Clin Nucl Med. 2023 Mar 1;48(3):273-275. doi: 10.1097/RLU.0000000000004479. Epub 2022 Dec 24.

ABSTRACT

Intracranial syphilitic gumma is a rare neurological disease. We present 68Ga-DOTA-FAPI-04 and 18F-FDG PET/CT findings of intracranial syphilitic gumma in a 46-year-old man with HIV. In this case, 68Ga-DOTA-FAPI-04 PET/CT outperforms 18F-FDG in helping to visualizing syphilitic gumma. Syphilitic gumma can also cause increase FAPI activity. Our findings suggest the potential value of 68Ga-DOTA-FAPI-04 in the diagnosis of syphilis.

PMID:36723888 | DOI:10.1097/RLU.0000000000004479

J Med Case Rep. 2023 Feb 1;17(1):31. doi: 10.1186/s13256-022-03746-4.

ABSTRACT

BACKGROUND: Presacral myelolipomas form a rare disease and are often found incidentally in imaging diagnostics.

CASE PRESENTATION: In this study, we report the case of a 71-year-old caucasian female with an incidental finding of a retroperitoneal tumor on magnetic resonance imaging scan. This report aimed at presenting the clinical course of this patient with emphasis on analysis of pathological, clinical, and epidemiological features in a meta-analysis of reported cases.

CONCLUSION: Presacral myelolipomas are rare and its etiology remains unclear. Surgical resection is indicated in symptomatic lesions and lesions > 4 cm. More clinical and pathological research on this rare entity is warranted.

PMID:36721209 | DOI:10.1186/s13256-022-03746-4

Orphanet J Rare Dis. 2023 Jan 31;18(1):20. doi: 10.1186/s13023-023-02619-3.

ABSTRACT

Pre-clinical research and development relies heavily upon translationally valid models of disease. A major difficulty in understanding the biology of, and developing treatments for, rare disease is the lack of animal models. It is important that these models not only recapitulate the presentation of the disease in humans, but also that they share functionally equivalent underlying genetic causes. Nonhuman primates share physiological, anatomical, and behavioral similarities with humans resulting from close evolutionary relationships and high genetic homology. As the post-genomic era develops and next generation sequencing allows for the resequencing and screening of large populations of research animals, naturally occurring genetic variation in nonhuman primates with clinically relevant phenotypes is regularly emerging. Here we review nonhuman primate models of multiple rare genetic diseases with a focus on the similarities and differences in manifestation and etiologies across species. We discuss how these models are being developed and how they can offer new tools and opportunities for researchers interested in exploring novel therapeutics for these and other genetic diseases. Modeling human genetic diseases in translationally relevant nonhuman primates presents new prospects for development of therapeutics and a better understanding of rare diseases. The post-genomic era offers the opportunity for the discovery and further development of more models like those discussed here.

PMID:36721163 | DOI:10.1186/s13023-023-02619-3

Am J Med Genet A. 2023 Feb 1. doi: 10.1002/ajmg.a.63128. Online ahead of print.

ABSTRACT

Tethered cord syndrome (TCS) is characterized by leg pain and weakness, bladder and bowel dysfunction, orthopedic malformations such as scoliosis, and motor deficits caused by the fixation of the spinal cord to surrounding tissues. TCS is surgically treatable and often found in conjunction with other syndromic conditions. KBG syndrome is caused by variants in the ANKRD11 gene and is characterized by short stature, developmental delay, macrodontia, and a triangular face. The current study explores the prevalence of TCS in pediatric KBG patients and their associated signs and symptoms. Patients with KBG were surveyed for signs and symptoms associated with TCS and asked if they had been diagnosed with the syndrome. We found a high proportion of patients diagnosed with (11%) or being investigated for TCS (24%), emphasizing the need to further characterize the comorbid syndromes. No signs or symptoms clearly emerged as indicative of TCS in KBG patients, but some the prevalence of some signs and symptoms varied by sex. Male KBG patients with diagnosed TCS were more likely to have coordination issues and global delay/brain fog than their female counterparts. Understanding the presentation of TCS in KBG patients is critical for timely diagnosis and treatment.

PMID:36722669 | DOI:10.1002/ajmg.a.63128

J Inherit Metab Dis. 2023 Jan 31. doi: 10.1002/jimd.12595. Online ahead of print.

