Search

While it is widely thought that de novo mutations (DNMs) occur randomly, we previously showed that some DNMs are enriched because they are positively selected in the testes of aging men. These "selfish" mutations cause disorders with a shared presentation of features, including exclusive paternal origin, significant increase of the father's age, and high apparent germline mutation rate. To date, all known selfish mutations cluster within the components of the RTK-RAS-MAPK signaling pathway, a critical modulator of testicular homeostasis. Here, we demonstrate the selfish nature of the SMAD4 DNMs causing Myhre syndrome (MYHRS). By analyzing 16 informative trios, we show that MYHRS-causing DNMs originated on the paternally derived allele in all cases. We document a statistically significant epidemiological paternal age effect of 6.3 years excess for fathers of MYHRS probands. We developed an ultra-sensitive assay to quantify spontaneous MYHRS-causing SMAD4 variants in sperm and show that pathogenic variants at codon 500 are found at elevated level in sperm of most men and exhibit a strong positive correlation with donor's age, indicative of a high apparent germline mutation rate. Finally, we performed in vitro assays to validate the peculiar functional behavior of the clonally selected DNMs and explored the basis of the pathophysiology of the different SMAD4 sperm-enriched variants. Taken together, these data provide compelling evidence that SMAD4 , a gene operating outside the canonical RAS-MAPK signaling pathway, is associated with selfish spermatogonial selection and raises the possibility that other genes/pathways are under positive selection in the aging human testis. Activating RAS-MAPK mutations occurring spontaneously in human spermatogonia cause clonal expansion of these stem cells with age, explaining the high birth prevalence of the associated disorders. We show that Myhre syndrome-causing mutations in SMAD4 , a gene operating outside the canonical RAS-MAPK signaling pathway, are positively selected in the male germline. [ABSTRACT FROM AUTHOR]

Marfan syndrome is a rare inherited connective tissue disease, which may be present in patients who have advanced hip pathologies that may require total hip arthroplasty (THA). The postoperative course of patients who have Marfan syndrome following THA has not yet been defined. Adult patients who have and do not have Marfan syndrome and underwent THA were identified in a national database. Patients diagnosed who had infection, trauma, or neoplasms within the 90 days prior to surgery were excluded. Those who have versus those who did not have Marfan syndrome were matched 1:10 based on age, sex, and a comorbidity index. After matching, 144 patients who have Marfan syndrome and 1,440 who do not have Marfan syndrome were identified. The 90-day postoperative adverse events and 5-year revisions were assessed and compared with multivariable analyses and log rank tests, respectively. Multivariable analyses demonstrated that Marfan syndrome was independently associated with greater odds of 90-day adverse events: venous thromboembolic events (odds ratio [OR]: 2.9, P =.001), cardiac events (OR: 4.5, P =.034), pneumonia (OR: 3.5, P <.001), and urinary tract infections (OR: 5.2, P <.001). There was no significant difference in 5-year rates of revision. Following THA, Marfan syndrome was independently associated with greater rates of several 90-day adverse events, but not higher 5-year rates of revision. The identified at-risk adverse events may help guide surgeons to improve perioperative care pathways, while having confidence regarding joint survival of THA in this rare disease population. [ABSTRACT FROM AUTHOR]

Abstract Background Before COVID-19, people with rare diseases (RD) experienced numerous disparities in quality of life and healthcare access and quality, yet little is known about the experiences of this underserved group during the pandemic. Results During the first wave of the COVID-19 pandemic in the United States, spring and summer of 2020, 759 participants representing 231 unique RDs responded to open-ended questions about the impact of the pandemic on life with a RD, healthcare access, and coping. Qualitative conventional content analysis was used to analyze responses. Identified themes represented positive and negative dimensions of change, including a shock to the (health) system, coping with uncertainty, and the value of social support while isolated. Conclusions Limitations in healthcare access and quality were the most frequently described as impacts of COVID-19. Other major negative impacts included exacerbation of symptoms, psychological distress, and a lack of usual social support and reliable information. However, participants also noted silver linings, especially in healthcare. For some, expanded telehealth enhanced their ability to access medical and mental health providers and RD specialists. Finally, many participants hoped that, by highlighting social and health inequities faced by people with RDs and other minorities, the pandemic would prompt greater understanding and policies that could improve the quality of life of the RD community.

Abstract Background Malakoplakia is a rare granulomatous inflammatory condition that can affect immunosuppressed patients. The genitourinary system is the most involved organ. We present a case of kidney failure caused by obstructing bladder lesions, clinically suspicious for malignancy and pathologically proven to be malakoplakia. Case presentation A 70-year-old woman presented with acute kidney injury and Escherichia coli (E.coli) bacteremia. Investigation showed bilateral hydronephrosis with thickening of the renal pelvises suggestive of urothelial malignancy. Cystourethroscopy revealed multiple bladder lesions completely obliterating both ureteral orifices. Pathology of the resected lesions confirmed the diagnosis of malakoplakia. Patient was treated with a prolonged antibiotic course over 6 months with recovery of her kidney function. Conclusion Malakoplakia can mimic invasive tumors, and the diagnosis is only attained through histopathology which uniquely demonstrates the pathognomonic Michaelis–Gutmann inclusions inside sheets of histiocytes. Treatment is largely dependent on prolonged antibiotics therapy that must cover the most common isolated pathogen, E.coli.

Congenital aniridia is a rare genetic disorder of the eye characterized by visual impairment and progressive vision loss. While prior research has focused on ocular manifestations in individuals with aniridia, there is a dearth of research on impacts on cognition and mental health. The aims of this study were to describe subjective symptoms of everyday executive functioning, fatigue and sleepiness in adults with aniridia and to compare self-reported health status with that of a normative reference group. Twenty-nine adults (aged 18–79 years) with congenital aniridia were included in this online survey, of whom 52% were females. Participants completed self-report measures of executive functioning (The Behavior Rating Inventory of Executive Function–Adult Version), sleepiness, fatigue, and health status (EQ-5D-5L). Participants reported relatively few problems in everyday executive functioning, with only 14% experiencing impaired executive functioning. Scores on the five EQ-5D-5L domains (mobility, self-care, usual activities, pain, and anxiety/depression) did not differ from those of the normative reference group. The frequencies of excessive daytime sleepiness and severe fatigue were 17% and 38%, respectively. Ocular pain was experienced by 62% of participants. The findings show that cognitive problems are related to and reflect self-reported health status and extent of fatigue. Moreover, those who suffered from ocular pain reported more difficulties with executive functioning, sleepiness and fatigue. These findings are important for understanding this disorder and supporting patients. [ABSTRACT FROM AUTHOR]

