Rare Disease Research Articles

Sustained remission of Cronkhite-Canada syndrome after corticosteroid and mesalazine treatment: A case report

BACKGROUND Cronkhite-Canada syndrome (CCS) is a rare disease of unknown etiology. The optimal treatment for CCS remains unknown. Treatment with corticosteroids is considered the mainstay treatment because of its high efficacy, but the therapeutic strategy for steroid-resistant CCS is not yet established. CASE SUMMARY This is the case of an 81-year-old woman who was diagnosed with CCS. Given her severe diarrhea, nausea, vomiting, and hypoproteinemia, hormone therapy (40 mg/d) was administered, and the symptoms improved within 1 wk. After 3 mo, the patient had no obvious symptoms. The polyps were significantly reduced on review gastroscopy and colonoscopy, thus hormone reduction gradually began. The hormone level was maintained at 10 mg/d after 6 mo. Despite the age of the patient and the side effects of hormones, the patient had no obvious discomfort. However, hormone drugs were discontinued, and mesalazine was administered orally at 3 g/d. The patient's symptoms continued to improve after a follow-up of 5 years. CONCLUSION Corticosteroids and mesalazine are potential treatment options for CCS.

Myositis as a prominent manifestation of primary skeletal muscle peripheral T-cell lymphoma: a case report and literature review.

The patient presented to the clinic with painful muscle swelling in the right lower extremity, which improved with immunosuppressive therapy. Initially, the condition was diagnosed as polymyositis but recurred soon after. After imaging and biopsy, the final diagnosis was primary skeletal muscle peripheral T-cell lymphoma, not otherwise specified (PSM-PTCL, NOS). In this report, we discuss the challenges in diagnosing and treating this aggressive malignancy and review the literature on PSM-PTCL, NOS. Key Points • To date, there are few reports of PSM-PTCL, NOS, and our case is the tenth. • It is crucial to consider PSM-PTCL, NOS, when presenting with localized muscle edema and unexplained pain. • Histopathological examination is likely the most effective method for diagnosing this rare disease.

Hereditary angioedema: current therapeutic management and future approaches.

The aim of this review is to provide an account of the focus of therapeutic strategies for hereditary angioedema (HAE), give a brief overview of those used in the past and set aside and toughly discuss those currently available as first line. Further research is ongoing and the future therapeutic approaches that are still in different phases of study will be reviewed as well. In the last two decades, major research advancements on HAE pathophysiology and management were made and numerous novel therapeutic options are now available. Compared to the past, drugs available nowadays are more effective, well tolerated, and possibly have a more convenient administration route. Moreover, numerous other drugs with innovative mechanisms of action are under development. HAE is a rare genetic disease that if not promptly treated, it can lead to death from asphyxiation. Furthermore, due to its disfiguring and painful manifestations, HAE implies an important burden on the quality of life. Recently, following great research progresses on HAE therapy, evidence-based guidelines on HAE management were released. The therapeutic landscape of HAE is still under florid development, and it is possible novel treatments will remarkably revolutionize HAE management in the future.

A case of non-traumatic rectus sheath hematoma in a post-kidney transplant patient undergoing catheter embolization during anticoagulation treatment for atrial fibrillation.

A 65-year-old man, a post living donor kidney transplant patient, was admitted to the intensive care unit (ICU) with a severe bacterial infection. He also tested positive for coronavirus disease and had a cough. On admission, heparin was administered for atrial fibrillation. On the third day of hospitalization, his general condition had recovered, and he was discharged from the ICU to the general ward. On the fourth day of hospitalization, he experienced abdominal pain, and a hard mass was palpated in the left lower abdomen. On the fifth day of hospitalization, contrast-enhanced computed tomography showed an extensive rectus sheath hematoma (RSH) extending from the left lower abdominal wall to the left side of the bladder, with extravasation from a small branch of the left inferior epigastric artery. Heparin was discontinued, and transcatheter arterial embolization was performed to control the bleeding. RSH is a rare disease, and cases of extensive hematoma in post-kidney transplant patients occur even less frequently. Patients taking anticoagulants and those with chronic kidney disease are at high risk for RSH, so physicians should be cognizant of this disease when these patients develop abdominal pain.

Genomic profiling of small bowel adenocarcinoma: a pooled analysis from 3 databases.

