Orphanet J Rare Dis. 2023 Mar 28;18(1):70. doi: 10.1186/s13023-023-02663-z.

ABSTRACT

BACKGROUND AND OBJECTIVE: The diagnosis of rare diseases (RDs) is often challenging due to their rarity, variability and the high number of individual RDs, resulting in a delay in diagnosis with adverse effects for patients and healthcare systems. The development of computer assisted diagnostic decision support systems could help to improve these problems by supporting differential diagnosis and by prompting physicians to initiate the right diagnostic tests. Towards this end, we developed, trained and tested a machine learning model implemented as part of the software called Pain2D to classify four rare diseases (EDS, GBS, FSHD and PROMM), as well as a control group of unspecific chronic pain, from pen-and-paper pain drawings filled in by patients.

METHODS: Pain drawings (PDs) were collected from patients suffering from one of the four RDs, or from unspecific chronic pain. The latter PDs were used as an outgroup in order to test how Pain2D handles more common pain causes. A total of 262 (59 EDS, 29 GBS, 35 FSHD, 89 PROMM, 50 unspecific chronic pain) PDs were collected and used to generate disease specific pain profiles. PDs were then classified by Pain2D in a leave-one-out-cross-validation approach.

RESULTS: Pain2D was able to classify the four rare diseases with an accuracy of 61-77% with its binary classifier. EDS, GBS and FSHD were classified correctly by the Pain2D k-disease classifier with sensitivities between 63 and 86% and specificities between 81 and 89%. For PROMM, the k-disease classifier achieved a sensitivity of 51% and specificity of 90%.

CONCLUSIONS: Pain2D is a scalable, open-source tool that could potentially be trained for all diseases presenting with pain.

PMID:36978184 | DOI:10.1186/s13023-023-02663-z

Anticancer Res. 2023 Apr;43(4):1397-1405. doi: 10.21873/anticanres.16288.

ABSTRACT

BACKGROUND/AIM: Small cell neuroendocrine carcinoma of the cervix (SCNEC) is a rare disease characterized by a higher incidence of lymphatic invasion, metastasis, and recurrence compared to the squamous cell carcinoma and adenocarcinoma subtypes. Furthermore, it is prone to early distant metastasis and has a poor prognosis. Chemotherapy has an important role in the management of cervical SCNEC. The effective treatment schemes for early-stage SCNEC are local treatment with radical surgery and systemic chemotherapy. However no standard treatment regimen exists because of a rare disease. We reviewed previous reports to determine whether etoposide/platinum, which is used for histopathologically similar small cell carcinoma of the lung, is an appropriate initial chemotherapy regimen for SCNEC of the cervix.

MATERIALS AND METHODS: In this review the Cochrane library sources, ClinicalTrials.gov, Web of Silence, PubMed and search engine of Google scholar were searched for all interventional studies, reviews, case reports and meta-analyses published in 1997-2021.

RESULTS: Etoposide/platinum (EP) is the most commonly used regimen and paclitaxel/carboplatin is the second most common, used as a part of multimodality therapy for SCNEC of the cervix in most studies. Cisplatin/vincristine/bleomycin, cisplatin/irinotecan, cisplatin/ifosfamide/etoposide were also reported in concurrence with EP; however no clinical trials are dedicated to SCNEC.

CONCLUSION: Etoposide and platinum tend to have a better prognosis compared to other regimens used for other subtypes of cervical cancer. For recurrent cervical SCNEC, treatment options for patients are very limited. The application of molecular testing for targeted mutations may suggest potential future therapies that may be useful in this disease.

PMID:36974776 | DOI:10.21873/anticanres.16288

Prostate. 2023 Jun;83(8):814-819. doi: 10.1002/pros.24521. Epub 2023 Mar 26.

ABSTRACT

BACKGROUND: Metastatic adenoid cystic (basal cell) carcinoma of the prostate is an exceedingly rare disease entity. As a result, no current consensus exists for optimal systemic therapy.

METHODS: We present a patient with metastatic adenoid cystic (basal cell) carcinoma of the prostate who subsequently received systemic treatment, including chemotherapy and immunotherapy. We comprehensively reviewed all published data on therapy outcomes in advanced disease.

