Eur Respir J. 2022 Aug 30:2201512. doi: 10.1183/13993003.01512-2022. Online ahead of print.

ABSTRACT

Childhood interstitial lung disease comprises a spectrum of rare ILDs affecting infants, children and adolescents. Nintedanib is a licensed treatment for pulmonary fibrosis in adults. The primary objectives of the InPedILD trial were to determine the dose-exposure and safety of nintedanib in children and adolescents with fibrosing ILD. Patients aged 6-17 years with fibrosing ILD on HRCT and clinically significant disease were randomised 2:1 to receive nintedanib or placebo for 24 weeks then open-label nintedanib. Dosing was based on weight-dependent allometric scaling. Co-primary endpoints were the area under the plasma concentration-time curve at steady state (AUCτ,ss) at weeks 2 and 26 and the proportion of patients with treatment-emergent adverse events at week 24. Twenty-six patients received nintedanib and 13 placebo. The geometric mean (gCV%) AUCτ,ss for nintedanib was 175 µg×h·L-1 (85.1) in patients aged 6-11 years and 160 µg×h·L-1 (82.7) in patients aged 12-17 years. In the double-blind period, adverse events were reported in 84.6% of patients in each treatment group. Two patients discontinued nintedanib due to adverse events. Diarrhoea was reported in 38.5% and 15.4% of the nintedanib and placebo groups, respectively. Adjusted mean (se) changes in FVC % predicted at week 24 were 0.3 (1.3) in the nintedanib group and -0.9 (1.8) in the placebo group. In conclusion, in children and adolescents with fibrosing ILD, a weight-based dosing regimen resulted in exposure to nintedanib similar to adults and an acceptable safety profile. These data provide a scientific basis for the use of nintedanib in this patient population.

PMID:36041751 | DOI:10.1183/13993003.01512-2022

Heliyon. 2022 Aug 13;8(8):e10227. doi: 10.1016/j.heliyon.2022.e10227. eCollection 2022 Aug.

ABSTRACT

BACKGROUND: Chordoma, the most frequent malignant primary spinal neoplasm, characterized by a high rate of recurrence, is an orphan disease where the clarification of the molecular oncogenesis would be crucial to developing new, effective therapies. Dysregulated expression of non-coding RNAs, especially microRNAs (miRNA) has a significant role in cancer development.

METHODS: Next-generation RNA sequencing (NGS) was used for the combinatorial analysis of mRNA-miRNA gene expression profiles in sacral chordoma and nucleus pulposus samples. Advanced bioinformatics workflow was applied to the data to predict miRNA-mRNA regulatory networks with altered activity in chordoma.

RESULTS: A large set of significantly dysregulated miRNAs in chordoma and their differentially expressed target genes have been identified. Several molecular pathways related to tumorigenesis and the modulation of the immune system are predicted to be dysregulated due to aberrant miRNA expression in chordoma. We identified a gene set including key regulators of the Hippo pathway, which is targeted by differently expressed miRNAs, and validated their altered expression by RT-qPCR. These newly identified miRNA/RNA interactions are predicted to have a role in the self-renewal process of chordoma stem cells, which might sustain the high rate of recurrence for this tumor.

CONCLUSIONS: Our results can significantly contribute to the designation of possible targets for the development of anti-chordoma therapies.

PMID:36033338 | PMC:PMC9404356 | DOI:10.1016/j.heliyon.2022.e10227

Orphanet J Rare Dis. 2022 Aug 26;17(1):323. doi: 10.1186/s13023-022-02489-1.

ABSTRACT

Rare disease registries increase research accessibility for patients, while providing clinicians/investigators with a coherent data ecosystem necessary to boost research and patient care. The IRD-PT registry is a national, web-based, interoperable registry for inherited retinal degenerations (IRDs) designed to generate scientific knowledge and collect high-quality data on the epidemiology, genomic landscape and natural history of IRDs in Portugal. In two years, the number of enrolled patients almost doubled (537 to 1060). Still, the registry has a lower-than-expected adoption rate, with only 4 centers across Portugal actively enrolling patients. This highlights a strong need to understand factors that may be hindering the registry's nationwide adoption. The purpose of this manuscript is to analyze challenges, facilitators and barriers to the adoption and use of the IRD-PT registry, and to discuss avenues for improvement, focusing on keeping the registry sustainable in the long run. We believe that this exercise may help other rare disease registries to improve user adherence and engagement, ultimately contributing to develop more sustainable and successful registries in the field.

