Expanding the pre- and postnatal phenotype of WASHC5 and CCDC22 -related Ritscher-Schinzel syndromes.

Ritscher-Schinzel syndrome (RTSCS) is a rare genetic condition characterized by peculiar craniofacial features and cerebellar and cardiovascular malformations. To date, four genes are implicated in this condition. The first two genes described were the autosomal recessive inherited gene WASHC5 associated with Ritscher-Schinzel syndrome 1 (RTSCS1), and CCDC22, an X-linked recessive gene causing Ritscher-Schinzel syndrome 2 (RTSCS2). In recent years, two other genes have been identified: VPS35L (RTSCS3) and DPYSL5 (RTSCS4). Only few patients with a molecular diagnosis of RTSCS have been reported, leaving the phenotypical spectrum and genotype-phenotype correlations ill-defined. We expand the number of genetically confirmed patients with RTSCS1 and 2; reporting three live born and three terminated pregnancies from two unrelated families. Four siblings carried compound heterozygous variants in WASHC5 while two siblings harboured a hemizygous CCDC22 variant. The most common findings in all patients were craniofacial dysmorphism, particularly macrocephaly, down slanted palpebral fissures and low set-ears. Developmental delay, intellectual disability and ataxic gait were present in all patients. One of the patients with the CCDC22 variant presented pubertas tarda. Elevation of nuchal translucency was observed in the first trimester ultrasound in three foetuses with compound heterozygous variants in WASHC5. None of the patients had epilepsy. The pre- and postnatal findings of this cohort expand the known phenotype of RTSCS1 and 2, with direct impact on postnatal outcome, management, and familial counseling.

Pulmonary Thrombosis or Embolism in a Large Cohort of Hospitalized Patients With Covid-19.

Objective: We set out to analyze the incidence and predictive factors of pulmonary embolism (PE) in hospitalized patients with Covid-19. Methods: We prospectively collected data from all consecutive patients with laboratory-confirmed Covid-19 admitted to the Hospital de la Santa Creu i Sant Pau, a university hospital in Barcelona, between March 9 and April 15, 2020. Patients with suspected PE, according to standardized guidelines, underwent CT pulmonary angiography (CTPA). Results: A total of 1,275 patients with Covid-19 were admitted to hospital. CTPA was performed on 76 inpatients, and a diagnosis of PE was made in 32 (2.6% [95%CI 1.7-3.5%]). Patients with PE were older, and they exhibited lower PaO2:FiO2 ratios and higher levels of D-dimer and C-reactive protein (CRP). They more often required admission to ICU and mechanical ventilation, and they often had longer hospital stays, although in-hospital mortality was no greater than in patients without PE. High CRP and D-dimer levels at admission (≥150 mg/L and ≥1,000 ng/ml, respectively) and a peak D-dimer ≥6,000 ng/ml during hospital stay were independent factors associated with PE. Prophylactic low molecular weight heparin did not appear to prevent PE. Increased CRP levels correlated with increased D-dimer levels and both correlated with a lower PaO2:FiO2. Conclusions: The 2.6% incidence of PE in Covid-19 hospitalized patients is clearly high. Higher doses of thromboprophylaxis may be required to prevent PE, particularly in patients at increased risk, such as those with high levels of CRP and D-dimer at admission. These findings should be validated in future studies.

Primary care and sleep unit agreement in management decisions for sleep apnea: a prospective study in Spain.

STUDY OBJECTIVES: Involvement of primary care teams in the care of patients with OSA is a focus of interest. The study objective was to compare diagnostic and therapeutic agreement between decisions taken by primary care professionals and sleep unit specialists. METHODS: This was a prospective multicenter study conducted at primary care and specialized care centers in the urban area of Barcelona, Spain. Men and women aged 18-75 years who visited the participating primary care centers for any reason were recruited. Both primary care physicians and sleep specialists made a diagnostic and therapeutic decision with clinical data and results of a home sleep apnea test. All patients were finally assessed with respiratory polygraphy or polysomnography as a gold-standard test. RESULTS: A total of 229 patients underwent a home sleep apnea test and were evaluated at the primary care centers and the sleep units. Diagnostic agreement using the same tools and excluding indeterminate decisions was 69.8% (Cohen's kappa = 0.64; 95% confidence interval, 0.56-0.72). Agreement for therapeutic decisions (PAP vs conservative treatment) was obtained in 82.5% of patients (Cohen's kappa = 0.62; 95% confidence interval, 0.51-0.73), increasing to 92.5% (Cohen's kappa = 0.49, 95% confidence interval, 0.40-0.58) when indeterminate options were excluded. As compared with the final therapeutic decisions made at the sleep unit with respiratory polygraphy/polysomnography, primary care physicians agreed regarding 83.3% (Cohen's kappa = 0.62; 95% confidence interval, 0.49-0.74) of patients. CONCLUSIONS: Primary care professionals may assume an important role in the management of OSA in coordination with sleep centers, identifying patients who require specific treatment and should be referred to specialized care. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: PASHOS Project: Advanced Platform for Sleep Apnea Syndrome Assessment; URL: https://clinicaltrials.gov/ct2/show/NCT02591979; Identifier: NCT02591979.

