Rare Association Research Articles

Periprosthetic metastases in carcinoma of unknown primary: A rare association.

Septic or aseptic loosening may cause bone loss around artificial prosthesis leading to prosthesis failure. This occurrence due to metastatic infiltration of bone or surrounding soft tissues is rare but has been occasionally reported. We report a case of an elderly lady presenting with swelling and pain at the site of previous hemiarthroplasty performed for traumatic injury. On evaluation, she was found to have a lytic femur lesion with a large soft-tissue component around the prosthetic joint. Biopsy suggested a metastatic carcinoma of renal origin, but screening of kidneys did not reveal any primary lesion. She had additional skeletal metastatic lesions but no other primary site was detected either. She was given palliative radiotherapy and systemic therapy (sunitinib) based on the histologic diagnosis of renal cell origin but did not tolerate it. Thereafter, she is continuing on zoledronate every 4 weeks and best supportive management since 4 months from diagnosis.

Bayesian LASSO for population stratification correction in rare haplotype association studies.

Population stratification (PS) is one major source of confounding in both single nucleotide polymorphism (SNP) and haplotype association studies. To address PS, principal component regression (PCR) and linear mixed model (LMM) are the current standards for SNP associations, which are also commonly borrowed for haplotype studies. However, the underfitting and overfitting problems introduced by PCR and LMM, respectively, have yet to be addressed. Furthermore, there have been only a few theoretical approaches proposed to address PS specifically for haplotypes. In this paper, we propose a new method under the Bayesian LASSO framework, QBLstrat, to account for PS in identifying rare and common haplotypes associated with a continuous trait of interest. QBLstrat utilizes a large number of principal components (PCs) with appropriate priors to sufficiently correct for PS, while shrinking the estimates of unassociated haplotypes and PCs. We compare the performance of QBLstrat with the Bayesian counterparts of PCR and LMM and a current method, haplo.stats. Extensive simulation studies and real data analyses show that QBLstrat is superior in controlling false positives while maintaining competitive power for identifying true positives under PS.

Thrombotic Thrombocytopenic Purpura Complicating Secondary Sjögren's Syndrome: A Rare and Serious Association from Africa

Thrombotic Thrombocytopenic Purpura is a potentially fatal disease that can be life-threatening. The association with Sjogren’s syndrome is rare entity that deserves special attention. To this end, we report the case of a Thrombotic thrombocytopenic purpura complicating secondary Sjögren's syndrome. This is a 49-year-old patient with a history of pure nephrotic syndrome with minimal glomerular lesions (LGM), who developed Sjögren's syndrome two years later. The diagnosis of Sjögren's syndrome was retained with an etiological investigation suggesting SS secondary to SLE systemic lupus erythematosus. Six months after the diagnosis of secondary SS, the patient was admitted with headache, ecchymotic and petechial lesions on the upper limbs. The laboratory analysis revealed severe thrombocytopenia, haemolytic anemia with a schizocyte count at 6% supporting the diagnosis of thrombotic microangiopathy. The ADAMTS 13 activity assay was less than 5% and the anti-ADAMTS 13 antibody test was positive, attesting thus, the diagnosis of acquired TTP complicating SS secondary to SLE. The patient received an emergency blood transfusion of fresh frozen plasma combined with corticosteroid therapy and mycophenolate mofetil. The clinico-biological outcome, at 6 month and 1 year, was favorable with complete remission. To the best of our knowledge, this is the first case report of TTP complicating Sjögren’s syndrome in Africa. It highlights the rarity of association between autoimmune disease particulary Sjögren’s syndrome and TTP.

A rare case of adult-onset spastic paraparesis associated with Klinefelter syndrome

ReportThe rare association of Klinefelter syndrome and the clinical presentation of a late onset chronic progressive spastic paresis.Clinical Presentation and GeneticsAn infertile, 61-year-old man, presented with late adult onset of gait problems, deep muscle pain, and bladder problems. He presented for the first time, years after onset with a spastic paraparesis with high arched feet. His parents had already died, but the patient described high arched feet with his mother. There is no further certain information about the parents. After thorough investigation, an additional X chromosome was found, whereafter the diagnosis of Klinefelter syndrome could be made. Other acquired and genetic causes for spastic paraparesis or hereditary motor neuropathy are excluded.ConclusionThis rare case, together with three other literature reports by Sasaki (Intern Med 58(3):437–440, 2019), Sajra (Med Arh 61(1):52–53, 2007) and Matsubara et al., (J Neurol Neurosurg Psychiatry 57(5):640–642, 1994). suggests that Klinefelter syndrome can be associated with spastic paraparesis, besides the other various neuropsychiatric symptoms that are more commonly described.