PMID:36028864 | PMC:PMC9419370 | DOI:10.1186/s13023-022-02489-1

Sci Rep. 2022 Aug 26;12(1):14589. doi: 10.1038/s41598-022-14161-6.

ABSTRACT

Recently, whole-exome sequencing (WES) has been used for genetic diagnoses of patients who remain otherwise undiagnosed. WES was performed in 177 Japanese patients with undiagnosed conditions who were referred to the Tokai regional branch of the Initiative on Rare and Undiagnosed Diseases (IRUD) (TOKAI-IRUD). This study included only patients who had not previously received genome-wide testing. Review meetings with specialists in various medical fields were held to evaluate the genetic diagnosis in each case, which was based on the guidelines of the American College of Medical Genetics and Genomics. WES identified diagnostic single-nucleotide variants in 66 patients and copy number variants (CNVs) in 11 patients. Additionally, a patient was diagnosed with Angelman syndrome with a complex clinical phenotype upon detection of a paternally derived uniparental disomy (UPD) [upd(15)pat] wherein the patient carried a homozygous DUOX2 p.E520D variant in the UPD region. Functional analysis confirmed that this DUOX2 variant was a loss-of-function missense substitution and the primary cause of congenital hypothyroidism. A significantly higher proportion of genetic diagnoses was achieved compared to previous reports (44%, 78/177 vs. 24-35%, respectively), probably due to detailed discussions and the higher rate of CNV detection.

PMID:36028527 | PMC:PMC9418234 | DOI:10.1038/s41598-022-14161-6

Sci Data. 2022 Aug 26;9(1):521. doi: 10.1038/s41597-022-01654-2.

ABSTRACT

Rare skin diseases include more than 800 diseases affecting more than 6.8 million patients worldwide. However, only 100 drugs have been developed for treating rare skin diseases in the past 38 years. To investigate potential treatments through drug repurposing for rare skin diseases, it is necessary to have a well-organized database to link all known disease causes, mechanisms, and related information to accelerate the process. Drug repurposing provides less expensive and faster potential options to develop treatments for known diseases. In this work, we designed and constructed a rare skin disease database (RSDB) as a disease-centered information depository to facilitate repurposing drug candidates for rare skin diseases. We collected and integrated associated genes, chemicals, and phenotypes into a network connected by pairwise relationships between different components for rare skin diseases. The RSDB covers 891 rare skin diseases defined by the Orphanet and GARD databases. The organized network for each rare skin disease comprises associated genes, phenotypes, and chemicals with the corresponding connections. The RSDB is available at https://rsdb.cmdm.tw .

PMID:36028515 | PMC:PMC9418253 | DOI:10.1038/s41597-022-01654-2

Medicina (Kaunas). 2022 Aug 17;58(8):1114. doi: 10.3390/medicina58081114.

ABSTRACT

Background and objectives: Rare diseases affect an estimated four million patients in Germany. Approximately 15% of the approximately 6000 to 8000 rare diseases known globally show manifestations in the dental, oral and maxillofacial regions. The present survey evaluated the knowledge and management of rare diseases and their orofacial alterations by dentists, dental specialists and oral and maxillofacial surgeons and dentists working at university hospitals for dentistry and/or oral and maxillofacial surgery. Materials and Methods: The study was designed as an anonymous cross-sectional study. Two anonymous online surveys were performed in all dentists in Germany using the open-source survey software limesurvey. The study cohorts were divided into dentists, dental specialists and oral and maxillofacial surgeons in practice, and dentists who worked in university dental and oral and maxillofacial surgery centers. The survey was performed between 1 October 2020 and 31 March 2021. Results: A total of 309 dentists and oral and maxillofacial surgeons in private practice and 18 dentists or oral and maxillofacial surgeons working at universities participated. A total of 209 (86.7%) study participants working in private practice indicated that the topic of rare diseases should be considered clinically relevant. University participants indicated that there was a lecture on rare diseases in only 7 (63.6%) cases. Only 2 (13.3%) participants reported active research on the topic in their department. Conclusions: The current knowledge on rare diseases is inadequate in suitable screening and therapy. Most of the participants believed that knowledge of rare diseases was very important for daily dental practice. The self-estimations showed that all of the participants estimated their knowledge as very good or inadequate, with a tendency in the direction of inadequate knowledge.