RESULTS: Our patient benefited from combination chemotherapy (carboplatin and paclitaxel), with objective radiographic response and reduction in cancer-related pain. However, chemotherapy was stopped due to cumulative neurotoxicity, and subsequent immunotherapy with atezolizumab did not produce any response. Our literature review revealed inconsistent outcomes with various treatments but showed most promise with chemotherapy. Targeted therapy and immunotherapy seem to benefit specific cases, and androgen deprivation therapy had minimal evidence of benefit.

CONCLUSION: Based on the findings of our case report and literature review, we suggest platinum-based chemotherapy doublets as first-line treatment for metastatic cases of adenoid cystic (basal cell) carcinoma of the prostate, reserving targeted therapy or immunotherapy for select cases based upon molecular profiles.

PMID:36967482 | DOI:10.1002/pros.24521

BMC Public Health. 2023 Mar 27;23(1):567. doi: 10.1186/s12889-023-15470-9.

ABSTRACT

BACKGROUND: Neurogenic limb deformity disorder (NLDD) refers to limb deformity disorders caused by various neurogenic disorders. However, there are no studies to systematically summarize and analyze these diseases in China, and we first proposed the concept of NLDD. We describe the epidemiological characteristics of NLDD in China based on the largest case database of limb orthopedics in China.

METHODS: This study analyzed parameters from the Qin Sihe Orthopedic Surgery Case Data (QSHOSCD). The database is based on the Rehabilitation Hospital affiliated to National Research Center for Rehabilitation, which has collected nearly 37,000 patients to date and includes a wide variety of limb deformities. The types of diseases are summarized and classified for all patients studied. Statistical analysis was based on the type of etiology, age, regional distribution, and historical surgical volume. Partial outcomes were statistically analyzed separately by common diseases (polio and cerebral palsy) and rare diseases (37 other diseases).

RESULTS: From 1979 to 2019, 30,194 patients with NLDD were treated surgically for 39 neurogenic disorders. The male to female ratio was 1.48:1, the mean age was 19.65 years, and most patients (82.38%) were aged between 6 and 30 years. Patients included from 32 provinces and cities across China, mainly concentrated in populous central provinces and Heilongjiang Province. The peak of annual surgical procedures was from 1988 to 1994, and the number of annual surgical procedures for common diseases gradually decreased from 1994 onwards, but the trending is opposite for rare diseases.

CONCLUSIONS: This study is the first to demonstrate the disease types, population characteristics and incidence trends of NLDD in China. It suggests that the prevention and treatment of NLDD should focus on the adolescent population and enhance the treatment of neurogenic diseases that cause limb deformities. The growth and adaption of the Ilizarov technique and its practice in Chinese orthopedic benefits the treatment of neurogenic limb deformity disorders.

PMID:36973707 | DOI:10.1186/s12889-023-15470-9

BMC Infect Dis. 2023 Mar 27;23(1):180. doi: 10.1186/s12879-023-08148-5.

ABSTRACT

BACKGROUND: Whipple's disease is known to cause multiple varied systemic symptoms, and is a well-documented cause of culture-negative endocarditis. Endocarditis secondary to Whipple disease, however, has rarely been known to present primarily as a cause of acute limb ischemia. We describe such a case here.

CASE PRESENTATION: A previously healthy 40 year old man presented to the emergency department with acute-onset right arm paresthesias. On exam, he was found to be tachycardic with a VI/VI systolic ejection murmur. He was diagnosed with critical limb ischemia and severe aortic regurgitation, and echocardiography showed a large mass on his bicuspid aortic valve. Thrombectomy was performed urgently, with aortic valve repair the following day. As blood cultures and valvular tissue culture remained unrevealing, the patient remained on empiric vancomycin and ceftriaxone for culture-negative endocarditis. 16 s rRNA nucleic acid amplification testing (NAAT) of his formalin-fixed, paraffin-embedded valvular tissue detected T. whipplei, after which the patient was transitioned to ceftriaxone and trimethoprim-sulfamethoxazole for a year of therapy. He continues to do clinically well.

CONCLUSIONS: We report an unusual presentation of Whipple endocarditis as an acute upper limb ischemia, absent other classic symptoms of Whipple's disease, and with diagnosis made by 16 s rRNA NAAT of valvular tissue in the setting of culture-negative endocarditis.

