Orphanet J Rare Dis. 2024 Apr 19;19(1):172. doi: 10.1186/s13023-024-03143-8.

ABSTRACT

BACKGROUND: The 'diagnostic odyssey' is a common challenge faced by patients living with rare diseases and poses a significant burden for patients, their families and carers, and the healthcare system. The diagnosis of rare diseases in clinical settings is challenging, with patients typically experiencing a multitude of unnecessary tests and procedures. To improve diagnosis of rare disease, clinicians require evidence-based guidance on when their patient may be presenting with a rare disease. This study aims to identify common experiences amongst patients with rare diseases, to inform a series of 'red flags' that can aid diagnosis of rare diseases in non-specialist settings. A questionnaire was developed by Medics for Rare Diseases, informed by the experiences of clinicians, rare disease patients and patient advocates, and was shared with UK-based rare disease patient groups. Study participants were engaged via social media platforms, blogs and email newsletters of three umbrella rare disease organisations. The questionnaire, comprising 22 questions, was designed to identify typical experiences relating to physical and psychosocial manifestations and presentation of disease, patient interactions with healthcare providers, and family history.

RESULTS: Questionnaire responses were received from 79 different rare disease patient groups and the common experiences identified were used to inform seven red flags of rare disease: multi-system involvement (3 or more); genetic inheritance pattern; continued presentation throughout childhood and adulthood; difficulties at school, especially relating to absences, difficulty participating in physical education and experiences of bullying or social isolation; multiple specialist referrals; extended period with unexplained symptoms; and misdiagnosis. In light of the red flags identified, recommendations for primary care and education settings have been proposed, focusing on the need for holistic assessment and awareness of both physical and psychosocial factors.

CONCLUSIONS: This study identified key commonalities experienced by patients with rare disease across physical and psychosocial domains, in addition to understanding patients' history and experiences with healthcare providers. These findings could be used to develop a clinical decision‑making tool to support non-specialist practitioners to consider when their patient may have an undiagnosed rare condition, which may minimise the challenges of the 'diagnostic odyssey' and improve the patient experience.

PMID:38641814 | PMC:PMC11031885 | DOI:10.1186/s13023-024-03143-8

Dis Model Mech. 2024 Jun 1;17(6):dmm050623. doi: 10.1242/dmm.050623. Epub 2024 Apr 19.

ABSTRACT

Effective gene therapy approaches have been developed for many rare diseases, including inborn errors of immunity and metabolism, haemoglobinopathies and inherited blindness. Despite successful pre-clinical and clinical results, these gene therapies are not widely available, primarily for non-medical reasons. Lack of commercial interest in therapies for ultra-rare diseases, costs of development and complex manufacturing processes required for advanced therapy medicinal products (ATMPs) are some of the main problems that are restricting access. The complexities and costs of navigating the regulatory environments in different jurisdictions for treatments that affect small numbers of patients is a problem unique to ATMPS for rare and ultra-rare diseases. In this Perspective, we outline some of the challenges and potential solutions that, we hope, will improve access to gene therapy for rare diseases.

PMID:38639083 | DOI:10.1242/dmm.050623

Am J Hum Genet. 2024 May 2;111(5):825-832. doi: 10.1016/j.ajhg.2024.03.016. Epub 2024 Apr 17.

ABSTRACT

Next-generation sequencing has revolutionized the speed of rare disease (RD) diagnoses. While clinical exome and genome sequencing represent an effective tool for many RD diagnoses, there is room to further improve the diagnostic odyssey of many RD patients. One recognizable intervention lies in increasing equitable access to genomic testing. Rural communities represent a significant portion of underserved and underrepresented individuals facing additional barriers to diagnosis and treatment. Primary care providers (PCPs) at local clinics, though sometimes suspicious of a potential benefit of genetic testing for their patients, have significant constraints in pursuing it themselves and rely on referrals to specialists. Yet, these referrals are typically followed by long waitlists and significant delays in clinical assessment, insurance clearance, testing, and initiation of diagnosis-informed care management. Not only is this process time intensive, but it also often requires multiple visits to urban medical centers for which distance may be a significant barrier to rural families. Therefore, providing early, "direct-to-provider" (DTP) local access to unrestrictive genomic testing is likely to help speed up diagnostic times and access to care for RD patients in rural communities. In a pilot study with a PCP clinic in rural Kansas, we observed a minimum 5.5 months shortening of time to diagnosis through the DTP exome sequencing program as compared to rural patients receiving genetic testing through the "traditional" PCP-referral-to-specialist scheme. We share our experience to encourage future partnerships beyond our center. Our efforts represent just one step in fostering greater diversity and equity in genomic studies.

