Am J Hum Genet. 2021 Feb 4;108(2):217-218. doi: 10.1016/j.ajhg.2021.01.003.

ABSTRACT

Danny is the father of two boys with MEPAN syndrome and a member of Global Genes' RARE Foundation Alliance Leadership Council.

PMID:33545028 | DOI:10.1016/j.ajhg.2021.01.003

Am J Hum Genet. 2021 Feb 4;108(2):213. doi: 10.1016/j.ajhg.2021.01.005.

NO ABSTRACT

PMID:33545026 | DOI:10.1016/j.ajhg.2021.01.005

Rare cancers are not rare in Asia as well: The rare cancer burden in East Asia.

Cancer Epidemiol. 2020 08;67:101702

Authors: Matsuda T, Won YJ, Chun-Ju Chiang R, Lim J, Saika K, Fukui K, Lee WC, Botta L, Bernasconi A, Trama A

Abstract
INTRODUCTION: Epidemiologic information on rare cancers is scarce outside of the Western countries. The project "surveillance of rare cancers in Asia" (RARECAREnet Asia) provides, for the first time, the burden of rare cancers in some Asian countries based on the latest list.
OBJECTIVES: 1) to assess whether the European list of rare cancers fits the Asian setting and 2) to compare the incidences of rare cancers between Europe and Asian countries.
MATERIAL AND METHODS: Population-based cancer registry data on patients diagnosed from 2011 to 2015 in Japan, Korea, and Taiwan and patients diagnosed from 2000 to 2007 in 94 European registries were analysed. The incidences for all cancers were calculated; they were then grouped into several tiers and families according to the rare cancer list, and whether cancers rare was examined.
RESULTS: Rare cancer counts according to the list in the observed population were 196 in Japan, 203 in Korea, 198 in Taiwan, and 198 in the EU. The proportions of rare in overall incidence were 16.3% in Japan, 23.7% in Korea, 24.2% in Taiwan, and 22.2% in the EU. The numbers of newly diagnosed rare cancer cases in 2015 were 140,188 in Japan, 52,071 in Korea, and 24,147 in Taiwan.
CONCLUSION: Most rare cancers in Europe were also rare in the Asian countries considered. The observed differences were due to well-known risk factors. The European definition and list of rare cancers appear to reflect well cancer incidence in East Asia.

PMID: 32535408 [PubMed - indexed for MEDLINE]

Rare cancers in Canada, 2006-2016: A population-based surveillance report and comparison of different methods for classifying rare cancers.

Cancer Epidemiol. 2020 08;67:101721

Authors: Walker EV, Maplethorpe E, Davis FG

Abstract
BACKGROUND: The cumulative burden from rare cancers has not been adequately explored in Canada. This analysis aims to characterize the occurrence of rare cancers among Canadians and estimate the probability of being diagnosed with a rare cancer among cancer patients with different demographic characteristics.
METHODS: The Canadian Cancer Registry was used for this analysis. Cancer types were classified in three ways: using the SEER site recode scheme; by histology group; and by site/histology group. The age-standardized incidence rate (ASIR) and 95 % confidence intervals (CI) for each cancer type was estimated for diagnoses from 2006 to 2016. Two ASIR thresholds were used to classify cancers as rare:6/100,000/year and 15/100,000/year. Log-binomial regression was used to estimate the adjusted probability of having a rare cancer among those with cancer by age, sex and geographic region.
RESULTS: Using the 6/100,000/year threshold, the incidence proportion (IP) of rare cancers ranged from 9.7 %(95 %CI:9.6,9.7 %)-17.0 %(95 %CI:16.9,17.0 %), and ranged from 19.2 %(95 %CI:19.1,19.3 %)-52.5 %(95 %CI:52.0,53.0 %) using the <15/100,000/year threshold. The adjusted probability of being diagnosed with a rare cancer was highest among those aged ≤19 years. There was higher concordance in estimates of the burden of rare cancers across methods to classify cancer types when the lower incidence rate threshold was used to define rare cancers.
INTERPRETATION: This analysis yielded evidence that rare cancers comprise a substantial proportion of annual cancer diagnoses among Canadians. Findings from this analysis point to using a lower incidence rate threshold, to generate estimates of the burden of rare cancers that are robust to different cancer classification schemes.

