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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.

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 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 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.

Background Stiff person syndrome (SPS) is a progressive neurological disorder characterized by axial muscle rigidity and involuntary spasms. Autoimmune and neoplastic diseases are associated with SPS. Our study objectives were to describe inpatient care for SPS in the United States and characterize 30-day readmissions. Methods We queried the 2014 Nationwide Readmission Database for hospitalizations where a diagnosis of SPS was recorded. For readmission analyses, we excluded encounters with missing length of stay, hospitalization deaths, and out-of-state and December discharges. National estimates of index hospitalizations and 30-day readmissions were computed using survey weighting methods. Unconditional logistic regression was used to examine associations between demographic, clinical, and hospital characteristics and readmission. Results There were 836 patients with a recorded diagnosis of SPS during a 2014 hospitalization. After exclusions, 703 patients remained, 9.4% of which were readmitted within 30 days. Frequent reasons for index hospitalization were SPS (27.8%) and diabetes with complications (5.1%). Similarly, readmissions were predominantly for diabetes complications (24.2%) and SPS. Most readmissions attributed to diabetes complications (87.5%) were to different hospitals. Female sex (OR, 3.29; CI: 1.22–8.87) and routine discharge (OR, 0.26; CI: 0.10–0.64) were associated with readmission, while routine discharge (OR, 0.18; CI: 0.04–0.89) and care at for-profit hospitals (OR, 10.87; CI: 2.03–58.25) were associated with readmission to a different hospital. Conclusions Readmissions in SPS may result from disease complications or comorbid conditions. Readmissions to different hospitals may reflect specialty care, gaps in discharge planning, or medical emergencies. Studies are required to determine if readmissions in SPS are preventable.

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.

Background Although research in this area remains sparse, raising a child with some genetic disorders has been shown to adversely impact maternal health and family quality of life. The aim of this study was to investigate such impacts in families with a child with the CDKL5 disorder, a newly recognised genetic disorder causing severe neurodevelopmental impairments and refractory epilepsy. Methods Data were sourced from the International CDKL5 Disorder Database to which 192 families with a child with a pathogenic CDKL5 mutation had provided data by January 2016. The Short Form 12 Health Survey Version 2, yielding a Physical Component Summary and a Mental Component Summary score, was used to measure primary caregiver’s wellbeing. The Beach Center Family Quality of Life Scale was used to measure family quality of life. Linear regression analyses were used to investigate relationships between child and family factors and the various subscale scores. Results The median (range) age of the primary caregivers was 37.0 (24.6–63.7) years and of the children was 5.2 (0.2–34.1) years. The mean (SD) physical and mental component scores were 53.7 (8.6) and 41.9 (11.6), respectively. In mothers aged 25–54 years the mean mental but not the physical component score was lower than population norms. After covariate adjustment, caregivers with a tube-fed child had lower mean physical but higher mean mental component scores than those whose child fed orally (coefficient = −4.80 and 6.79; p = 0.009 and 0.012, respectively). Child sleep disturbances and financial hardship were negatively associated with the mental component score. The mean (SD) Beach Center Family Quality of Life score was 4.06 (0.66) and those who had used respite services had lower scores than those who had not across the subscales. Conclusions Emotional wellbeing was considerably impaired in this caregiver population, and was particularly associated with increased severity of child sleep problems and family financial difficulties. Family quality of life was generally rated lowest in those using respite care extensively, suggesting that these families may be more burdened by daily caregiving.

A report on the European Society of Human Genetics conference, held in Paris, France, June 8-11, 2013.