Rare disorders impact millions of children worldwide, and developing new medicines in this setting is associated with multiple challenges. In this paper, we share a successful story of how real-world data (RWD) were leveraged to accelerate evidence generation and patient access to a life-changing therapy in patients with severe manifestations of PIK3CA-related overgrowth spectrum who require systemic therapy. Despite all the existing regulatory guidelines considering real-world evidence (RWE), there is limited regulatory precedent of the use of this framework in support of a new indication. Thus, our case study illustrates design innovations based on the use of a compassionate use program, primarily in children, as a RWD source for approval of a new therapy in a rare disorder. We highlight the systematic considerations and mitigation of potential sources of bias in order to transform the data into actionable evidence. Our experience shows that RWE can be successfully used with appropriate study planning and mitigation in the context of a rare disorder with a high unmet medical need. Some lessons learned from this case study can benefit therapeutic development in rare disorders. [ABSTRACT FROM AUTHOR]

ABSTRACTBackground Congenital aniridia is a rare genetic disorder of the eye characterized by visual impairment and progressive vision loss. While prior research has focused on ocular manifestations in individuals with aniridia, there is a dearth of research on impacts on cognition and mental health. The aims of this study were to describe subjective symptoms of everyday executive functioning, fatigue and sleepiness in adults with aniridia and to compare self-reported health status with that of a normative reference group.Methods Twenty-nine adults (aged 18–79 years) with congenital aniridia were included in this online survey, of whom 52% were females. Participants completed self-report measures of executive functioning (The Behavior Rating Inventory of Executive Function–Adult Version), sleepiness, fatigue, and health status (EQ-5D-5L).Results Participants reported relatively few problems in everyday executive functioning, with only 14% experiencing impaired executive functioning. Scores on the five EQ-5D-5L domains (mobility, self-care, usual activities, pain, and anxiety/depression) did not differ from those of the normative reference group. The frequencies of excessive daytime sleepiness and severe fatigue were 17% and 38%, respectively. Ocular pain was experienced by 62% of participants.Conclusions The findings show that cognitive problems are related to and reflect self-reported health status and extent of fatigue. Moreover, those who suffered from ocular pain reported more difficulties with executive functioning, sleepiness and fatigue. These findings are important for understanding this disorder and supporting patients.

Lysosomal storage diseases (LSDs) consist of about 60 different monogenic disorders. Most of them occur due to protein misfolding. Only a few of those have been treated with molecular chaperones; the remaining either have limited treatment options or only management therapies. About 1860 single amino-acid substitutions (SAS) have been identified under LSDs. Merely, a handful of mutations have been studied experimentally. Availability of computational tools has made researchers turn toward genetic disorders to focus light on unexplored disorders and their mutations. Since all the LSDs are rare genetic disorders, not much research is carried out in this area. However, a mutational effect on protein function could be predicted, through bioinformatics tools. On that note, out of 1860 SAS, 58 predictions were neutral and 778 were predicted to be disease associated by all programs included in this study. The result of the prediction analysis of all mutations in each of the LSDs is curated into a database. This would make researchers know the deleterious nature of a mutation causing LSD. The database is available at http://lsddb.vit.ac.in:3000/. Lysosomal storage diseases (LSDs) are rare yet cytotoxic inherent metabolic aberrations, elucidated by excess accumulation of biomolecular substrates in cells of various organs, due to lysosomal defective functioning. To formulate effective analeptics against this detrimental and potentially life-threatening affliction, and to better comprehend the pathological mechanism behind LSDs, it is essential to know the integral detrimental mutations that actuate LSDs. To make researchers and the general populace aware of this pertinent information, we have designed a database that includes all the disorders categorized under LSDs. [ABSTRACT FROM AUTHOR]

Background: More than 80 genes are involved in the pathogenesis of the most common single gene peripheral neuropathies denoted as Charcot-Marie-Tooth (CMT). Only a few studies have investigated the pathological molecular mechanisms of Iranian patients affected with CMT. The aim of this study is to identify the clinical manifestation, mutational spectrum and phenotypic correlation of a cohort of patients with Charcot-Marie-Tooth disease (CMT) in Iran. Methods: We conducted a comprehensive gene panel sequencing consisting of 80 genes in a cohort of 23 patients with CMT referred between January 2015 and March 2021. The recruited samples indicated almost an equal distribution of demyelinating and axonal types of CMT, with practically no difference between AD or AR patterns of inheritance. Results: Four novel mutations, including c.271C>T in LITAF and c.205+1delG in NDRG1, c.2455A>C in KIF1B and c.1728A>G in FIGF were detected in four patients affected with demyelinating CMT types (CMT1C and CMT4D), and characterized phenotypically. Conclusion: Our promising results unravel the complicated genetic architecture of Iranian CMT patients and help physicians and researchers achieve earlier diagnosis, better clinical management and recognizing high risk families. Further large-scale studies are needed to improve our understanding of CMT complex genetic architecture. [ABSTRACT FROM AUTHOR]

Frontotemporal disorders are a group of rare young-onset dementias for which there is no cure, nor is there any way to slow the underlying progressive brain degeneration. To date those affected have typically received very little, if any, follow-up care after diagnosis, particularly in the early stages of their disease. I have received a clinical diagnosis, supported by imaging, of primary progressive aphasia, a form of frontotemporal degeneration characterized in the initial phase by progressive impairment of language ability. From the onset, I have been fortunate to receive excellent ongoing palliative care from a multidisciplinary team, some of whom had never previously seen anyone with this disorder. My quality of life has been enhanced by an evolving range of creative strategies and adaptations targeted to my deficits as they have arisen. In this paper, I discuss my experience of the process underlying this personalized plan, which serves as a paradigm for the development of novel palliative care approaches for people living with rare disorders, both neurodegenerative diseases and other conditions. [ABSTRACT FROM AUTHOR]

Abstract Background Mutations of the human FAM111B gene are associated with hereditary fibrosing poikiloderma with tendon contracture, myopathy, and pulmonary fibrosis (POIKTMP), a rare and autosomal dominant multi-systemic fibrosing disease. To date, a total of 36 cases are documented, with eleven associated mutations identified and confirmed by Whole-Exome Sequencing and Sanger sequencing. However, these methods require a certain level of expertise. The FAM111B gene was annotated using the SNAPGENE tool to identify various restriction enzymes. The enzymes that cut at the positions where mutations of interest have been reported were selected. The method was implemented using the DNA samples extracted from the skin fibroblast collected from an affected South African family and unrelated control. Results The findings showed that of the eleven FAM111B mutational sites investigated with this method, ten mutations can be identified including the known mutation FAM111B NM_198947.4: c.1861T>G (pTyr621Asp) associated with the POIKTMP in South Africa. Conclusions Limited access to molecular diagnosis contributes to why POIKTMP is rarely diagnosed. Our study describes an inexpensive PCR–RFLP method to screen for POIKTMP FAM111B gene mutations. The PCR–RFLP can be used as a cost-effective method for diagnosing FAM111B mutations in POIKTMP, and it does not require having robust experience in molecular biology.