PMID:36013581 | PMC:PMC9415404 | DOI:10.3390/medicina58081114

Int J Environ Res Public Health. 2022 Aug 19;19(16):10366. doi: 10.3390/ijerph191610366.

ABSTRACT

Families with rare diseases (RDs) have unmet needs that are often overlooked by health professionals. Describing these needs and the impact of the disease could improve their medical care. A total of 163 surveys were obtained from patients visiting primary care centres in the Valencian Region (Spain), during 2015-2017, with a confirmed or suspected diagnosis of RD. Of the 84.7% with a confirmed diagnosis, 50.4% had a diagnostic delay exceeding one year, and it was more prevalent among adults (62.2%). Families with paediatric patients were in a worse economic situation, with lower incomes and higher monthly disease-related expenses (€300 on average). These expenses were incurred by 66.5% of families and were mainly for medication (40.3%). Among them, 58.5% reported not being able to afford adjuvant therapies. The disease had an impact on 73.1% of families, especially on their routine and emotional state. Expenses, needs, and impacts were more frequent among families of patients with a history of hospitalisation or deterioration. Patients with delayed diagnosis had a higher consumption of drugs prior to diagnosis. People affected by RDs in the Valencian Region need therapies to improve their autonomy and emotional state. Health professionals should be aware of these needs.

PMID:36012000 | PMC:PMC9408677 | DOI:10.3390/ijerph191610366

Nucleic Acids Res. 2022 Aug 26:gkac706. doi: 10.1093/nar/gkac706. Online ahead of print.

ABSTRACT

Mutations in DKC1 (encoding dyskerin) cause telomere diseases including dyskeratosis congenita (DC) by decreasing steady-state levels of TERC, the non-coding RNA component of telomerase. How DKC1 mutations variably impact numerous other snoRNAs remains unclear, which is a barrier to understanding disease mechanisms in DC beyond impaired telomere maintenance. Here, using DC patient iPSCs, we show that mutations in the dyskerin N-terminal extension domain (NTE) dysregulate scaRNA13. In iPSCs carrying the del37L NTE mutation or engineered to carry NTE mutations via CRISPR/Cas9, but not in those with C-terminal mutations, we found scaRNA13 transcripts with aberrant 3' extensions, as seen when the exoribonuclease PARN is mutated in DC. Biogenesis of scaRNA13 was rescued by repair of the del37L DKC1 mutation by genome-editing, or genetic or pharmacological inactivation of the polymerase PAPD5, which counteracts PARN. Inspection of the human telomerase cryo-EM structure revealed that in addition to mediating intermolecular dyskerin interactions, the NTE interacts with terminal residues of the associated snoRNA, indicating a role for this domain in 3' end definition. Our results provide mechanistic insights into the interplay of dyskerin and the PARN/PAPD5 axis in the biogenesis and accumulation of snoRNAs beyond TERC, broadening our understanding of ncRNA dysregulation in human diseases.

PMID:36018809 | DOI:10.1093/nar/gkac706

J Fungi (Basel). 2022 Aug 10;8(8):838. doi: 10.3390/jof8080838.

ABSTRACT

Coccidioidomycosis is an endemic fungal infection that is reported in up to 20,000 persons per year and has an economic impact close to $1.5 billion. Natural infection virtually always confers protection from future exposure, and this suggests that a preventative vaccine strategy is likely to succeed. We here review progress toward that objective. There has been ongoing research to discover a coccidioidal vaccine over the past seven decades, including one phase III clinical trial, but for reasons of either efficacy or feasibility, a safe and effective vaccine has not yet been developed. This review first summarizes the past research to develop a coccidioidal vaccine. It then details the evidence that supports a live, gene-deletion vaccine candidate as suitable for further development as both a veterinary and a human clinical product. Finally, a plausible vaccine development plan is described which would be applicable to this vaccine candidate and also useful to other future candidates. The public health and economic impact of coccidioidomycosis fully justifies a public private partnership for vaccine development, and the development of a vaccine for this orphan disease will likely require some degree of public funding.

PMID:36012826 | DOI:10.3390/jof8080838

Prog Mol Biol Transl Sci. 2022;190(1):127-146. doi: 10.1016/bs.pmbts.2022.04.002. Epub 2022 Jun 3.