Small bowel adenocarcinoma is a rare disease. The genomic profiling tumours according to clinical characteristics and its impact on the prognosis remains unclear. A pooled analysis of clinical data, genomic profiling and MisMatch Repair (MMR) status from three databases was performed. A total of 188 tumour samples were analysed. A predisposing disease was reported in 22.3%, mainly Lynch syndrome and Crohn's disease. The tumours were localized in 80.2% and metastatic in 18.8%. The most frequent mutations were KRAS (42.0%) among them 7/79 are G12C, TP53 (40.4%), APC (19.1%), PIK3CA (18.6%), SMAD4 (12.8%) and ERBB2 (9.6%). Mutation distribution differed according to predisposing disease for TP53, ERBB2, IDH1, FGFR3, FGFR1 and KDR. KRAS and SMAD4 mutations were more frequent in metastatic tumour, whereas ERBB2 mutations were absent in metastatic tumour. For localized tumour, APC mutation was independently associated with a poor overall survival (OS) (p = 0.0254). 31.8% of localized tumours and 11.3% of metastatic tumours were dMMR (29.8% of the entire cohort). A dMMR status was associated with a better OS (HR = 0.61 [0.39-0.96], p = 0.0316). There is a different genomic profile according to the stage and predisposing disease. dMMR and APC mutation in localized tumour predict a better prognosis.

Elevated serum levels of soluble B-cell maturation antigen as a prognostic biomarker for multiple myeloma.

Serum B-cell maturation antigen (sBCMA) levels can serve as a sensitive biomarker in multiple myeloma (MM). In the research setting, sBCMA levels can be accurately detected by enzyme-linked immunosorbent assay (ELISA), but the approach has not been approved for clinical use. Here, we used a novel chemiluminescence method to assess sBCMA levels in 759 serum samples from 17 healthy donors and 443 patients with plasma cell (PC) diseases including AL amyloidosis, POEMS syndrome and MM. Serum BCMA levels were elevated 16.1-fold in patients with newly diagnosed MM compared to healthy donors and rare PC diseases patients. Specifically, the sBCMA levels in patients with progressive disease were 64.6-fold higher than those who showed partial response or above to treatment. The sBCMA level also correlated negatively with the response depth of MM patients. In newly diagnosed and relapsed MM patients, survival was significantly longer among those subjects whose sBCMA levels are below the median levels compared with those above the median value. We optimized the accuracy of the survival prediction further by integrating sBCMA level into the Second Revised International Staging System (R2-ISS). Our findings provide evidence that the novel chemiluminescence method is sensitive and practical for measuring sBCMA levels in clinical samples and confirm that sBCMA might serve as an independent prognostic biomarker for MM.

Exploring the role of digital tools in rare disease management: An interview-based study.

While digital tools, such as the Internet, smartphones, and social media, are an important part of modern society, little is known about the specific role they play in the healthcare management of individuals and caregivers affected by rare disease. Collectively, rare diseases directly affect up to 10% of the global population, suggesting that a significant number of individuals might benefit from the use of digital tools. The purpose of this qualitative interview-based study was to explore: (a) the ways in which digital tools help the rare disease community; (b) the healthcare gaps not addressed by current digital tools; and (c) recommended digital tool features. Individuals and caregivers affected by rare disease who were comfortable using a smartphone and at least 18 years old were eligible to participate. We recruited from rare disease organizations using purposive sampling in order to achieve a diverse and information rich sample. Interviews took place over Zoom and reflexive thematic analysis was utilized to conceptualize themes. Eight semistructured interviews took place with four individuals and four caregivers. Three themes were conceptualized which elucidated key aspects of how digital tools were utilized in disease management: (1) digital tools should lessen the burden of managing a rare disease condition; (2) digital tools should foster community building and promote trust; and (3) digital tools should provide trusted and personalized information to understand the condition and what the future may hold. These results suggest that digital tools play a central role in the lives of individuals with rare disease and their caregivers. Digital tools that centralize trustworthy information, and that bring the relevant community together to interact and promote trust are needed. Genetic counselors can consider these ideal attributes of digital tools when providing resources to individuals and caretakers of rare disease.

Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets

Abstract Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease- causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein-protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration- approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.

Fair Funding Decisions: Consistency of the Time Horizons Used in the Calculation of Quality-Adjusted Life Years for Therapies for Very Rare Diseases by the National Institute for Health and Care Excellence in England

Fair Funding Decisions: Consistency of the Time Horizons Used in the Calculation of Quality-Adjusted Life Years for Therapies for Very Rare Diseases by the National Institute for Health and Care Excellence in England

Patient experiences of interprofessional collaboration and intersectoral communication in rare disease healthcare in Germany – a mixed-methods study