Transthyretin cardiac amyloidosis (ATTR-CM) is a rare and under-recognized disorder characterized by the aggregation of transthyretin-derived insoluble amyloid fibrils in the myocardium. Heterogeneity of symptoms at presentation, makes its diagnosis often delayed. An expert panel gathered on a virtual platform across India to conduct a meeting for developing a guiding tool for ATTR-CM diagnosis. The panel recommended younger age (≥40 years) for suspecting ATTR-CM and thick-walled non-dilated hypokinetic ventricle was considered as one of the important red flags. Electrocardiogram (ECG) and echocardiography (ECHO) findings were recommended as primary tests to raise the suspicion while nuclear scintigraphy and hematological tests were recommended to confirm the diagnosis and rule out amyloid light-chain (AL) amyloidosis. Cardiac magnetic resonance (CMR) and biopsy were recommended in case of ambiguity in the presence of red flags. Considering the lack of expert guidelines in the Indian scenario, a standardized diagnostic algorithm was also proposed.

Abstract Background People with rare disorders face significant global health inequalities; the challenge is how to raise awareness and develop a nucleus of experts in a country who are then able to provide guidance to others in that country. The International Prader–Willi Syndrome Organisation (IPWSO) established Project ECHO® with the aim of facilitating the sharing of knowledge and the building of international partnerships to reduce global health inequalities for a particular rare genetically-determined neurodevelopmental disorder, Prader–Willi Syndrome (PWS). Four different ECHO programmes were established for the following groups: (a) Individuals (usually parents) who had taken on a leadership role in their country; (b) health professionals interested in PWS; (c) professional care providers supporting children and adults with PWS; and (d) a Latin American ECHO in Spanish. The programme started in 2020 and an evaluation was undertaken after one year to determine: the extent to which IPWSO had been able to recruit and retain individuals globally; the nature and extent of any benefits gained from the sessions; and examples of how individual involvement in the programme had led to local benefits. The methods included analysing routinely kept process indicators and survey data from the attendees of one component of the programme (the Leadership ECHO), together with a qualitative analysis of survey data and recorded interviews of attendees from countries of differing socio-economic status. Results We describe the IPWSO ECHO programme and report on the outcomes from the evaluation of one aspect of the programme, the Leadership ECHO. Attendance of the Leadership ECHO sessions was satisfactory, with a mean of 24.7 participants, with participants attending a mean of 5.67 sessions, i.e., 30% of sessions. There was also good global reach, with individuals attending from 34 countries, although there were notable geographic regions with very limited representation. Feedback and interviews demonstrated the positive impact of the programme with some early evidence of positive developments at national level. Conclusions Families and professionals from countries with a range of expertise and services offered to people with PWS remained engaged throughout the ECHO programme, established networks of support and fostered the development of good practice.

Nummular headache is an unusual facial pain disorder with no evidence-based therapy recommendations. The ketogenic diet is an alternative therapy that demonstrated to be effective in migraineurs, but it was never used in the setting of nummular headache. We describe a 58-years old female patient with nummular headache successfully treated with a 6-months ketogenic diet and botulinum toxin type A injections. Ketogenic diet could be an effective alternative/complementary therapy in nummular headache patients although more studies are needed to confirm our results. [ABSTRACT FROM AUTHOR]

Nummular headache is an unusual facial pain disorder with no evidence-based therapy recommendations. The ketogenic diet is an alternative therapy that demonstrated to be effective in migraineurs, but it was never used in the setting of nummular headache. We describe a 58-years old female patient with nummular headache successfully treated with a 6-months ketogenic diet and botulinum toxin type A injections. Ketogenic diet could be an effective alternative/complementary therapy in nummular headache patients although more studies are needed to confirm our results.

Primary Hyperoxaluria Type 1 (PH1) is a rare autosomal disease caused by mutations in AGXT that lead to the deficiency of alanine:glyoxylate aminotransferase (AGT). AGT is a liver pyridoxal 5′-phosphate (PLP)-dependent enzyme that detoxifies glyoxylate inside peroxisomes. The lack of AGT activity results in a build-up of glyoxylate that is oxidized to oxalate, then culminating in hyperoxaluria often leading to kidney failure. Most pathogenic mutations reduce AGT specific activity because of catalytic defects, improper folding, mistargeting to mitochondria, reduced intracellular stability, dimerization, and/or aggregation. Administration of pyridoxine (PN), a precursor of PLP, is a therapeutic option available for PH1 patients carrying responsive genotypes through the ability of the coenzyme to behave as a chaperone. Here, we report the clinical and biochemical characterization of the novel mutation c.1093G > T (p.Gly365Cys) identified in a Japanese patient. In silico studies predict that the p.Gly365Cys mutation causes a steric clash resulting in a local rearrangement of the region surrounding the active site, thus possibly affecting PLP binding and catalysis. Indeed, the purified p.Gly365Cys mutant displays proper folding but shows an extensive decrease of catalytic efficiency due to an altered PLP-binding. When expressed in AGXT1 -KO HepG2 cells the variant shows reduced specific activity and protein levels in comparison with wild type AGT that cannot be rescued by PN treatment. Overall, our data indicate that the mutation of Gly365 induces a conformational change at the AGT active site translating into a functional and structural defect and allow to predict that the patients will not be responsive to vitamin B6, thus supporting the usefulness of preclinical studies to guide therapeutic decisions in the era of precision medicine. • The novel mutation p.Gly365Cys on the AGXT gene associated to PH1 has been identified. • The p.Gly365Cys mutation mainly affects PLP binding and catalysis. • The p.Gly365Cys variant undergoes degradation and intracellular aggregation. • The p.Gly365Cys variant does not respond to PN in a HepG2 cellular model of PH1. • Biochemical and cellular studies reveal mechanisms underlying pathogenicity in PH1. [ABSTRACT FROM AUTHOR]