ABSTRACT

The healthcare systems in the developed economies were established primarily to address the more prevalent diseases and have been customized to support the provision of therapeutics to rare patients. However, with the ever-broader implementation of genomic sequencing, it is clear that there are significantly more disease-causing mutations in the human genome than realized and that many mutations are much rarer than current definitions of rare disease populations. Given this, I propose parsing patient populations and defining patient populations more precisely. Nano-rare patients are defined as patients having disease-causing mutations that are unique to a single patient or having a known worldwide prevalence of less than 30. These patient populations present unique challenges to healthcare systems that demand the development of novel models for delivery of therapeutics and novel, more efficient drug discovery technologies, such as antisense technology. The challenges presented by nano-rare patients, a novel non-profit model as a means of providing experimental treatments rather than the traditional commercial model, and progress in establishing a non-profit solution are discussed.

PMID:36007997 | DOI:10.1016/bs.pmbts.2022.04.002

J Med Internet Res. 2022 Aug 25;24(8):e39172. doi: 10.2196/39172.

ABSTRACT

BACKGROUND: Patients struggling with rare diseases may face challenges caused by care providers being unfamiliar with their condition. The life span of people with rare diseases may be the same as that of healthy people, but their quality of life is different. Patients with chronic pain are constantly looking for ways to mitigate their pain. Pain killers are not a permanent solution. In addition to the medical and nonmedical costs of rare diseases for both patients and health care providers, there is a need for sustainable sources of information that are available to help with pain and improve their quality of life, with the goal of reducing physician visits and hospital admissions.

OBJECTIVE: This study investigated the challenges that patients with genetic disorders face in managing their health conditions and finding disease-related information as well as the effect of online peer support groups on pain mitigation and care management.

METHODS: Interviews were conducted via Zoom between July 2021 and December 2021. Eligible participants were those who were aged >18 years, had a medical diagnosis of any type of Ehlers-Danlos syndrome (EDS) with chronic pain, and were members of any support group. Participants were recruited through an announcement in the research and survey section of The Ehlers-Danlos Syndrome Society web page. Interviews were analyzed using the framework approach. Data were systematically searched to identify patterns, analyze them, and identify themes. Interview audio files were transcribed and independently coded by two researchers (SA and AT). Through an iterative process, a final coding table was agreed upon by the researchers and used to thematically analyze the data.

RESULTS: We interviewed 30 participants (mean age 37.7, SD 15 years; n=28, 93% were women; n=23, 77% were residing in the United States). Thematic analysis revealed that participants (patients with EDS) were constantly in pain and most of them have not received accurate and timely diagnoses for many years. They expressed their challenges with health care providers regarding diagnosis and treatment, and complained about their providers' lack of support and knowledge. Participants' main sources of information were web-based searches, academic journals, The Ehlers-Danlos Syndrome Society web page, and online peer support groups on Facebook, Reddit, Twitter, and Instagram. Although pain killers, cannabis, and opioids are providing some pain relief, most patients (28/30, 93%) focused on nonmedical approaches, such as hot or ice packs, physical therapy, exercises, massage, mindfulness, and meditation.

CONCLUSIONS: This study highlights the information gap between health care providers and patients with genetic disorders. Patients with EDS seek access to information from different web-based sources. To meet the needs of patients with genetic disorders, future interventions via web-based resources for improving the quality of care must be considered by health care professionals and government agencies.

PMID:36006679 | DOI:10.2196/39172

Vestn Oftalmol. 2022;138(4):94-100. doi: 10.17116/oftalma202213804194.

ABSTRACT

Marfan syndrome is an orphan disease that is caused by a mutation in the FBN1 gene located on chromosome 15 (15q21.1) and is usually inherited in an autosomal dominant manner. The article reviews the results of studies concerning the potential ocular manifestations of Marfan syndrome.

PMID:36004597 | DOI:10.17116/oftalma202213804194

Am J Psychiatry. 2022 Aug 24:appiajp21111175. doi: 10.1176/appi.ajp.21111175. Online ahead of print.

ABSTRACT

OBJECTIVE: Copy number variants (CNVs) are strongly associated with neurodevelopmental and psychotic disorders. Early-onset psychosis (EOP), where symptoms appear before 18 years of age, is thought to be more strongly influenced by genetic factors than adult-onset psychotic disorders. However, the prevalence and effect of CNVs in EOP is unclear.

