Phenotypes in adult patients with Rett syndrome: results of a 13-year experience and insights into healthcare transition.

BACKGROUND: Rett syndrome is a complex genetic disorder with age-specific manifestations and over half of the patients surviving into middle age. However, little information about the phenotype of adult individuals with Rett syndrome is available, and mainly relies on questionnaires completed by caregivers. Here, we assess the clinical manifestations and management of adult patients with Rett syndrome and present our experience in transitioning from the paediatric to the adult clinic. METHODS: We analysed the medical records and molecular data of women aged ≥18 years with a diagnosis of classic Rett syndrome and/or pathogenic variants in MECP2, CDKL5 and FOXG1, who were in charge of our clinic. RESULTS: Of the 50 women with classic Rett syndrome, 94% had epilepsy (26% drug-resistant), 20% showed extrapyramidal signs, 40% sleep problems and 36% behavioural disorders. Eighty-six % patients exhibited gastrointestinal problems; 70% had scoliosis and 90% low bone density. Breathing irregularities were diagnosed in 60%. None of the patients had cardiac issues. CDKL5 patients experienced fewer breathing abnormalities than women with classic Rett syndrome. CONCLUSION: The delineation of an adult phenotype in Rett syndrome demonstrates the importance of a transitional programme and the need of a dedicated multidisciplinary team to optimise the clinical management of these patients.

The DAMA Project - Disabled Advanced Medical Assistance.

The Convention on the Rights of Persons with Disabilities (CRPD) enshrines the right of persons with disabilities to enjoy the highest standard of health and access to health care without discrimination, but persons with disabilities have logistical and assistive support needs that must be known in order to build a health service offer that meets their needs and respects their rights in line with the CRPD. Examples of accessibility of medical care include the removal of an architectural barrier, the adaptation of a protocol, and ensuring information about care is delivered using easy to understand means of communications. An example of full inclusion and accessibility of the healthcare system for persons with intellectual disabilities is the DAMA (Disabled Advanced Medical Assistance), a project developed and tested at the Milan San Paolo Hospital. DAMA is an inclusive service provision methodology and offers a model that can follow, with a multidisciplinary approach, the person at every stage of the diagnostic and clinical pathway, and to support his or her family in dealing with the hospital. The diffusion of the DAMA model has demonstrated the flexibility of the model itself and its ability to adapt to hospitals with different characteristics and dimensions. The future is the institution of an organized network of all DAMA centres that share common clinical protocols and homogeneous archives. It will grant us the capability of collecting consistent epidemiological and clinical data, valuable for scientific researching and for training health personnel.

COVID-19 pandemic, the scarcity of medical resources, community-centred medicine and discrimination against persons with disabilities.

This research aims to examine access to medical treatment during the COVID-19 pandemic for people living with disabilities. During the COVID-19 pandemic, the practical and ethical problems of allocating limited medical resources such as intensive care unit beds and ventilators became critical. Although different countries have proposed different guidelines to manage this emergency, these proposed criteria do not sufficiently consider people living with disabilities. People living with disabilities are therefore at a higher risk of exclusion from medical treatments as physicians tend to assume they have poor quality of life, whereas access to medical treatment should be based on several parameters, including clinical data and prognosis. However, the COVID-19 pandemic shifts the medical paradigm from person-centred medicine to community-centred medicine, challenging the main ethical theories. We reviewed the main guidelines and recommendations for resources allocation and examined their position toward persons with disabilities. Based on our findings, we propose criteria for not discriminating against people with disabilities in allocating resources. The shift from person-centred to community-centred medicine offers opportunities but also risks sacrificing the most vulnerable people. The principle of reasonable accommodation must always be considered to guarantee the rights of persons with disabilities.

Medical thoracoscopy treatment for pleural infections: a systematic review and meta-analysis.