PMID:38636509 | DOI:10.1016/j.ajhg.2024.03.016

PLoS One. 2024 Apr 18;19(4):e0300350. doi: 10.1371/journal.pone.0300350. eCollection 2024.

ABSTRACT

Monogenic diabetes is characterized as a group of diseases caused by rare variants in single genes. Like for other rare diseases, multiple genes have been linked to monogenic diabetes with different measures of pathogenicity, but the information on the genes and variants is not unified among different resources, making it challenging to process them informatically. We have developed an automated pipeline for collecting and harmonizing data on genetic variants linked to monogenic diabetes. Furthermore, we have translated variant genetic sequences into protein sequences accounting for all protein isoforms and their variants. This allows researchers to consolidate information on variant genes and proteins linked to monogenic diabetes and facilitates their study using proteomics or structural biology. Our open and flexible implementation using Jupyter notebooks enables tailoring and modifying the pipeline and its application to other rare diseases.

PMID:38635808 | PMC:PMC11025945 | DOI:10.1371/journal.pone.0300350

Orphanet J Rare Dis. 2024 Apr 17;19(1):162. doi: 10.1186/s13023-024-03123-y.

ABSTRACT

Recently, Ombashi et al. published a systematic review aiming to identify the pitfalls in the development and implementation as well as factors influencing long-term success of a multidisciplinary, international registry for cleft care on a global scale. The purpose of this letter to the editor is to highlight that the review failed to include the Swedish quality registry for patients born with cleft lip and palate, which fulfils the inclusion criteria. The Swedish cleft lip and palate registry is multidisciplinary, has a high coverage and reporting degree, and most outcome measures have been checked for reliability and validity. It is regularly used for open comparisons between treatment centers. Several research studies have been published based on the Swedish cleft lip and palate registry, and more are ongoing. The information we provide about the Swedish cleft lip and palate registry complements and expands the information of the results reported by Ombashi et al. in their research.

PMID:38632666 | DOI:10.1186/s13023-024-03123-y

BMJ Case Rep. 2024 Apr 17;17(4):e257572. doi: 10.1136/bcr-2023-257572.

ABSTRACT

Aplasia cutis congenita (ACC) is a group of rare heterogeneous disorders characterised by absent areas of skin at birth. The majority of cases involve the scalp region. ACC limited to one lower limb is extremely rare. We report an usual case of ACC limited to the left thigh of which healing occurred in utero. The case was managed conservatively and the disease course has been favourable with no limitations in limb function and an entirely normal development. Most cases of ACC are self-healing, justifying a conservative approach. This holds further true for ACC limited to one lower limb where the majority of cases reported to date show a favourable disease course with minimal conservative treatment.

PMID:38631814 | DOI:10.1136/bcr-2023-257572

Lancet Neurol. 2024 May;23(5):447. doi: 10.1016/S1474-4422(24)00136-4.

NO ABSTRACT

PMID:38631752 | DOI:10.1016/S1474-4422(24)00136-4

BMC Med Genomics. 2024 Apr 17;17(Suppl 1):92. doi: 10.1186/s12920-024-01860-4.

ABSTRACT

BACKGROUND: Repressor element 1 (RE1) silencing transcription factor (REST) is a transcriptional repressor abundantly expressed in aging human brains. It is known to regulate genes associated with oxidative stress, inflammation, and neurological disorders by binding to a canonical form of sequence motif and its non-canonical variations. Although analysis of genomic sequence motifs is crucial to understand transcriptional regulation by transcription factors (TFs), a comprehensive characterization of various forms of RE1 motifs in human cell lines has not been performed.