Inherited blood cancer predisposition through altered transcription elongation

Despite advances in defining diverse somatic mutations that cause myeloid malignancies, a significant heritable component for these cancers remains largely unexplained. Here, we perform rare variant association studies in a large population cohort to identify inherited predisposition genes for these blood cancers. CTR9, which encodes a key component of the PAF1 transcription elongation complex, is among the significant genes identified. The risk variants found in the cases cause loss of function and result in a ∼10-fold increased odds of acquiring a myeloid malignancy. Partial CTR9 loss of function expands human hematopoietic stem cells (HSCs) by increased super elongation complex-mediated transcriptional activity, which thereby increases the expression of key regulators of HSC self-renewal. By following up on insights from a human genetic study examining inherited predisposition to the myeloid malignancies, we define a previously unknown antagonistic interaction between the PAF1 and super elongation complexes. These insights could enable targeted approaches for blood cancer prevention.

Rare copy-number variants as modulators of common disease susceptibility

BackgroundCopy-number variations (CNVs) have been associated with rare and debilitating genomic disorders (GDs) but their impact on health later in life in the general population remains poorly described.MethodsAssessing four modes of CNV action, we performed genome-wide association scans (GWASs) between the copy-number of CNV-proxy probes and 60 curated ICD-10 based clinical diagnoses in 331,522 unrelated white British UK Biobank (UKBB) participants with replication in the Estonian Biobank.ResultsWe identified 73 signals involving 40 diseases, all of which indicating that CNVs increased disease risk and caused earlier onset. We estimated that 16% of these associations are indirect, acting by increasing body mass index (BMI). Signals mapped to 45 unique, non-overlapping regions, nine of which being linked to known GDs. Number and identity of genes affected by CNVs modulated their pathogenicity, with many associations being supported by colocalization with both common and rare single-nucleotide variant association signals. Dissection of association signals provided insights into the epidemiology of known gene-disease pairs (e.g., deletions in BRCA1 and LDLR increased risk for ovarian cancer and ischemic heart disease, respectively), clarified dosage mechanisms of action (e.g., both increased and decreased dosage of 17q12 impacted renal health), and identified putative causal genes (e.g., ABCC6 for kidney stones). Characterization of the pleiotropic pathological consequences of recurrent CNVs at 15q13, 16p13.11, 16p12.2, and 22q11.2 in adulthood indicated variable expressivity of these regions and the involvement of multiple genes. Finally, we show that while the total burden of rare CNVs—and especially deletions—strongly associated with disease risk, it only accounted for ~ 0.02% of the UKBB disease burden. These associations are mainly driven by CNVs at known GD CNV regions, whose pleiotropic effect on common diseases was broader than anticipated by our CNV-GWAS.ConclusionsOur results shed light on the prominent role of rare CNVs in determining common disease susceptibility within the general population and provide actionable insights for anticipating later-onset comorbidities in carriers of recurrent CNVs.

Hidden vegetable matter in tissue sections – A case series

Food particles get frequently impacted in the oral cavity in varying sites. Oral pulse granuloma develops as a consequence of implantation of food particles of plant or vegetable origin in oral tissues. The lesion might be central or peripheral. It has a differing histological picture and may be confused with many other lesions including parasitic infection. Impacted vegetable matter is rarely associated with multiple myeloma, bacterial and fungal osteomyelitis, and squamous cell carcinoma and has never been reported in the literature before. Thus, in the present case series, we have discussed about the above three rare associations along with pulse granulomas associated with periapical granuloma and periapical cyst. The paper aims to discuss the clinical, histological, and polarising microscopic features of the cases and theories substantiating aetiology and in general about the differential diagnosis.