BACKGROUND: Complicated parapneumonic effusions and empyema represent advanced stages of pleural infections and are characterized by a high mortality. Medical thoracoscopy is a safe and minimally invasive endoscopic technique prescribed to treat severe pleural infections. However, only a few studies evaluated its success rate. A systematic review of observational studies was performed to assess the efficacy of medical thoracoscopy in patients with complicated parapneumonic effusions and empyema, as well as its predictive factors. METHODS: A search of the scientific evidence was carried out using PubMed, EMBASE, and Cochrane Central Register of Controlled Trials. Articles describing observational studies on medical thoracoscopy in patients with parapneumonic effusions and empyema were selected. RESULTS: Eight studies met the inclusion criteria. The pooled treatment success rate of thoracoscopy was 85% (95% CI 80.0-90.0%; I2: 61.8%) when used as first-line intervention or after failure of chest tube. The pooled complication rate was 9.0% (95% CI 6.0-14.0%; I2: 58.8%). A pooled difference of treatment success of 9.0% (95% CI 1.0-18.0%) was found when post-thoracoscopy intra-pleural fibrinolysis was prescribed. Pooled success rate was higher in cases with pleural fluid culture negativity (pooled difference: 14.0%; 95% CI 4.0-24.0%). CONCLUSIONS: Medical thoracoscopy is effective and safe when prescribed for complicated parapneumonic effusions and empyema. Bacteriological negativity of pleural effusion specimens and administration of adjuvant intra-pleural fibrinolysis after the procedure are associated with a higher success rate.

Odontogenic rhinosinusitis and sinonasal complications of dental disease or treatment: prospective validation of a classification and treatment protocol.

PURPOSE: Odontogenic sinusitis and sinonasal complications of dental disease or treatment (SCDDT) represent a heterogeneous group of conditions that often require multidisciplinary care. The present study aims to prospectively validate a classification and treatment protocol for SCDDT patients. METHODS: One hundred twenty-eight consecutive patients (73 females and 45 males, mean age 52.4 years) affected by SCDDT not responding to dental and medical therapy were classified and surgically treated according to the proposed protocol. The protocol classified patients into three aetiology-based groups (preimplantologic, implantologic, and related to traditional dental diseases and procedures, respectively). The groups were further divided into classes according to the presence of oro-antral communications and/or dislocated dental hardware. Each condition was treated according to the class-related, protocol-defined treatment, by either a transnasal or combined transnasal/transoral approach. All patients were successfully classified according to our protocol. None of the proposed classes were redundant, and no condition fell outside the definitions. RESULTS: The surgical treatment protocol proved to be adequate and effective, in that 125 of the 128 patients completely recovered after surgical treatment. CONCLUSIONS: The term SCDDT and the consequent classification proposed by the authors appear, therefore, to be nosologically correct. Furthermore, the protocol-related proposed treatment appears to be clinically sound, with a success rate nearing 98%.

Healthcare transition from childhood to adulthood in Tuberous Sclerosis Complex.

Healthcare transition from childhood to adulthood is required to ensure continuity of care of an increasing number of individuals with chronic conditions surviving into adulthood. The transition for patients with tuberous sclerosis complex (TSC) is complicated by the multisystemic nature of this condition, age-dependent manifestations, and high clinical variability and by the presence of intellectual disability in at least half of the individuals. In this article, we address the medical needs regarding each TSC-related manifestation in adulthood, and the services and support required. We review existing models of transition in different chronic conditions, discuss our experience in transitioning from the pediatric to the adult TSC Clinic at our Institution, and propose general rules to follow when establishing a transition program for TSC. Although a generalizable transition model for TSC is likely not feasible for all Institutions, a multidisciplinary TSC clinic is probably the best model, developed in accordance with the resources available and country-specific healthcare systems. Coordination of care and education of the adult team should be always sought regardless of the transition model.

Do patients with tuberous sclerosis complex have an increased risk for malignancies?