PMID:36973675 | DOI:10.1186/s12879-023-08148-5

Intern Med J. 2023 Mar;53(3):449-450. doi: 10.1111/imj.16018.

NO ABSTRACT

PMID:36972997 | DOI:10.1111/imj.16018

Front Neurol. 2023 Mar 8;14:1098454. doi: 10.3389/fneur.2023.1098454. eCollection 2023.

ABSTRACT

Substantial challenges in study design and methodology exist during clinical trial development to examine treatment response in patients with a rare disease, especially those with predominant central nervous system involvement and heterogeneity in clinical manifestations and natural history. Here we discuss crucial decisions which may significantly impact success of the study, including patient selection and recruitment, identification and selection of endpoints, determination of the study duration, consideration of control groups including natural history controls, and selection of appropriate statistical analyses. We review strategies for the successful development of a clinical trial to evaluate treatment of a rare disease with a focus on inborn errors of metabolism (IEMs) that present with movement disorders. The strategies presented using pantothenate kinase-associated neurodegeneration (PKAN) as the rare disease example can be applied to other rare diseases, particularly IEMs with movement disorders (e.g., other neurodegeneration with brain iron accumulation disorders, lysosomal storage disorders). The significant challenges associated with designing a clinical trial in rare disease can sometimes be successfully met through strategic engagement with experts in the rare disease, seeking regulatory and biostatistical guidance, and early involvement of patients and families. In addition to these strategies, we discuss the urgent need for a paradigm shift within the regulatory processes to help accelerate medical product development and bring new innovations and advances to patients with rare neurodegenerative diseases who need them earlier in disease progression and prior to clinical manifestations.

PMID:36970548 | PMC:PMC10032345 | DOI:10.3389/fneur.2023.1098454

Nat Commun. 2023 Mar 25;14(1):1677. doi: 10.1038/s41467-023-37092-w.

ABSTRACT

DICER1 syndrome is a tumor predisposition syndrome that is associated with up to 30 different neoplastic lesions, usually affecting children and adolescents. Here we identify a group of mesenchymal tumors which is highly associated with DICER1 syndrome, and molecularly distinct from other DICER1-associated tumors. This group of DICER1-associated mesenchymal tumors encompasses multiple well-established clinicopathological tumor entities and can be further divided into three clinically meaningful classes designated "low-grade mesenchymal tumor with DICER1 alteration" (LGMT DICER1), "sarcoma with DICER1 alteration" (SARC DICER1), and primary intracranial sarcoma with DICER1 alteration (PIS DICER1). Our study not only provides a combined approach to classify DICER1-associated neoplasms for improved clinical management but also suggests a role for global hypomethylation and other recurrent molecular events in sarcomatous differentiation in mesenchymal tumors with DICER1 alteration. Our results will facilitate future investigations into prognostication and therapeutic approaches for affected patients.

PMID:36966138 | PMC:PMC10039902 | DOI:10.1038/s41467-023-37092-w

Curr Neuropharmacol. 2023;21(3):438-439. doi: 10.2174/1570159X2103230207104332.

NO ABSTRACT

PMID:36960641 | DOI:10.2174/1570159X2103230207104332

Expert Rev Clin Immunol. 2023 Mar 24. doi: 10.1080/1744666X.2023.2195165. Online ahead of print.

ABSTRACT

INTRODUCTION: Generalized pustular psoriasis (GPP), is a rare cutaneous and systemic inflammatory disease which is characterized by flares of widespread painful pustulation of the skin, often associated with fever and elevated inflammatory markers. Although it has historically been regarded as a severe variant of plaque psoriasis, genetic and immunological developments over the past decade have revealed that it is a distinct auto-inflammatory entity, in which over-activity of the interleukin-36 signaling pathway is fundamental. Treatments targeting the IL-36 pathway are under investigation, and in 2022 spesolimab, a monoclonal antibody against the IL-36 receptor, was licensed for treating flares of GPP.

AREAS COVERED: In this review I discuss the epidemiology, clinical features, genetics, patho-mechanisms and current treatment options for GPP. I describe the results of clinical trials that led to the licensing of spesolimab for flares of GPP.