ABSTRACT

Congenital disorders of glycosylation (CDG) and Niemann-Pick type C (NPC) disease are inborn errors of metabolism that can both present with infantile-onset severe liver disease and other multisystemic manifestations. Plasma bile acid and N-palmitoyl-O-phosphocholineserine (PPCS) are screening biomarkers with proposed improved sensitivity and specificity for NPC. We report an infant with ATP6AP1-CDG who presented with cholestatic liver failure and elevated plasma oxysterols and bile acid, mimicking NPC clinically and biochemically. On further investigation, PPCS, but not the bile acid derivative N-(3β,5α,6β-trihydroxy-cholan-24-oyl) glycine (TCG), were elevated in plasma samples from individuals with ATP6AP1-, ALG1-, ALG8-, and PMM2-CDG. These findings highlight the importance of keeping CDG within the diagnostic differential when evaluating children with early onset severe liver disease and elevated bile acid or PPCS to prevent delayed diagnosis and treatment.

PMID:36719165 | DOI:10.1002/jimd.12595

Front Immunol. 2023 Jan 13;13:1099918. doi: 10.3389/fimmu.2022.1099918. eCollection 2022.

ABSTRACT

Scleromyxedema is a rare idiopathic fibromucinous disorder characterized by a generalized papular and sclerodermoid cutaneous eruption. Patients often have praraproteinemia and extracutaneous, even lethal, manifestations. Yet the prognostic and therapeutic features of scleromyxedema are poorly documented. High-dose intravenous immunoglobulin (IVIG), used either alone or in conjunction with systemic steroids and/or thalidomide, has been suggested as a first-line treatment. We report the case of a 45-year-old woman diagnosed with scleromyxedema with paraproteinemia that initially did not respond to systemic steroids, retinoids, and thalidomide but greatly improvement in terms of systemic and cutaneous symptoms after treatment with IVIG.

PMID:36713453 | PMC:PMC9880447 | DOI:10.3389/fimmu.2022.1099918

J Indian Assoc Pediatr Surg. 2022 Nov-Dec;27(6):747-750. doi: 10.4103/jiaps.jiaps_4_22. Epub 2022 Nov 14.

ABSTRACT

Pancreatoblastoma, an orphan disease, is the most common malignant epithelial neoplasm of the pancreas in children. With vague clinical features, diagnosis is made by radiological suggestions and histopathology. The presence of metastatic disease and inoperable/incomplete excision remains the poor prognostic markers. We present a rare instance of an adolescent who has survived metastatic pancreatoblastoma after neoadjuvant chemoreduction/complete surgical excision.

PMID:36714488 | PMC:PMC9878534 | DOI:10.4103/jiaps.jiaps_4_22

Annu Rev Med. 2023 Jan 27;74:489-502. doi: 10.1146/annurev-med-042921-110721.

ABSTRACT

Exome sequencing (ES) and genome sequencing (GS) have radically transformed the diagnostic approach to undiagnosed rare/ultrarare Mendelian diseases. Next-generation sequencing (NGS), the technology integral for ES, GS, and most large (100+) gene panels, has enabled previously unimaginable diagnoses, changes in medical management, new treatments, and accurate reproductive risk assessments for patients, as well as new disease gene discoveries. Yet, challenges remain, as most individuals remain undiagnosed with current NGS. Improved NGS technology has resulted in long-read sequencing, which may resolve diagnoses in some patients who do not obtain a diagnosis with current short-read ES and GS, but its effectiveness is unclear, and it is expensive. Other challenges that persist include the resolution of variants of uncertain significance, the urgent need for patients with ultrarare disorders to have access to therapeutics, the need for equity in patient access to NGS-based testing, and the study of ethical concerns. However, the outlook for undiagnosed disease resolution is bright, due to continual advancements in the field.

PMID:36706750 | DOI:10.1146/annurev-med-042921-110721

Comput Biol Med. 2023 Mar;154:106555. doi: 10.1016/j.compbiomed.2023.106555. Epub 2023 Jan 13.