The Surprises of Molecular Testing in Neurofibromatosis Type 1: Rare Association between Two Mutational Variants

The Surprises of Molecular Testing in Neurofibromatosis Type 1: Rare Association between Two Mutational Variants

Juvenile idiopathic arthritis presenting with rare extra-articular manifestations: A report of two cases

Abstract Juvenile idiopathic arthritis (JIA), a common rheumatic disease of childhood, is a consolidated term used for all chronic childhood arthritis affecting joints and extra-articular structures. Involvement of skin and internal organs such as liver, spleen, intestine, peritoneum, pleura, pericardium and myocardium will cause systemic symptoms leading to disability and mortality. Despite advanced treatment options, significant morbidity still occurs due to an unpredictable clinical course and risk of joint restriction. We describe polyarticular rheumatoid factor-negative JIA with extra-articular manifestations involving pericardium causing chronic constrictive pericarditis in a 16-year-old girl and her sibling a 13-year-old boy. The female patient developed cardiac cirrhosis, portal hypertension and oesophageal varices. Screening evaluation of this patient’s asymptomatic sibling with similar articular manifestations revealed the rare occurrence of chronic constrictive pericarditis without symptoms. Both were treated with pericardiectomy and were relieved of symptoms. Two patients of JIA from the same family presenting with constrictive pericarditis is a rare association.

Crossed Fused Renal Ectopia with Transitional Cell Carcinoma of Kidney: A Rare Association

Crossed Fused Renal Ectopia with Transitional Cell Carcinoma of Kidney: A Rare Association

A Rare Tumor at an Unusual Site with a Rare Association.

A Rare Tumor at an Unusual Site with a Rare Association.

Good Syndrome: Cytomegalovirus retinitis case challenge.

To describe cytomegalovirus retinitis in a patient with Good syndrome (hypogammaglobulinemia and thymoma), ocular progression despite treatment, and fatal outcome. A 71-year-old woman with unilateral panuveitis of unknown cause and a history of thymoma resection was referred to our clinic. Visual acuity (VA) was 20/100 in her right eye (OD) and light perception in her left eye (OS). In slit-lamp examination, OD had inferior fine pigmented keratic precipitates, 2+ anterior chamber (AC) cells, cataract, and 2+ vitreous cells, no fundus detail, and normal ocular ultrasound. OS presented a white cataract, chronic hypotony, and increased choroidal thickness with calcifications. Laboratory evaluations were normal or negative for common causes of infection and inflammation. Prednisolone acetate eye drops were started, with improvement of AC inflammation. Cataract surgery was performed, reaching VA of 20/30. Two years later, VA had decreased and 2+ vitritis and retinitis were found. On clinical suspicion of masquerade syndrome, a vitrectomy biopsy was performed; pathology reported no data on ocular lymphoma. Leukopenia and lymphopenia were found: immunoglobulin levels, CD4 count, and viral load revealed systemic immunosuppression. The aqueous tap was positive for cytomegalovirus. Oral valganciclovir and intravitreal ganciclovir were initiated. In a patient with previous resection of thymoma and hypogammaglobulinemia, final diagnosis was Good syndrome, with CMVR being secondary to immunosuppression. Despite treatment, CMVR progressed and systemic deterioration resulted in mortal outcome. Good syndrome is an extremely rare disease and association with CMVR is uncommon. To our knowledge, only 14 cases exist in the literature.

A rare association of non-IBD-related giant filiform polyposis and diverticular disease.

A rare association of non-IBD-related giant filiform polyposis and diverticular disease.

The Nexus of Hyperparathyroidism and Thyroid Carcinoma: Insights into Pathogenesis and Diagnostic Challenges-A Narrative Review.

This review investigates the intricate relationship between hyperparathyroidism (HPT) and thyroid carcinoma (TC), aiming to elucidate their coexistence, potential pathogenetic mechanisms, and clinical implications. A systematic search strategy, employing the MeSH terms 'Hyperparathyroidism' and 'Thyroid Carcinoma', spanned publications from 2013 to 2023 across the PubMed, Web of Science, and Scopus databases. Fifteen selected articles were analyzed. Studies unanimously confirm the notable association between primary hyperparathyroidism (PHPT) and thyroid nodules/cancer, with incidences ranging from 2.8% to 47.1%. Key findings reveal a predilection for papillary thyroid carcinoma (PTC) in this association, showcasing varying tumor characteristics and gender disparities. Lower preoperative serum parathyroid hormone (PTH) levels are a potential risk factor for thyroid cancer in PHPT patients. Diverse surgical approaches and tumor characteristics between PHPT and secondary hyperparathyroidism (SHPT) cases were noted. Moreover, this review underscores the scarcity of definitive guidelines in managing concurrent PHPT and thyroid conditions, advocating for comprehensive assessments to enhance diagnostic accuracy and refine therapeutic interventions. Rare coincidental associations, as highlighted by case reports, shed light on unique clinical scenarios. In essence, this review amalgamates evidence to deepen the understanding of the interplay between HPT and TC, emphasizing the need for further research to elucidate underlying mechanisms and guide clinical management.

