M. Saleh, S. Colaiacovo, M. Napier, A. Prasad, C. Rupar, C. Prasad
We describe the diagnostic odyssey of an eight-year-old female born to consanguineous parents. Our patient presented with global developmental delay, regression, microcephaly, spastic diplegia, and leukodystrophy confirmed on brain magnetic resonance imaging (MRI). She was found on whole exome sequencing (WES) to have dual genetic diagnoses. The first was a homozygous pathogenic HERC2 gene partial deletion of exons 43–45 that causes HERC2-related disorder. The second was a homozygous pathogenic variant (c.836 C > T, p.A279 V) in the SUMF1 gene responsible for multiple sulfatase deficiency. This case highlights some of the challenges in diagnosing consanguineous pediatric populations where standard genetic and metabolic testing may not provide answers. Our case further supports the recent American College of Medical Genetics and Genomics (ACMG) recommendation of WES as a first or second-tier test for patients with developmental delay, particularly in a population where the chances of dual diagnosis is high.
我们描述的诊断奥德赛一个八岁的女孩出生的近亲父母。我们的患者表现出全面发育迟缓，退化，小头畸形，痉挛性双瘫和脑白质营养不良，经脑磁共振成像(MRI)证实。全外显子组测序(WES)发现双基因诊断。第一个是纯合子致病性HERC2基因43-45外显子部分缺失，导致HERC2相关疾病。第二种是导致多重硫酸酯酶缺乏的SUMF1基因的纯合致病变异(C .836 C > T, p.A279 V)。这个病例突出了诊断近亲儿科人群的一些挑战，标准的基因和代谢测试可能无法提供答案。我们的病例进一步支持了最近美国医学遗传学和基因组学学院(ACMG)的建议，将WES作为发育迟缓患者的第一或第二级检测，特别是在双重诊断机会很高的人群中。
{"title":"Pitfalls in Genetic Testing for Consanguineous Pediatric Populations","authors":"M. Saleh, S. Colaiacovo, M. Napier, A. Prasad, C. Rupar, C. Prasad","doi":"10.1155/2022/9393042","DOIUrl":"https://doi.org/10.1155/2022/9393042","url":null,"abstract":"We describe the diagnostic odyssey of an eight-year-old female born to consanguineous parents. Our patient presented with global developmental delay, regression, microcephaly, spastic diplegia, and leukodystrophy confirmed on brain magnetic resonance imaging (MRI). She was found on whole exome sequencing (WES) to have dual genetic diagnoses. The first was a homozygous pathogenic HERC2 gene partial deletion of exons 43–45 that causes HERC2-related disorder. The second was a homozygous pathogenic variant (c.836 C > T, p.A279 V) in the SUMF1 gene responsible for multiple sulfatase deficiency. This case highlights some of the challenges in diagnosing consanguineous pediatric populations where standard genetic and metabolic testing may not provide answers. Our case further supports the recent American College of Medical Genetics and Genomics (ACMG) recommendation of WES as a first or second-tier test for patients with developmental delay, particularly in a population where the chances of dual diagnosis is high.","PeriodicalId":30325,"journal":{"name":"Case Reports in Genetics","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75566678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rubinstein–Taybi syndrome (RSTS) is a rare genetic disorder characterized by dysmorphic facial features, broad thumbs and halluces, intellectual disability, and postnatal growth retardation. This report presents a male infant with microcephaly and characteristic facial features, namely, low anterior hairline, hirsutism, thin upper lip and micrognathia, broad thumbs and first toes, cryptorchidism, recurrent pneumonia, developmental delay, and growth retardation. Genetic testing showed a novel pathogenic variant in the CREBBP gene which is consistent with the clinical diagnosis of RSTS.
