The Efficacy of Anti-Tumor Necrosis Factor Therapy in Cryopyrin-Associated Periodic Syndromes: A Report of Two CasesRead the full article
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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The Missing LNK: Evolution from Cytosis to Chronic Myelomonocytic Leukemia in a Patient with Multiple Sclerosis and Germline SH2B3 Mutation
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.
Farber Disease Mimicking Juvenile Idiopathic Arthritis: The First Reported Case in Qatar and Review of the Literature
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.
A Chinese Patient with Spastic Paraplegia Type 4 with a De Novo Mutation in the SPAST Gene
Background. Spastic paraplegia type 4 (SPG4) is the most common type of hereditary spastic paraplegia (HSP) caused by mutations in the SPAST gene. Case Presentation. We report the case of a 27-year-old pregnant Chinese woman with HSP in whom we identified a missense mutation in the SPAST gene (c.1496G>A, p.Arg499His) and a nonsense mutation in the NEFH gene (c.289G>T, p.Glu97) via whole-exome sequencing; this finding corroborated that of Sanger sequencing. The patient exhibited the pure SPG4 phenotype with onset during childhood. The SPAST mutation was absent in the parents and paternal relatives. However, the NEFH mutation was identified in five people with no clinical phenotype. Based on theoretical conjecture and the family gene segregation information, we concluded that the SPAST mutation, but not the NEFH mutation, accounted for the proband’s phenotype. Eventually, the woman gave birth to a healthy baby girl with the NEFH mutation. Conclusion. In this report, we identified a missense mutation in the SPAST gene (p.Arg499His) in a 27-year-old pregnant Chinese woman with HSP. We believe that this study expands the knowledge about the clinical parameters and mutation spectrum of SPG4.
Delayed Diagnosis of McCune–Albright Syndrome
Background. McCune–Albright syndrome (MAS) is a rare heterogeneous genetic disorder that is characterized by a triad of polyostotic fibrous dysplasia (FD), café au lait spots (CAL), and multiple hyperfunctional endocrinopathies. In general, it is diagnosed clinically. From the triads, two of the findings are enough to make the diagnosis, but genetic testing can be done if it is available. Case Presentation. We report a female child who was symptomatic since the neonatal period with skin hyperpigmentation, breast enlargement, and vaginal bleeding. She was diagnosed with MAS at the age of five years. She had pathological fractures at multiple sites and had raised thyroid hormones since the age of 3½ years. The child developed severe morbidity as the result of delayed diagnosis and currently became wheelchair dependent. Conclusion. Thorough patient evaluation and appropriate interpretation of findings are crucial steps for timely diagnosis of MAS and better patient care outcomes.
Whole-Exome Sequencing Identifies a Novel POLG Frameshift Variant in an Adult Patient Presenting with Progressive External Ophthalmoplegia and Mitochondrial DNA Depletion
Mitochondrial DNA (mtDNA) depletion syndromes are a group of autosomal recessive disorders associated with a spectrum of clinical diseases, which include progressive external ophthalmoplegia (PEO). They are caused by variants in nuclear DNA (nDNA) encoded genes, and the gene that encodes for mtDNA polymerase gamma (POLG) is commonly involved. A splice-site mutation in POLG, c.3104+3A > T, was previously identified in three families with findings of PEO, and studies demonstrated this variant to result in skipping of exon 19. Here, we report a 57-year-old female who presented with ophthalmoplegia, ptosis, muscle weakness, and exercise intolerance with a subsequent muscle biopsy demonstrating mitochondrial myopathy on histopathologic evaluation and multiple mtDNA deletions by southern blot analysis. Whole-exome sequencing identified the previously characterized c. 3104+3A > T splice-site mutation in compound heterozygosity with a novel frameshift variant, p.Gly23Serfs236 (c.67_88del). mtDNA copy number analysis performed on the patient’s muscle showed mtDNA depletion, as expected in a patient with biallelic pathogenic mutations in POLG. This is the first reported case with POLG p.Gly23Serfs236, discovered in a patient presenting with features of PEO.
Overlapping Phenotypes in Osteopetrosis and Pycnodysostosis in Asian-Indians
Osteopetrosis is a disorder characterized by high bone density, hepatosplenomegaly, visual and hearing loss, and anemia. Pycnodysostosis presents with short stature, acroosteolysis, and dense bones. We, hereby, present here a family with autosomal dominant osteopetrosis and also children with recessive osteopetrosis and pycnodysostosis. The molecular confirmation was done in 3 cases. Genetic heterogeneity in clinical presentation is discussed here. Further studies will help in identifying epigenetic alterations and population-specific variants and also developing targeted therapies.