Coordinated program between primary care and sleep unit for the management of obstructive sleep apnea.

The purpose of this study is to develop and validate a work model in the primary health-care setting for identifying patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) based on clinical variables and an ambulatory sleep monitoring study. After screening, patients with mild-moderate OSAHS could be managed by primary care physicians, whereas those identified with severe OSAHS would be referred to specialists from sleep units for starting specific treatment. The proposed model does not move the entire health-care process to a generally overburdened primary care level and favors the coordinated work and the necessary flexibility to adapt the model to challenges and perspectives of OSAHS.

Two Novel Pathogenic MID1 Variants and Genotype-Phenotype Correlation Reanalysis in X-Linked Opitz G/BBB Syndrome.

X-linked Opitz G/BBB syndrome (XLOS) is a multisystemic congenital condition, caused by mutations in the midline-1 gene (MID1), characterized by a large inter- and intrafamilial phenotypic variability and often associated with intellectual disability (ID). We report clinical, genetic, and molecular findings in 4 patients with typical XLOS dysmorphic features belonging to 2 unrelated families. Two novel pathogenic loss-of-function MID1 variants, a maternally inherited c.1656del and a de novo c.1215_1228dup, were identified. Subsequently, we performed a genotype-phenotype analysis using data from 91 male XLOS patients. To test the mutation impact on the phenotype; the type of mutation, the MID1-impaired domain and function were compared with the presence of each of the major clinical features (hypertelorism, clefts of the lip and/or palate, laryngo-tracheo-esophageal abnormalities, hypospadias and ID) and minor clinical features (brain, heart, and anal defects). No statistically significant correlation was found with these features. Further investigations, as well as exhaustive and unequivocal phenotyping, may be required to improve our knowledge of the biological mechanisms underlying this syndrome and to provide more adequate disease management.

Efficacy of home single-channel nasal pressure for recommending continuous positive airway pressure treatment in sleep apnea.

INTRODUCTION: Unlike other prevalent diseases, obstructive sleep apnea (OSA) has no simple tool for diagnosis and therapeutic decision-making in primary healthcare. Home single-channel nasal pressure (HNP) may be an alternative to polysomnography for diagnosis but its use in therapeutic decisions has yet to be explored. OBJECTIVES: To ascertain whether an automatically scored HNP apnea-hypopnea index (AHI), used alone to recommend continuous positive airway pressure (CPAP) treatment, agrees with decisions made by a specialist using polysomnography and several clinical variables. METHODS: Patients referred by primary care physicians for OSA suspicion underwent randomized polysomnography and HNP. We analyzed the total sample and both more and less symptomatic subgroups for Bland and Altman plots to explore AHI agreement; receiver operating characteristic curves to establish area under the curve (AUC) measurements for CPAP recommendation; and therapeutic decision efficacy for several HNP AHI cutoff points. RESULTS: Of the 787 randomized patients, 35 (4%) were lost, 378 (48%) formed the more symptomatic and 374 (48%) the less symptomatic subgroups. AHI bias and agreement limits were 5.8 ± 39.6 for the total sample, 5.3 ± 38.7 for the more symptomatic, and 6 ± 40.2 for the less symptomatic subgroups. The AUC were 0.826 for the total sample, 0.903 for the more symptomatic, and 0.772 for the less symptomatic subgroups. In the more symptomatic subgroup, 70% of patients could be correctly treated with CPAP. CONCLUSION: Automatic HNP scoring can correctly recommend CPAP treatment in most of more symptomatic patients with OSA suspicion. Our results suggest that this device may be an interesting tool in initial OSA management for primary care physicians, although future studies in a primary care setting are necessary. CLINICAL TRIALS INFORMATION: Clinicaltrial.gov identifier: NCT01347398.

Effectiveness of home single-channel nasal pressure for sleep apnea diagnosis.

