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.

Hongyan Chai

Fang Xu

Autumn DiAdamo

Brittany Grommisch

Huanzhi Mao

Peining Li

Cytogenomic Characterization of Giant Ring or Rod Marker Chromosome in Four Cases of Well-Differentiated and Dedifferentiated Liposarcoma

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&#x2009;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&#x2009;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.

Yanjie Qian

Xiaoying Wang

Wei Tang

Chaochun Zou

Microdeletion of 4p16.2 in Children: A Case Report and Literature Review

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<svg xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg" style="vertical-align:-0.04990005pt" id="M1" height="10.1524pt" version="1.1" viewBox="-0.0498162 -10.1025 6.17869 10.1524" width="6.17869pt"><g transform="matrix(.0091,0,0,-0.0091,0,-5.741)"><path id="g50-43" d="M486 158C486 177 478 202 466 220C413 228 386 236 336 262C386 288 413 297 466 304C478 323 486 347 485 366C470 376 444 381 422 380C389 338 368 319 321 288C323 345 329 372 349 422C339 442 322 461 305 470C289 461 271 442 262 422C281 372 287 345 290 288C243 319 222 338 189 380C167 381 142 376 125 366C125 347 133 322 145 304C198 296 225 288 275 262C225 236 198 227 145 220C133 201 125 177 126 158C141 148 167 143 189 144C222 186 243 205 290 236C288 179 282 152 262 102C272 82 289 63 306 54C322 63 340 82 350 102C330 152 324 179 321 236C368 205 390 186 422 144C444 143 470 148 486 158Z"/></g></svg>63), and a known pathogenic nonsense variant, c.160C &gt; T (p.Arg54<svg xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg" style="vertical-align:-0.04990005pt" id="M2" height="10.1524pt" version="1.1" viewBox="-0.0498162 -10.1025 6.17869 10.1524" width="6.17869pt"><g transform="matrix(.0091,0,0,-0.0091,0,-5.741)"><use xlink:href="#g50-43"/></g></svg>). 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<svg xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg" style="vertical-align:-0.04990005pt" id="M3" height="10.1524pt" version="1.1" viewBox="-0.0498162 -10.1025 6.17869 10.1524" width="6.17869pt"><g transform="matrix(.0091,0,0,-0.0091,0,-5.741)"><use xlink:href="#g50-43"/></g></svg>63). We suggest that this RDH5 genotype may be associated with a more progressive phenotype of FA contributing to macular atrophy.

Hyelin You

David Sierpina

A Novel Pathogenic Variant in the RDH5 Gene in a Patient with Fundus Albipunctatus and Severe Macular Atrophy

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&#x2013;Dietz syndrome (LDS) and Shprintzen&#x2013;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.

Jonas Gustafson

Maria Bjork

Conny M. A. van Ravenswaaij-Arts

Michael L. Cunningham

Mechanism of Disease: Recessive ADAMTSL4 Mutations and Craniosynostosis with Ectopia Lentis

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.

Fatemeh Tahghighi

Mahdieh Vahedi

Nima Parvaneh

Mohammad Shahrooei

Vahid Ziaee

The Efficacy of Anti-Tumor Necrosis Factor Therapy in Cryopyrin-Associated Periodic Syndromes: A Report of Two Cases

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&#x0025; 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.

Krishna Gundabolu

Bhavana J. Dave

Carmelita J. Alvares

Jeffrey J. Cannatella

Vijaya R. Bhatt

Lori J. Maness

Zaid S. Al-Kadhimi

Rana K. Zabad

Allison M. Cushman-Vokoun

The Missing LNK: Evolution from Cytosis to Chronic Myelomonocytic Leukemia in a Patient with Multiple Sclerosis and Germline SH2B3 Mutation

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&#x2019; 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&#x2009;&#x3e;&#x2009;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.

Amal Al-Naimi

Haneen Toma

Sara G. Hamad

Tawfeg Ben Omran

Farber Disease Mimicking Juvenile Idiopathic Arthritis: The First Reported Case in Qatar and Review of the Literature

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Case Reports in Genetics publishes case reports and case series focusing on diseases caused by hereditary predisposition or genetic variation in individuals and families.

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Case Reports in Genetics - Table of contents 2022

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Case Reports in Genetics publishes case reports and case series focusing on diseases caused by hereditary predisposition or genetic variation in individuals and families.

Case Reports in Genetics