BackgroundRare diseases are often complex, chronic and many of them life-shortening. In Germany, healthcare for rare diseases is organized in expert centers for rare diseases. Most patients additionally have regional general practicioners and specialists for basic medical care. Thus, collaboration and information exchange between sectors is highly relevant. Our study focuses on the patient and caregiver perspective on intersectoral and interdisciplinary care between local healthcare professionals (HCPs) and centers for rare diseases in Germany. The aims were (1) to investigate patients’ and caregivers’ general experience of healthcare, (2) to analyse patients’ and caregivers’ perception of collaboration and cooperation between local healthcare professionals and expert centers for rare diseases and (3) to investigate patients’ and caregivers’ satisfaction with healthcare in the expert centers for rare diseases.ResultsIn total 299 individuals of whom 176 were patients and 123 were caregivers to pediatric patients participated in a survey using a questionnaire comprising several instruments and constructs. Fifty participants were additionally interviewed using a semistructured guideline. Most patients reported to receive written information about their care, have a contact person for medical issues and experienced interdisciplinary exchange within the centers for rare diseases. Patients and caregivers in our sample were mainly satisfied with the healthcare in the centers for rare diseases. The qualitative interviews showed a rather mixed picture including experiences of uncoordinated care, low engagement and communication difficulties between professionals of different sectors. Patients reported several factors that influenced the organization and quality of healthcare e.g. engagement and health literacy in patients or engagement of HCPs.ConclusionsOur findings indicate the high relevance of transferring affected patients to specialized care as fast as possible to provide best medical treatment and increase patient satisfaction. Intersectoral collaboration should exceed written information exchange and should unburden patients of being and feeling responsible for communication between sectors and specialists. Results indicate a lack of inclusion of psychosocial aspects in routine care, which suggests opportunities for necessary improvements.

Medullary Thyroid Cancer: Epidemiology and Characteristics According to Data From the Marne-Ardennes Register 1975-2018.

Medullary thyroid cancer (MTC) is a rare disease. The main objective of our study was to analyze the incidence evolution of MTC with a follow-up of more than 40 years. Further, a descriptive and survival analysis was performed according to the Kaplan-Meier analysis. This is a retrospective epidemiological study using data from the Marne-Ardennes registry from 1975 to 2018. Two hundred sixty patients with MTC were included. The incidence was calculated in the territory of the register (Marne and Ardennes departments of France) and standardized on the demographic structure of France. Patient and tumor characteristics were described. An analysis in a subgroup comparing hereditary and sporadic forms was performed. An analysis of survival was performed. The standardized incidence shows an increasing trend over time. The incidence increased significantly from 0.41 to 0.57/100 000 person-years between 1986 and 1996 and 2008 and 2018. The MTC was hereditary in 21.2% of cases. The sex ratio (males:females) was 0.73. The average age at diagnosis was 53 years. Ninety-seven patients (37.3%) were N1, 26 (10%) were M1, and 56 (21.5%) developed metastases during the follow-up. Complete remission was obtained in 58.5% of patients. The disease was refractory for 18.1% of patients. The 5-year survival rate was 88.4%. Sporadic cases had a poorer prognosis than hereditary MTC. Our study demonstrates a moderate increase in the incidence of MTC between 1975 and 2018. The prognosis remains worse for sporadic MTC than for hereditary MTC.

Contemporary Surgical Management of Craniofacial Fibrous Dysplasia Using Computer-Assisted Surgery and Intraoperative Navigation.

Craniofacial fibrous dysplasia (CFD) is a rare developmental disease of bone, which typically presents as a painless, expansile mass causing deformity of the craniofacial skeleton. In rare circumstances, compression of neurovascular structures may arise, causing symptoms such as pain, visual impairment, and hearing loss. Traditionally, CFD debulking has been performed with "freehand" techniques using preoperative imaging and anthropometric norms to determine the ideal amount of tissue removal. The advent of computer-assisted surgery, computer-aided design, and computer-aided manufacturing (CAD/CAM) has revolutionized the management of CFD. Surgeons can now fabricate patient-specific osteotomy/ostectomy guides, allowing for increased accuracy in bone removal and improved cosmetic outcomes. This series of 3 cases describe our institution's technique using patient-specific ostectomy "depth guides", which allow for maximum removal of fibro-osseous tissue while sparing deep and adjacent critical structures. These techniques can be widely applied to the craniofacial skeleton to assist in the surgical management of CFD.

Riedel's thyroiditis: report of 7 patients and review of literature.

Riedel's thyroiditis is a rare inflammatory-sclerosing thyroid disease, and its aetiology remains unknown. After a surgical biopsy to establish the diagnosis, the treatment of Riedel's thyroiditis is still challenging in most patients. The aim of this article is to report seven patients with Riedel's thyroiditis seen in a department of Endocrinology and Metabolic diseases over a period of 24 years, and based on the patient's data and the review of the literature to discuss the indications of surgery, glucocorticoids, tamoxifen and immunosuppressive drugs in the personalized treatment of patients with Riedel's thyroiditis.

