PXR is a member of the nuclear receptor superfamily and previous studies have demonstrated a pleiotropic effect of PXR on malignant transformation. Expression analysis showed that cell proliferation, apoptosis and inflammation related genes were deregulated, in homozygous <em>PXR</em> HL cases. This study provided clinical evidence to previously reported <em>Sxr</em>^{<em>−/−</em>} mice model that develop multifocal lymphomas, had an aberrantly increased NF-κB expression and consistent inflammation. Further functional studies are needed to elucidate the exact mechanisms of action of PXR in HL pathogenesis.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"72 ","pages":"Article 104975"},"PeriodicalIF":1.6,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142344065","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":"ITGB4-Related pyloric atresia without epidermolysis in two siblings","authors":"Lamiya Aliyeva ,&nbsp;Serdar Beken ,&nbsp;Hanifenur Mancilar ,&nbsp;Eda Albayrak ,&nbsp;Ayse Korkmaz ,&nbsp;Burak Tander ,&nbsp;Yasemin Alanay","doi":"10.1016/j.ejmg.2024.104971","DOIUrl":"10.1016/j.ejmg.2024.104971","url":null,"abstract":"<div><div>Pyloric atresia is a rare gastrointestinal anomaly with an incidence of 1/100,000 in live births. It is usually seen as an isolated condition or in combination with other congenital or hereditary anomalies. Autosomal recessive inherited either fatal or non-fatal variants of pyloric atresia with epidermolysis bullosa are known due to mutations in <em>ITGA6</em>, <em>ITGB4,</em> and <em>PLEC</em> genes. <em>ITGB4</em> gene mutation was recently identified in 5 siblings in 2 families associated with familial isolated pyloric atresia. Herein, we present two siblings who had pyloric atresia together with a homozygous variant in the <em>ITGB4</em> gene and without epidermolysis bullosa. The development of isolated familial pyloric atresia without epidermolysis bullosa may occur due to homozygous variants of the <em>ITGB4</em> gene. Detection of more variants in this gene may help to establish a genotype-phenotype correlation and may suggest the <em>ITGB4</em> gene in patients who have pyloric atresia without epidermolysis bullosa.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"72 ","pages":"Article 104971"},"PeriodicalIF":1.6,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142344066","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":"Exploring Kleefstra syndrome cohort phenotype characteristics: Prevalence insights from caregiver-reported outcomes","authors":"Tanja Zdolšek Draksler ,&nbsp;Arianne Bouman ,&nbsp;Alenka Guček ,&nbsp;Erik Novak ,&nbsp;Pauline Burger ,&nbsp;Florent Colin ,&nbsp;Tjitske Kleefstra","doi":"10.1016/j.ejmg.2024.104974","DOIUrl":"10.1016/j.ejmg.2024.104974","url":null,"abstract":"<div><p>Kleefstra syndrome (KLEFS1) is a rare genetic neurodevelopmental disorder affecting multiple body systems. It continues to be under-researched, and its prevalence remains unknown. This paper builds on the international KLEFS1 cohort of 172 individuals based on the caregiver-reported outcomes collected within the online data collection platform GenIDA and reports the occurrence, frequency and severity of symptoms in KLEFS1. The study clearly shows the importance of caregiver-reported outcomes collections in the rare disease domain. Moreover, the study emphasizes the need for more specific and enhanced data collection methods, suggesting recommendations to optimize caregiver-reported registries and foster an even more profound understanding of rare diseases.