RESULTS: Here, we analyzed 23 ENCODE REST ChIP-seq datasets from diverse human cell lines and identified a non-redundant set of 68,975 loci with ChIP-seq peaks. Our systematic characterization of these binding sites revealed that the canonical form of REST binding motif was found primarily in ChIP-seq peaks shared across multiple cell lines, while non-canonical forms of motifs were identified in both cell-line-specific binding sites and those shared across cell lines. Remarkably, we observed a notable prevalence of non-canonical motifs that corresponded to half segments of the canonical motif. Furthermore, our analysis unveiled the presence of cell-line-specific REST binding patterns, as evidenced by the clustering of ChIP-seq experiments according to their respective cell lines. This observation underscores the cell-line specificity of REST binding at certain genomic loci, implying intricate cell-line-specific regulatory mechanisms.

CONCLUSIONS: Overall, our study provides a comprehensive characterization of REST binding motifs in human cell lines and genome-wide RE1 motif profiles. These findings contribute to a deeper understanding of REST-mediated transcriptional regulation and highlight the importance of considering cell-line-specific effects in future investigations.

PMID:38632583 | DOI:10.1186/s12920-024-01860-4

Tex Heart Inst J. 2024 Apr 16;51(1):e238382. doi: 10.14503/THIJ-23-8382.

ABSTRACT

Dextrocardia with situs inversus totalis is a rare hereditary condition characterized by reversed orientation of the major thoracic and abdominal organs. Though dextrocardia itself is not believed to increase the risk of coronary artery disease, the workup and surgical management of patients with this condition may be technically challenging to heart team clinicians. This report describes the case management of a high-risk 56-year-old man with dextrocardia who presented with multivessel coronary artery disease.

PMID:38623731 | DOI:10.14503/THIJ-23-8382

Orv Hetil. 2024 Apr 14;165(15):595-600. doi: 10.1556/650.2024.33021. Print 2024 Apr 14.

ABSTRACT

A gerincfájdalom hátterében a gyakoribb benignus kórképek mellett malignus elváltozások és súlyos gyulladással jellemezhető kórképek is előfordulhatnak. A kivizsgálás során a részletes laboratóriumi vizsgálatok mellett a képalkotó diagnosztikának kiemelkedő jelentősége van. A csontfájdalom hátterében ritkán a krónikus nem bakteriális osteomyelitis is állhat. A szerzők egy 9 éves leánygyermek esetét mutatják be, aki több hónapja fennálló, progrediáló háti gerincfájdalommal jelentkezett szakvizsgálaton. A laboratóriumi vizsgálatok során enyhén emelkedett gyulladásos aktivitáson kívül kórjelző eltérés nem volt. A mágnesesrezonancia-vizsgálat (MRI) a thoracalis VIII. csigolyakompresszió mellett a csigolyatestben, az alsó zárólemez mentén körülírt, hiperintenzíven halmozó képletet írt le. A pontos etiológia tisztázására biopsziás mintavétel történt. A szövettani vizsgálat a malignitást kizárta, krónikus gyulladásra utaló eltérést mutatott. A beteg átmenetileg szteroidkezelésben részesült, de relapsus jelentkezett, ezért biológiai terápia, adalimumab került bevezetésre. A terápia hatásosnak bizonyult, mind a klinikai tünetek, mind a képalkotó vizsgálatok alapján tartós remisszió észlelhető. A jelen esettanulmány a gerincfájdalom hátterében álló ritka kórképre hívja fel a figyelmet. A kórkép diagnózisában az MRI kiemelkedő fontossággal bír. A betegség kezelésében immunszuppresszív terápia alkalmazása szükséges. Orv Hetil. 2024; 165(15): 595–600.

PMID:38619881 | DOI:10.1556/650.2024.33021

Int J Health Policy Manag. 2024;13:7494. doi: 10.34172/ijhpm.2024.7494. Epub 2024 Feb 10.

ABSTRACT

BACKGROUND: There is a lack of guidance on approaches to formulary management and funding for high-cost drugs and therapeutics by individual healthcare institutions. The objective of this review was to assess institutional approaches to resource allocation for such therapeutics, with a particular focus on paediatric and rare disease populations.