PMID: 32416499 [PubMed - indexed for MEDLINE]

A phenotypically severe, biochemically "silent" case of HIBCH deficiency in a newborn diagnosed by rapid whole exome sequencing and enzymatic testing.

Am J Med Genet A. 2020 04;182(4):780-784

Authors: D'Gama AM, Brucker WJ, Zhang T, Gubbels CS, Ferdinandusse S, Shi J, Grant PE, VanNoy G, Genetti CA, Juusola J, Yu TW, Kritzer A, Agrawal PB

Abstract
3-Hydroxyisobutyryl-CoA dehydrogenase (HIBCH) deficiency is a rare error in valine catabolism associated with a Leigh syndrome-like phenotype, mitochondrial dysfunction, and increased C4-OH. We report the most severe case to date in a full-term female who presented with poor feeding and nystagmus on day of life (DOL) 1. Although initial neuroimaging findings were concerning for metabolic disease, further metabolic testing was nondiagnostic and she was discharged on DOL 18. She was readmitted on DOL 22 after severe apneic episodes requiring intubation, with EEG demonstrating multifocal seizures and MRI/MRS demonstrating worsening findings. Care was withdrawn DOL 27 and she expired. Rapid whole exome sequencing (WES) demonstrated compound heterozygous variants in HIBCH with a paternal pathogenic variant (c.852delA, p.L284FfsX10) and a maternal likely pathogenic variant (c.488G>T, p.C163F). Fibroblast enzymatic testing demonstrated marked reduction in HIBCH levels. This case demonstrates the importance of rapid WES and follow-up functional testing in establishing a diagnosis when metabolic disease is suspected but lacks an expected biochemical signature.

PMID: 32022391 [PubMed - indexed for MEDLINE]

Diagnostic utility of transcriptome sequencing for rare Mendelian diseases.

Genet Med. 2020 03;22(3):490-499

Authors: Lee H, Huang AY, Wang LK, Yoon AJ, Renteria G, Eskin A, Signer RH, Dorrani N, Nieves-Rodriguez S, Wan J, Douine ED, Woods JD, Dell'Angelica EC, Fogel BL, Martin MG, Butte MJ, Parker NH, Wang RT, Shieh PB, Wong DA, Gallant N, Singh KE, Tavyev Asher YJ, Sinsheimer JS, Krakow D, Loo SK, Allard P, Papp JC, Undiagnosed Diseases Network, Palmer CGS, Martinez-Agosto JA, Nelson SF

Abstract
PURPOSE: We investigated the value of transcriptome sequencing (RNAseq) in ascertaining the consequence of DNA variants on RNA transcripts to improve the diagnostic rate from exome or genome sequencing for undiagnosed Mendelian diseases spanning a wide spectrum of clinical indications.
METHODS: From 234 subjects referred to the Undiagnosed Diseases Network, University of California-Los Angeles clinical site between July 2014 and August 2018, 113 were enrolled for high likelihood of having rare undiagnosed, suspected genetic conditions despite thorough prior clinical evaluation. Exome or genome sequencing and RNAseq were performed, and RNAseq data was integrated with genome sequencing data for DNA variant interpretation genome-wide.
RESULTS: The molecular diagnostic rate by exome or genome sequencing was 31%. Integration of RNAseq with genome sequencing resulted in an additional seven cases with clear diagnosis of a known genetic disease. Thus, the overall molecular diagnostic rate was 38%, and 18% of all genetic diagnoses returned required RNAseq to determine variant causality.
CONCLUSION: In this rare disease cohort with a wide spectrum of undiagnosed, suspected genetic conditions, RNAseq analysis increased the molecular diagnostic rate above that possible with genome sequencing analysis alone even without availability of the most appropriate tissue type to assess.