ABSTRACT

Hypopharyngeal cancer (HPC) is a rare disease. Therefore, it is a challenge to automatically segment HPC tumors and metastatic lymph nodes (HPC risk areas) from medical images with the small-scale dataset. Combining low-level details and high-level semantics from feature maps in different scales can improve the accuracy of segmentation. Herein, we propose a Multi-Modality Transfer Learning Network with Hybrid Bilateral Encoder (Twist-Net) for Hypopharyngeal Cancer Segmentation. Specifically, we propose a Bilateral Transition (BT) block and a Bilateral Gather (BG) block to twist (fuse) high-level semantic feature maps and low-level detailed feature maps. We design a block with multi-receptive field extraction capabilities, M Block, to capture multi-scale information. To avoid overfitting caused by the small scale of the dataset, we propose a transfer learning method that can transfer priors experience from large computer vision datasets to multi-modality medical imaging datasets. Compared with other methods, our method outperforms other methods on HPC dataset, achieving the highest Dice of 82.98%. Our method is also superior to other methods on two public medical segmentation datasets, i.e., the CHASE_DB1 dataset and BraTS2018 dataset. On these two datasets, the Dice of our method is 79.83% and 84.87%, respectively. The code is available at: https://github.com/zhongqiu1245/TwistNet.

PMID:36701967 | DOI:10.1016/j.compbiomed.2023.106555

Nursing. 2023 Feb 1;53(2):24-30. doi: 10.1097/01.NURSE.0000905700.44849.f4.

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a rare and serious disease affecting approximately 20,000 people in the US. This article details the signs, symptoms, and diagnosis of ALS and important management considerations.

PMID:36700810 | DOI:10.1097/01.NURSE.0000905700.44849.f4

Genome Med. 2023 Jan 27;15(1):5. doi: 10.1186/s13073-023-01157-8.

ABSTRACT

BACKGROUND: Rare diseases collectively impose a significant burden on healthcare systems, especially in underserved regions, like the Middle East, which lack access to genomic diagnostic services and the associated personalized management plans.

METHODS: We established a clinical genomics and genetic counseling facility, within a multidisciplinary tertiary pediatric center, in the United Arab Emirates to locally diagnose and manage patients with rare diseases. Clinical genomic investigations included exome-based sequencing, chromosomal microarrays, and/or targeted testing. We assessed the diagnostic yield and implications for clinical management among this population. Variables were compared using the Fisher exact test. Tests were 2-tailed, and P < .05 was considered statistically significant.

RESULTS: We present data on 1000 patients with rare diseases (46.2% females; average age, 4.6 years) representing 47 countries primarily from the Arabian Peninsula, the Levant, Africa, and Asia. The cumulative diagnostic yield was 32.5% (95% CI, 29.7-35.5%) and was higher for genomic sequencing-based testing than chromosomal microarrays (37.9% versus 17.2%, P = 0.0001) across all indications, consistent with the higher burden of single gene disorders. Of the 221 Mendelian disorders identified in this cohort, the majority (N = 184) were encountered only once, and those with recessive inheritance accounted for ~ 62% of sequencing diagnoses. Of patients with positive genetic findings (N = 325), 67.7% were less than 5 years of age, and 60% were offered modified management and/or intervention plans. Interestingly, 24% of patients with positive genetic findings received delayed diagnoses (average age, 12.4 years; range 7-37 years), most likely due to a lack of access to genomic investigations in this region. One such genetic finding ended a 15-year-long diagnostic odyssey, leading to a life-threatening diagnosis in one patient, who was then successfully treated using an experimental allogenic bone marrow transplant. Finally, we present cases with candidate genes within regions of homozygosity, likely underlying novel recessive disorders.

CONCLUSIONS: Early access to genomic diagnostics for patients with suspected rare disorders in the Middle East is likely to improve clinical outcomes while driving gene discovery in this genetically underrepresented population.

PMID:36703223 | PMC:PMC9881316 | DOI:10.1186/s13073-023-01157-8

Orphanet J Rare Dis. 2023 Jan 26;18(1):18. doi: 10.1186/s13023-022-02611-3.

ABSTRACT

BACKGROUND: Rare bone diseases (RBDs) are a set of inherited rare diseases that can cause disability and have a devastating impact on families affected, which may lead to a particular high prevalence of psychological disorders in patients and caregivers. Social support plays a role in the well-being of families with rare disease patients, but its effect on psychology of RBD families remains unclear. The purpose of the current cross-sectional quantitative study was to investigate the frequency of depression and anxiety, and their relationship with social support among RBD patients and family caregivers.