Objectives: To explore patterns of parafunction, and bruxism, and its relationships with genotype and snoring in individuals with Rett syndrome (RTT). Methods: Retrospective observational data of those with confirmed MECP2 mutations in the InterRett database (n = 216) were used to investigate experience of parafunctional habits, and bruxism and their relationships with genotype and snoring using multivariable linear regression. Results: The prevalence of parafunction was 98.2%. Bruxism was reported (66.2%) with the patterns mostly both diurnal and nocturnal (44.1%) and exclusively diurnal (42.7%). Compared to individuals with C‐terminal deletion, individuals with p.Arg106Trp mutations were less likely to have bruxism reported (aOR = 0.15; 95% CI 0.02–0.98, p = 0.05) and those with p.Arg168* mutation were more likely to have frequent bruxism than none or occasional bruxism reported (aROR 3.4; 95% CI 1.1–10.7 p = 0.04). The relative odds of having nocturnal bruxism constantly, compared to none/occasionally, were higher among those 'always' snoring (aROR 6.24; 95% CI 2.1–18.2, p = 0.001) than those with no snoring. Conclusions: There appeared to be genotypic association with bruxism in p.Arg168* and p.Arg106Trp mutations and association between nocturnal bruxism and frequent snoring in an international sample of individuals with RTT. Clinical significance of the high prevalence of bruxism should be highlighted in relation to difficulty communicating pain and increased dental treatment need in RTT. [ABSTRACT FROM AUTHOR]

In a two-study project, researchers used qualitative methods and inductive thematic analyses to investigate the lived awareness- and advocacy-related experiences of 27 adults with over 35 different rare diseases, disorders, or disabilities (RDs). In Study 1, participants in two focus groups described how a lack of RD awareness led to experiences with several types of stigma, complicated their expressions and disclosures of disability, and spurred them to work towards awareness. Participant priorities identified in Study 1 motivated researchers to design and conduct Study 2. In Study 2, researchers interviewed 18 RD self-advocates about their lived experiences with and ideas regarding advocacy. Their recommendations included increasing social and systemic support, education, and media and professional representation. Advocates in Study 2 also warned of potential roadblocks to self-advocacy and change, including systemic invalidation and bias, lack of access to activist spaces, and limited time and energy for advocacy. Overall, analyses exposed the complex and interwoven influences of RD awareness and advocacy. [ABSTRACT FROM AUTHOR]

Abstract Background Experienced fatigue is an under-recognized and under-researched feature in persons with many different rare diseases. A better overview of the characteristics of existing research on experienced fatigue in children and adults with rare diseases is needed. The purpose of this review was to map and describe characteristics of existing research on experienced fatigue in a selection of rare diseases in rare developmental defects or anomalies during embryogenesis and rare genetic diseases. Furthermore, to identify research gaps and point to research agendas. Methods We applied a scoping review methodology, and performed a systematic search in March 2020 in bibliographic databases. References were sorted and evaluated for inclusion using EndNote and Rayyan. Data were extracted on the main research questions concerning characteristics of research on experienced fatigue (definition and focus on fatigue, study populations, research questions investigated and methods used). Results This review included 215 articles on ten different rare developmental defects/anomalies during embryogenesis and 35 rare genetic diseases. Of the 215 articles, 82 had investigation of experienced fatigue as primary aim or outcome. Included were 9 secondary research articles (reviews) and 206 primary research articles. A minority of articles included children. There were large differences in the number of studies in different diseases. Only 29 of 215 articles gave a description of how they defined the concept of experienced fatigue. The most common research-question reported on was prevalence and/ -or associations to fatigue. The least common was diagnostics (development or validation of fatigue assessment methods for a specific patient group). A large variety of methods were used to investigate experienced fatigue, impeding comparisons both within and across diagnoses. Conclusion This scoping review on the characteristics of fatigue research in rare diseases found a large variety of research on experienced fatigue. However, the minority of studies had investigation of experienced fatigue as a primary aim. There was large variation in how experienced fatigue was defined and also in how it was measured, both within and across diagnoses. More research on experienced fatigue is needed, both in children and adults with rare diseases. This review offers a basis for further research.

Background: Mutations of the human FAM111B gene are associated with hereditary fibrosing poikiloderma with tendon contracture, myopathy, and pulmonary fibrosis (POIKTMP), a rare and autosomal dominant multi-systemic fibrosing disease. To date, a total of 36 cases are documented, with eleven associated mutations identified and confirmed by Whole-Exome Sequencing and Sanger sequencing. However, these methods require a certain level of expertise. The FAM111B gene was annotated using the SNAPGENE tool to identify various restriction enzymes. The enzymes that cut at the positions where mutations of interest have been reported were selected. The method was implemented using the DNA samples extracted from the skin fibroblast collected from an affected South African family and unrelated control. Results: The findings showed that of the eleven FAM111B mutational sites investigated with this method, ten mutations can be identified including the known mutation FAM111B NM_198947.4: c.1861T>G (pTyr621Asp) associated with the POIKTMP in South Africa. Conclusions: Limited access to molecular diagnosis contributes to why POIKTMP is rarely diagnosed. Our study describes an inexpensive PCR–RFLP method to screen for POIKTMP FAM111B gene mutations. The PCR–RFLP can be used as a cost-effective method for diagnosing FAM111B mutations in POIKTMP, and it does not require having robust experience in molecular biology. [ABSTRACT FROM AUTHOR]

Objectives: Turner syndrome (TS) is a rare sex chromosome aneuploidy, with an incidence of four in 10,000 new-born girls. TS is often associated with impaired social communication skills, but the extent to which these are attributable to Autism Spectrum Disorders (ASD) is uncertain. We made standardized assessments of the mental health and associated neurodevelopmental disorders in children and adolescents with TS and report on the prevalence of concurrent conditions. Methods: Our sample comprised 127 girls with TS, 5–19 years of age. We obtained reports of their mental health from a combination of diagnostic interview (the Development and Wellbeing Assessment (DAWBA)), from the Strengths and Difficulties Questionnaire (SDQ) and from the Social Responsiveness Scale (SRS-2). Sources of information included parents, teachers and self-reports. The prevalence of mental health disorders in this sample was compared with age/sex matched national English data from typical controls. Results: Most individuals with TS (83%) had experienced significant social communication difficulties and nearly one in four (23%) met diagnostic criteria for ASD on the DAWBA. One-third (34%) had at least one mental health or neurodevelopmental condition, and those girls with an ASD were at a greater risk of a co-occurring emotional disorder and/or attention deficit hyperactivity disorder (ADHD). Conclusion: Children and adolescents with TS are substantially more likely to meet criteria for ASD than their typically developing peers. Our finding has clinical implications for appropriate behavioural management from preschool through to adolescence. [ABSTRACT FROM AUTHOR]

