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Background: Among aneuploidies compatible with life, trisomy 22 mosaicism is extremely rare, and only about 25 postnatal and 18 prenatal cases have been described in the literature so far. The condition is mainly characterized by facial and body asymmetry, cardiac heart defects, facial dysmorphisms, growth failure, delayed puberty, and variable degrees of neurodevelopmental delay. Problem: The scattered information regarding the condition and the dearth of data on its natural history and developmental outcomes restrict genetic counseling, particularly in prenatal settings. Moreover, a prompt diagnosis is frequently delayed by the negative selection of trisomic cells in blood, with mosaicism percentage varying among tissues, which often entails the need for further testing. Purpose/topic: The aim of our work is to provide assistance in prenatal and postnatal genetic counseling by systematically delineating the current knowledge of the condition. This entails defining the prenatal and postnatal characteristics of the condition and presenting novel data from three cases, both prenatally and postnatally. Additionally, we report the developmental outcomes observed in two new patients.

Achondroplasia (ACH), the most common form of skeletal dysplasia, is characterized by severe disproportionate short stature, rhizomelia, exaggerated lumbar lordosis, brachydactyly, macrocephaly with frontal bossing and midface hypoplasia. Ligamentous laxity has been reported as a striking feature of ACH, but its prevalence and characteristics have not been systematically evaluated yet. There is growing evidence that ligamentous laxity can be associated with chronic musculoskeletal problems and may affect motor development leading to abnormal developmental trajectories. This study aimed to assess the prevalence of ligamentous laxity in children with ACH through standardized tools, the Beighton scale and its modified version for preschool-age children. A total of 33 children (mean age 6.4 ± 3.2 years; age range 1–12.5 years) diagnosed with ACH by the demonstration of a pathogenic variant in the FGFR3 gene and 33 age- and sex-matched healthy controls were included in the study. Both ligamentous laxity assessment and neurological examinations were performed; medical history was also collected from caregivers. Children with ACH showed a 2 times higher risk of ligamentous laxity than the group without skeletal dysplasia (OR = 2.2; 95% CI = 1.0 to 4.7), with 55% of children meeting the diagnostic criteria for hypermo bility. No significant difference in ligamentous laxity was observed between males and females. Joint involvement analysis revealed characteristic patterns, with knee hypermobility observed in 67% of patients, while rare was elbow hypermobility. Longitudinal assessments indicated a decreasing trend in ligamentous laxity scores over time, suggesting a potential decrease in hypermobility issues during adulthood. The findings of this study provide valuable insights into the prevalence and characteristics of ligamentous laxity in ACH. Implementation of standardized ligamentous laxity assessments might guide patients’ follow-up and facilitate early interventions, h

Achondroplasia is an autosomal dominant genetic disease representing the most common form of human skeletal dysplasia: almost all individuals with achondroplasia have identifiable mutations in the fibroblast growth factor receptor type 3 (FGFR3) gene. The cardinal features of this condition and its inheritance have been well-established, but the occurrence of feeding and nutritional complications has received little prominence. In infancy, the presence of floppiness and neurological injury due to foramen magnum stenosis may impair the feeding function of a newborn with achondroplasia. Along with growth, the optimal development of feeding skills may be affected by variable interactions between midface hypoplasia, sleep apnea disturbance, and structural anomalies. Anterior open bite, prognathic mandible, retrognathic maxilla, and relative macroglossia may adversely impact masticatory and respiratory functions. Independence during mealtimes in achondroplasia is usually achieved later than peers. Early supervision of nutritional intake should proceed into adolescence and adulthood because of the increased risk of obesity and respiratory problems and their resulting sequelae. Due to the multisystem involvement, oral motor dysfunction, nutrition, and gastrointestinal issues require special attention and personalized management to facilitate optimal outcomes, especially because of the novel therapeutic options in achondroplasia, which could alter the progression of this rare disease.