PMID: 31607746 [PubMed - indexed for MEDLINE]

Survey of Japanese Orphan Drug Program: Factors Related to Successful Marketing Approval.

J Clin Pharmacol. 2020 01;60(1):117-124

Authors: Harada K, Toriyabe K, Ono S

Abstract
The basic components of regulatory and supporting policies for orphan drug development appear similar between the United States and Japan, but drugs designated as orphan drugs have been different between the 2 countries. The probabilities of development success (ie, marketing approval) in designated orphan drugs have also been significantly different. In this study, we analyzed recent outcomes of development for orphan drugs designated from 1993 to 2017 in Japan, considering their development and approval status in the United States. Our analysis showed that success for orphan drug development in Japan was apparently associated with prior approval status in the United States. Company size, orphan development experience, and patient enrichment were also positively associated with successful marketing approval. Although similar designations and priority review systems for orphan drugs have been enacted, economic incentives and regulatory conditions provided by the systems seem to be different between the 2 countries, which may lead to varied performance in orphan designation and approval. We need to pay close attention to the impact of industrial global development strategies when comparing the outcomes and performance of different orphan drug promotion systems.

PMID: 31364772 [PubMed - indexed for MEDLINE]

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2021/02/03

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Int J Environ Res Public Health. 2021 Jan 26;18(3):1101. doi: 10.3390/ijerph18031101.

ABSTRACT

In the field of rare diseases (RDs), the evidence standard is often lower than that required by health technology assessment (HTA) and payer authorities. In this commentary, we propose that appropriate economic evaluation for rare disease treatments should be initially informed by cost-of-illness (COI) studies conducted using a societal perspective. Such an approach contributes to improving countries' understanding of RDs in their entirety as societal and not merely clinical, or product-specific issues. In order to exemplify how the disease burden's distribution has changed over the last fifteen years, key COI studies for Hemophilia, Fragile X Syndrome, Cystic Fibrosis, and Juvenile Idiopathic Arthritis are examined. Evidence shows that, besides methodological variability and cross-country differences, the disease burden's share represented by direct costs generally grows over time as novel treatments become available. Hence, to support effective decision-making processes, it seems necessary to assess the re-allocation of the burden produced by new medicinal products, and this approach requires identifying cost drivers through COI studies with robust design and standardized methodology.

PMID:33530652 | PMC:PMC7908548 | DOI:10.3390/ijerph18031101

10 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2021/02/02

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Eur J Hum Genet. 2021 Feb 1. doi: 10.1038/s41431-021-00812-1. Online ahead of print.

ABSTRACT

WNT2B is a member of the Wnt family, a group of signal transduction proteins involved in embryologic development and stem cell renewal and maintenance. We recently reported homozygous nonsense variants in WNT2B in three individuals with severe, neonatal-onset diarrhea, and intestinal failure. Here we present a fourth case, from a separate family, with neonatal diarrhea associated with novel compound heterozygous WNT2B variants. One of the two variants was a frameshift variant (c.423del [p.Phe141fs]), while the other was a missense change (c.722 G > A [p.G241D]) that we predict through homology modeling to be deleterious, disrupting post-translational acylation. This patient presented as a neonate with severe diet-induced (osmotic) diarrhea and growth failure resulting in dependence on parenteral nutrition. Her gastrointestinal histology revealed abnormal cellular architecture particularly in the stomach and colon, including oxyntic atrophy, abnormal distribution of enteroendocrine cells, and a paucity of colonic crypt glands. In addition to her gastrointestinal findings, she had bilateral corneal clouding and atypical genital development later identified as a testicular 46,XX difference/disorder of sexual development. Upon review of the previously reported cases, two others also had anterior segment ocular anomalies though none had atypical genital development. This growing case series suggests that variants in WNT2B are associated with an oculo-intestinal (and possibly gonadal) syndrome, due to the protein's putative involvement in multiple developmental and stem cell maintenance pathways.