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"72 ","pages":"Article 104974"},"PeriodicalIF":1.6,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000661/pdfft?md5=e94c78b3aeabf529c0f697b4bc6baa91&pid=1-s2.0-S1769721224000661-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142239254","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 families with spondylo-epi-metaphyseal dysplasia due to compound heterozygocity in the vWFA domain of MATN3","authors":"Tae-Joon Cho ,&nbsp;Hyeran Lee ,&nbsp;Jung Min Ko ,&nbsp;Mihyun Song ,&nbsp;Chang-Ho Shin ,&nbsp;Hae Ryong Song ,&nbsp;Ok-Hwa Kim","doi":"10.1016/j.ejmg.2024.104972","DOIUrl":"10.1016/j.ejmg.2024.104972","url":null,"abstract":"<div><p>Heterozygous variants of <em>MATN3</em> is one of the common causes of multiple epiphyseal dysplasia (MED). Here we report three individuals from two unrelated families who harbor compound heterozygous variants in <em>MATN3</em> (p.Arg121Trp and p.Val220Ala). Contrary to the MED phenotype, these individuals exhibit spondyloepimetaphyseal dysplasia (SEMD) resembling the phenotypes caused by homozygous <em>MATN3</em> variants. Clinical manifestations included short stature, aggravating genu varum, joint laxity, and spinal abnormalities. Radiographic findings were distinct from typical MED. These compound heterozygous variants in the von Willebrand factor A domain of <em>MATN3</em> expand the phenotypic spectrum associated with <em>MATN3</em>, and suggest that extreme MATN3 dysfunction resulting from dual variants can lead to a specific pattern of SEMD.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"72 ","pages":"Article 104972"},"PeriodicalIF":1.6,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000648/pdfft?md5=a3e0a2d5fd5456fb9607145433c071bc&pid=1-s2.0-S1769721224000648-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142239622","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":"Novel CTR9 germline pathogenic splice site variant in siblings with Wilms tumor from Tanzania","authors":"Ali Iman ,&nbsp;Esther Majaliwa ,&nbsp;Lossim G. Kambainei ,&nbsp;Alex Mremi ,&nbsp;Arjen R. Mensenkamp ,&nbsp;Ben C. Hamel","doi":"10.1016/j.ejmg.2024.104973","DOIUrl":"10.1016/j.ejmg.2024.104973","url":null,"abstract":"<div><div>Wilms tumor is the most common childhood renal malignancy. Though mostly non-genetic, it can be syndromic with the involvement of many Wilms tumor predisposing genes and non-syndromic with the involvement of four genes: <em>WT1</em>, <em>REST, TRIM28,</em> and <em>CTR9</em>. Familial and bilateral Wilms tumors do occur, but these are rare. So far, four Wilms tumor families with pathogenic variants in the <em>CTR9</em> gene have been described, all (presumably) inherited from unaffected fathers, and three leading to deletion of exon 9. We are reporting female siblings, of whom one has a bilateral Wilms tumor, with a novel pathogenic splice site variant in the <em>CTR9</em> gene, leading to deletion of exon 9, and inherited from their asymptomatic father. The loss of heterozygosity in the tumor was confirmed. In conclusion, <em>CTR9</em> pathogenic variants are a very rare cause of Wilms tumors and typically result in familial Wilms tumors.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"72 ","pages":"Article 104973"},"PeriodicalIF":1.6,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S176972122400065X/pdfft?md5=70b5699e9b0e63dd77631839ef4ead00&pid=1-s2.0-S176972122400065X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282353","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":"Economic evaluation of extended panel analysis in cancer patients with historical NHS diagnostic germline genetic testing – A modeling study based on real-world data","authors":"Qin Xi ,&nbsp;Rahul Patel ,&nbsp;Thomas Linton-Willoughby ,&nbsp;John Short ,&nbsp;Marc Tischkowitz ,&nbsp;Katie Snape ,&nbsp;Stephen Morris","doi":"10.1016/j.ejmg.2024.104969","DOIUrl":"10.1016/j.ejmg.2024.104969","url":null,"abstract":"<div><h3>Background</h3><p>The South West Thames Centre for Genomics implemented a wider diagnostic Next Generation Sequencing (NGS) gene panel for eligible cancer patients undergoing diagnostic testing whilst restricting data analysis and reporting for BRCA1/BRCA2/PALB2/CHEK2 1100delC only as per contemporaneous guidelines. This study investigated the cost-utility of reanalyzing existing diagnostic grade extended panel data for truncating germline pathogenic variants (GPVs) in known moderate risk cancer susceptibility genes (CSGs) and performing follow-up genetic testing for first-degree relatives if patients have an identified CSG allele.