Feeding, eating and deglutition difficulties are key concerns in patients with cardiofaciocutaneous syndrome (CFCS). This study intends to quantify the development of feeding skills from birth to adulthood in patients with CFCS. Twenty-seven patients (eight males; mean age: 16.7 ± 8.3 years; median age: 15 years, age range: 1.5–38 years) with molecularly confirmed clinical diagnosis of CFCS were prospectively recruited from the Rare Disease Unit, Paediatrics Department, Fondazione Policlinico Agostino Gemelli-IRCCS, Rome, Italy, over a one-year period. Pathogenic variants along with key information regarding oro-motor features were collected. Sialorrhea was quantified using the Drooling Quotient 5. Feeding abilities were screened using the Italian version of the Montreal Children’s Hospital Feeding Scale (I-MCH-FS). The oral sensory processing section of the Sensory Profile completed the assessment. Mild-to-profuse drooling was experienced by 25% of patients, and food taste selectivity was a constant during infancy (65%), with persistence even beyond adolescence. Nineteen percent of participants with long-term enteral feeding dependency had BRAF, KRAS and MAP2K1 mutations. These findings document that mealtime challenges in CFCS do not remain restricted only to the paediatric age, and that supportive care until adulthood plays a key role.

Background: Smith-Magenis syndrome (SMS) is caused by either interstitial deletions in the 17p11.2 region or pathogenic variants in the RAI1 gene and is marked by a distinct set of physical, developmental, neurological, and behavioral features. Hypercholesterolemia has been described in SMS, and obesity is also commonly found. Aim: To describe and characterize the metabolic phenotype of a cohort of SMS patients with an age range of 2.9–32.4 years and to evaluate any correlations between their body mass index and serum lipids, glycated hemoglobin (HbA1c), and basal insulin levels. Results: Seven/thirty-five patients had high values of both total cholesterol and low-density lipoprotein cholesterol; 3/35 had high values of triglycerides; none of the patients with RAI1 variants presented dyslipidemia. No patients had abnormal fasting glucose levels. Three/thirty-five patients had HbA1c in the prediabetes range. Ten/twenty-two patients with 17p11.2 deletion and 2/3 with RAI1 variants had increased insulin basal levels. Three/twenty-three patients with the 17p11.2 deletion had prediabetes. Conclusion: Our investigation suggests that SMS ‘deleted’ patients may show a dyslipidemic pattern, while SMS ‘mutated’ patients are more likely to develop early-onset obesity along with hyperinsulinism.

CTNNB1 syndrome is an autosomal-dominant neurodevelopmental disorder featuring developmental delay; intellectual disability; behavioral disturbances; movement disorders; visual defects; and subtle facial features caused by de novo loss-of-function variants in the CTNNB1 gene. Due to paucity of data, this study intends to describe feeding issues and oral-motor dyspraxia in an unselected cohort of 10 patients with a confirmed molecular diagnosis. Pathogenic variants along with key information regarding oral-motor features were collected. Sialorrhea was quantified using the Drooling Quotient 5. Feeding abilities were screened using the Italian version of the Montreal Children’s Hospital Feeding Scale (I-MCH-FS). Mild-to-severe coordination difficulties in single or in a sequence of movements involving the endo-oral and peri-oral muscles were noticed across the entire cohort. Mild-to-profuse drooling was a commonly complained-about issue by 30% of parents. The mean total I-MCH-FS t-score equivalent was 43.1 ± 7.5. These findings contribute to the understanding of the CTNNB1 syndrome highlighting the oral motor phenotype, and correlating specific gene variants with clinical characteristics.

The clinical features of achondroplasia can cause acute self-limited pain that can evolve into chronic pain. Pain causes a low quality of life, in terms of physical, emotional, social, and school functioning in both adult and children with achondroplasia. We conducted a systematic review according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement to describe prevalence, assessment tools, causes and management strategies of pain in this rare disease. We found that shoulder and knee pain is typically referred during infancy, while knee pain is generally referred around 5–6 years of age. The prevalence of general pain in adolescence can be as high as 90%. Chronic pain in the achondroplasia population increases with age, with up to 70% of adults reporting general pain and back pain. Recognizing the multiple determinants of acute and chronic pain in patients with achondroplasia may enable physicians to better understand and manage this burden, particularly with the advent of new drugs that may modify some of the striking features of achondroplasia.

