Project description:PurposeSingleton-Merten syndrome manifests as dental dysplasia, glaucoma, psoriasis, aortic calcification, and skeletal abnormalities including tendon rupture and arthropathy. Pathogenic variants in IFIH1 have previously been associated with the classic Singleton-Merten syndrome, while variants in DDX58 has been described in association with a milder phenotype, which is suggested to have a better prognosis. We studied a family with severe, "classic" Singleton-Merten syndrome.MethodsWe undertook clinical phenotyping, next-generation sequencing, and functional studies of type I interferon production in patient whole blood and assessed the type I interferon promoter activity in HEK293 cells transfected with wild-type or mutant DDX58 stimulated with Poly I:C.ResultsWe demonstrate a DDX58 autosomal dominant gain-of-function mutation, with constitutive upregulation of type I interferon.ConclusionsDDX58 mutations may be associated with the classic features of Singleton-Merten syndrome including dental dysplasia, tendon rupture, and severe cardiac sequela.
Project description:BackgroundRett syndrome (RTT) is a severe, progressive neurodevelopmental disorder with multisystem comorbidities that evolve across a patient's lifespan requiring attentive coordination of subspecialty care by primary care providers. A comprehensive, up-to-date synthesis of medical comorbidities in RTT would aid care coordination and anticipatory guidance efforts by healthcare providers. Our objective was to review and summarise published evidence regarding prevalence of RTT medical comorbidities across all relevant organ systems.MethodsSearch of PubMed from January 2000 to July 2019 was performed using the search terms (Rett and MECP2 AND patient) OR (Rett and MECP2 AND cohort). Articles reporting the prevalence of clinical findings in RTT were assessed with respect to the size and nature of the cohorts interrogated and their relevance to clinical care.ResultsAfter review of over 800 records, the multisystem comorbidities of RTT were summarised quantitatively from 18 records comprising both retrospective and prospective cohorts (31-983 subjects). Neurological comorbidities had the highest prevalence, occurring in nearly all individuals with gastrointestinal and orthopaedic concerns almost as prevalent as neurological. With the exception of low bone mineral content which was relatively common, endocrine comorbidities were seen in only around one-third of patients. Although more prevalent compared with the general population, cardiac conduction abnormalities were the least common comorbidity in RTT.ConclusionsEffective care coordination for RTT requires knowledge of and attention to multiple comorbidities across multiple unrelated organ systems. Many issues common to RTT can potentially be managed by a primary care provider but the need for sub-specialist referral can be anticipated. Since the median life expectancy extends into the sixth decade with evolving subspecialty requirements throughout this time, paediatric providers may be tasked with continued coordination of these comorbidities or transitioning to adult medicine and specialists with experience managing individuals with complex medical needs.
Project description:Despite the incompletely understood multiple etiologies and underlying mechanisms, cardiorenal syndrome is characterized by decreased glomerular filtration and sodium avidity. The underlying level of renal sodium avidity is of primary importance in driving a congested heart failure phenotype and ultimately determining the response to diuretic therapy. Historically, mechanisms of kidney sodium avidity and resultant diuretic resistance were primarily extrapolated to cardiorenal syndrome from non-heart failure populations. Yet, the mechanisms appear to differ between these populations. Recent literature in acute decompensated heart failure has refuted several classically accepted diuretic resistance mechanisms and reshaped how we conceptualize diuretic resistance mechanisms in cardiorenal syndrome. Herein, we propose an anatomically based categorization of diuretic resistance mechanisms to establish the relative importance of specific transporters and translate findings toward therapeutic strategies. Within this categorical structure, we discuss classic and novel mechanisms of diuretic resistance.
Project description:BackgroundKleefstra syndrome is a rare genetic disorder, with core phenotypic features encompassing developmental delay/intellectual disability, characteristic facial features - brachy(micro)cephaly, unusual shaped eyebrows, flat face with hypertelorism, short nose with anteverted nostrils, thickened lower lip, carpmouth with macroglossia - and childhood hypotonia. Some additional symptoms are observed in different percentage of the patients. Epilepsy is common symptom as well. The underlying cause of the syndrome is a submicroscopic deletion in the chromosomal region 9q34.3 or disruption of the euchromatin histone methyl transferase 1.Case presentationWe describe two Hungarian Kleefstra syndrome patients, one with the classic phenotype of the syndrome, the diagnosis was confirmed by subtelomeric FISH. Meanwhile in our second patient beside the classic phenotype a new symptom - abnormal antiepileptic drug metabolic response - could be observed. Subtelomere FISH confirmed the 9q34.3 terminal deletion. Because of the abnormal drug metabolism in our second patient, we performed array CGH analysis as well searching for other rearrangements. Array CGH analysis indicated a large - 1.211 Mb -, deletion only in the 9q subtelomeric region with breakpoints ch9:139,641,471-140,852,911.ConclusionsThis is the first report on Kleefstra syndrome in patients describing a classical and a complex phenotype involving altered drug metabolism.