METHODS: A search of Embase and MEDLINE was conducted for studies relevant to decision-making for off-formulary, high-cost drugs and therapeutics. Abstracts were evaluated for inclusion based on the Simple Multiple-Attribute Rating Techniques (SMART) criteria. A framework of 30 topics across 4 categories was used to guide data extraction and was based on findings from the initial abstract review and previous health technology assessment (HTA) publications. Reflexive thematic analysis was conducted using QSR NVivo 12 software.

RESULTS: A total of 168 studies were included for analysis. Only 4 (2%) focused on paediatrics, while 21 (12%) centred on adults and the remainder (85%) did not specify. Thirty-two (19%) studies discussed the importance of high-cost therapeutics and 34 (23%) focused on rare/orphan drugs. Five themes were identified as being relevant to institutional decision-making for high-cost therapeutics: institutional strategy, substantive criteria, procedural considerations, guiding principles and frameworks, and operational activities. Each of these themes encompassed several sub-themes and was complemented by a sixth category specific to paediatrics and rare diseases.

CONCLUSION: The rising cost of novel drugs and therapeutics underscores the need for robust, evidence-based, and ethically defensible decision-making processes for health technology funding, particularly at the hospital level. Our study highlights practices and themes to aid decision-makers in thinking critically about institutional, substantive, procedural, and operational considerations in support of legitimate decisions about institutional funding of high-cost drugs and therapeutics, as well as opportunities and challenges that exist for paediatric and rare disease populations.

PMID:38618836 | DOI:10.34172/ijhpm.2024.7494

Tremor Other Hyperkinet Mov (N Y). 2024 Apr 10;14:16. doi: 10.5334/tohm.858. eCollection 2024.

ABSTRACT

BACKGROUND: Spinocerebellar ataxia 21 (SCA21) is a rare neurological disorder caused by heterozygous variants in TMEM240. A growing, yet still limited number of reports suggested that hyperkinetic movements should be considered a defining component of the disease.

CASE SERIES: We describe two newly identified families harboring the recurrent pathogenic TMEM240 p.Pro170Leu variant. Both index patients and the mother of the first proband developed movement disorders, manifesting as myoclonic dystonia and action-induced dystonia without co-occurring ataxia in one case, and pancerebellar syndrome complicated by action-induced dystonia in the other. We reviewed the literature on TMEM240 variants linked to hyperkinetic disorders, comparing our cases to described phenotypes.

DISCUSSION: Adding to prior preliminary observations, our series highlights the relevance of hyperkinetic movements as clinically meaningful features of SCA21. TMEM240 mutation should be included in the differential diagnosis of myoclonic dystonia and ataxia-dystonia syndromes.

PMID:38617829 | PMC:PMC11012930 | DOI:10.5334/tohm.858

Harefuah. 2024 Apr;163(4):217-219.

ABSTRACT

INTRODUCTION: Thyroid hemiagenesis is a rare congenital anomaly characterized by the absence of one thyroid lobe and the isthmus. This case report presents a 4-year-old girl with a history of prematurity. Incidentally, during a routine ultrasound evaluation of the neck, thyroid hemiagenesis was detected along with the presence of normal lymph nodes. The right thyroid lobe was absent, while the left thyroid lobe was preserved. No previous neck or thyroid surgeries were reported.

DISCUSSION: This provides an overview of thyroid hemiagenesis, including its prevalence, predominant involvement of the left lobe, possible genetic and environmental factors, and associations with thyroid and extrathyroidal pathologies. Imaging modalities, such as ultrasound and scintigraphy, play a crucial role in diagnosing thyroid hemiagenesis and identifying additional thyroid gland abnormalities. Long-term follow-up and careful monitoring are recommended to assess thyroid function and identify potential structural abnormalities. The optimal therapeutic approach for thyroid hemiagenesis remains controversial, and further studies are needed to determine the clinical significance and long-term outcomes of this rare condition.

PMID:38616630

J Cardiothorac Surg. 2024 Apr 15;19(1):209. doi: 10.1186/s13019-024-02681-3.