The clinical features of achondroplasia can cause acute self-limited pain that can develop into chronic pain. Pain causes a low quality of life, in terms of physical, emotional, social, and school functioning in both adult and children with achondroplasia. We conducted a systematic review according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement to describe prevalence, assessment tools, causes and management strategies of pain in this rare disease. We found that shoulder and knee pain is typically referred during infancy, while knee pain is generally referred around 5-6 years of age. The prevalence of general pain in adolescence can be as high as 90%. Chronic pain in the achondroplasia population increases with age, with up to 70% of adults reporting general pain and back pain. Recognizing the multiple determinants of acute and chronic pain in patients with achondroplasia may enable physicians to better understand and manage this burden, particularly with the advent of new drugs that may modify some of the known features of achondroplasia.

Background: The Montreal Children's Hospital Feeding Scale (MCH-FS) allows paediatricians and other health care professionals to identify feeding difficulties among children. Aim: To translate and adapt the MCH-FS into Italian, and to evaluate the validity and reliability of this Italian version of the Montreal Children's Hospital Feeding Scale (I-MCH-FS). Methods & procedures: A total of 150 children with special healthcare needs were admitted to the Rare Disease Unit of the Paediatrics Department at the Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy, between March 2021 and March 2022 (74 males; mean age = 3.85 ± 1.96 years; median age = 4 years; age range = 6 months-6 years and 11 months) and 150 healthy participants (83 males; mean age = 3.5 ± 1.98 years; median age = 3 years; age range = 6 months-6 years and 11 months) were included in the study, which was approved by the local ethics committee. The original version of the MCH-FS was translated and cross-cultural adapted through five stages: (1) initial translation, (2) synthesis of the translations, (3) back translation, (4) expert committee and (5) test of the prefinal version. Test-retest reliability and internal consistency were assessed using Pearson r, Spearman r and Cronbach's alpha, respectively. Construct validity was established by comparing data obtained from patients with those of healthy participants using the Mann-Whitney U-test. Outcomes & results: A Pearson r of 0.98, a Spearman r of 0.95 and Cronbach's alpha value of 0.86 were obtained. In the clinical group, 40.6% children were classified as having feeding disorders (n = 61), while in the normative group 4.7% were diagnosed with feeding problems (n = 7). Mean total score of the clinical group was significatively different from the normative's. Conclusions & implications: The I-MCH-FS is a valid and reliable one-page, quick screening tool used to identify feeding disorders among children with special needs i

To date, the feeding and oral-motor abilities of patients with CHARGE syndrome (CS) have not been longitudinally assessed. This study aims to investigate the level of these abilities at different ages and evaluate how they evolve during growth. We retrospectively analysed oral-motor features of 16 patients with molecularly confirmed CS (age range 4-21 years old; mean 11 years; SD 6 years; median 10 years). Nearly 100% of CS new-borns had weak sucking at birth, and half of them demonstrated poor coordination between breathing and swallowing. Over time, the percentages of children with tube feeding dependence (60% at birth) faced a slow but steady decrease (from 33% at 6 months, 25% at 12 months, to 13% at school age) in tandem with the decreasing risk of aspiration. The ability of eating foods requiring chewing was achieved at school age, after the acquisition of an adequate oral sensory processing. A mature chewing pattern with a variety of food textures was not achieved by more than half of patients, including those requiring artificial enteral nutrition. Most patients started prolonged oral-motor treatments with speech language therapists in early childhood. Conclusions: Although feeding and swallowing disorders are constant features in CS patients, a slow and gradual development of feeding abilities occurs in most cases. Rehabilitation plays a key role in overcoming structural and functional difficulties and attaining appropriate eating skills.

Severe gastrointestinal symptoms are one of the main reasons for switching from conventional artificial tube feeding to blenderized tube feeding (BTF). This study aimed to describe and quantify the impact of BTF on gastrointestinal symptoms in children and adults. We analyzed four databases (PubMed, Scopus, Cochrane Library, and Google Scholar). The review was performed following the PRISMA extension for Scoping Reviews checklist. The methodological quality of articles was assessed following the NIH quality assessment tools. The initial search yielded 535 articles and, after removing duplicates and off-topic articles, 12 met the inclusion criteria. All included papers unanimously converged in defining an improvement of gastrointestinal symptoms during blenderized feeding: the eight studies involving pediatric cohorts report a decrease from 30 to over 50% in gagging and retching after commencing BTF. Similar rates are reported for constipation and diarrhea improvement in most critically ill adults. Experimental studies and particularly randomized controlled trials are needed to develop robust evidence on the effectiveness of BTF in gastrointestinal symptom improvement with prolonged follow-up and adequate medical monitoring.