{"title":"Rubinstein–Taybi Syndrome in a Filipino Infant with a Novel CREBBP Gene Pathogenic Variant","authors":"Rhea Camille R. Yumul, M. A. Chiong","doi":"10.1155/2022/3388879","DOIUrl":"https://doi.org/10.1155/2022/3388879","url":null,"abstract":"Rubinstein–Taybi syndrome (RSTS) is a rare genetic disorder characterized by dysmorphic facial features, broad thumbs and halluces, intellectual disability, and postnatal growth retardation. This report presents a male infant with microcephaly and characteristic facial features, namely, low anterior hairline, hirsutism, thin upper lip and micrognathia, broad thumbs and first toes, cryptorchidism, recurrent pneumonia, developmental delay, and growth retardation. Genetic testing showed a novel pathogenic variant in the CREBBP gene which is consistent with the clinical diagnosis of RSTS.","PeriodicalId":30325,"journal":{"name":"Case Reports in Genetics","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90165322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shir Wey Gloria Pang, Hencher Han Chih Lee, Carol Ng Wing kei, E. Yau, J. Hui
A curious triad of retinitis pigmentosa, external ophthalmoplegia, and complete heart block was presented by Sayre et al. in 1958. Since then, the disorder named Kearns–Sayre syndrome (KSS) has come to represent patients with mitochondrial DNA deletions presenting before adulthood, primarily with chronic progressive external ophthalmoplegia (CPEO) and pigmentary retinopathy. However, it is increasingly noted that the presentations can well be variable despite similar genetic deletions. Here, we present two cases with identical large-scale mitochondrial DNA deletions but very dissimilar outlook.
{"title":"Kearns–Sayre Syndrome Minus: Two Cases of Identical Large-Scale Mitochondrial DNA Deletions with Presentations outside the Classical Triad","authors":"Shir Wey Gloria Pang, Hencher Han Chih Lee, Carol Ng Wing kei, E. Yau, J. Hui","doi":"10.1155/2022/4153357","DOIUrl":"https://doi.org/10.1155/2022/4153357","url":null,"abstract":"A curious triad of retinitis pigmentosa, external ophthalmoplegia, and complete heart block was presented by Sayre et al. in 1958. Since then, the disorder named Kearns–Sayre syndrome (KSS) has come to represent patients with mitochondrial DNA deletions presenting before adulthood, primarily with chronic progressive external ophthalmoplegia (CPEO) and pigmentary retinopathy. However, it is increasingly noted that the presentations can well be variable despite similar genetic deletions. Here, we present two cases with identical large-scale mitochondrial DNA deletions but very dissimilar outlook.","PeriodicalId":30325,"journal":{"name":"Case Reports in Genetics","volume":"36 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79780800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chromosome and array comparative genomic hybridization (aCGH) analyses were performed on two cases of well-differentiated liposarcoma (WDLPS) and two cases of dedifferentiated liposarcoma (DDLPS). The results revealed the characteristic giant ring (GR) or giant rod marker (GRM) chromosomes in all four cases and amplification of numerous somatic copy number alterations (SCNAs) involving a core segment of 12q14.1q15 and other chromosomal regions in three cases. The levels of amplification for oncogenes OS9, CDK4, HMGA2, NUP107, MDM2, YEATS4, and FRS2 at the core segment or other SCNAs should be characterized to facilitate pathologic correlation and prognostic prediction. Further studies for the initial cellular crisis event affecting chromosome intermingling regions for cell-type specific gene regulation may reveal the underlying mutagenesis mechanism for GR and GRM in WDLPS and DDLPS.
{"title":"Cytogenomic Characterization of Giant Ring or Rod Marker Chromosome in Four Cases of Well-Differentiated and Dedifferentiated Liposarcoma","authors":"Hongyan Chai, Fang Xu, Autumn Diadamo, Brittany Grommisch, Huanzhi Mao, Peining Li","doi":"10.1155/2022/6341207","DOIUrl":"https://doi.org/10.1155/2022/6341207","url":null,"abstract":"Chromosome and array comparative genomic hybridization (aCGH) analyses were performed on two cases of well-differentiated liposarcoma (WDLPS) and two cases of dedifferentiated liposarcoma (DDLPS). The results revealed the characteristic giant ring (GR) or giant rod marker (GRM) chromosomes in all four cases and amplification of numerous somatic copy number alterations (SCNAs) involving a core segment of 12q14.1q15 and other chromosomal regions in three cases. The levels of amplification for oncogenes OS9, CDK4, HMGA2, NUP107, MDM2, YEATS4, and FRS2 at the core segment or other SCNAs should be characterized to facilitate pathologic correlation and prognostic prediction. Further studies for the initial cellular crisis event affecting chromosome intermingling regions for cell-type specific gene regulation may reveal the underlying mutagenesis mechanism for GR and GRM in WDLPS and DDLPS.","PeriodicalId":30325,"journal":{"name":"Case Reports in Genetics","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81326135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yanjie Qian, Xiaoying Wang, Wei Tang, Chaochun Zou
Copy number variations (CNV) are thought to play an important role in causing human diseases, including congenital anomalies, psychiatric disorders, and intellectual disabilities. We report here a one-year-old boy presented to our clinic as developmental delay. He presented a birth weight of 4.5 kg, motor delay, mental retardation, mild hypertonia, and some dysmorphic features (mild frontal bossing, hypertelorism, epicanthus, concave nasal ridge, slightly sparse hair, short hands, and mild nail dysplasia). The brain MRI indicated brain abnormalities; the Gross Motor Function Measure-66 score was 23.37; the Gesell test result showed the development quotient was 50, suggesting mental retardation. Chromosomal microarray analysis showed an approximately 97 kb microdeletion at 4p16.2 (4p16.2 CNV), including part of EVC and EVC2 genes, which were associated with Ellis-van Creveld syndrome (EvC) and Weyers acrofacial dysostosis (WAD). This report suggests 4p16.2 microdeletion may be associated with multiple developmental abnormalities, including motor delay and mental retardation.