Elevation of D-dimer in eosinophilic gastrointestinal diseases in the absence of venous thrombosis: A case series and literature review

Abstract Introduction Eosinophilic gastrointestinal diseases (EGIDs) are rare and heterogeneous diseases characterized by excessive eosinophilic infiltration of the digestive system. D-dimer levels and its possible association with disease course were not reported. Case series We reported a series of three EGID cases presenting with high levels of D-dimer. No evidence for potential venous thromboembolism was found through computed tomography pulmonary angiogram and vascular ultrasounds. Moreover, D-dimer levels decreased after short-time systemic prednisolone administration, accompanied by remission of clinical symptoms and decrease of peripheral eosinophil counts and IgE levels. Conclusion Elevation of D-dimer in EGID may not represent thrombotic events but is possibly associated with disease severity. More population-based studies are needed to delineate the potential relationship among D-dimer, thrombosis, and inflammation in EGID.

Clinical Features and Treatment Outcome of Pediatric Acute Promyelocytic Leukemia in Combined Military Hospital, Dhaka

Background: Acute promyelocytic leukemia (APML) is a relatively rare blood disease in children that is highly curable with current treatment strategies. It is a distinct type of AML characterized by chromosomal translocations involving the retinoid acid receptor (RAR-A) gene on chromosome 17. It accounts for 20-25% of all AML cases. The aim of this study was to describe the diagnostic features of pediatric APL and the result with ATRA and ATO based protocol. Methods: It was a descriptive type of cross-sectional study with purposively selected 10 newly diagnosed APML patients treated in the Pediatric Oncology unit of the Department of Pediatrics in CMH Dhaka during the period of 2018 to 2022. Diagnosis of all patients were done by aspirating bone marrow morphology and cytogenetic t(15:17) or t(11:17) transcript. Informed written consent was taken from parents. Data were collected by semi-structured questionnaire and analyzed by Statistical Package for Social Sciences (SPSS version 25). Results: Among 10 respondents median age was 4.2 years with female predominant (60%). Most common clinical presentations at diagnosis were fever (100%), bleeding manifestations (100%), Hepatomegaly (90%) bony tenderness (90%), splenomegaly (70%), and lymphadenopathy (70%). Almost all the patients had low Hb & low platelet count & WBC were variable. Cytogenetic analysis revealed 90% had PML/RARA positive & 30% had FLT3/ITD positive. All of these patients were treated with trans-retinoic acid (ATRA) based treatment, which led to 80% cases ATRA syndrome. Other common toxicities noticed febrile neutropenia (50%), severe headache (30%), hyperpigmented skin (10%), pseudotumor cerebri (10%) and others. There were 10% relapse cases, which later proceeded to relapse protocol and were in remission. The remaining 90% of patients were alive and in remission until the last day of follow-up. Conclusion: With ATRA-based treatment overall survival is good achieved remission and only 10% of patients developed relapse. Bangladesh Armed Forces Med J Vol 56 No (2) December 2023, pp 1-9

Epithelioid Hemangioma: Report of a Case Series of 4 Patients

Epithelioid hemangioma or Angiolymphoid Hyperplasia with Eosinophilia (ALHE) is a rare benign vascular disease, characterized by solitary or multiple angiomatous papules and nodules, which are usually located on the skin of scalp and face (mainly in the preauricular zone); these have characteristic histological and immunohistochemical patterns, in particular characterized by an important lymphocytic inflammatory infiltrated with many eosinophils and vascular proliferation of capillaries with endothelial cellular changes. In this paper, four cases of this disease are reported, in the first series of Ecuadorian cases described in the literature.

4-Octyl itaconate inhibits inflammation via the NLRP3 pathway in neuromyelitis optica spectrum disorders.