Background: People with rare disorders face significant global health inequalities; the challenge is how to raise awareness and develop a nucleus of experts in a country who are then able to provide guidance to others in that country. The International Prader-Willi Syndrome Organisation (IPWSO) established Project ECHO® with the aim of facilitating the sharing of knowledge and the building of international partnerships to reduce global health inequalities for a particular rare genetically-determined neurodevelopmental disorder, Prader-Willi Syndrome (PWS). Four different ECHO programmes were established for the following groups: (a) Individuals (usually parents) who had taken on a leadership role in their country; (b) health professionals interested in PWS; (c) professional care providers supporting children and adults with PWS; and (d) a Latin American ECHO in Spanish. The programme started in 2020 and an evaluation was undertaken after one year to determine: the extent to which IPWSO had been able to recruit and retain individuals globally; the nature and extent of any benefits gained from the sessions; and examples of how individual involvement in the programme had led to local benefits. The methods included analysing routinely kept process indicators and survey data from the attendees of one component of the programme (the Leadership ECHO), together with a qualitative analysis of survey data and recorded interviews of attendees from countries of differing socio-economic status.Results: We describe the IPWSO ECHO programme and report on the outcomes from the evaluation of one aspect of the programme, the Leadership ECHO. Attendance of the Leadership ECHO sessions was satisfactory, with a mean of 24.7 participants, with participants attending a mean of 5.67 sessions, i.e., 30% of sessions. There was also good global reach, with individuals attending from 34 countries, although there were notable geographic regions with very limited representation. Feedback and interviews demonstrated the positive impact of the programme with some early evidence of positive developments at national level.Conclusions: Families and professionals from countries with a range of expertise and services offered to people with PWS remained engaged throughout the ECHO programme, established networks of support and fostered the development of good practice. [ABSTRACT FROM AUTHOR]

Background: Experienced fatigue is an under-recognized and under-researched feature in persons with many different rare diseases. A better overview of the characteristics of existing research on experienced fatigue in children and adults with rare diseases is needed. The purpose of this review was to map and describe characteristics of existing research on experienced fatigue in a selection of rare diseases in rare developmental defects or anomalies during embryogenesis and rare genetic diseases. Furthermore, to identify research gaps and point to research agendas. Methods: We applied a scoping review methodology, and performed a systematic search in March 2020 in bibliographic databases. References were sorted and evaluated for inclusion using EndNote and Rayyan. Data were extracted on the main research questions concerning characteristics of research on experienced fatigue (definition and focus on fatigue, study populations, research questions investigated and methods used). Results: This review included 215 articles on ten different rare developmental defects/anomalies during embryogenesis and 35 rare genetic diseases. Of the 215 articles, 82 had investigation of experienced fatigue as primary aim or outcome. Included were 9 secondary research articles (reviews) and 206 primary research articles. A minority of articles included children. There were large differences in the number of studies in different diseases. Only 29 of 215 articles gave a description of how they defined the concept of experienced fatigue. The most common research-question reported on was prevalence and/ -or associations to fatigue. The least common was diagnostics (development or validation of fatigue assessment methods for a specific patient group). A large variety of methods were used to investigate experienced fatigue, impeding comparisons both within and across diagnoses. Conclusion: This scoping review on the characteristics of fatigue research in rare diseases found a large variety of research on experienced fatigue. However, the minority of studies had investigation of experienced fatigue as a primary aim. There was large variation in how experienced fatigue was defined and also in how it was measured, both within and across diagnoses. More research on experienced fatigue is needed, both in children and adults with rare diseases. This review offers a basis for further research. [ABSTRACT FROM AUTHOR]

The National Organization for Rare Disorders, or NORD®, is a robust resource suitable for patients, families, clinicians, researchers, and advocates of those living with or impacted by rare diseases. Given that rare diseases affect around 30 million people in the United States, half of which are estimated to be children, it is vital to have access to credible and accessible information. An added bonus of NORD is their staunch advocacy platform, which brings to light other consumer health information which may otherwise be hard to find. This consumer health resource review covers the consumer-focused aspects of NORD. [ABSTRACT FROM AUTHOR]

The National Organization for Rare Disorders, or NORD®, is a robust resource suitable for patients, families, clinicians, researchers, and advocates of those living with or impacted by rare diseases. Given that rare diseases affect around 30 million people in the United States, half of which are estimated to be children, it is vital to have access to credible and accessible information. An added bonus of NORD is their staunch advocacy platform, which brings to light other consumer health information which may otherwise be hard to find. This consumer health resource review covers the consumer-focused aspects of NORD. [ABSTRACT FROM AUTHOR]

Background: Malakoplakia is a rare granulomatous disease that commonly involves the genitourinary tract with the urinary bladder being the most frequently affected site. It is characterized by histiocytes containing distinct basophilic calcified inclusions called Michaelis-Gutmann bodies. It is believed to result from abnormally functioning macrophages, with inclusions representing calcifications around incompletely digested bacteria. Although its pathogenesis remains unknown, it is well-documented that the condition is associated with chronic urinary tract infections and immunosuppression. Grossly, it can present as soft, yellow plaques, nodules, bladder mass, or even without any visible lesion. It poses a huge diagnostic challenge as it tends to mimic malignancy., Case Presentation: Described here is an 86-year-old female with recurrent bladder malakoplakia who presented with foul-smelling urine, hematuria, and dysuria. The clinicopathological features of this rare bladder lesion are described along with a review of the literature., Conclusion: Early identification of malakoplakia's features by pathologists is essential for effective patient management. This condition should be considered in the differential diagnosis of bladder lesions, especially when Escherichia coli is present., Competing Interests: The author declares no conflict of interest., (© 2024 Bladder, All rights reserved.)