{"title":"Microdeletion of 4p16.2 in Children: A Case Report and Literature Review","authors":"Yanjie Qian, Xiaoying Wang, Wei Tang, Chaochun Zou","doi":"10.1155/2022/6253690","DOIUrl":"https://doi.org/10.1155/2022/6253690","url":null,"abstract":"Copy number variations (CNV) are thought to play an important role in causing human diseases, including congenital anomalies, psychiatric disorders, and intellectual disabilities. We report here a one-year-old boy presented to our clinic as developmental delay. He presented a birth weight of 4.5 kg, motor delay, mental retardation, mild hypertonia, and some dysmorphic features (mild frontal bossing, hypertelorism, epicanthus, concave nasal ridge, slightly sparse hair, short hands, and mild nail dysplasia). The brain MRI indicated brain abnormalities; the Gross Motor Function Measure-66 score was 23.37; the Gesell test result showed the development quotient was 50, suggesting mental retardation. Chromosomal microarray analysis showed an approximately 97 kb microdeletion at 4p16.2 (4p16.2 CNV), including part of EVC and EVC2 genes, which were associated with Ellis-van Creveld syndrome (EvC) and Weyers acrofacial dysostosis (WAD). This report suggests 4p16.2 microdeletion may be associated with multiple developmental abnormalities, including motor delay and mental retardation.","PeriodicalId":30325,"journal":{"name":"Case Reports in Genetics","volume":"202 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77469257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Purpose To report a novel 11-cis retinol dehydrogenase gene (RDH5) variant discovered in a 57-year-old male with fundus albipunctatus (FA) complicated by severe macular atrophy. Methods The patient was evaluated with a complete ophthalmic examination, optical coherence tomography (OCT), color fundus photography, green wavelength fundus autofluorescence, visual field testing, full-field ERG (ffERG), and multifocal ERG (mfERG). Genetic analysis investigating gene variants involved in inherited retinal disorders was performed. Results The patient presented with a rapid decline in visual acuity and a history of poor night vision. On fundoscopy, he exhibited a phenotype characteristic of FA accompanied by severe macular atrophy bilaterally. Heterozygous variants in the RDH5 gene were identified, including a novel missense variant, c.814_815del (p.Leu272Aspfs∗63), and a known pathogenic nonsense variant, c.160C > T (p.Arg54∗). Fundus autofluorescence demonstrated bull's eye maculopathy and hyperautofluorescent perifoveal rings bilaterally. OCT showed foveal atrophy of the outer retina and scattered hyper-reflective lesions in the peripheral macula. The ffERG results showed a severely diminished scotopic and photopic response. The mfERG results demonstrated minimal response in the central macula. Conclusions Fundus albipunctatus is a rare, congenital form of stationary night blindness caused almost exclusively by the RDH5 gene. This patient's clinical presentation, diagnostic studies, and genetic testing confirmed the diagnosis of FA. Additionally, he exhibited severe macular atrophy, not typically found in FA. Two RDH5 gene variants were identified, one of which is the novel variant, c.814_815del (p.Leu272Aspfs∗63). We suggest that this RDH5 genotype may be associated with a more progressive phenotype of FA contributing to macular atrophy.