PMID:33526876 | DOI:10.1038/s41431-021-00812-1

Cancers (Basel). 2021 Jan 28;13(3):498. doi: 10.3390/cancers13030498.

ABSTRACT

Desmoplastic small round cell tumor (DSRCT) is an extremely rare, aggressive sarcoma affecting adolescents and young adults with male predominance. Generally, it originates from the serosal surface of the abdominal cavity. The hallmark characteristic of DSRCT is the EWSR1-WT1 gene fusion. This translocation up-regulates the expression of PDGFRα, VEGF and other proteins related to tumor and vascular cell proliferation. Current management of DSRCT includes a combination of chemotherapy, radiation and aggressive cytoreductive surgery plus intra-peritoneal hyperthermic chemotherapy (HIPEC). Despite advances in multimodal therapy, outcomes remain poor since the majority of patients present disease recurrence and die within three years. The dismal survival makes DSRCT an orphan disease with an urgent need for new drugs. The treatment of advanced and recurrent disease with tyrosine kinase inhibitors, such as pazopanib, sunitinib, and mTOR inhibitors was evaluated by small trials. Recent studies using comprehensive molecular profiling of DSRCT identified potential therapeutic targets. In this review, we aim to describe the current studies conducted to better understand DSRCT biology and to explore the new therapeutic strategies under investigation in preclinical models and in early phase clinical trials.

PMID:33525546 | PMC:PMC7865637 | DOI:10.3390/cancers13030498

Medicina (Kaunas). 2021 Jan 28;57(2):119. doi: 10.3390/medicina57020119.

ABSTRACT

Uncertainty analysis is the process of identifying limitations in knowledge and evaluating their implications for scientific conclusions. Uncertainty analysis is a stable component of risk assessment and is increasingly used in decision making on complex health issues. Uncertainties should be identified in a structured way and prioritized according to their likely impact on the outcome of scientific conclusions. Uncertainty is inherent to the rare diseases (RD) area, where research and healthcare have to cope with knowledge gaps due to the rarity of the conditions; yet a systematic approach toward uncertainties is not usually undertaken. The uncertainty issue is particularly relevant to multifactorial RD, whose etiopathogenesis involves environmental factors and genetic predisposition. Three case studies are presented: the newly recognized acute multisystem inflammatory syndrome in children and adolescents associated with SARS-CoV-2 infection; the assessment of risk factors for neural tube defects; and the genotype-phenotype correlation in familial Mediterranean fever. Each case study proposes the initial identification of the main epistemic and sampling uncertainties and their impacts. Uncertainty analysis in RD may present aspects similar to those encountered when conducting risk assessment in data-poor scenarios; therefore, approaches such as expert knowledge elicitation may be considered. The RD community has a main strength in managing uncertainty, as it proactively develops stakeholder involvement, data sharing and open science. The open science approaches can be profitably integrated by structured uncertainty analysis, especially when dealing with multifactorial RD involving environmental and genetic risk factors.

PMID:33525390 | DOI:10.3390/medicina57020119

Orphanet J Rare Dis. 2021 Feb 1;16(1):61. doi: 10.1186/s13023-021-01711-w.

ABSTRACT

PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic has had unprecedented impact on the provision of medical care for genetic disorders. The purpose of this study was to assess the effects of the pandemic on neurofibromatosis (NF) care and research.

METHODS: Sixty-three United States NF clinics were surveyed to identify the impact of the pandemic on clinician role, patient volume, continuity of guideline-driven surveillance, research protocols, and use of (and satisfaction with) telehealth for the delivery of NF care.