Tuberous Sclerosis Complex (TSC) is generally characterized by the presence of benign tumors, but some patients with malignancies have been reported in the literature. We examined a large Italian TSC population (240 individuals followed from 2001 to 2015, aged 3 months-74 years), assessing the frequency of malignancies to determine whether there is an increased risk for cancer in this disorder, and looking for possible features associated with the development of neoplasia. Fifteen patients had malignancies (6.25%); median age at diagnosis was 37.5 years (range of 1.6-58). Five of seven renal tumors were renal cell carcinomas. Eight patients had a non-renal malignancy (3.3%), but we did not find a more prevalent type of cancer. No patient developed more than one malignancy. The prevalence of all malignant tumors was compatible with the prevalence in the general population (5.6%, 95%CI 2.99-9.31%, vs. 4.4% in Italy). Median age at cancer diagnosis was lower (37.5 years, 95%CI 28.6-44.7, vs. 66.0 years). Two patients (13.3%) died of their cancer, while outcome was favorable in the remaining individuals. Malignant tumors were more frequently diagnosed in patients with mutations in TSC1 when compared to TSC2 and patients with no mutation identified (P = 0.032). Our study demonstrated that TSC patients do not seem to have an increased risk for malignancies besides renal cell carcinoma. However, when cancer develops, age at diagnosis is lower than in the general population, and malignant tumors are more frequently diagnosed in patients with mutations in TSC1. Further studies are needed to confirm these data. ©2016 Wiley Periodicals, Inc.

KMT2A: Umbrella Gene for Multiple Diseases.

KMT2A (Lysine methyltransferase 2A) is a member of the epigenetic machinery, encoding a lysine methyltransferase responsible for the transcriptional activation through lysine 4 of histone 3 (H3K4) methylation. KMT2A has a crucial role in gene expression, thus it is associated to pathological conditions when found mutated. KMT2A germinal mutations are associated to Wiedemann-Steiner syndrome and also in patients with initial clinical diagnosis of several other chromatinopathies (i.e., Coffin-Siris syndromes, Kabuki syndrome, Cornelia De Lange syndrome, Rubinstein-Taybi syndrome), sharing an overlapping phenotype. On the other hand, KMT2A somatic mutations have been reported in several tumors, mainly blood malignancies. Due to its evolutionary conservation, the role of KMT2A in embryonic development, hematopoiesis and neurodevelopment has been explored in different animal models, and in recent decades, epigenetic treatments for disorders linked to KMT2A dysfunction have been extensively investigated. To note, pharmaceutical compounds acting on tumors characterized by KMT2A mutations have been formulated, and even nutritional interventions for chromatinopathies have become the object of study due to the role of microbiota in epigenetic regulation.

Expanding the phenotype associated to KMT2A variants: overlapping clinical signs between Wiedemann-Steiner and Rubinstein-Taybi syndromes.

Lysine-specific methyltransferase 2A (KMT2A) is responsible for methylation of histone H3 (K4H3me) and contributes to chromatin remodeling, acting as "writer" of the epigenetic machinery. Mutations in KMT2A were first reported in Wiedemann-Steiner syndrome (WDSTS). More recently, KMT2A variants have been described in probands with a specific clinical diagnosis comprised in the so-called chromatinopathies. Such conditions, including WDSTS, are a group of overlapping disorders caused by mutations in genes coding for the epigenetic machinery. Among them, Rubinstein-Taybi syndrome (RSTS) is mainly caused by heterozygous pathogenic variants in CREBBP or EP300. In this work, we used next generation sequencing (either by custom-made panel or by whole exome) to identify alternative causative genes in individuals with a RSTS-like phenotype negative to CREBBP and EP300 mutational screening. In six patients we identified different novel unreported variants in KMT2A gene. The identified variants are de novo in at least four out of six tested individuals and all of them display some typical RSTS phenotypic features but also WDSTS specific signs. This study reinforces the concept that germline variants affecting the epigenetic machinery lead to a shared molecular effect (alteration of the chromatin state) determining superimposable clinical conditions.