Unlabelled: To date, the feeding and oral-motor abilities of patients with CHARGE syndrome (CS) have not been longitudinally assessed. This study aims to investigate the level of these abilities at different ages and evaluate how they evolve during growth. We retrospectively analysed oral-motor features of 16 patients with molecularly confirmed CS (age range 4-21 years old; mean 11 years; SD 6 years; median 10 years). Nearly 100% of CS new-borns had weak sucking at birth, and half of them demonstrated poor coordination between breathing and swallowing. Over time, the percentages of children with tube feeding dependence (60% at birth) faced a slow but steady decrease (from 33% at 6 months, 25% at 12 months, to 13% at school age) in tandem with the decreasing risk of aspiration. The ability of eating foods requiring chewing was achieved at school age, after the acquisition of an adequate oral sensory processing. A mature chewing pattern with a variety of food textures was not achieved by more than half of patients, including those requiring artificial enteral nutrition. Most patients started prolonged oral-motor treatments with speech language therapists in early childhood. Conclusions: Although feeding and swallowing disorders are constant features in CS patients, a slow and gradual development of feeding abilities occurs in most cases. Rehabilitation plays a key role in overcoming structural and functional difficulties and attaining appropriate eating skills. What is known: • Feeding problems and swallowing dysfunction have been noted in CHARGE syndrome. • The involvement of multiple factors, including structural problems in the mouth, throat, or esophagus, and neurological impairment, make feeding a complicated task in CHARGE individuals. What is new: • Dysphagia gradually improves in most CHARGE children over time, though with a wide interindividual variability. • The percentages of children with tube feeding dependence decrease over

Noonan, Costello, and cardio-facio-cutaneous syndrome are neurodevelopmental disorders belonging to the RASopathies, a group of syndromes caused by alterations in the RAS/MAPK pathway. They are characterized by similar clinical features, among which feeding difficulties, growth delay, and gastro-intestinal disorders are frequent, causing pain and discomfort in patients. Hereby, we describe the main nutritional and gastrointestinal issues reported in individuals with RASopathies, specifically in Noonan syndrome, Noonan syndrome-related disorders, Costello, and cardio-facio-cutaneous syndromes. Fifty percent of children with Noonan syndrome may experience feeding difficulties that usually have a spontaneous resolution by the second year of life, especially associated to genes different than PTPN11 and SOS1. More severe manifestations often require artificial enteral nutrition in infancy are observed in Costello syndrome, mostly associated to c.34G>A substitution in the HRAS gene. In cardio-facio-cutaneous syndrome feeding issues are usually present (90-100% of cases), especially in individuals carrying variants in BRAF, MAP2K1, and MAP2K2 genes, and artificial enteral intervention, even after scholar age, may be required. Moreover, disorders associated with gastrointestinal dysmotility as gastro-esophageal reflux and constipation are commonly reported in all the above-mentioned syndromes. Given the impact on growth and on the quality of life of these patients, early evaluation and prompt personalized management plans are fundamental.

Drooling, or sialorrhea, is a common condition in patients with cerebral palsy, rare diseases, and neurodevelopmental disorders. The goal of this review was to identify the different properties of sialorrhea outcome measures in children. Four databases were analysed in search of sialorrhea measurement tools, and the review was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. The COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) checklist was used for quality appraisal of the outcome measures. The initial search yielded 891 articles, 430 of which were duplicates. Thus, 461 full-text articles were evaluated. Among these, 21 met the inclusion criteria, reporting 19 different outcome measures that encompassed both quantitative measures and parent/proxy questionnaires. Conclusions: Among the outcome measures found through this review, the 5-min Drooling Quotient can objectively discriminate sialorrhea frequency in patients with developmental disabilities. The Drooling Impact Scale can be used to evaluate changes after treatment. The modified drooling questionnaire can measure sialorrhea severity and its social acceptability. To date, the tests proposed in this review are the only tools displaying adequate measurement properties. The acquisition of new data about reliability, validity, and responsiveness of these tests will confirm our findings.What is Known:• Although sialorrhea is a recognized problem in children with disabilities, especially those with cerebral palsy (CP), there is a lack of confidence among physicians in measuring sialorrhea.What is New:• Few sialorrhea measures are available for clinicians that may guide decision-making and at the same time have strong evidence to provide confidence in the results.• A combination of both quantitative measures and parent/proxy questionnaires might provide an adequate measurement of sialorrhea in