RESULTS: Fifty-two clinic directors or their representatives completed the survey (83% response rate). About 2/3 of the clinics reported a greater than 50% decrease in the number of available patient appointments, and modified clinical surveillance and research protocols. Fifty-one clinics (98%) newly instituted telehealth during the pandemic. Barriers to telehealth prior to the pandemic were insurance reimbursement concerns and lack of infrastructure. Since telehealth was initiated, high provider satisfaction was reported with ease of use. The most common area of concern was related to inability to perform a physical examination.

CONCLUSION: Results show marked impacts on NF care and research since the beginning of the pandemic, with potential long-term changes related to the introduction (or adoption) of telehealth for clinical care.

PMID:33522938 | PMC:PMC7848872 | DOI:10.1186/s13023-021-01711-w

Leg lengthening and deformity correction in rare bone diseases: a multidisciplinary approach.

Wien Med Wochenschr. 2021 Jan 29;:

Authors: Mindler GT, Stauffer A, Ganger R

Abstract
Congenital and acquired conditions presenting with leg length discrepancy, leg deformity or short stature are not only a challenge for paediatric orthopaedic surgeons in terms of treatment options but may also involve a number of medical specialties due to the complex clinical manifestations of the diseases. Various surgical treatment options are available for these rare genetic diseases, including bone lengthening and growth inhibition techniques for lower limb discrepancy, as well as guided growth and other surgical procedures for correction of angular deformities. Surgical techniques may be similar, but the treatment plans and specific multidisciplinary approaches may differ. The present report is focused on paediatric orthopaedic and multidisciplinary aspects of the treatment of rare bone diseases. We address the clinical presentation of these diseases, gait and surgical procedures for conditions such as achondroplasia, X‑linked hypophosphatemia and osteogenesis imperfecta. We also provide a short overview of other rare bone diseases.

PMID: 33512619 [PubMed - as supplied by publisher]

[The influence of orphan drug policy on the development of anti-tumor drugs].

Zhonghua Nei Ke Za Zhi. 2021 Feb 01;60(2):171-174

Authors: Feng S, Gong MC, Bai H, Shen Y, Zhang SY

PMID: 33503733 [PubMed - indexed for MEDLINE]

Delusional infestation: a prototype of psychodermatological disease.

Int J Dermatol. 2020 May;59(5):551-560

Authors: Katsoulis K, Rutledge KJ, Jafferany M

Abstract
Delusional infestation (DI) is a disorder in which patients express a firm, unwavering belief that they are infested with some type of organism but otherwise have a typical grasp on reality with relatively normal cognitive functioning. Although classified as a somatic delusional disorder, DI requires special consideration due to its complicated clinical presentation, requiring attention to several possible explanations for the symptoms the patients describe. The purpose of the current review is to first summarize the clinical background and features of the diagnosis then explore treatment options. DI is a rare disorder though has reported cases dating back to the 19th century and spanning across the globe. Patients often experience the disorder as secondary to a medical condition, including substance use/withdrawal. However, there have also been many reported cases of primary DI, occurring in the absence of any other psychiatric or medical disorder. Clinically, DI is a diagnosis of exclusion, where the physician must rule out other medical conditions, including genuine dermatological disorders or infestations, or contributions from medications or substances. Patients with the disorder more commonly present to nonpsychiatric healthcare providers, making it essential for all clinicians to be able to identify the disease. Treatment can include either first or second generation antipsychotics, but it is important to proceed tactfully in discourse with the patient, being careful to address patients in a straightforward manner without reinforcing or questioning the delusion and focusing conversation on what can be done for the symptoms. Future research can continue to evaluate pathophysiology underlying primary DI, which historically has been an under-studied topic.

PMID: 31773724 [PubMed - indexed for MEDLINE]

Phenotypic expansion of Bosch-Boonstra-Schaaf optic atrophy syndrome and further evidence for genotype-phenotype correlations.