ABSTRACT

Uterine leiomyoma invading internal iliac vein and consequently disseminating into the right atrium is an extremely rare condition, and surgical strategy is controversial. Here, we reported a specific case with successful surgical resection through one-stage total hysterectomy, bilateral oophorectomy, and the intracardiovascular lesion. This procedure would be an optimal choice for uterine leiomyoma invading inferior vena cava and spreading to right atrium.

PMID:38616243 | PMC:PMC11017587 | DOI:10.1186/s13019-024-02681-3

J Nepal Health Res Counc. 2024 Mar 22;21(3):530-533. doi: 10.33314/jnhrc.v21i3.4573.

ABSTRACT

Mayer-Rokitansky-Kuster-Hauser syndrome also known as mullerian agenesis is a rare congenital condition in which there is absence of uterus along with upper vagina. Patient usually presents with primary amenorrhea with or without cyclical lower abdominal pain but have normal secondary sexual characters. Modified McIndoe Vaginoplasty with amnion graft is the commonest surgery performed worldwide. A 23 year old girl with normal secondary sexual characters presented with primary amenorrhea with cyclical lower abdominal pain; on examination blind vagina was present. Vaginoplasty with amnion graft was done and vaginal mould was placed. Vaginal dilatation with Hegar's dilator was done weekly until 6 weeks. She is under regular follow-up at present and advised for regular manual dilation at home. McIndoe Vaginoplasty with amnion graft is a simple yet rewarding procedure especially in low resource countries like ours, with good success rate and with minimal postoperative complications. Keywords: Amnion graft; Mayer-Rokitansky-Kuster-Hauser Syndrome; Modified McIndoe Vaginoplasty; Primary amenorrhea; Secondary sexual characters.

PMID:38615228 | DOI:10.33314/jnhrc.v21i3.4573

ESMO Open. 2024 Apr;9(4):102981. doi: 10.1016/j.esmoop.2024.102981. Epub 2024 Apr 12.

ABSTRACT

BACKGROUND: Comprehensive genome profiling (CGP) serves as a guide for suitable genomically matched therapies for patients with cancer. However, little is known about the impact of the timing and types of cancer on the therapeutic benefit of CGP.

MATERIALS AND METHODS: A single hospital-based pan-cancer prospective study (TOP-GEAR; UMIN000011141) was conducted to examine the benefit of CGP with respect to the timing and types of cancer. Patients with advanced solid tumors (>30 types) who either progressed with or without standard treatments were genotyped using a single CGP test. The subjects were followed up for a median duration of 590 days to examine therapeutic response, using progression-free survival (PFS), PFS ratio, and factors associated with therapeutic response.

RESULTS: Among the 507 patients, 62 (12.2%) received matched therapies with an overall response rate (ORR) of 32.3%. The PFS ratios (≥1.3) were observed in 46.3% (19/41) of the evaluated patients. The proportion of subjects receiving such therapies in the rare cancer cohort was lower than that in the non-rare cancer cohort (9.6% and 17.4%, respectively; P = 0.010). However, ORR of the rare cancer patients was higher than that in the non-rare cancer cohort (43.8% and 20.0%, respectively; P = 0.046). Moreover, ORR of matched therapies in the first or second line after receiving the CGP test was higher than that in the third or later lines (62.5% and 21.7%, respectively; P = 0.003). Rare cancer and early-line treatment were significantly and independently associated with ORR of matched therapies in multivariable analysis (P = 0.017 and 0.004, respectively).

CONCLUSION: Patients with rare cancer preferentially benefited from tumor mutation profiling by increasing the chances of therapeutic response to matched therapies. Early-line treatments after profiling increase the therapeutic benefit, irrespective of tumor types.

PMID:38613908 | PMC:PMC11033064 | DOI:10.1016/j.esmoop.2024.102981

BMC Anesthesiol. 2024 Apr 13;24(1):143. doi: 10.1186/s12871-024-02508-7.

ABSTRACT

BACKGROUND: The Koolen-de Vries syndrome (KdVS) is a relatively new rare disease caused by micro-deletion of 17q21.31 which was first reported by Koolen in 2006. Typical phenotypes for KdVS include hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Up to now, there was only one case report about anesthesia management of patient diagnosed KdVS. It was a 2-year-old girl who experienced an MRI exam under anesthesia.