Objective: There are more than 6,000 known rare diseases (RDs), which are often serious, chronic, and progressive conditions. Cumulatively, having a RD is actually common, impacting an estimated 300 million people worldwide. While the stigmatization of some specific RDs has been studied, examining stigma in a large sample of many RDs allows for a broader understanding of patterns. Design: We used inductive qualitative content analysis to analyze survey responses to an open-ended question about challenges of living with a RD among 384 people with 178 distinct RDs. Results: We identified eight codes which were organized under the following three themes: structurally enacted, interpersonally enacted, and felt stigma. People with RDs experience structurally enacted stigma in the forms of healthcare stigma, education/workplace stigma, and an overall lack of accessibility. They also face interpersonally enacted stigma, including insufficient social support, a lack of understanding from others, and capitalist norms of productivity and self-sufficiency. Additionally, they experience felt stigma related to shame and the pressure to pass as able-bodied. Conclusion: Possible solutions to RD stigma include increased education about RDs for healthcare professionals, a societal shift towards prioritizing accessibility, strengthened legal protections for disabled people, and expanded disability justice-focused community organizing. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study is to make a review of the literature about bladder malakoplakia. Material and Methods: We searched articles on the PUBMED web-literature database with the following keywords: "vesical malakoplakia" and "bladder malakoplakia". In the literature we found 254 articles. At final we have excluded 219 articles, including in our study only 35 articles. Results: The overall average age found was 50.85 years. The average age of men was 43.22 years, while that of women was 53.37 years. 75% of the patient cases were women and 25% were men. Regarding comorbidities, in 5.55% of the cases were missing whereas 47.22% of the patients suffered from recurrent urinary tract infection (UTI) and 19.44% from immune system disorders. Urine culture was positive in 69.44% with E.coli being isolated in 92% of cases. Hydroureteronephrosis was present in 44.44% of the cases: left in 6.25% of cases, right in 18.75% and bilateral in 75%. The mean serum creatinine of patients with hydroureteronephrosis was 5.11 (1-21) mg/dl. The most frequent site of the lesion was the vesicoureteral junction (VUJ) (42.31%), followed by the trigone (38.46%). 30.56% of patients were treated with antibiotic and surgery (transurethral resection of bladder, partial or radical cystectomy), less frequent options were antibiotics alone and surgery alone. The recurrence rate was 15%. Conclusions: Malakoplakia is a disorder usually related to other affections, like UTI and immunodepression, and it seem to be caused by an abnormal macrophage function. In almost half of the described cases of isolated bladder malakoplakia, hydroureteronephrosis and renal failure were present. Treatment is not standardized, but both medical and surgical therapies are effective to avoid recurrence. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study is to make a review of the literature about bladder malakoplakia. Material and Methods: We searched articles on the PUBMED web-literature database with the following keywords: “vesical malakoplakia” and “bladder malakoplakia”. In the literature we found 254 articles. At final we have excluded 219 articles, including in our study only 35 articles. Results: The overall average age found was 50.85 years. The average age of men was 43.22 years, while that of women was 53.37 years. 75% of the patient cases were women and 25% were men. Regarding comorbidities, in 5.55% of the cases were missing whereas 47.22% of the patients suffered from recurrent urinary tract infection (UTI) and 19.44% from immune system disorders. Urine culture was positive in 69.44% with E.coli being isolated in 92% of cases. Hydroureteronephrosis was present in 44.44% of the cases: left in 6.25% of cases, right in 18.75% and bilateral in 75%. The mean serum creatinine of patients with hydroureteronephrosis was 5.11 (1-21) mg/dl. The most frequent site of the lesion was the vesicoureteral junction (VUJ) (42.31%), followed by the trigone (38.46%). 30.56% of patients were treated with antibiotic and surgery (transurethral resection of bladder, partial or radical cystectomy), less frequent options were antibiotics alone and surgery alone. The recurrence rate was 15%. Conclusions: Malakoplakia is a disorder usually related to other affections, like UTI and immunodepression, and it seem to be caused by an abnormal macrophage function. In almost half of the described cases of isolated bladder malakoplakia, hydroureteronephrosis and renal failure were present.Treatment is not standardized, but both medical and surgical therapies are effective to avoid recurrence.

Lysosomal storage disorders are rare multiorgan, degenerative conditions requiring invasive treatment. Rare disorders pose unique challenges; therefore, exploring their impact is crucial for understanding family needs. This novel review aimed to understand the psychosocial outcomes for parents of children with lysosomal storage disorders. Five electronic databases were systematically searched. Thirty‐eight (23 qualitative, 10 qualitative and 5 mixed methods) studies were included, analysed using a sequential explanatory narrative synthesis and appraised for their methodological quality. Quantitative data revealed the multifaceted impact on parents' psychological and social wellbeing. Qualitative data informed the challenges that these parents faced which were expressed within three main themes: (a) Uncertainty and the unknown, (b) All‐encompassing impact and (c) Finding a way forward. The synthesis demonstrated that factors associated with the condition (symptoms, behaviour and severity) had a substantial negative impact on parental outcomes, upheld by concurrent loss (deterioration and poor prognosis) and uncertainty. This substantive integrated review revealed considerable unmet parental psychosocial needs. [ABSTRACT FROM AUTHOR]

Abstract Background Acroscyphodysplasia has been described as a phenotypic variant of acrodysostosis type 2 and pseudohypoparathyroidism. In acrodysostosis, skeletal features can include brachydactyly, facial hypoplasia, cone-shaped epiphyses, short stature, and advanced bone age. To date, reports on this disorder have focused on phenotypic findings, endocrine changes, and genetic variation. We present a 14-year overview of a patient, from birth to skeletal maturity, with acroscyphodysplasia, noting the significant orthopaedic challenges and the need for a multidisciplinary team, including specialists in genetics, orthopaedics, endocrinology, and otolaryngology, to optimize long-term outcomes. Case presentation The patient presented as a newborn with dysmorphic facial features, including severe midface hypoplasia, malar flattening, nasal stenosis, and feeding difficulties. Radiologic findings were initially subtle, and a skeletal survey performed at age 7 months was initially considered normal. Genetic evaluation revealed a variant in PDE4D and subsequent pseudohypoparathyroidism. The patient presented to the department of orthopaedics, at age 2 years 9 months with a leg length discrepancy, right knee contracture, and severely crouched gait. Radiographs demonstrated cone-shaped epiphyses of the right distal femur and proximal tibia, but no evidence of growth plate changes in the left leg. The child developed early posterior epiphyseal arrest on the right side and required multiple surgical interventions to achieve neutral extension. Her left distal femur developed late posterior physeal arrest and secondary contracture without evidence of schypho deformity, which improved with anterior screw epiphysiodesis. The child required numerous orthopaedic surgical interventions to achieve full knee extension bilaterally. At age 13 years 11 months, she was an independent ambulator with erect posture. The child underwent numerous otolaryngology procedures and will require significant ongoing care. She has moderate intellectual disability. Discussion and conclusions Key challenges in the management of this case included the subtle changes on initial skeletal survey and the marked asymmetry of her deformity. While cone-shaped epiphyses are a hallmark of acrodysostosis, posterior tethering/growth arrest of the posterior distal femur has not been previously reported. Correction of the secondary knee contracture was essential to improve ambulation. Children with acroscyphodysplasia require a multidisciplinary approach, including radiology, genetics, orthopaedics, otolaryngology, and endocrinology specialties.