EXPERT OPINION: The marked efficacy of spesolimab in GPP opens a new era of highly effective, scientifically-rational and evidence-based treatment for this orphan disease, and has implications for other diseases in which interleukin 36 signaling is involved.

PMID:36960829 | DOI:10.1080/1744666X.2023.2195165

Front Oncol. 2023 Mar 7;13:1128994. doi: 10.3389/fonc.2023.1128994. eCollection 2023.

ABSTRACT

Thrombosis is the most common and a life-threatening complication in patients with Paroxysmal Nocturnal Hemoglobinuria. One-third of patients with PNH experience at least one thromboembolic event during the course of the disease, with thrombosis being the most common cause of death in these patients. The mechanism of thrombosis in PNH is complex and continues to be of great research interest. Since the introduction of C5 complement inhibitors in the treatment of PNH, the incidence of thromboembolic events has decreased substantially. We retrospectively analyzed data concerning the thrombotic episodes of 41 patients with PNH from 14 different national hematology centers in Greece. Sixteen patients (39%) experienced at least one episode of thrombosis, including, seven (43.8%) at diagnosis, seven (43.8%) during the course of the disease and two (12.5%) patients prior to PNH diagnosis. Nearly half of these individuals (n=7, 43.8%) had multiple episodes of thrombosis during the course of their disease. The most common sites of thrombosis were intra-abdominal veins. Three out of 26 patients developed thrombosis while on eculizumab. In none of the 16 patients, the thrombotic event was fatal. Our findings, despite the small number of patients, confirmed that thrombosis continues to be a significant complication of PNH affecting more than one third of the patients.

PMID:36959785 | PMC:PMC10028290 | DOI:10.3389/fonc.2023.1128994

Patient. 2023 May;16(3):183-199. doi: 10.1007/s40271-023-00619-w. Epub 2023 Mar 22.

ABSTRACT

Patient registries fulfill a number of key roles for clinicians, researchers, non-profit organizations, payers, and policy makers. They can help the field understand the natural history of a condition, determine the effectiveness of interventions, measure safety, and audit the quality of care provided. Successful registries in cystic fibrosis, Duchenne's muscular dystrophy, and other rare diseases have become a model for accelerating progress. However, the complex tasks required to develop a modern registry can seem overwhelming, particularly for those who are not from a technical background. In this Education article, a team of co-authors from across patient advocacy, technology, privacy, and commercial perspectives who have worked on a number of such projects offer a "Registry 101" primer to help get started. We will outline the promise and potential of patient registries with worked case examples, identify some of the key technical considerations you will need to consider, describe the type of data you might want to collect, consider privacy risks to protect your users, sketch out some of the paths towards long-term financial sustainability we have observed, and conclude with plans to mitigate some of the challenges that can occur and signpost interested readers to further resources. While rapid growth in the digital health market has presented numerous opportunities to those at the beginning of their journey, it is important to start with the long-term goals in mind and to benefit from the learnings of those who have walked this path before.

PMID:36947286 | PMC:PMC10031688 | DOI:10.1007/s40271-023-00619-w

J Coll Physicians Surg Pak. 2023 Mar;33(3):364. doi: 10.29271/jcpsp.2023.03.364.

ABSTRACT

Null.

PMID:36945174 | DOI:10.29271/jcpsp.2023.03.364

Zhongguo Dang Dai Er Ke Za Zhi. 2023 Mar 15;25(3):308-314. doi: 10.7499/j.issn.1008-8830.2211010.

ABSTRACT

Rare diseases refer to a group of single diseases with low incidence rates, complex pathogeneses, severe disease conditions, and rapid progression. Most rare diseases have a genetic background and may occur in childhood. Paying attention to the rare genetic diseases in children and performing early diagnosis and treatment can effectively delay the course of disease and improve the quality of life of children. Many rare diseases can be diagnosed with the help of various experimental techniques, but the diagnosis of rare diseases is still not widely understood. This article summarizes the laboratory diagnostic techniques currently used for rare genetic diseases in children, so as to provide clues for the diagnosis and treatment of such diseases and help to enhance the theoretical understanding and precise medical treatment of rare genetic diseases in children.

