We hypothesized that changes in skin characteristics on the forearm could be useful for early diagnosis of systemic sclerosis (SSc). We used VISIA digital imaging system to investigate this possibility for the first time. Twenty-eight Japanese patients who were diagnosed with typical or very early diagnosis of SSc (VEDOSS) were enrolled in this study, and ten age- and gender-matched patients with other disorders were included as a control group. Eight skin characteristics were analyzed. Our method of evaluating forearm skin characteristics was shown to be reproducible. The scores of WRINKLES, TEXTURE, PORES, and PORPHYRINS were higher in SSc subjects with sclerotic forearm skin (SSc forearm+; 11.004, 5.116, 3.230, and 0.084, respectively) and those without (SSc forearm-: 11.915, 4.898, 2.624, 0.0616, respectively) than in the non-SSc control subjects (10.075, 4.496, 2.459, 0.0223, respectively). Also, the scores of SPOTS, TEXTURE, PORES, UV SPOTS, BROWN SPOTS, and PORPHYRINS were elevated in SSc forearm+ (3.182, 5.116, 3.230, 5.761, 6.704, 0.084, respectively) and SSc forearm- patients (2.391, 4.898, 2.624, 9.835, 5.798, 0.0616, respectively) compared with those with VEDOSS (2.362, 4.738, 2.234, 5.999, 4.898, 0.0169, respectively). We found statistical significance in the difference in score of PORPHYRINS between SSc forearm- and VEDOSS groups (p = 0.044), and between SSc forearm+ and VEDOSS groups (p = 0.012). Therefore, they can be used to differentiate VEDOSS from early or mild SSc cases, which is sometimes clinically problematic. Our study also suggests that the porphyrin research will lead to a better understanding of SSc pathogenesis.

Pseudoxanthoma elasticum (PXE) is a rare, heritable disease caused by various, mainly recessively transmitted mutations in the ABCC6 gene. Due to calcification of soft connective tissue phenotypic hallmarks are progressive loss of vision, alternation of the skin and early onset atherosclerosis. Beside these main features patients also suffer from impaired alveolar diffusion. The present study focused on impaired lung functioning based on a large cohort of patients with PXE, its long-term development, and genotype-phenotype correlation. Retrospectively, 98 patients and 45 controls were enrolled. All patients underwent body plethysmography and carbon monoxide diffusion testing. Of 35 patients three or more body plethysmographic records were available for long-term analysis. For genotype-phenotype analysis ABCC6 genotypes were grouped as two missense, mixed, or two nonsense mutations. Patients with PXE showed significantly reduced vital capacity (p < 0.05), diffusion capacity (p < 0.01), and diffusion transfer coefficient (p < 0.05). Over a mean period of 38 months diffusion capacity (p < 0.05) and diffusion transfer coefficient (p < 0.01) dropped significantly whereas lung volumes remained unchanged. Genotype-phenotype correlation revealed no connection between gene variants and lung functioning. In conclusion, PXE is accompanied by progressive reduction of alveolar diffusion indicating progressive alterations of lung tissue. Genotype-phenotype correlation with genotypes sorted as missense and nonsense mutations do not explain impaired lung functioning.

Osteogenesis imperfecta (OI) type VI causative gene SERPINF1, encodes a member of the serpin family that does not display the serine protease inhibitory activity shown by many of the other serpin proteins. The encoded protein (pigment epithelium-derived factor, PEDF) has anti-tumor, anti-angiogenesis, anti-inflammation, nutrition and nerve protection functions, and participates in fat metabolism. In this paper, a series of bioinformatics analyses were conducted based on the regulation of SERPINF1 in the human. Pan-cancer analysis of SERPINF1 revealed it to play a role in the prognosis of tumors, especially in KIRC, and that high expression of SERPINF1 leads to a poor prognosis of the disease, the occurrence of which is largely related to the high expression of SERPINF1 leading to immune infiltration of cancer associated fibroblasts. Mutation analysis found that SERPINF1 had eight identical amino acids alterations sites with different in both cancer and OI patients. which hints the possible relationship between genotype and phenotype.