</p></div><div><h3>Methods</h3><p>Reanalysis of existing NGS data was undertaken in 889 samples from cancer patients contemporaneously eligible through the NHS England National Genomic Test Directory (NGTD) codes R207 (ovarian) or R208 (breast) who had tested negative for <em>BRCA1/BRCA2/PALB2</em> and <em>CHEK2</em> 1100delC founder variant. We modeled the cost and health outcomes for comparisons between: 1. Extending reanalysis to <em>ATM</em> truncating GPVs (partial extended testing) versus historical genetic testing, and 2. Extending analysis to <em>ATM</em> truncating GPV/<em>BRIP1</em> truncating <em>GPV</em>/<em>CHEK2</em> truncating GPV excluding <em>CHEK2</em> 1100delC/<em>RAD51C</em> truncating GPV/<em>RAD51D</em> truncating GPV (full extended testing) versus historical genetic testing.</p></div><div><h3>Results</h3><p>For partial extended testing, the ICER compared with historical genetic testing was UK£49,671/QALY. For full extended testing, the ICER compared with historical genetic testing of historical genetic testing was UK£5716/QALY. The full extended testing remained cost-effective with a 30% increase in genetic testing cost.</p></div><div><h3>Conclusion</h3><p>Where existing NGS data for cancer susceptibility genes is stored to diagnostic standard in UK laboratories, this study suggests it is cost-effective to analyze, report and clinically manage patients and relatives by extended analysis to an 8-gene panel compared to the historical genetic testing.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"72 ","pages":"Article 104969"},"PeriodicalIF":1.6,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000612/pdfft?md5=50cb4a23057fdd510638f4a901c6c944&pid=1-s2.0-S1769721224000612-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142167594","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":"Mutation spectrum of Tyrosinemia type I in Iran, A retrospective cohort study","authors":"Zahra Beyzaei ,&nbsp;Zahra Goudarzi ,&nbsp;Seyed Mohsen Dehghani ,&nbsp;Hossein Moravej ,&nbsp;Mohammad Hadi Imanieh ,&nbsp;Maryam Ataollahi ,&nbsp;Mozhdeh Heidari ,&nbsp;Bita Geramizadeh","doi":"10.1016/j.ejmg.2024.104970","DOIUrl":"10.1016/j.ejmg.2024.104970","url":null,"abstract":"<div><p>Hereditary Tyrosinemia Type 1 (HT1) is a genetic disorder characterized by an autosomal recessive inheritance pattern, caused by mutations in the fumarylacetoacetate hydrolase (<em>FAH</em>) gene, which results in a deficiency of fumarylacetoacetase. In our study, we identified a total of 15 mutations, including 12 newly discovered and 3 previously reported pathogenic mutations, in a cohort of 19 Iranian patients with the acute form of HT1. Out of the 12 novel variants identified, 11 were missense variants: p.Asp126His, p.Gln75Glu, p.Leu385Pro, p.Ser92Thr, p.Leu96Arg, p.Val167Glu, p.Ala94Asp, p.Gly353Trp, p.Ser164Pro, p.Glu86His and p.Ala163Pro. Additionally, there was one nonsense variant, p.Try244X, that had not been previously reported. Interestingly, the Arg237X variant was found to be particularly prevalent in this study. Notably, three exons, namely exons 9, 3, and 6, exhibited a higher frequency of mutations. All of the identified variants are presumed to result in loss of function, impacting the clinical signs, disease progression, increasing tyrosine level, and the specific location of the mutation. Our study has provided valuable insights into the mutation spectrum of variants associated with HT1 disease which is reported for the first time from Iran. This information can facilitate the development of targeted mutation screening protocols, focusing on the most prevalent mutations within specific regions or ethnic groups.