INTRODUCTION: Home single-channel nasal pressure (HNP) may be an alternative to polysomnography (PSG) for obstructive sleep apnea (OSA) diagnosis, but no cost studies have yet been carried out. Automatic scoring is simpler but generally less effective than manual scoring. OBJECTIVES: To determine the diagnostic efficacy and cost of both scorings (automatic and manual) compared with PSG, taking as a polysomnographic OSA diagnosis several apnea-hypopnea index (AHI) cutoff points. METHODS: We included suspected OSA patients in a multicenter study. They were randomized to home and hospital protocols. We constructed receiver operating characteristic (ROC) curves for both scorings. Diagnostic efficacy was explored for several HNP AHI cutoff points, and costs were calculated for equally effective alternatives. RESULTS: Of 787 randomized patients, 752 underwent HNP. Manual scoring produced better ROC curves than automatic for AHI < 15; similar curves were obtained for AHI ≥ 15. A valid HNP with manual scoring would determine the presence of OSA (or otherwise) in 90% of patients with a polysomnographic AHI ≥ 5 cutoff point, in 74% of patients with a polysomnographic AHI ≥ 10 cutoff point, and in 61% of patients with a polysomnographic AHI ≥ 15 cutoff point. In the same way, a valid HNP with automatic scoring would determine the presence of OSA (or otherwise) in 73% of patients with a polysomnographic AHI ≥ 5 cutoff point, in 64% of patients with a polysomnographic AHI ≥ 10 cutoff point, and in 57% of patients with a polysomnographic AHI ≥ 15 cutoff point. The costs of either HNP approaches were 40% to 70% lower than those of PSG at the same level of diagnostic efficacy. Manual HNP had the lowest cost for low polysomnographic AHI levels (≥ 5 and ≥ 10), and manual and automatic scorings had similar costs for higher polysomnographic cutoff points (AHI ≥ 15) of diagnosis. CONCLUSION: Home single-channel nasal pressure (HNP) is a cheaper alternative than polysomnography for obstructive sleep apnea diagnosis. HNP with manual scoring seems to have better diagnostic accuracy and a lower cost than automatic scoring for patients with low apnea-hypopnea index (AHI) levels, although automatic scoring has similar diagnostic accuracy and cost as manual scoring for intermediate and high AHI levels. Therefore, automatic scoring can be appropriately used, although diagnostic efficacy could improve if we carried out manual scoring on patients with AHI < 15. CLINICAL TRIALS INFORMATION: Clinicaltrials.gov identifier: NCT01347398.

Optimizing screening of severe obstructive sleep apnea in patients undergoing bariatric surgery.

BACKGROUND: Obstructive sleep apnea is common in patients waiting for bariatric surgery (BS). International consensuses have recommended assessment of obstructive sleep apnea in the preoperative evaluation to avoid perioperative complications. Polysomnography is the standard diagnostic method but is expensive and time-consuming. The aim of our study was to detect those patients who merit treatment before BS using a simple predictor model. The study was conducted at 3 university hospitals (Hospital de Bellvitge, Hospital de la Santa Creu i Sant Pau, Hospital Clinic de Barcelona). METHODS: A prospective cross-sectional study was conducted of 136 consecutive bariatric subjects. The outcome variable was severe obstructive sleep apnea, defined as an apnea-hypoapnea index of ≥30 events/hr by polysomnography. The predictors evaluated were anthropometric and clinical in the first model, with an oxygen desaturation index of ≥3% added to the second model. Predictive models were constructed using multivariate logistic regression analysis. The best model was selected according to the area under the receiver operating characteristic curve. RESULTS: The first model identified 4 independent factors: age, waist circumference, systolic blood pressure, and witnessed apnea episodes, with a sensitivity of 78%, specificity of 68%, and area under the receiver operating characteristic curve of .83 (95% confidence interval .76-.90, P < .001). The second model identified 2 independent factors (witness apnea episodes, oxygen desaturation index of ≥3%), with a sensitivity of 91%, specificity of 85%, and area under the receiver operating characteristic curve of .94 (95% confidence interval .89-.98, P < .001). The 2-step model predictive values were sensitivity of 90%, specificity of 91%, and accuracy of 90% (95% confidence interval 84-94%). After applying the first model and then the second, 45% of subjects would have been ruled out (15% and 30%, respectively) and 55% would require additional sleep management before BS. CONCLUSION: The proposed model could be useful for improving the management of complex patients before BS and optimizing limited polysomnography resources.

FXTAS is rare among Portuguese patients with movement disorders: FMR1 premutations may be associated with a wider spectrum of phenotypes.

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by expansions of 55-200 CGG repeats in the 5'UTR of the FMR1 gene. These FMR1 premutation expansions have relatively high frequency in the general population. To estimate the frequency of FMR1 premutations among Portuguese males with non-familial, late-onset movement disorders of unknown etiology, we assessed CGG repeat size in males with disease onset after the age of 50 and negative or unknown family history for late-onset movement disorders, who were sent for SCA, HD, or PD genetic testing at a reference laboratory. The selected patients had a primary clinical diagnosis based on one of the following cardinal features of FXTAS: ataxia, tremor, or cognitive decline. A total of 86 subjects were genotyped for the CGG repeat in the FMR1 gene. We detected one patient with an expansion in the premutation range. The frequency of FMR1 premutations was 1.9% (1/54) in our group of patients with ataxia as the primary clinical feature, and 1.2% (1/86) in the larger movement disorders group. In the family of the FXTAS case, premutation-transmitting females presented a history of psychiatric symptoms, suggesting that, given the wide phenotypical expression of the premutation in females, neuropsychiatric surveillance is necessary. In conclusion, genetic testing for FXTAS should be made available to patients with adult-onset movement disorders to enable adequate genetic counseling to family members.