The methylation of the TSC2 promoter underlies the abnormal growth of TSC2 angiomyolipoma-derived smooth muscle cells.

Tuberous sclerosis complex (TSC) is an autosomal-dominant disease that is caused by mutations in either the TSC1 or TSC2 gene. Smooth muscle-like cells (ASMs) were isolated from an angiomyolipoma of a patient with TSC. These cells lacked tuberin, were labeled by both HMB45 and CD44v6 antibodies, and had constitutive S6 phosphorylation. The cells bear a germline TSC2 intron 8-exon 9 junction mutation, but DNA analysis and polymerase chain reaction amplification failed to demonstrate loss of heterozygosity. Testing for an epigenetic alteration, we detected methylation of the TSC2 promoter. Its biological relevance was confirmed by tuberin expression and a reduction in HMB45 labeling and S6 constitutive phosphorylation after exposure to the chromatin-remodeling agents, trichostatin A and 5-azacytidine. These cells were named TSC2(-/meth) ASMs. Their proliferation required epidermal growth factor in the medium as previously described for TSC2(-/-) ASMs. Blockade of epidermal growth factor with monoclonal antibodies caused the death of TSC2(-/meth) ASMs. In addition, rapamycin effectively blocked the proliferation of these cells. Our data show for the first time that methylation of the TSC2 promoter might cause a complete loss of tuberin in TSC2 cells, and that the pathogenesis of angiomyolipomas might also originate from epigenetic defects in smooth muscle cells. Additionally, the effect of chromatin-remodeling agents in these cells suggests a further avenue for the treatment of TSC as well as lymphangioleiomyomatosis.

Metastatic lung cancer presenting as thoracic empyema. A Case report.

Increased cancer risk in patients with inflammatory and infectious diseases has been reported in many studies and lung cancer-associated empyema in <0.3% patients. We present a patient with empyema in whom the final diagnosis was metastatic lung adenocarcinoma. Purulent pleural fluid obtained by drainage or thoracentesis must always been examined because the association of malignant tumors and empyema should be taken into consideration.

Erythropoietin in amyotrophic lateral sclerosis: a pilot, randomized, double-blind, placebo-controlled study of safety and tolerability.

Preclinical studies demonstrated that erythropoietin is neuroprotective in different models of peripheral and central nervous system diseases. We investigated safety and tolerability of recombinant human erythropoietin (rhEPO) in amyotrophic lateral sclerosis (ALS). We performed a phase II double-blind, randomized, placebo-controlled study. After screening, 23 patients were randomly assigned to rhEPO or placebo arm. Patients were examined during a six-month lead-in period, and then they received fortnightly either 40,000 units of rhEPO or placebo for 24 months. Primary outcomes were adverse events, safety, and death or tracheotomy. Treatment was safe and well tolerated. One patient in the rhEPO arm dropped out for a superficial phlebitis. Median values of haematocrit, haemoglobin, red cells, and reticulocytes were non-significantly higher in rhEPO than placebo arm. Haemoglobin did not increase >1 g/dl between subsequent doses. Anti-rhEPO antibodies were not detected. Survival and slope of ALSFRS-R curves did not significantly differ between treatment groups. RhEPO treatment was safe and well tolerated in ALS patients. Our results suggest that larger studies are warranted to confirm safety of treatment and to investigate different dose schedule and efficacy.

[Descending necrotising mediastinitis: report of two cases]. / Descrizione di due casi di mediastinite discendente.