RESULTS: A total of 196 participants responded to the questionnaire, including 72 patients and 124 caregivers. Depression was detected among 33.8% of patients and 57% of caregivers, and anxiety disorder was presented in 28.6% of patients and 50% of caregivers. Higher depression scores and anxiety scores were found in both patients and caregivers with an education level of ≤ middle school and monthly income of ≤ ￥2000 (all P < 0.05). The mean (SD) scores of Social Support Rating Scales in patients and caregivers were 37.06 (8.05) and 38.31 (5.76), respectively. After adjusting for gender, age, monthly income, education, employment and marital status, the reverse associations between depression scores, anxiety scores and social support were found merely in caregivers (depression & social support: β = - 0. 46, P < 0.001, anxiety & social support: β = - 0. 44, P < 0.001), specifically for subjective support (depression & subjective support: β = - 0.94, P < 0.001, anxiety & subjective support: β = - 0.87, P < 0.001).

CONCLUSIONS: The study identified a high prevalence of depression and anxiety among RBD patients and caregivers, and pointed out the significance of social support in alleviating psychological distress. In order to provide RBD families with comprehensive assistance, the government should actively develop programs aimed at psychological aid, policy advocacy and tangible support.

PMID:36703212 | PMC:PMC9878818 | DOI:10.1186/s13023-022-02611-3

J Patient Exp. 2023 Jan 17;10:23743735231151768. doi: 10.1177/23743735231151768. eCollection 2023.

ABSTRACT

Systemic sclerosis (SSc) is a rare orphan disease, characterized by skin thickening, vascular insufficiency, and fibrosis of internal organs. SSc affects about 100,000 people in the United States. This study explored perceived benefits and challenges of patient partners and stakeholders, who were team members on a project to revise and test a self-management program (Taking Charge of Systemic Sclerosis). Five patient partners, 1 stakeholder from the Scleroderma Foundation and 1 stakeholder from a state chapter of the Scleroderma Foundation were interviewed. Conversations were audio recorded and transcribed verbatim and analyzed. Four themes emerged from the analysis with corresponding subthemes: contributions to study, benefits of involvement, challenges, and project leadership. The themes and subthemes were generally similar to those expressed in other studies. However, additional benefits from engagement were identified: acceptance, increased knowledge of SSc, and helping others. Participants reported feeling supported and valued as members of the team and that their opinions mattered which is in contrast with findings from other studies.

PMID:36698624 | PMC:PMC9869235 | DOI:10.1177/23743735231151768

Bioorg Med Chem. 2023 Feb 15;80:117170. doi: 10.1016/j.bmc.2023.117170. Epub 2023 Jan 18.

ABSTRACT

Many new drugs have been approved over the past decade for rare or orphan diseases. The passage of the Orphan Drug Act (ODA) in 1983 has provided key economic and regulatory incentives to provide medicines for patients who are suffering from rare diseases that may not be commercially attractive for research and development. We have analyzed 497 novel drugs approved from 2010 - June 13, 2022, of which 220 were given orphan designation status. We discuss trends over this time period, potential risks for long development times, and provide example case studies of successful development and launch of novel drugs for rare diseases.

PMID:36696875 | DOI:10.1016/j.bmc.2023.117170

BMJ Case Rep. 2023 Jan 25;16(1):e252359. doi: 10.1136/bcr-2022-252359.

ABSTRACT

A young adult man presented to an outlying emergency department with a sore throat, fever and chills. Upon failure of symptomatic management and a course of amoxicillin, he developed rectal pain and loose stools. Despite outpatient doxycycline treatment for presumed chlamydial proctitis, he developed worsening rectal pain and bloody stools. Results on abdominal and pelvic CT were consistent with proctitis. His symptoms worsened despite added metronidazole for bacterial proctitis. Workup revealed an elevated erythrocyte sedimentation rate, C reactive protein and calprotectin, suggestive of a diagnosis of inflammatory bowel disease (IBD). A colonoscopy revealed proximal tightness of the rectum, and pathology reported features suggestive of IBD. He was treated with prednisone and mesalamine. However, immunostaining positive for cytomegalovirus (CMV) confirmed a diagnosis of tissue-invasive CMV proctitis. This was further supported by serological testing for CMV consistent with a diagnosis of CMV proctitis preceded by a primary CMV infection of the pharynx.