Neuromyelitis optica spectrum disorders (NMOSD) are rare inflammatory astrocytic diseases of the central nervous system (CNS). The roles of immune response gene-1 (IRG1) and the IRG1-itaconic acid-NLRP3 inflammatory pathway in the pathogenesis of NMOSD and the effects of 4-octyl itaconate (4-OI) on the NLRP3 inflammatory pathway in NMOSD are unclear. This study aimed to determine the role of IRG1 and the activation status of the NLRP3 inflammatory pathway in acute-onset NMOSD and to investigate the inhibitory effects of 4-OI on NLRP3 inflammasome activation via the IRG1-itaconic acid-NLRP3 pathway in monocytes and macrophages by using in vitro models. Peripheral blood mononuclear cells (PBMCs) and serum were collected from patients with acute NMOSDs and healthy controls (HC), followed by monocyte typing and detection of the expression of NLRP3-related inflammatory factors. Subsequently, the effects of 4-OI on the IRG1-itaconic acid-NLRP3 pathway were investigated in peripheral monocytes from patients with NMOSD and in macrophages induced by human myeloid leukemia mononuclear cells (THP-1 cells) via in vitro experiments. Patients with acute NMOSD exhibited upregulated IRG1 expression. In particular, the upregulation of the expression of the NLRP3 inflammasome and proinflammatory factors was notable in monocytes in acute NMOSD patients. 4-OI inhibited the activation of the IRG1-itaconic acid-NLRP3 inflammatory pathway in the PBMCs of patients with NMOSD. 4-OI could effectively inhibit NLRP3 signaling, leading to the inhibition of proinflammatory cytokine production in patients with NMOSD-derived PBMCs and in a human macrophage model. Thus, 4-OI and itaconate could have important therapeutic value for the treatment of NMOSD in the future.

The role of claudins in renal transepithelial transport and kidney disease.

25 years after the discovery of claudins as the central constituents of tight junctions, the "hunter-gatherer phase" of claudin research is coming to an end. Deficiency in individual claudins as a cause of rare hereditary diseases is well documented. However, knowledge about the involvement of renal claudins in common kidney diseases and strategies to utilize claudins or their regulators for intervention are still scarce. The present review summarizes novel approaches to address these questions. Publicly accessible omics data provide new insights not only into general claudin expression patterns along the nephron, but also into sex-specific differences in claudin expression and into claudin dysregulation in renal injury. Computational association studies identify claudin variants as risk factors for kidney disease such as nephrolithiasis or loss of filtration capacity. The establishment of innovative cell culture and organoid models contributes to a better understanding of junctional and extra-junctional functions of individual claudins. The current studies lay the foundation for the identification of upstream regulators of renal claudin expression and thus for the development of new concepts for the treatment of kidney disease.

Filippi syndrome: Three new families suggest that urinary system abnormalities may belong to clinical spectrum of the disease.

Filippi syndrome is a rare genetic disorder characterized by growth and neurodevelopmental delays, dysmorphism, and selective limb abnormalities. Although the syndrome was described approximately four decades ago, only a few families with molecularly confirmed diagnoses have been reported. In this article, we present three new patients of Filippi syndrome with unusual clinical and genetic aspects. These patients exhibited novel clinical features that have not previously been associated with Filippi syndrome, including renal hypoplasia/aplasia, renal cysts, renal cortical thinning, hypomelanotic, and hypermelanotic macules. All three patients had homozygous frameshift variants of the CKAP2L gene, specifically NM_152515.3: c.554_555del, c.981_982del, and c.1463_1467del, with the second being a novel variant. Given the limited number of reported Filippi syndrome patients to date and the ongoing discovery of new clinical aspects of the disease, exploring its potential connection with kidney and skin pigmentation abnormalities could be valuable for future research.

A Young Man With Hereditary Motor And Sensory Neuropathy: A Rare Genetic Association

Hereditary motor and sensory neuropathies with early onset are uncommon conditions that include Dejerine-Sottas neuropathy, which begins in infancy, and congenital hypomyelinating neuropathy, which manifests in the early postnatal period. However, these two historically defined disease entities are only small parts of the clinical spectrum. It is well recognized that very early onset hereditary neuropathies are frequently caused by de novo dominant mutations in PMP22, MPZ, and EGR2. In addition, mutations in several other dominant and recessive genes for Charcot-Marie-Tooth disease may lead to similar phenotypes. A 20-year-old boy had complaints of weakness of both lower limbs for 1 year, followed by wasting and foot drop, which subsequently involved the upper limbs. Nerve conduction velocity and electromyography of both lower limbs revealed demyelinating sensory motor polyneuropathy. Histological examination of the sural nerve revealed a nerve trunk with perineural soft tissue, with the nerve bundles being irregular and separated by fibrous tissue bands. The later reveals small perivascular infiltration of chronic inflammatory cells, and no granuloma or AFB is seen. The genetic test of whole exome screening for heriditatory neuropathy showed pathogenic (PM2, PVS, PP5) with a gene impact of (NF2: c.363+1G>T), which is a rare entity in our case study to consider the diagnosis despite negative family history. We highlight this rare disease in young man with a high index of clinical suspicion for its diagnosis. Bangladesh J Medicine 2024; 35: 101-105