The use of phototrophic organisms in wastewater treatment is gaining increasing interest, due to the possibility of exploiting photosynthetic oxygenation, thus lowering treatment costs and environmental impacts. Mixed consortia of phototrophic organisms and aerobic bacteria rapidly develop in photobioreactors receiving wastewaters; in this case, the complex mutualistic interactions among microorganisms cannot be easily described, making difficult to forecast removal efficiencies and biomass productivities. Respirometric methods are applied for evaluating bacterial activity in activated sludge (conventional respirometry) or photosynthetic activity in phototrophic organisms (photorespirometry). Photo-respirometric methods can be also exploited for monitoring algae-bacteria systems and for calibrating mathematical models, allowing for a better comprehension of the interactions involved and a more accurate prediction of system efficiencies. A general protocol and a series of guidelines for conducting photorespirometric tests on algal-bacterial suspensions are here proposed, based on the review of experimental protocols applied to evaluate the effects of several parameters on these systems.

Background: Sleep apnoea syndrome (SAS), one of the main medical causes of excessive daytime sleepiness, has been shown to be a risk factor for traffic accidents. Treating SAS results in a normalized rate of traffic accidents. As part of the COST Action B-26, we looked at driving license regulations, and especially at its medical aspects in the European region. Methods: We obtained data from Transport Authorities in 25 countries (Austria, AT; Belgium, BE; Czech Republic, CZ; Denmark, DK; Estonia, EE; Finland, FI; France, FR; Germany, DE; Greece, GR; Hungary, HU; Ireland, IE; Italy, IT; Lithuania, LT; Luxembourg, LU; Malta, MT; Netherlands, NL; Norway, EC; Poland, PL; Portugal, PT; Slovakia, SK; Slovenia, SI; Spain, ES; Sweden, SE; Switzerland, CH; United Kingdom, UK). Results: Driving license regulations date from 1997 onwards. Excessive daytime sleepiness is mentioned in nine, whereas sleep apnoea syndrome is mentioned in 10 countries. A patient with untreated sleep apnoea is always considered unfit to drive. To recover the driving capacity, seven countries rely on a physician’s medical certificate based on symptom control and compliance with therapy, whereas in two countries it is up to the patient to decide (on his doctor’s advice) to drive again. Only FR requires a normalized electroencephalography (EEG)-based Maintenance of Wakefulness Test for professional drivers. Rare conditions (e.g., narcolepsy) are considered a driving safety risk more frequently than sleep apnoea syndrome. Conclusion: Despite the available scientific evidence, most countries in Europe do not include sleep apnoea syndrome or excessive daytime sleepiness among the specific medical conditions to be considered when judging whether or not a person is fit to drive. A unified European Directive seems desirable.

Background: Sleep apnoea syndrome (SAS), one of the main medical causes of excessive daytime sleepiness, has been shown to be a risk factor for traffic accidents. Treating SAS results in a normalized rate of traffic accidents. As part of the COST Action B-26, we looked at driving license regulations, and especially at its medical aspects in the European region. Methods: We obtained data from Transport Authorities in 25 countries (Austria, AT; Belgium, BE; Czech Republic, CZ; Denmark, DK; Estonia, EE; Finland, FI; France, FR; Germany, DE; Greece, GR; Hungary, HU; Ireland, IE; Italy, IT; Lithuania, LT; Luxembourg, LU; Malta, MT; Netherlands, NL; Norway, EC; Poland, PL; Portugal, PT; Slovakia, SK; Slovenia, SI; Spain, ES; Sweden, SE; Switzerland, CH; United Kingdom, UK). Results: Driving license regulations date from 1997 onwards. Excessive daytime sleepiness is mentioned in nine, whereas sleep apnoea syndrome is mentioned in 10 countries. A patient with untreated sleep apnoea is always considered unfit to drive. To recover the driving capacity, seven countries rely on a physician's medical certificate based on symptom control and compliance with therapy, whereas in two countries it is up to the patient to decide (on his doctor's advice) to drive again. Only FR requires a normalized electroencephalography (EEG)-based Maintenance of Wakefulness Test for professional drivers. Rare conditions (e.g., narcolepsy) are considered a driving safety risk more frequently than sleep apnoea syndrome. Conclusion: Despite the available scientific evidence, most countries in Europe do not include sleep apnoea syndrome or excessive daytime sleepiness among the specific medical conditions to be considered when judging whether or not a person is fit to drive. A unified European Directive seems desirable. (C) 2007 Elsevier B.V. All rights reserved Udgivelsesdato: 2008/5