PMID:36697111 | DOI:10.1136/bcr-2022-252359

Healthc Pap. 2023 Jan;21(1):74-80. doi: 10.12927/hcpap.2023.26992.

ABSTRACT

Expensive drugs for rare diseases pose unique economic, evidentiary and ethical challenges, and these will continue to escalate unless steps are taken urgently to address these challenges. We propose concrete actions that all stakeholders (federal and provincial/territorial governments, patients, healthcare providers, the public and drug manufacturers) could take now as a first step toward enhancing sustainability in the use of innovative (albeit expensive) therapies within our publicly funded healthcare system.

PMID:36692920 | DOI:10.12927/hcpap.2023.26992

Healthc Pap. 2023 Jan;21(1):66-72. doi: 10.12927/hcpap.2023.26993.

ABSTRACT

Significant challenges are associated with the availability of and access to treatments for rare diseases. In this issue, Sirrs et al. (2023) frame challenges in terms of evidence, economics and ethics and describe how they manifest in the Canadian context. This short response paper argues that although interesting initiatives exist internationally to deal with some of these challenges, a plug-and-play approach will not suffice given the particularities of the Canadian system. Rather than seeking international lessons on how to deal with Canadian challenges, the emerging interdisciplinary framework of social pharmaceutical innovation is advanced here as a whole-systems approach that stands to address interconnected components of the rare disease ecosystem, and in doing so, a made-in-Canada approach is advocated for.

PMID:36692919 | DOI:10.12927/hcpap.2023.26993

Healthc Pap. 2023 Jan;21(1):59-65. doi: 10.12927/hcpap.2023.26994.

ABSTRACT

Expensive drugs for rare diseases (EDRDs) pose challenges for regulatory and reimbursement decision makers. Managed access agreements (MAAs), conditional reimbursement schemes that use a variety of price and evidence generation mechanisms to support value-based decision making, have the potential to address the evidentiary, economic and ethical issues associated with EDRDs. Several jurisdictions have successfully used MAAs to manage budget impact and evidentiary uncertainties, demonstrating the promise of this approach. We comment on the feasibility of adopting MAAs in Canada to address challenges associated with EDRDs. Adopting MAAs in the Canadian context requires attention to Canada's federated healthcare and drug coverage system and will require investing in robust data infrastructure and governance systems.

PMID:36692918 | DOI:10.12927/hcpap.2023.26994

Healthc Pap. 2023 Jan;21(1):52-58. doi: 10.12927/hcpap.2023.26995.

ABSTRACT

Patient advocacy groups can push regulators to approve and pay for expensive drugs despite weak evidence of efficacy and/or safety. Advocacy organizations that critique high prices for rare diseases are less publicized but can also influence policy. The funding and relationships many groups have with the pharmaceutical industry may contribute to patient advocates' differing perspectives, but the leaders' values and experiences are an overlooked factor. We need to understand the dominant public-private partnership model of patient advocacy, its historical roots, justification and how key advocacy actors respond to it if we are to advance policies that will contain expensive drugs for rare diseases.

PMID:36692917 | DOI:10.12927/hcpap.2023.26995

Healthc Pap. 2023 Jan;21(1):44-51. doi: 10.12927/hcpap.2023.26996.

ABSTRACT

Cancer medicines comprise the largest proportion of expensive drugs for rare diseases (EDRDs). The US Orphan Drug Act (ODA) (Office of Inspector General, Department of Health and Human Services 2001) encourages pharmaceutical manufacturers to develop medicines for rare diseases through a range of financial incentives, which has shifted the development of cancer medicines to rare cancer subtypes. Although certain medicines approved through the ODA have revolutionized cancer treatment, only half demonstrate added therapeutic benefit compared to existing alternatives. Canadian regulators should ensure that cancer medicines that receive fast-track approval through the Health Canada Notice of Compliance with conditions offer benefit to Canadian patients. Furthermore, payers might engage in methods for reassessment and renegotiations over the medicines' lifespan.

PMID:36692916 | DOI:10.12927/hcpap.2023.26996