{"title":"A Novel Pathogenic Variant in the RDH5 Gene in a Patient with Fundus Albipunctatus and Severe Macular Atrophy","authors":"H. You, David I Sierpina","doi":"10.1155/2022/1183772","DOIUrl":"https://doi.org/10.1155/2022/1183772","url":null,"abstract":"Purpose To report a novel 11-cis retinol dehydrogenase gene (RDH5) variant discovered in a 57-year-old male with fundus albipunctatus (FA) complicated by severe macular atrophy. Methods The patient was evaluated with a complete ophthalmic examination, optical coherence tomography (OCT), color fundus photography, green wavelength fundus autofluorescence, visual field testing, full-field ERG (ffERG), and multifocal ERG (mfERG). Genetic analysis investigating gene variants involved in inherited retinal disorders was performed. Results The patient presented with a rapid decline in visual acuity and a history of poor night vision. On fundoscopy, he exhibited a phenotype characteristic of FA accompanied by severe macular atrophy bilaterally. Heterozygous variants in the RDH5 gene were identified, including a novel missense variant, c.814_815del (p.Leu272Aspfs∗63), and a known pathogenic nonsense variant, c.160C > T (p.Arg54∗). Fundus autofluorescence demonstrated bull's eye maculopathy and hyperautofluorescent perifoveal rings bilaterally. OCT showed foveal atrophy of the outer retina and scattered hyper-reflective lesions in the peripheral macula. The ffERG results showed a severely diminished scotopic and photopic response. The mfERG results demonstrated minimal response in the central macula. Conclusions Fundus albipunctatus is a rare, congenital form of stationary night blindness caused almost exclusively by the RDH5 gene. This patient's clinical presentation, diagnostic studies, and genetic testing confirmed the diagnosis of FA. Additionally, he exhibited severe macular atrophy, not typically found in FA. Two RDH5 gene variants were identified, one of which is the novel variant, c.814_815del (p.Leu272Aspfs∗63). We suggest that this RDH5 genotype may be associated with a more progressive phenotype of FA contributing to macular atrophy.","PeriodicalId":30325,"journal":{"name":"Case Reports in Genetics","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85610988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jonas A. Gustafson, Maria Bjork, C. V. van Ravenswaaij-Arts, M. Cunningham
Craniosynostosis, the premature fusion of the calvarial bones, has numerous etiologies. Among them, several involve mutations in genes related to the TGFb signaling pathway, a critical molecular mediator of human development. These TGFb pathway-associated craniosynostosis syndromes include Loeys–Dietz syndrome (LDS) and Shprintzen–Goldberg syndrome (SGS). LDS and SGS have many similarities common to fibrillinopathies, specifically Marfan syndrome (MFS), which is caused by mutations in FBN1. Historically discriminating features of MFS from LDS and SGS are (1) the presence of ectopia lentis (the subluxation/dislocation of the ocular lens) and (2) the absence of craniosynostosis. Curiously, several instances of a seemingly novel syndrome involving only craniosynostosis and ectopia lentis have recently been reported to be caused by recessive mutations in ADAMTSL4, a poorly characterized gene as of yet. Here, we report on two new cases of craniosynostosis with ectopia lentis, each harboring recessive mutations in ADAMTSL4. We also discuss a proposed mechanism for the relationship between ADAMTSL4, FBN1, and TGFb pathway-related syndromes.