Background: Sleep apnoea syndrome (SAS), one of the main medical causes of excessive daytime sleepiness, has been shown to be a risk factor for traffic accidents. Treating SAS results in a normalized rate of traffic accidents. As part of the COST Action B-26, we looked at driving license regulations, and especially at its medical aspects in the European region. Methods: We obtained data from Transport Authorities in 25 countries (Austria, AT; Belgium, BE; Czech Republic, CZ; Denmark, DK; Estonia, EE; Finland, FI; France, FR; Germany, DE; Greece, GR; Hungary, HU; Ireland, IE; Italy, IT; Lithuania, LT; Luxembourg, LU; Malta, MT; Netherlands, NL; Norway, EC; Poland, PL; Portugal, PT; Slovakia, SK; Slovenia, SI; Spain, ES; Sweden, SE; Switzerland, CH; United Kingdom, UK). Results: Driving license regulations date from 1997 onwards. Excessive daytime sleepiness is mentioned in nine, whereas sleep apnoea syndrome is mentioned in 10 countries. A patient with untreated sleep apnoea is always considered unfit to drive. To recover the driving capacity, seven countries rely on a physician's medical certificate based on symptom control and compliance with therapy, whereas in two countries it is up to the patient to decide (on his doctor's advice) to drive again. Only FR requires a normalized electroencephalography (EEG)-based Maintenance of Wakefulness Test for professional drivers. Rare conditions (e.g., narcolepsy) are considered a driving safety risk more frequently than sleep apnoea syndrome. Conclusion: Despite the available scientific evidence, most countries in Europe do not include sleep apnoea syndrome or excessive daytime sleepiness among the specific medical conditions to be considered when judging whether or not a person is fit to drive. A unified European Directive seems desirable. (C) 2007 Elsevier B.V. All rights reserved Udgivelsesdato: 2008/5

Effective compliance (time spent at the effective pressure) with nasal CPAP in obstructive sleep apnea has been reported to be poor. The aim of our study was to evaluate effective compliance in a large European multicenter study. One hundred twenty-one consecutive newly treated patients (initial apnea-hypopnea index [AHI] = 62.0 +/- 29.5/h, AHI under CPAP = 6.4 +/- 8.1/h, CPAP pressure = 8.7 +/- 2.6 cm H2O, BMI = 33.1 +/- 6.8 kg/m(2)) were randomly allocated to a group with (MC+) (n = 58) or without (MC-) (n = 63) a control unit measuring effective compliance at 1, 2 and 3 mo, which was compared with the built-in time counter data. MC+ data were 94 +/- 10, 98 +/- 5, and 96 +/- 9% of counter data at 1, 2, and 3 mo, respectively. Using criteria of regular use already reported in the literature (at least 4 h of nCPAP per day of use and nCPAP administered more than 70% of the days) we found 77, 82, and 79% compliant patients at 1, 2, and 3 mo, respectively, 79% of the patients meeting these criteria each month. Although there were no pulmonary functions or polysomnographic differences between the two subgroups, the compliant patients did report a greater improvement in minor symptoms. We found a close correlation between effective use of CPAP and the machine run time. The main result of our study was a higher effective compliance than previously reported, approximately 80% of the patients being regular users versus 46% in a previously published study. This may result from different technical and medical follow-up.