Background: There is a dearth of literature available on the comparative oral health status of those with Rett syndrome (RTT) despite diurnal bruxism being a supportive diagnostic criterion for the disorder. This study was designed to investigate the dental experiences of individuals with RTT in terms of perceived at‐home and professional dental care. Methods: Using data in the InterRett database, provided by English‐speaking families of individuals with a confirmed MECP2 genetic mutation, the study investigated relationships between dental problems, oral care, child factors including bruxism and use of gastrostomy, and socioeconomic indicators. The study also explored relationships between dental presentations and socioeconomic, child, and family‐related factors. Results: Individuals with RTT exhibiting bruxism were more likely to access dental treatment. Those who had full oral feeding had a higher incidence rate of dental treatment than those with full tube feeding. A conservative (under) estimation of the overall dental caries progression rate revealed that this may be similar to that of the normal population. Conclusions: Drivers for dental treatment in RTT include bruxism as well as dental caries. Those who have full oral feeding experience more dental treatment than those with full tube feeding. A higher maternal education level may confer a protective effect for oral health outcomes in those with RTT. Nevertheless, families generally tended to value the importance of oral health despite reported difficulties in day‐to‐day mouth care. [ABSTRACT FROM AUTHOR]

RASopathies are rare developmental genetic syndromes caused by germline pathogenic variants in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway. Although the incidence of each RASopathy syndrome is rare, collectively, they represent one of the largest groups of multiple congenital anomaly syndromes and have severe developmental consequences. Here, we review our understanding of how RAS/MAPK dysregulation in RASopathies impacts skeletal muscle development and the importance of RAS/MAPK pathway regulation for embryonic myogenesis. We also discuss the complex interactions of this pathway with other intracellular signaling pathways in the regulation of skeletal muscle development and growth, and the opportunities that RASopathy animal models provide for exploring the use of pathway inhibitors, typically used for cancer treatment, to correct the unique skeletal myopathy caused by the dysregulation of this pathway., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

CACNA1A-related disorders are rare neurodevelopmental disorders linked to variants in the CACNA1A gene. This gene encodes the α1 subunit of the P/Q-type calcium channel Cav2.1, which is globally expressed in the brain and crucial for fast synaptic neurotransmission. The broad spectrum of CACNA1A-related neurological disorders includes developmental and epileptic encephalopathies, familial hemiplegic migraine type 1, episodic ataxia type 2, spinocerebellar ataxia type 6, together with unclassified presentations with developmental delay, ataxia, intellectual disability, autism spectrum disorder, and language impairment. The severity of each disorder is also highly variable. The spectrum of CACNA1A-related seizures is broad across both loss-of-function and gain-of-function variants and includes absence seizures, focal seizures with altered consciousness, generalized tonic-clonic seizures, tonic seizures, status epilepticus, and infantile spasms. Furthermore, over half of CACNA1A-related epilepsies are refractory to current therapies. To date, almost 1700 CACNA1A variants have been reported in ClinVar, with over 400 listed as Pathogenic or Likely Pathogenic, but with limited-to-no clinical or functional data. Robust genotype-phenotype studies and impacts of variants on protein structure and function have also yet to be established. As a result, there are few definitive treatment options for CACNA1A-related epilepsies. The CACNA1A Foundation has set out to change the landscape of available and effective treatments and improve the quality of life for those living with CACNA1A-related disorders, including epilepsy. Established in March 2020, the Foundation has built a robust preclinical toolbox that includes patient-derived induced pluripotent stem cells and novel disease models, launched clinical trial readiness initiatives, and organized a global CACNA1A Research Network. This Research Network is currently composed of over 60 scientists and clinicians committed to collaborating to accelerate the path to CACNA1A-specific treatments and one day, a cure., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Abstract Background There is relatively little literature on the oral health experiences of individuals with Rett syndrome. This study described the incidence of dental extractions and restorations in a population-based cohort, according to a range of demographic and clinical factors. The association between bruxism and age was also investigated. Methods Existing questionnaire data in the population-based Australian Rett Syndrome Database for the years 2004, 2006, 2009 or 2011 on genetically confirmed female cases (n = 242) were analysed. Results The incidence rate of restorations and extractions were 6.8 per 100 person years (py) and 9.3 per 100 py respectively. The incidence of extractions decreased with increasing levels of income. Compared to those with a C-terminal mutation, the incidence rate of extraction was higher for those with large deletions (Incidence Rate Ratio (IRR) 4.93; 95% CI 1.46–16.7, p = 0.01). There was a 5% decrease in the risk of frequent bruxism for every one-year increase in age (Risk Ratio 0.95; 95% CI 0.94–0.97). Conclusions Social advantage may provide some protection for dental health in individuals with Rett syndrome. Those with more severe genotypes seemed to have poorer oral health outcomes.

Abstract Background Pathologic mutations in SYNGAP1 cause a genetically defined form of intellectual disability (ID) with comorbid epilepsy and autistic features. While only recently discovered, pathogenicity of this gene is a relatively frequent genetic cause of classically undefined developmental delay that progresses to ID with commonly occurring comorbidities. Main body A meeting of 150 people was held that included affected individuals and their caregivers, clinicians that treat this and related brain disorders, neuroscientists that study SYNGAP1 biology or the function of related genes, and representatives from government agencies that fund science and approve new medical treatments. The meeting focused on developing a consensus among all stakeholders as to how best to achieve a more fundamental and profound understanding of SYNGAP1 biology and its role in human disease. Short conclusion From all of these proceedings, several areas of consensus emerged. The clinicians and geneticists agreed that the prevalence of epilepsy and sensory processing impairments in SYNGAP1-related brain disorders approached 100%. The neurobiologists agreed that more basic research is needed to better understand the molecular and cellular functions of the Syngap1 gene, which will lead to targets for therapeutic intervention. Finally, everyone agreed that there is a pressing need to form a robust patient registry as an initial step toward a prospective natural history study of patients with pathogenic SYNGAP1 variants.

Objective: Facial paralysis (FP) may impact emotional clarity, attachment, stigma, anxiety, and depression. The distinction between being born with it or acquiring it later may prompt developmental differences with consequences into adulthood, yet this has not been systematically studied. Two competing hypotheses were tested. First, the acquired advantage hypothesis states facial expression early in development plays a crucial role in socioemotional functioning, perhaps via facial feedback, and people with acquired FP would function better. Second, the congenital advantage hypothesis states impaired facial expression during early development promotes adaptation for socioemotional functioning, and people with congenital FP would function better. Method: Adults with congenital (n = 112) or acquired (n = 434) FP completed survey measures of emotional clarity, attachment security, stigma, anxiety symptoms, and depression symptoms. Results: One-sample t tests showed that congenital and acquired participants had greater anxiety, depression, and stigma compared with the measures' norm data, and only acquired participants had more problems with emotional clarity and attachment than norms. ANCOVAs indicated that acquired, compared with congenital, participants had greater problems with emotional clarity, anxiety, and depression, controlling for age, gender, and FP severity. Hierarchical multiple regressions found that stigma, emotional clarity problems, younger age, insecure attachment, and acquired onset predicted anxiety and depression. Conclusion: People with FP, especially acquired FP, are at greater risk of socioemotional problems, yet no interventions exist. Contrary to work suggesting that facial feedback is crucial for socioemotional development, results suggest that those born with FP are better adapted than those who acquire it. [ABSTRACT FROM AUTHOR]