Cutaneous Disorders Masking Celiac Disease: Case Report and Mini Review with Proposal for a Practical Clinical Approach.

Celiac disease (CD) is an immune-mediated systemic gluten-related disorder characterized by a wide spectrum of intestinal and extra-intestinal manifestations, including damage to cutaneous and connective tissue. We report a rare case of chronic severe dermatitis involving connective tissue and cutaneous vascular vessels as the main clinical presentation of undiagnosed seronegative gluten disorder. A gluten-free diet dramatically improved the intestinal and cutaneous clinical damage in the patient. Pitfalls and the steps of differential diagnosis are described. We also review the literature regarding studies of CD and connective tissue diseases to extend the knowledge of these rare associations. We propose a practical diagnostic approach in suspected CD in autoimmune cutaneous disorders.

Unprecedented Coexistence of Autoinflammatory Myositis and Chronic Thrombosis with heterozygotic M694V mutation: An atypical presentation of Familial Mediterranean Fever.

Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disorder predominantly characterized by periodic fever, abdominal pain, and joint manifestations. It can exhibit various atypical presentations and affects individuals globally. However, cases of FMF concurrently presenting with chronic thrombosis and myositis have not been previously reported. A 41-year-old male presented with alternating severe bilateral leg pain, stiffness, and localized swellings without fever or abdominal symptoms. His history included recurrent inflammatory joint pain treated with prednisolone. Physical examination revealed leg pain, limited ankle joint movement, and tender swellings in thighs, forearms, and feet. Collateral abdominal veins were also observed. Unresponsive to prednisolone and colchicine, the patient underwent MRI, revealing muscle inflammation in both legs and thighs and chronic thrombosis in the infrarenal inferior vena cava. Genetic testing confirmed the heterozygotic M694V mutation, diagnosing an atypical FMF. Anakinra treatment led to substantial clinical and laboratory improvement. Although FMF diagnosis typically relies on characteristic clinical features and genetic analysis, atypical presentations challenge established criteria. This case uniquely showcases coexisting myositis and chronic thrombosis in FMF. Myalgia is common in FMF, with M694V mutation associated with severe muscular symptoms. The lack of fever and myositis findings differentiate our case from protracted febrile myalgia syndrome. FMF's chronic inflammatory state is known to influence thrombosis risk, and our findings align with this association. Chronic thromboembolism and myositis together signify an unusual clinical presentation of FMF. This case highlights the potential for FMF to present with complex manifestations beyond the conventional symptoms. Myositis and vascular involvement should prompt consideration of FMF diagnosis when combined with patient history, clinical features, and laboratory results. These rare associations underscore the need for further research to enhance understanding of FMF's diverse clinical spectrum.

Anesthetic management of diphallia with anorectal malformation posted for colostomy: a rare association

BackgroundDuplication of the penis or Diphallia is a rare abnormality of the urogenital tract present once in every 5–6 million live births with varied presentations and associated systemic anomalies.Case presentationWe present the anesthetic management of a neonate presenting with duplication of penis, urethra, and anorectal malformation.ConclusionsWith this rare case, we aim to shed light on the various perioperative anesthetic concerns of such neonates presenting with surgical emergencies and their successful management.