Am J Med Genet A. 2020 06;182(6):1426-1437

Authors: Rech ME, McCarthy JM, Chen CA, Edmond JC, Shah VS, Bosch DGM, Berry GT, Williams L, Madan-Khetarpal S, Niyazov D, Shaw-Smith C, Kovar EM, Lupo PJ, Schaaf CP

Abstract
Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS) is an autosomal dominant neurodevelopmental disorder caused by loss-of-function variants in NR2F1 and characterized by visual impairment, developmental delay, and intellectual disability. Here we report 18 new cases, provide additional clinical information for 9 previously reported individuals, and review an additional 27 published cases to present a total of 54 patients. Among these are 22 individuals with point mutations or in-frame deletions in the DNA-binding domain (DBD), and 32 individuals with other types of variants including whole-gene deletions, nonsense and frameshift variants, and point mutations outside the DBD. We corroborate previously described clinical characteristics including developmental delay, intellectual disability, autism spectrum disorder diagnoses/features thereof, cognitive/behavioral anomalies, hypotonia, feeding difficulties, abnormal brain MRI findings, and seizures. We also confirm a vision phenotype that includes optic nerve hypoplasia, optic atrophy, and cortical visual impairment. Additionally, we expand the vision phenotype to include alacrima and manifest latent nystagmus (fusional maldevelopment), and we broaden the behavioral phenotypic spectrum to include a love of music, an unusually good long-term memory, sleep difficulties, a high pain tolerance, and touch sensitivity. Furthermore, we provide additional evidence for genotype-phenotype correlations, specifically supporting a more severe phenotype associated with DBD variants.

PMID: 32275123 [PubMed - indexed for MEDLINE]

Limitations of exome sequencing in detecting rare and undiagnosed diseases.

Am J Med Genet A. 2020 06;182(6):1400-1406

Authors: Burdick KJ, Cogan JD, Rives LC, Robertson AK, Koziura ME, Brokamp E, Duncan L, Hannig V, Pfotenhauer J, Vanzo R, Paul MS, Bican A, Morgan T, Duis J, Newman JH, Hamid R, Phillips JA, Undiagnosed Diseases Network

Abstract
While exome sequencing (ES) is commonly the final diagnostic step in clinical genetics, it may miss diagnoses. To clarify the limitations of ES, we investigated the diagnostic yield of genetic tests beyond ES in our Undiagnosed Diseases Network (UDN) participants. We reviewed the yield of additional genetic testing including genome sequencing (GS), copy number variant (CNV), noncoding variant (NCV), repeat expansion (RE), or methylation testing in UDN cases with nondiagnostic ES results. Overall, 36/54 (67%) of total diagnoses were based on clinical findings and coding variants found by ES and 3/54 (6%) were based on clinical findings only. The remaining 15/54 (28%) required testing beyond ES. Of these, 7/15 (47%) had NCV, 6/15 (40%) CNV, and 2/15 (13%) had a RE or a DNA methylation disorder. Thus 18/54 (33%) of diagnoses were not solved exclusively by ES. Several methods were needed to detect and/or confirm the functional effects of the variants missed by ES, and in some cases by GS. These results indicate that tests to detect elusive variants should be considered after nondiagnostic preliminary steps. Further studies are needed to determine the cost-effectiveness of tests beyond ES that provide diagnoses and insights to possible treatment.

PMID: 32190976 [PubMed - indexed for MEDLINE]

Paces of Costly Care: Rare Disease Drug Access in Canada.

Med Anthropol. 2020 May-Jun;39(4):319-332

Authors: McGuire M

Abstract
Pharmaceutical industry representatives and public drug plan managers hold competing visions of drug access, ones I theorize as "fast" and "slow" care paces. The relationship between free market imaginaries and population-based biopolitics is negotiated through these paces from within the flexible political category of rare disease. In this article, I explore expensive rare disease drug access in Canada's universal health system through a temporal lens. I show how two families navigate these powerful negotiations, asserting themselves as deserving of resources while finding ways to consider life and death outside of this clash between health system pragmatics and pharmaceutical promise.

PMID: 30892965 [PubMed - indexed for MEDLINE]