METHODS: The authors documented the prevalence of recurrent CNVs and the functional impact of deletions and duplications genome-wide in 137 children and adolescents with EOP compared with 5,540 individuals with autism spectrum disorder (ASD) and 16,504 population control subjects. Specifically, the frequency of 47 recurrent CNVs previously associated with neurodevelopmental and neuropsychiatric illnesses in each cohort were compared. Next, CNV risk scores (CRSs), indices reflecting the dosage sensitivity for any gene across the genome that is encapsulated in a deletion or duplication separately, were compared between groups.

RESULTS: The prevalence of recurrent CNVs was significantly higher in the EOP group than in the ASD (odds ratio=2.30) and control (odds ratio=5.06) groups. However, the difference between the EOP and ASD groups was attenuated when EOP participants with co-occurring ASD were excluded. CRS was significantly higher in the EOP group compared with the control group for both deletions (odds ratio=1.30) and duplications (odds ratio=1.09). In contrast, the EOP and ASD groups did not differ significantly in terms of CRS.

CONCLUSIONS: Given the high frequency of recurrent CNVs in the EOP group and comparable CRSs in the EOP and ASD groups, the findings suggest that all children and adolescents with a psychotic diagnosis should undergo genetic screening, as is recommended in ASD.

PMID:36000218 | DOI:10.1176/appi.ajp.21111175

Am J Hum Genet. 2022 Sep 1;109(9):1591-1604. doi: 10.1016/j.ajhg.2022.08.002. Epub 2022 Aug 22.

ABSTRACT

Diagnosis for rare genetic diseases often relies on phenotype-driven methods, which hinge on the accuracy and completeness of the rare disease phenotypes in the underlying annotation knowledgebase. Existing knowledgebases are often manually curated with additional annotations found in published case reports. Despite their potential, real-world data such as electronic health records (EHRs) have not been fully exploited to derive rare disease annotations. Here, we present open annotation for rare diseases (OARD), a real-world-data-derived resource with annotation for rare-disease-related phenotypes. This resource is derived from the EHRs of two academic health institutions containing more than 10 million individuals spanning wide age ranges and different disease subgroups. By leveraging ontology mapping and advanced natural-language-processing (NLP) methods, OARD automatically and efficiently extracts concepts for both rare diseases and their phenotypic traits from billing codes and lab tests as well as over 100 million clinical narratives. The rare disease prevalence derived by OARD is highly correlated with those annotated in the original rare disease knowledgebase. By performing association analysis, we identified more than 1 million novel disease-phenotype association pairs that were previously missed by human annotation, and >60% were confirmed true associations via manual review of a list of sampled pairs. Compared to the manual curated annotation, OARD is 100% data driven and its pipeline can be shared across different institutions. By supporting privacy-preserving sharing of aggregated summary statistics, such as term frequencies and disease-phenotype associations, it fills an important gap to facilitate data-driven research in the rare disease community.

PMID:35998640 | DOI:10.1016/j.ajhg.2022.08.002

Br J Biomed Sci. 2022 Jan 10;79:10221. doi: 10.3389/bjbs.2021.10221. eCollection 2022.

ABSTRACT

The definition of a rare disease in the European Union describes genetic disorders that affect less than 1 in 2,000 people per individual disease; collectively these numbers amount to millions of individuals globally, who usually manifest a rare disease early on in life. At present, there are at least 8,000 known rare conditions, of which only some are clearly molecularly defined. Over the recent years, the use of genetic diagnosis is gaining ground into informing clinical practice, particularly in the field of rare diseases, where diagnosis is difficult. To demonstrate the complexity of genetic diagnosis for rare diseases, we focus on Ciliopathies as an example of a group of rare diseases where an accurate diagnosis has proven a challenge and novel practices driven by scientists are needed to help bridge the gap between clinical and molecular diagnosis. Current diagnostic difficulties lie with the vast multitude of genes associated with Ciliopathies and trouble in distinguishing between Ciliopathies presenting with similar phenotypes. Moreover, Ciliopathies such as Autosomal Recessive Polycystic Kidney Disease (ARPKD) and Meckel-Gruber syndrome (MKS) present with early phenotypes and may require the analysis of samples from foetuses with a suspected Ciliopathy. Advancements in Next Generation Sequencing (NGS) have now enabled assessing a larger number of target genes, to ensure an accurate diagnosis. The aim of this review is to provide an overview of current diagnostic techniques relevant to Ciliopathies and discuss the applications and limitations associated with these techniques.