Project description:Nursing becoming a respectable, decent profession for educated Chinese women was a challenging undertaking. The early advancement of nursing in China was a collective effort of the missionary medicine, the private foundations, and the endurance, dedication and hardworking of the Chinese as well as foreign nurses. Western missionary introduced modern nursing in China and laid the preliminary foundation for its development, while the upgrading of nursing education from training to higher learning was a contribution by the School of Nursing Peking Union Medical College (PUMC), envisioned and supported by the China Medical Board. Its state-of-the-art and visionary education model, the high standard and the initiatives in public health nursing, and the heroic and patriotic military nursing created by the PUMC's outstanding graduates produced a cohort of leaders in nursing education and profession in China before 1949. All these efforts acting together shaped the modern nursing in China, leaving a great heritage to nursing education and practice to New China.
Project description:Background: IgG4-related disease is a rare, chronic inflammatory disorder characterized by lymphoplasmacytic infiltration, 'storiform' fibrosis, and elevated IgG4 levels in affected tissues. This disease has a broad and heterogeneous clinical spectrum that includes four main phenotypes: pancreatic-hepatobiliary disease, retroperitoneal/aortic fibrosis, head and neck disease, and Mikulicz syndrome. Case Description: An 85-year-old male patient with a clinical presentation, which is unusual outside Asia, of IgG4-related disease phenotype Mikulicz syndrome, characterized by bilateral dacryoadenitis, orbital pseudotumor, and no evidence of significant systemic participation. Despite extensive involvement in the orbital and glandular region, the patient did not develop serious organ complications, a behavior rarely documented in the literature. Despite the serum IgG4 levels being normal (<135 mg/dL), the clinical and radiological picture suggested IgG4-RD, emphasizing the need for a biopsy for a definitive diagnosis. Histopathological examination revealed a dense lymphoplasmacytic infiltrate, storiform fibrosis, and more than 40% IgG4-positive cells, confirming the diagnosis. Results: Treatment with prednisone was initiated alongside azathioprine for long-term control. Calcium and vitamin D3 supplementation were added to prevent glucocorticoid-induced osteoporosis. Remarkable clinical improvement was observed within 24 h, with progressive orbital and glandular symptoms resolution. Over a year, the patient exhibited complete resolution of the orbital tumors, total recovery of vision, and no relapses. The only sequelae observed were dry eye. Conclusions: This case highlights the need to consider IgG4-RD with normal serum IgG4 levels, the importance of histopathology for diagnosis, and the efficacy of steroids as first-line treatment. A multidisciplinary approach is essential for timely treatment.
Project description:POEMS syndrome is a rare conglomeration of disorders associated with plasma cell dyscrasia. The acronym POEMS is derived from main features of the syndrome namely 'polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin lesions'. Other clinical features include presence of sclerotic bone lesions, Castleman's disease, papilledema, pleural effusion, edema, ascites, erythrocytosis and thrombocytosis. Myeloma is the most common plasma cell dyscrasia associated with POEMS syndrome. Renal involvement is rare and renal biopsy is characterized by glomerular involvement with membranoproliferative glomerulonephritis and endothelial injury. We report a case of a 67-year-old male who presented with clinical features satisfying the diagnostic criteria of POEMS syndrome and had rapidly progressive renal failure. Renal biopsy showed extensive interstitial infiltration by plasma cells and concomitant presence of classic polyarteritis nodosa. Although association with small-vessel vasculitis has been reported in patients with POEMS syndrome, to the best of our knowledge, this is the first report of POEMS syndrome associated with medium-sized vessel vasculitis.
Project description:FAM20C is a gene coding for a protein kinase that targets S-X-E/pS motifs on different phosphoproteins belonging to diverse tissues. Pathogenic variants of FAM20C are responsible for Raine syndrome (RS), initially described as a lethal and congenital osteosclerotic dysplasia characterized by generalized atherosclerosis with periosteal bone formation, characteristic facial dysmorphisms and intracerebral calcifications. The aim of this review is to give an overview of targets and variants of FAM20C as well as RS aspects. We performed a wide phenotypic review focusing on clinical aspects and differences between all lethal (LRS) and non-lethal (NLRS) reported cases, besides the FAM20C pathogenic variant description for each. As new targets of FAM20C kinase have been identified, we reviewed FAM20C targets and their functions in bone and other tissues, with emphasis on novel targets not previously considered. We found the classic lethal and milder non-lethal phenotypes. The milder phenotype is defined by a large spectrum ranging from osteonecrosis to osteosclerosis with additional congenital defects or intellectual disability in some cases. We discuss our current understanding of FAM20C deficiency, its mechanism in RS through classic FAM20C targets in bone tissue and its potential biological relevance through novel targets in non-bone tissues.