Objective: A single rare disorder or disease (RD) affects fewer than 200,000 Americans. Combined, RDs affect 30 million Americans. Collectively, people with RDs have higher levels of anxiety and depression compared with those with prevalent diseases. Previous attempts to study psychological distress within individual RDs or disease classification systems are limited by low power, generalizability, and predictive utility. The present study used mixture modeling to identify meaningful RD clusters associated with anxiety and depression. Method: One-thousand and 218 participants with 232 RDs were surveyed on RD characteristics and anxiety and depression symptoms. Mixture modeling identified symptom clusters based on RD characteristics (i.e., age of symptom onset, disease course, fatigue, pain, physical function, duration of symptoms, and visibility). Results: The following six clusters were identified (most frequently represented RD in parentheses): stable (cutaneous T cell lymphoma), late onset and visible (spinocerebellar ataxia), moderate symptoms (spinocerebellar ataxia), invisible and tiring (idiopathic hypersomnia), severe symptoms (spinocerebellar ataxia), and early onset with severe symptoms (Ehlers-Danlos syndrome). There was a significant relationship between cluster membership and anxiety and depression symptoms. Clusters in order from least to most distress were: stable; late onset and visible; moderate symptoms; invisible and tiring; severe symptoms; and early onset with very severe symptoms. The last two clusters had clinically significantly more distress than the stable cluster. Conclusions: Researchers, clinicians, RD organizations, and policymakers could make wide-reaching impacts by prioritizing funding, research, and interventions for people likely to fall in a cluster at high risk for distress. [ABSTRACT FROM AUTHOR]

Costello syndrome is a rare genetic disorder that affects virtually all aspects of an individual's life. Few specialists have been trained to understand the condition and provide guidance to caregivers and virtually no traditional information sources (e.g. books, websites) exist to provide information to caregivers. In this case, the community becomes a major source of information for caregivers of individuals with this condition. This study examines the types of information that need to be expressed in one of these communities: an online Facebook group. The categories of information need to be identified in the study to demonstrate areas of concern to caregivers and offer areas for further research or publication for researchers of rare disorders and health conditions. The role of information professionals in satisfying these information needs of caregivers of individuals with Costello syndrome and other rare disorders. [ABSTRACT FROM AUTHOR]

Abstract Background Twenty-five to 30 million Americans live with a rare disease (RD) and share challenges unique to RD. The majority of research on RDs has focused on etiology, treatment and care, while the limited health-related quality of life (HRQL) research has been restricted to single RDs, small samples, or non-validated measures. This study reports HRQL among adults with diverse RDs, and compares their scores to those of the U.S. population and people with common chronic health conditions. Methods We conducted a cross-sectional survey of adults living in the U.S. diagnosed with any RD. Participants were recruited through RD organizations and completed the online survey between December 2016 and May 2017 (n = 1218). HRQL was assessed using the standardized Patient-Reported Outcomes Measurement Information System (PROMIS). RDs were classified into categories defined by Orphanet. Means and 95% confidence intervals were calculated for the main sample and for RD categories and were compared to published U.S. population norms and common chronic disease norms. Intercorrelations were conducted between HRQL, demographics, and RD experiences. Results When compared to the norms for the U.S. population and for those with common chronic diseases, mean HRQL scores were significantly poorer across all six PROMIS domains for the main sample, and were usually poorer when analyzed by sub-sets of specific RD classifications. People with rare systemic and rheumatologic, neurological, and immune diseases had the poorest HRQL. Participants had poorer HRQL if they had multiple RDs, lower income, were female, or older. Having symptoms longer was associated with worse HRQL, however, having a formal diagnosis longer was associated with better HRQL. Conclusions This study is the first to examine HRQL in a large, heterogeneous sample of RDs using validated measures. There is a significant disparity in HRQL among people with RD compared to the general population and people with common chronic diseases. Poor HRQL could be attributed to challenges accessing diagnoses, medical information, treatment, psychosocial support, and coping with stigma and uncertainty. As most individuals with RDs will not be cured in their lifetimes, identifying ways to improve HRQL is crucial to patient-centered care and should be a funding priority.

Congenital Traumatic neuroma is a rare disorder that represents a reactive proliferation of neural tissue followingdamage to an adjacent nerve. Rarely these lesions appear in the oral cavity with certain predilection for the mental foramen and the tongue area. However, its presentation on lip is more unusual with only few cases being reported in the literature. Typically diagnosed in middle-aged women, patient complains of pain as a frequent symptom. Clinically, the lip lesions appear as a normal or grayish white nodule with a smooth surface that typically resembles a mucocele. We report here a case of a 37-year old female who presented with similar signs and symptoms and was diagnosed clinically as a mucocele. However, histopathological examination revealed it as a traumatic neuroma that was surgically excised. The patient is under follow-up with no signs of recurrence for 18 months.

Abstract Background Rett syndrome is a severe neurodevelopmental disorder associated with mutations in the MECP2 gene. Irregular breathing patterns and abdominal bloating are prominent but poorly understood features. Our aims were to characterize the abnormal breathing patterns and abdominal bloating, investigate the distribution of these by age and mutation type and examine their impact and management from a caregiver perspective. Methods We invited previously recruited families from the International Rett Syndrome Study to complete a web-based questionnaire concerning their family member with Rett syndrome aged between 2 and 57 years. We used logistic regression to investigate presence, frequency and impact of breath-holding, hyperventilation, or abdominal bloating by age group and mutation type. Age of onset for both breathing abnormalities was investigated using time-to-onset analysis, and the Kaplan–Meier method was used to estimate the failure function for the study sample. Descriptive statistics were used to characterize the management of irregular breathing. Results Questionnaires were returned by 413/482 (85.7%) families. Breath-holding was reported for 68.8%, hyperventilation for 46.4% and abdominal bloating for 42.4%. Hyperventilation was more prevalent and frequent in those younger than 7 years of age and abdominal bloating in those aged over 20 years. Onset of breathing irregularities usually occurred during early childhood. Caregivers perceived that daily life was considerably impacted for almost half (44.1%) of those with abdominal bloating and in just over than a third of those with breath-holding (35.8%) or hyperventilation (35.1%). Although perceived impact was broadly comparable between age and mutation groups for breath-holding, hyperventilation and abdominal bloating, girls and women with a p.Arg294* mutation were considered to be more affected by all three conditions. Only 31 individuals had received medically prescribed treatments including 12 different medications, added oxygen, rebreathing apparatus or non-invasive ventilation. Conclusions Autonomic disturbances are prevalent and burdensome in Rett syndrome. This information may guide the design of inclusion criteria and outcome measures for clinical intervention trials targeting autonomic abnormalities. Further investigation of available treatments is necessary to delineate evidence-based management pathways.