PMID:35996505 | PMC:PMC8915726 | DOI:10.3389/bjbs.2021.10221

Med Sci (Basel). 2022 Aug 22;10(3):44. doi: 10.3390/medsci10030044.

ABSTRACT

Polyamines are small polycationic alkylamines involved in many fundamental cellular processes, including cell proliferation, survival, and protection from oxidative stress. Polyamine homeostasis is tightly regulated through coordinated biosynthesis, catabolism, and transport. Due to their continual proliferation, cancer cells maintain elevated intracellular polyamine pools. Both polyamine metabolism and transport are commonly dysregulated in cancer, and as such, polyamine analogues are a promising strategy for exploiting the increased polyamine requirement of cancer cells. One potential polyamine analogue resistance mechanism is the downregulation of the poorly defined polyamine transport system. Recent advances in nanomedicine have produced nanostructures with polyamine analogue-based backbones (nanopolyamines). Similar nanostructures with non-polyamine backbones have been shown to be transported by endocytosis. As these polyamine-based nanoparticles could be a method for polyamine analogue delivery that bypasses polyamine transport, we designed the current studies to determine the efficacy of polyamine-based nanoparticles in cells lacking intact polyamine transport. Utilizing polyamine transport-deficient derivatives of lung adenocarcinoma lines, we demonstrated that cells unable to transport natural polyamines were also resistant to nanopolyamine-induced cytotoxicity. This resistance was a result of transport-deficient cells being incapable of importing and accumulating nanopolyamines. Pharmacological modulation of polyamine transport confirmed these results in polyamine transport competent cells. These studies provide additional insight into the polyamine transport pathway and suggest that receptor-mediated endocytosis is a likely mechanism of transport for higher-order polyamines, polyamine analogues and the nanopolyamines.

PMID:35997336 | DOI:10.3390/medsci10030044

Am J Case Rep. 2022 Aug 21;23:e936906. doi: 10.12659/AJCR.936906.

ABSTRACT

BACKGROUND Pityriasis rubra pilaris (PRP) is a rare chronic inflammatory skin condition characterized by follicular, papulosquamous, reddish-orange scaling, palmoplantar keratoderma, and erythema with islands of sparing. Its heterogeneous clinical presentation makes the diagnosis of PRP quite challenging, especially at the initial presentation, as it can mimic common skin conditions. CASE REPORT We present a case with an early presentation of PRP in a 61-year-old Malay woman with underlying uncontrolled diabetes, and discuss evolving clinical course of her disease. She presented to a primary care clinic with a 3-week history of itchy, ring-like skin lesions that started on her neck and chest but subsequently spread widely on her chest, back, and upper extremities. She was first treated as having extensive tinea corporis but responded poorly to multiple courses of antifungal treatment. An initial skin biopsy that was taken at the dermatology clinic revealed features suggestive of erythema annulare centrifugum. However, despite topical steroid treatment, her skin condition evolved further and she developed generalized erythroderma along with follicular hyperkeratosis and palmoplantar keratoderma. A repeat biopsy finally confirmed the diagnosis of PRP. CONCLUSIONS Making the diagnosis of PRP is challenging for clinicians. However, clinicians should approach any common skin problem that does not respond to treatment appropriately, with consideration of other uncommon skin disorders. A repeat skin biopsy may be considered if there are any doubts about the diagnosis. A clinical and histopathological correlation is important to aid in the diagnosis of PRP.

PMID:35988013 | DOI:10.12659/AJCR.936906

Orphanet J Rare Dis. 2022 Aug 20;17(1):317. doi: 10.1186/s13023-022-02467-7.

ABSTRACT

BACKGROUND: Around 8000 rare diseases are currently defined. In the context of individual vulnerability and more specifically the one induced by rare diseases, ensuring oral health is a particularly important issue. The objective of the study is to evaluate the pattern of oral health care course for patients with any rare genetic disease. Description of oral phenotypic signs-which predict a theoretical dental health care course-and effective orientation into an oral healthcare were evaluated.