PMID:36946168 | DOI:10.7499/j.issn.1008-8830.2211010

Orphanet J Rare Dis. 2023 Mar 21;18(1):63. doi: 10.1186/s13023-023-02628-2.

ABSTRACT

BACKGROUND: GLUT1 deficiency syndrome is a rare, genetically determined neurological disorder for which Ketogenic Dietary Treatment represents the gold standard and lifelong treatment. Patient registries are powerful tools providing insights and real-world data on rare diseases.

OBJECTIVE: To describe the implementation of a national web-based registry for GLUT1-DS.

METHODS: This is a retrospective and prospective, multicenter, observational registry developed in collaboration with the Italian GLUT1-DS association and based on an innovative, flexible and configurable cloud computing technology platform, structured according to the most rigorous requirements for the management of patient's sensitive data. The Glut1 Registry collects baseline and follow-up data on the patient's demographics, history, symptoms, genotype, clinical, and instrumental evaluations and therapies.

RESULTS: Five Centers in Italy joined the registry, and two more Centers are currently joining. In the first two years of running, data from 67 patients (40 females and 27 males) have been collected. Age at symptom onset was within the first year of life in most (40, 60%) patients. The diagnosis was formulated in infancy in almost half of the cases (34, 51%). Symptoms at onset were mainly paroxysmal (mostly epileptic seizure and paroxysmal ocular movement disorder) or mixed paroxysmal and fixed symptoms (mostly psychomotor delay). Most patients (53, 79%) are currently under Ketogenic dietary treatments.

CONCLUSIONS: We describe the principles behind the design, development, and deployment of the web-based nationwide GLUT1-DS registry. It represents a stepping stone towards a more comprehensive understanding of the disease from onset to adulthood. It also represents a virtuous model from a technical, legal, and organizational point of view, thus representing a possible paradigmatic example for other rare disease registry implementation.

PMID:36944981 | DOI:10.1186/s13023-023-02628-2

Front Public Health. 2023 Mar 3;11:1051851. doi: 10.3389/fpubh.2023.1051851. eCollection 2023.

ABSTRACT

INTRODUCTION: This study aims to determine the out-of-pocket health expenditures of households in Turkey where individuals with rare diseases are residing.

METHODS: The research population consisted registered members of associations who are members of the Rare Diseases Network. In addition to the general analysis including all participants, expenditures based on characteristics of disease holders were also calculated.

RESULTS: A total of 439 participants were included in the analysis. We determined that special nutrition was the highest expenditure group and emergency departments were the lowest expenditure group. When all the participants were evaluated, the average cost of rare diseases was found to be Ł22,743 (€2,877). A significant relationship was found between income status and out-of-pocket health expenditures (p = 0.012).

DISCUSSION: Policy makers should consider inclusion of special nutritional products and medical/non-medical devices used in treatment of rare diseases within the scope of reimbursement and the development of orphan drug legislation as the first actions to be taken.

PMID:36935729 | PMC:PMC10020592 | DOI:10.3389/fpubh.2023.1051851

Front Public Health. 2023 Mar 2;11:1079601. doi: 10.3389/fpubh.2023.1079601. eCollection 2023.

ABSTRACT

INTRODUCTION: Rare diseases (RD) are a health priority worldwide, overall affecting hundreds of millions of people globally. Early and accurate diagnosis is essential to support clinical care but remains challenging in many countries, especially the low- and medium-income ones. Hence, undiagnosed RD (URD) account for a significant portion of the overall RD burden.

METHODS: In October 2020, the Developing Nations Working Group of the Undiagnosed Diseases Network International (DNWG-UDNI) launched a survey among its members, belonging to 20 countries across all continents, to map unmet needs and opportunities for patients with URD. The survey was based on questions with open answers and included eight different domains. Conflicting interpretations were resolved in contact with the partners involved.

RESULTS: All members responded to the survey. The results indicated that the scientific and medical centers make substantial efforts to respond to the unmet needs of patients. In most countries, there is a high awareness of RD issues. Scarcity of resources was highlighted as a major problem, leading to reduced availability of diagnostic expertise and research. Serious equity in accessibility to services were highlighted both within and between participating countries. Regulatory problems, including securing informed consent, difficulties in sending DNA to foreign laboratories, protection of intellectual property, and conflicts of interest on the part of service providers, remain issues of concern. Finally, most respondents stressed the need to strengthen international cooperation in terms of data sharing, clinical research, and diagnostic expertise for URD patients in low and medium income countries.