CASE PRESENTATION: We described a 21-month-old boy who planned to undergo an orchidopexy under general anesthesia diagnosed with KdVS. He had an intellectual disability, characteristic facial dysmorphism, tracheo/laryngomalacia, patent foramen ovale, and cryptorchidism related to KdVS. Due to the complex condition especially the presence of tracheo/laryngomalacia, we took some special measures, including reducing the amount of long-acting opioid, keeping the spontaneous breath, performing a caudal block, and applying the laryngeal mask. But the laryngeal mask was changed to an endotracheal tube because it failed to provide adequate ventilation. The boy experienced mild laryngeal spasm and hypoxia after extubation, but lateral position and etomidate eased his breathing problem and re-intubation was avoided. It is indicated that anesthesia management for patients with orphan disease is a real challenge for all anesthesia providers.

CONCLUSIONS: The Koolen-de Vries syndrome is a relatively new orphan disease involving multiple systems. Keeping spontaneous breath, evaluating airway potency to anesthetics, applying endotracheal tube, and post-extubation lateral or prone position may be helpful for airway management for patient with hypotonia and tracheo/laryngomalacia. KdVS patient needs prolonged post-anesthesia monitoring and/or medication for airway complications.

PMID:38614993 | DOI:10.1186/s12871-024-02508-7

J R Coll Physicians Edinb. 2024 Mar;54(1):41-43. doi: 10.1177/14782715241237283.

ABSTRACT

Whipple's disease is a multisystemic chronic infectious condition caused by Tropheryma whipplei (T. whipplei). Though characterised often by insidious weight loss, diarrhoea, and arthralgia, three other distinct manifestations can be observed, namely localised disease, acute infection and asymptomatic carriage. The diagnosis relies on histopathological examination of duodenal biopsies and polymerase chain reaction analysis of the 16S rRNA gene for T. whipplei. We report the case of a middle-aged man admitted for etiologic investigation of prolonged, migrating, and inflammatory arthralgias and subsequent development of gastrointestinal symptoms. Despite its reputation as a great mimicker of many different illnesses, the difficulty in diagnosis probably lies with its rarity rather than its masking.

PMID:38606805 | DOI:10.1177/14782715241237283

Pathol Oncol Res. 2024 Mar 28;30:1611705. doi: 10.3389/pore.2024.1611705. eCollection 2024.

ABSTRACT

BACKGROUND: Langerhans cell histiocytosis is a rare disease characterized by the abnormal proliferation of Langerhans cells within a single organ or multiple organs. This case report aims to improve the knowledge of the presentation of gastrointestinal Langerhans cell histiocytosis to facilitate the diagnosis and management of this rare disorder.

CASE PRESENTATION: A 19-month-old female presented with repeatedly mucinous bloody stools. The abdominal ultrasound revealed a slightly enlarged spleen. The initial colonoscopy revealed chronic enteritis with a very early onset inflammatory bowel disease. After anti-inflammatory treatment without improvement, an intestinal biopsy was performed at The Forth Affiliated Hospital of Zhejiang University. The final intestinal biopsy and histopathology examination confirmed the presence of Langerhans cell histiocytosis. After diagnosis, additional lung and head imaging examinations revealed no abnormalities. Her condition improved gradually after being treated with chemotherapy (vincristine and prednisone) and molecular-targeted drug(dalafinil) treatment.

CONCLUSION: The clinical symptoms of Langerhans cell histiocytosis involving the gastrointestinal tract are not specific and may resemble symptoms observed in inflammatory bowel disease and other primary gastrointestinal tumors. Therefore, in cases of infants presenting with inflammatory gastrointestinal symptoms that do not resolve after treatment, a biopsy is essential to obtain a differential diagnosis.

PMID:38605931 | PMC:PMC11007090 | DOI:10.3389/pore.2024.1611705

Eur J Paediatr Neurol. 2024 Mar;49:A1. doi: 10.1016/j.ejpn.2024.04.002. Epub 2024 Apr 6.

NO ABSTRACT

PMID:38600015 | DOI:10.1016/j.ejpn.2024.04.002