Descending necrotising mediastinitis is a severe infection spreading from the cervical region to the mediastinal connective tissue. It represents a virulent form of mediastinal infection, requiring prompt diagnosis and treatment to reduce the high mortality associated. An optimal debridement and drainage through an open thoracotomy access are the keys for a successful outcome. Two patients, males, 70 and 75-years-old with descending necrotising mediastinitis were treated in our Institution in April '05. One had an odontogenic abscess and the other had a retropharyngeal abscess. Operative procedures included thoracotomy with radical surgical debridement of the mediastinum and excision of necrotic tissue associated with transcervical surgical debridement and drainage. Postoperatively mediastinum-pleural and cervical irrigation with iodopovidone 2 per thousand was performed until a culture of pleural effusion become negative. Postoperatively both patients suffered from severe complication including septic shock and acute respiratory distress syndrome. The 70-years-old patient had an acute renal failure too. Postoperatively the length of the intensive care unit stay was 40 and 42 days, respectively. The outcome was favorable in both patients. Early detection and immediate open surgical treatment could be the best way to reduce morbidity and mortality rate. Descending Necrotising Mediastinitis cannot be adequately treated without mediastinal and cervical excision of necrotic tissue and drainage including an open thoracic and cervical approach.

Deep phenotyping of patients with Tuberous Sclerosis Complex and no mutation identified in TSC1 and TSC2.

Tuberous Sclerosis Complex (TSC) is a multisystemic condition caused by mutations in TSC1 or TSC2, but a pathogenic variant is not identified in up to 10% of the patients. The aim of this study was to delineate the phenotype of pediatric and adult patients with a definite clinical diagnosis of TSC and no mutation identified in TSC1 or TSC2. We collected molecular and clinical data of 240 patients with TSC, assessing over 50 variables. We compared the phenotype of the homogeneous group of individuals with No Mutation Identified (NMI) with that of TSC patients with a TSC1 and TSC2 pathogenic variant. 9.17% of individuals were classified as NMI. They were diagnosed at an older age (p = 0.001), had more frequent normal cognition (p < 0.001) and less frequent epilepsy (p = 0.010), subependymal nodules (p = 0.022) and giant cell astrocytomas (p = 0.008) than patients with TSC2 pathogenic variants. NMI individuals showed more frequent bilateral and larger renal angiomyolipomas (p = 0.001; p = 0.003) and pulmonary involvement (trend) than patients with TSC1 pathogenic variants. Only one NMI individual had intellectual disability. None presented with a subependymal giant cell astrocytoma. Other medical problems not typical of TSC were found in 42.86%, without a recurrent pattern of abnormalities. Other TSC-associated neuropsychiatric disorders and drug-resistance in epilepsy were equally frequent in the three groups. This study provides a systematic clinical characterization of patients with TSC and facilitates the delineation of a distinctive phenotype indicative of NMI patients, with important implications for surveillance.

Women with TSC: Relationship between Clinical, Lung Function and Radiological Features in a Genotyped Population Investigated for Lymphangioleiomyomatosis.

The advent of pharmacological therapies for lymphangioleiomyomatosis (LAM) has made early diagnosis important in women with tuberous sclerosis complex (TSC), although the lifelong cumulative radiation exposure caused by chest computer tomography (CT) should not be underestimated. We retrospectively investigated, in a cohort of TSC outpatients of San Paolo Hospital (Milan, Italy) 1) the role of pulmonary function tests (PFTs) for LAM diagnosis, 2) the association between LAM and other features of TSC (e.g. demography, extrapulmonary manifestations, genetic mutations, etc.), and 3) the characteristics of patients with multifocal micronodular pneumocyte hyperplasia (MMPH). Eighty-six women underwent chest CT scan; pulmonary involvement was found in 66 patients (77%; 49% LAM with or without MMPH, and 28% MMPH alone). LAM patients were older, with a higher rate of pneumothorax, presented more frequently with renal and hepatic angiomyolipomas, and tended to have a TSC2 mutation profile. PFTs, assessed in 64% of women unaffected by cognitive impairments, revealed a lower lung diffusion capacity in LAM patients. In multivariate analysis, age, but not PFTs, resulted independently associated with LAM diagnosis. Patients with MMPH alone did not show specific clinical, functional or genetic features. A mild respiratory impairment was most common in LAM-TSC patients: In conclusions, PFTs, even if indicated to assess impairment in lung function, are feasible in a limited number of patients, and are not significantly useful for LAM diagnosis in women with TSC.