MATERIALS AND METHODS: We set up a retrospective cohort study to describe the consideration of patient oral health and potential orientation to an oral health care course who have at least been seen once between 1 January 2017 and 1 January 2020 in Necker Enfants Malades Hospital. We recruited patients from this study using the data warehouse, Dr Warehouse® (DrWH), from Necker-Enfants Malades Hospital.

RESULTS: The study sample included 39 rare diseases, 2712 patients, with 54.7% girls and 45.3% boys. In the sample studied, 27.9% of patients had an acquisition delay or a pervasive developmental disorder. Among the patient files studied, oral and dental phenotypic signs were described for 18.40% of the patients, and an orientation in an oral healthcare was made in 15.60% of patients. The overall "network" effect was significantly associated with description of phenotypic signs (corrected p = 1.44e-77) and orientation to an oral healthcare (corrected p = 23.58e-44). Taking the Defiscience network (rare diseases of cerebral development and intellectual disability) as a reference for the odd ratio analysis, OSCAR, TETECOU, FILNEMUS, FIMARAD, MHEMO networks stand out from the other networks for their significantly higher consideration of oral phenotypic signs and orientation in an oral healthcare.

CONCLUSION: To our knowledge, no study has explored the management of oral health in so many rare diseases. The expected benefits of this study are, among others, a better understanding, and a better knowledge of the oral care, or at least of the consideration of oral care, in patients with rare diseases. Moreover, with the will to improve the knowledge on genetic diseases, oral heath must have a major place in the deep patient phenotyping. Therefore, interdisciplinary consultations with health professionals from different fields are crucial.

PMID:35987771 | DOI:10.1186/s13023-022-02467-7

J Neurosurg Spine. 2022 Aug 19:1-11. doi: 10.3171/2022.6.SPINE211011. Online ahead of print.

ABSTRACT

OBJECTIVE: Since its initial description, the definition of Ehlers-Danlos syndrome (EDS) has notably changed. At present, it broadly refers to disorders of the connective tissue that are heritable and have similar features including joint hypermobility, dermal dysplasia, and vascular as well as internal organ fragility. There has been no comprehensive review of spinal manifestations of EDS in the recent literature. That has led to controversies in management protocols of this so-called orphan disease.

METHODS: The authors used the latest version of the EDS classification from 2017, in which 13 subtypes were recognized. EDS has 19 different causal genes, mainly associated with collagen synthesis. Of these, 5 subtypes have associated spinal manifestations.

RESULTS: Some of the spinal pathologies associated with EDS include Chiari malformation, craniocervical instability, kyphoscoliosis, segmental instability and kyphosis, spontaneous CSF leaks, Tarlov cyst syndrome, tethered cord, and problems associated with wound healing. Here, the authors briefly discuss the demographics, etiology, pathophysiology, clinical features, management strategies, and directions for further research for each of these manifestations.

CONCLUSIONS: EDS belongs to the group of orphan diseases, with the total patient population being below 200,000. Further research on spinal manifestations of EDS is the need of the hour to establish clinical practice guidelines and close the significant knowledge gaps that currently exist.

PMID:35986728 | DOI:10.3171/2022.6.SPINE211011

Ital J Pediatr. 2022 Aug 19;48(1):152. doi: 10.1186/s13052-022-01340-4.

ABSTRACT

BACKGROUND: Noonan and Noonan-like syndromes are multisystem genetic disorders, mainly with autosomal dominant trasmission, caused by mutations in several genes. Missense pathogenetic variants of SOS1 gene are the second most common cause of Noonan syndrome (NS) and account approximately for 13% to 17% of cases. Subjects carrying a pathogenetic variant in SOS1 gene tend to exhibit a distinctive phenotype that is characterized by ectodermal abnormalities. Cutis verticis gyrata (CVG) is a rare disease, congenital or acquired, characterized by the redundancy of skin on scalp, forming thick skin folds and grooves of similar aspect to cerebral cortex gyri. Several references in the literature have reported association between nonessential primary form of CVG and NS.

CASE PRESENTATION: we report two cases of newborns with CVG and phenotype suggestive for NS who have been diagnosed to harbour the same pathogenetic variant in SOS1 gene.

CONCLUSIONS: previously described patients with NS presenting CVG had received only clinical diagnosis. Therefore we report the first patients with CVG in which the clinical suspicion of NS is confirmed by molecolar analysis.

PMID:35986401 | DOI:10.1186/s13052-022-01340-4