{"title":"Mechanism of Disease: Recessive ADAMTSL4 Mutations and Craniosynostosis with Ectopia Lentis","authors":"Jonas A. Gustafson, Maria Bjork, C. V. van Ravenswaaij-Arts, M. Cunningham","doi":"10.1155/2022/3239260","DOIUrl":"https://doi.org/10.1155/2022/3239260","url":null,"abstract":"Craniosynostosis, the premature fusion of the calvarial bones, has numerous etiologies. Among them, several involve mutations in genes related to the TGFb signaling pathway, a critical molecular mediator of human development. These TGFb pathway-associated craniosynostosis syndromes include Loeys–Dietz syndrome (LDS) and Shprintzen–Goldberg syndrome (SGS). LDS and SGS have many similarities common to fibrillinopathies, specifically Marfan syndrome (MFS), which is caused by mutations in FBN1. Historically discriminating features of MFS from LDS and SGS are (1) the presence of ectopia lentis (the subluxation/dislocation of the ocular lens) and (2) the absence of craniosynostosis. Curiously, several instances of a seemingly novel syndrome involving only craniosynostosis and ectopia lentis have recently been reported to be caused by recessive mutations in ADAMTSL4, a poorly characterized gene as of yet. Here, we report on two new cases of craniosynostosis with ectopia lentis, each harboring recessive mutations in ADAMTSL4. We also discuss a proposed mechanism for the relationship between ADAMTSL4, FBN1, and TGFb pathway-related syndromes.","PeriodicalId":30325,"journal":{"name":"Case Reports in Genetics","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79319102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
F. Tahghighi, Mahdieh Vahedi, N. Parvaneh, Mohammad Shahrooei, V. Ziaee
Background Cryopyrin-associated periodic syndromes (CAPSs) are a group of autoinflammatory disorders caused by a mutation in the NLRP3 gene. NLRP3 mutations increase inflammasome activation; therefore, IL-1 targeted therapies are frequently used in the aforementioned disorders. Case Presentation. We report two cases of CAPS in which the diagnosis was confirmed by genetic tests and an evaluation of the therapeutic response to anti-tumor necrosis factor (anti-TNF) agents. Conclusion IL-1 inhibitors are highly effective in treating CAPS patients. Most patients with severe symptoms such as neurologic involvement improve with IL-1 blockade. Anti-TNF agents might be effective in reducing mild manifestation; however, they are not effective in improving more severe complications.
{"title":"The Efficacy of Anti-Tumor Necrosis Factor Therapy in Cryopyrin-Associated Periodic Syndromes: A Report of Two Cases","authors":"F. Tahghighi, Mahdieh Vahedi, N. Parvaneh, Mohammad Shahrooei, V. Ziaee","doi":"10.1155/2022/2898553","DOIUrl":"https://doi.org/10.1155/2022/2898553","url":null,"abstract":"Background Cryopyrin-associated periodic syndromes (CAPSs) are a group of autoinflammatory disorders caused by a mutation in the NLRP3 gene. NLRP3 mutations increase inflammasome activation; therefore, IL-1 targeted therapies are frequently used in the aforementioned disorders. Case Presentation. We report two cases of CAPS in which the diagnosis was confirmed by genetic tests and an evaluation of the therapeutic response to anti-tumor necrosis factor (anti-TNF) agents. Conclusion IL-1 inhibitors are highly effective in treating CAPS patients. Most patients with severe symptoms such as neurologic involvement improve with IL-1 blockade. Anti-TNF agents might be effective in reducing mild manifestation; however, they are not effective in improving more severe complications.","PeriodicalId":30325,"journal":{"name":"Case Reports in Genetics","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84097209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Krishna Gundabolu, B. Dave, C. Alvares, J. J. Cannatella, V. Bhatt, L. Maness, Z. Al-Kadhimi, R. Zabad, A. Cushman-Vokoun
Chronic myelomonocytic leukemia (CMML) is a rare but distinct hematological neoplasm with overlapping features of myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). Individuals with CMML have persistent monocytosis and bone marrow dyspoiesis associated with various constitutional symptoms like fevers, unintentional weight loss, or night sweats. It is established that there is a strong association of CMML with preceding or coexisting autoimmune diseases and systemic inflammatory syndromes affecting around 20% of patients. Various molecular abnormalities like TET2, SRSF2, ASXL1, and RAS are reported in the pathogenesis of CMML, but no such mutations have been described to explain the strong association of autoimmune diseases and severe inflammatory phenotype seen in CMML. Germline mutation in SH2B adaptor protein 3 (SH2B3) had been reported before to affect a family with autoimmune disorders and acute lymphoblastic leukemia. In this report, we describe the first case of a female subject with many years of preceding history of multiple sclerosis before the diagnosis of CMML. We outline the evidence supporting the pathogenic role of SH2B3 p.E395K germline mutation, connecting the dots of association between autoimmune diseases and CMML genesis.