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"71 ","pages":"Article 104970"},"PeriodicalIF":1.6,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000624/pdfft?md5=2ff717015c567d947ff336c82e8aaf24&pid=1-s2.0-S1769721224000624-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142167268","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":"Biallelic potential disease-causing missense variants in TAF1A in two siblings with infantile restrictive cardiomyopathy","authors":"Nan Jiang ,&nbsp;Wenyuan Xu ,&nbsp;Aliaa Abdelhakim ,&nbsp;Anastasiya Matveyenko ,&nbsp;Matthias Szabolcs ,&nbsp;William C. Copeland ,&nbsp;Michele Disco ,&nbsp;Alejandro Iglesias ,&nbsp;Teresa M. Lee ,&nbsp;Ali Naini ,&nbsp;Mythily Ganapathi","doi":"10.1016/j.ejmg.2024.104968","DOIUrl":"10.1016/j.ejmg.2024.104968","url":null,"abstract":"<div><p><em>TAF1A</em>, a gene encoding a TATA-box binding protein involved in ribosomal RNA synthesis, is a candidate gene for pediatric cardiomyopathy as biallelic <em>TAF1A</em> variants were reported in two families with affected individuals. Here, we report a third family with two siblings who presented with infantile restrictive cardiomyopathy and carried biallelic missense variants in <em>TAF1A</em> (NM_001201536.1:c.1021G&gt;A p.(Gly341Arg) and c.781A&gt;C p.(Thr261Pro)). Additional shared clinical features in the siblings included feeding intolerance, congenital leukoencephalopathy, ventriculomegaly and concern for primary immunodeficiency. The first-born sibling passed away at 6 months of age due to complications of hemophagocytic lymphohistiocytosis (HLH) whereas the second sibling underwent cardiac transplantation at 1 year of age and is currently well. We compare the clinical and molecular features of all the <em>TAF1A</em> associated cardiomyopathy cases. Our study adds evidence for the gene-disease association of <em>TAF1A</em> with autosomal recessive pediatric cardiomyopathy.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"71 ","pages":"Article 104968"},"PeriodicalIF":1.6,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000600/pdfft?md5=1959d5f52aa2dc3b3ac19996e8660d8d&pid=1-s2.0-S1769721224000600-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105651","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":"Digital clubbing without hypoxia for lysinuric protein intolerance","authors":"Daisuke Watanabe ,&nbsp;Yuko Tsujioka ,&nbsp;Daisuke Nakato ,&nbsp;Mamiko Yamada ,&nbsp;Hisato Suzuki ,&nbsp;Takuma Ohnishi ,&nbsp;Naotaka Tamai ,&nbsp;Toshihide Kijima ,&nbsp;Toshiki Takenouchi ,&nbsp;Fuyuki Miya ,&nbsp;Satoshi Narumi ,&nbsp;Kenjiro Kosaki","doi":"10.1016/j.ejmg.2024.104967","DOIUrl":"10.1016/j.ejmg.2024.104967","url":null,"abstract":"<div><p>Digital clubbing is characterized by bulbous enlargement of the terminal segments of the fingers. Hypotheses including hypoxia have been proposed for the pathogenesis of digital clubbing, but the exact pathogenesis of digital clubbing is still uncertain. Lysinuric protein intolerance (LPI) is caused by pathogenic variants in <em>SLC7A7</em> and is often associated with interstitial lung disease. Previously two patients of LPI with digital clubbing but without hypoxia have been reported. It is unclear whether digital clubbing in LPI is secondary to hypoxia or directly related to SLC7A7 deficiency. Here we report a 6-year-old Japanese boy presented with digital clubbing without hypoxia. He had episodic vomiting, each episode consisting of a single vomiting event occurring once a month, and his growth had been delayed. He had interstitial lung disease and hepatomegaly. He had compound heterozygous pathogenic variants in the <em>SLC7A7</em>, leading to the diagnosis of LPI. Together with the two previously reported patients mentioned above, we conclude that digital clubbing can occur in the absence of hypoxia. Digital clubbing in the absence of hypoxia has been observed in two genetic disorders related to prostaglandin (PG) E2, <em>HPGD</em> and <em>SLCO2A1</em>. PGE2 synthesis is primarily regulated by the cyclooxygenase 2, which plays a critical role in the control of inflammation. A high urine PGE level in the patient was compatible with the notion that PGE2 production may be increased in LPI. The occurrence of digital clubbing in the absence of hypoxia in LPI patients with <em>SLC7A7</em> may be attributed to the mechanism of increased PGE2 production.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"71 ","pages":"Article 104967"},"PeriodicalIF":1.6,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000594/pdfft?md5=4840da5efaafd99cd62004e70f0a1188&pid=1-s2.0-S1769721224000594-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141990764","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}