A Rare Coexistence: Breast Cancer, Pheochromocytoma and Von Recklinghausen Disease

Breast cancer associated with type-1 neurofibromatosis is a rare clinical entity. These patients have a higher risk of developing various types of cancers, especially tumors derived from the embryogenic neural crest, such as pheochromocytoma. This publication aims to add to the literature a rare association between Type-1 Neurofibromatosis, breast cancer, and pheochromocytoma. We present a rare case of a 51-year-old Tunisian woman with neurofibromatosis who was diagnosed with breast cancer and pheochromocytoma. The breast tumor was classified as T4b N1M0, and the discovery of the pheochromocytoma was incidental to thoracic-abdominal-pelvic CT. She underwent surgery to remove the adrenal gland and was referred to medical oncologists to receive chemotherapy for her breast cancer. Type-1 Neurofibromatosis disorder is a benign disease but can expose patients to numerous neoplasms. The challenging diagnosis at an early stage can worsen the prognosis and make medical care more difficult.

Prostate cancer genetic risk and associated aggressive disease in men of African ancestry

African ancestry is a significant risk factor for prostate cancer and advanced disease. Yet, genetic studies have largely been conducted outside the context of Sub-Saharan Africa, identifying 278 common risk variants contributing to a multiethnic polygenic risk score, with rare variants focused on a panel of roughly 20 pathogenic genes. Based on this knowledge, we are unable to determine polygenic risk or differentiate prostate cancer status interrogating whole genome data for 113 Black South African men. To further assess for potentially functional common and rare variant associations, here we interrogate 247,780 exomic variants for 798 Black South African men using a case versus control or aggressive versus non-aggressive study design. Notable genes of interest include HCP5, RFX6 and H3C1 for risk, and MKI67 and KLF5 for aggressive disease. Our study highlights the need for further inclusion across the African diaspora to establish African-relevant risk models aimed at reducing prostate cancer health disparities.

Association of Common and Rare Variants with Alzheimer’s Disease in 16,905 individuals with Whole‐Genome Sequence Data from the Alzheimer’s Disease Sequencing Project

AbstractBackgroundWhole genome sequencing (WGS) data enables assessment of common and rare variants for association with human diseases. Here we report our analysis using ADSP R3 WGS data to discover genetic variants associated with AD.MethodWe performed association testing of common variants (minor allele frequency [MAF] > 0.5%) as well as aggregates of rare (MAF < 1%) coding and non‐coding variants. Given that ADSP is composed of multiple ancestry groups, we performed association testing across all participants (pooled population [PP], Ncases = 6,519 and Ncontrol = 6,852) and within the following populations: African Americans (AA, Ncases = 1,137 and Ncontrol = 1,707), Hispanics (HIS, Ncases = 1,021 and Ncontrol = 1,988), and Non‐Hispanic White (NHW, Ncases = 4,230 and Ncontrol = 3,109) defined by self‐reported race and ethnicity (Table 1).ResultAs expected, our most significant associations are at the APOE locus (chr19:44,905,796‐44,909,393) (Figure 1). In the pooled‐population analysis, we observed known AD associations for BIN1 (p = 3.2×10−09) variants with AD status. In the NHW analysis, we observed AD associations for variants in CR1 (p = 7.97×10−08), BIN1 (p = 2.16×10−08), ARHGEF33 (p = 4.85×10−8), ANK3 (p = 1.43×10−12) and MYCBP2‐AS1 (p = 4.59×10−08), and in the AA analysis, we observed a significant variant near LINC00320 (p = 1.5×10−8). In the HIS subset, a region (chr14:72,698,038‐75,846,454) has 31 significant variants (p = 3.9×10−11) crossing multiple genes. This region covers PSEN1 G206A (rs63750082), a well‐known early‐onset AD mutation. Local‐ancestry analysis shows that the mutations, including G206A, are of African ancestry. Using kinship coefficients calculated within this dataset, it was determined that the signals are not driven by a familial linkage disequilibrium.We observed gene‐based aggregation of coding variants in PSEN1 in the pooled‐population and HIS analyses (p<5×10−8) (Figure 2). In our gene‐centric noncoding aggregates analysis, we identified noncoding variants in the promotor of TOMM40 in the pooled‐population analysis (p = 7.2×10−08). After adjusting for APOE e4 (rs429358) and e2 (rs7412) alleles, there was an attenuation, but the association remained suggestive (p = 7.1×10−06).ConclusionWe performed common and rare association analysis of AD on ADSP WGS data. We observed associations with variants in known AD loci. We also observed population‐specific associations and an association of AD with rare noncoding variants in TOMM40, indicating WGS in diverse populations can lead to novel genetic associations with AD.