{"title":"The Missing LNK: Evolution from Cytosis to Chronic Myelomonocytic Leukemia in a Patient with Multiple Sclerosis and Germline SH2B3 Mutation","authors":"Krishna Gundabolu, B. Dave, C. Alvares, J. J. Cannatella, V. Bhatt, L. Maness, Z. Al-Kadhimi, R. Zabad, A. Cushman-Vokoun","doi":"10.1155/2022/6977041","DOIUrl":"https://doi.org/10.1155/2022/6977041","url":null,"abstract":"Chronic myelomonocytic leukemia (CMML) is a rare but distinct hematological neoplasm with overlapping features of myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). Individuals with CMML have persistent monocytosis and bone marrow dyspoiesis associated with various constitutional symptoms like fevers, unintentional weight loss, or night sweats. It is established that there is a strong association of CMML with preceding or coexisting autoimmune diseases and systemic inflammatory syndromes affecting around 20% of patients. Various molecular abnormalities like TET2, SRSF2, ASXL1, and RAS are reported in the pathogenesis of CMML, but no such mutations have been described to explain the strong association of autoimmune diseases and severe inflammatory phenotype seen in CMML. Germline mutation in SH2B adaptor protein 3 (SH2B3) had been reported before to affect a family with autoimmune disorders and acute lymphoblastic leukemia. In this report, we describe the first case of a female subject with many years of preceding history of multiple sclerosis before the diagnosis of CMML. We outline the evidence supporting the pathogenic role of SH2B3 p.E395K germline mutation, connecting the dots of association between autoimmune diseases and CMML genesis.","PeriodicalId":30325,"journal":{"name":"Case Reports in Genetics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82471148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-02-10eCollection Date: 2022-01-01DOI: 10.1155/2022/2555235
Amal Al-Naimi, Haneen Toma, Sara G Hamad, Tawfeg Ben Omran
Farber disease (FD) is an extremely rare autosomal recessive disorder caused by the deficiency of lysosomal acid ceramidase. It is characterized by a triad of progressive multiple joints' involvement, subcutaneous nodules, and hoarseness of voice. In this report, we describe a 23-month-old boy diagnosed with Farber disease. Initially, he was misdiagnosed as juvenile idiopathic arthritis (JIA) because he presented with joint swelling. However, the associated hoarseness of voice, subcutaneous nodules, and poor response to treatment all have questioned the diagnosis of JIA and prompted the suspicion of Farber disease as an alternative diagnosis. The diagnosis was later confirmed genetically by the presence of a homozygous pathogenic variant (p.Gly213Glu; c.638G > A in exon 8) in the ASAH1 gene. The present case illustrates the diagnostic journey of a child with Farber disease as well as highlights that FD should be considered in the differential diagnosis of early onset arthritis in the presence of subcutaneous nodules and/or hoarseness of voice.
{"title":"Farber Disease Mimicking Juvenile Idiopathic Arthritis: The First Reported Case in Qatar and Review of the Literature.","authors":"Amal Al-Naimi, Haneen Toma, Sara G Hamad, Tawfeg Ben Omran","doi":"10.1155/2022/2555235","DOIUrl":"https://doi.org/10.1155/2022/2555235","url":null,"abstract":"<p><p>Farber disease (FD) is an extremely rare autosomal recessive disorder caused by the deficiency of lysosomal acid ceramidase. It is characterized by a triad of progressive multiple joints' involvement, subcutaneous nodules, and hoarseness of voice. In this report, we describe a 23-month-old boy diagnosed with Farber disease. Initially, he was misdiagnosed as juvenile idiopathic arthritis (JIA) because he presented with joint swelling. However, the associated hoarseness of voice, subcutaneous nodules, and poor response to treatment all have questioned the diagnosis of JIA and prompted the suspicion of Farber disease as an alternative diagnosis. The diagnosis was later confirmed genetically by the presence of a homozygous pathogenic variant (p.Gly213Glu; c.638G > A in exon 8) in the ASAH1 gene. The present case illustrates the diagnostic journey of a child with Farber disease as well as highlights that FD should be considered in the differential diagnosis of early onset arthritis in the presence of subcutaneous nodules and/or hoarseness of voice.</p>","PeriodicalId":30325,"journal":{"name":"Case Reports in Genetics","volume":" ","pages":"2555235"},"PeriodicalIF":0.0,"publicationDate":"2022-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8853810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39940403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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