DISCUSSION: The survey highlighted that many countries experienced a discrepancy between the growing expertise and scientific value, the level of awareness and commitment on the part of relevant parties, and funding bodies. Country-tailored public health actions, including general syllabus of medical schools and of the education of other health professionals, are needed to reduce such gaps.

PMID:36935719 | PMC:PMC10017550 | DOI:10.3389/fpubh.2023.1079601

Front Public Health. 2023 Mar 2;11:1127713. doi: 10.3389/fpubh.2023.1127713. eCollection 2023.

ABSTRACT

In Latin America (LA), 40-50 million people live with rare diseases (RDs) that require constant monitoring, care, and attention. Caregivers help them with their basic life activities and medication administration, which they would otherwise be unable to perform. Family caregivers complement healthcare and social security systems; however, their unpaid work is often underappreciated and under-protected. Recognizing the need to address these unrecognized and undervalued women, the Americas Health Foundation (AHF) convened a panel of LA experts on caregiving for people with RDs to provide recommendations to support the undervalued family caregivers. A panel of LA experts in caregiving for RDs were given questions to address the challenges faced by family caregivers of people with RDs in LA. During a 3-day conference, the panelists' responses were discussed and edited until the panel agreed on recommendations to address the challenges. The identified challenges for caregivers included physical, emotional, and economical areas. Caregivers, primarily women, experienced physical pain, and social isolation, and were forced to pay substantial out-of-pocket expenses in their caregiving roles. Brazil and Colombia are at the forefront of policies to protect caregivers and their experiences in attempting to provide for this group are outlined as case studies for what is possible in LA. Finally, recognizing that caregivers must be included in formulating, executing, and evaluating care policies for people living with RDs and that the caregivers themselves require social assurances, the panel suggested policy objectives aimed at protecting caregivers of people living with RDs. The recommendations ranged from recognizing the role of the family caregiver as an essential supplement to the formal healthcare system to providing financial assistance, training, and workplace protection, among others. Finally, monitoring and evaluating the impact of policies is necessary to ensure that LA is moving forward in caring for family caregivers for people with RDs.

PMID:36935700 | PMC:PMC10017724 | DOI:10.3389/fpubh.2023.1127713

Nat Med. 2023 Mar;29(3):543-544. doi: 10.1038/s41591-023-02218-6.

NO ABSTRACT

PMID:36928822 | DOI:10.1038/s41591-023-02218-6

Nat Med. 2023 Mar;29(3):679-688. doi: 10.1038/s41591-023-02211-z. Epub 2023 Mar 16.

ABSTRACT

The genetic etiologies of more than half of rare diseases remain unknown. Standardized genome sequencing and phenotyping of large patient cohorts provide an opportunity for discovering the unknown etiologies, but this depends on efficient and powerful analytical methods. We built a compact database, the 'Rareservoir', containing the rare variant genotypes and phenotypes of 77,539 participants sequenced by the 100,000 Genomes Project. We then used the Bayesian genetic association method BeviMed to infer associations between genes and each of 269 rare disease classes assigned by clinicians to the participants. We identified 241 known and 19 previously unidentified associations. We validated associations with ERG, PMEPA1 and GPR156 by searching for pedigrees in other cohorts and using bioinformatic and experimental approaches. We provide evidence that (1) loss-of-function variants in the Erythroblast Transformation Specific (ETS)-family transcription factor encoding gene ERG lead to primary lymphoedema, (2) truncating variants in the last exon of transforming growth factor-β regulator PMEPA1 result in Loeys-Dietz syndrome and (3) loss-of-function variants in GPR156 give rise to recessive congenital hearing impairment. The Rareservoir provides a lightweight, flexible and portable system for synthesizing the genetic and phenotypic data required to study rare disease cohorts with tens of thousands of participants.

PMID:36928819 | PMC:PMC10033407 | DOI:10.1038/s41591-023-02211-z