Genetic constraint metrics such as the gnomAD probability of being loss-of-function (LoF) intolerant (pLI) are used to prioritize candidate genes but the mode of inheritance of highly constrained genes has never specifically been studied. We compared 605 genes with a pLI of 1 (pLI1 group) with a random sample of 635 genes from gnomAD (the random group) in terms of genetic constraint metrics, associations with Mendelian disease, modes of inheritance, and two intragenic constraint scores: the percentage of constraint coding regions (CCR) in the 99^th percentile and the gene variation intolerance rank (GeVIR). The proportion of genes associated with a Mendelian disease was 35.9% (217/605) in the pLI1 group and 19.5% (124/635) in the random group (p < 0.0001). The modes of inheritance in the random group were autosomal dominant for 35 genes (28.2%), autosomal recessive for 69 (55.6%), mixed for 14 (11.3%) and X-linked for 6 genes (4.8%). The corresponding distribution in the pLI1 group was 150 (69.1%), 26 (12.0%), 14 (6.5%) and 27 (12.4%) (p < 0.0001). The percentage of CCRs in the 99th percentile was 0.3 in the random group versus 1.12 in the pLI1 group (p < 0.0001). The GeVIR score was 50.9 for the random group versus 15.1 for the pLI1 group (p < 0.0001). High genetic constraint does not seem to be associated with a particular mode of inheritance but does seem to be associated with the intragenic constraint scores considered here. Some highly constrained genes are associated with two different modes of inheritance.

The latest definition of rare disease in China was released on September 11, 2021 at the third multidisciplinary expert seminar on the definition of rare diseases/orphan drugs in China. A rare disease is defined as a condition satisfying at least one of the following three criteria: an incidence among newborns of less than 1/10,000, a prevalence of less than 1/10,000, and an affected population of less than 140,000. Before this new definition, rare diseases were defined by different agencies with different parameters in China. The 2021 definition is a milestone, it could further spur the development of rare diseases beyond China's First List of Rare Disease in May 2018. This definition also provides a reference for the total number of rare diseases in China.

Recently, a few randomized control trials (RCTs) suggested that finerenone has been shown to reduce cardiovascular events in patients with CKD and DM-2. We aimed to analyze the cardiovascular benefits of using finerenone in patients with CKD and DM-2. Electronic databases were systematically searched to identify only RCTs comparing finerenone versus placebo. Pooled risk ratios (RR) and their 95% confidence intervals (CI) were calculated using random-effects models. Three RCTs were included, with a total of 13,847 patients. Compared with the placebo group, the use of finerenone was associated with significantly lower rates of cardiovascular events (RR: 0.88; 95% CI: 0.80, 0.96; p < 0.01), which was mainly driven by lower hospitalizations for heart failure (RR: 0.79; 95% CI: 0.66, 0.94; p = 0.01). However, there were no significant differences between groups in terms of cardiovascular death (RR: 0.88; 95% CI: 0.76, 1.02; p = 0.09), non-fatal myocardial infarction (RR: 0.91; 95% CI: 0.74, 1.12;p = 0.38), non-fatal stroke (RR: 0.99; 95% CI: 0.80, 1.22; p = 0.90).

Fabry disease (FD) is a rare lysosomal storage disease. FD is caused by the presence of a deleterious mutation in the GLA gene encoding the enzyme alpha galactosidase A (αGAL A) on the X chromosome. The accumulation of Gb3 and lyso-GL-3 in nerve fiber cells, endothelium, vascular muscle cells, mesangial cells, podocytes, renal tubular epithelial cells and cardiomyocytes is the most important pathogenetic factor. The rate of disease progression depends on residual conserved enzymatic activity. In this article we present an example of a 25-year-old patient with FD with an initial asymptomatic course. The first manifestation of FD developed in the third decade of life. These include high blood pressure, urinary changes and grade V renal failure, requiring renal replacement therapy. The diagnosis was made very late, when renal failure and cerebro-cardiac complications occurred, including stroke and dangerous cardiac tamponade.

Lemierre's syndrome (LS) is a "forgotten" condition characterized by septic thrombophlebitis of the jugular vein that follows an otolaryngological infection. Fusobacterium necrophorum is the aetiological agent responsible for the syndrome in adolescents and young adults whereas in older people even common bacteria are involved. Complications arise from spreading of septic emboli distally, i.e. to the brain, lungs, bones and internal organs everywhere in the body. We report a middle-aged woman who presented with headache and bilateral sixth cranial nerve palsy following a sphenoidal sinusitis and left mastoiditis. Imaging revealed thrombotic involvement of the left internal jugular vein as well as of several cerebral venous sinuses thrombosis (CVT). Currently, precise management protocols of LS with CVT complication do not exist although a combination of macrolides and second or third-generation cephalosporins, as well as anti-coagulants represent the mainstream of therapeutics. Surgical drainage is associated to remove septic foci but is burdened by severe complications and side effects. Complete recovery was achieved following pharmacological treatment in our patient. This report adds further evidence that LS complicated by CVT may be effectively treated adopting a conservative approach thus avoiding surgical drainage and severe complications.

Autonomic dysregulation of cardiovascular functions marks early Huntington’s disease (HD). Blood-brain barrier (BBB) is dysfunctional in HD. A 37-year-old female carrying 41 CAG triplets in the huntingtin gene acutely presented with a multifaceted syndrome attributable to posterior reversible encephalopathy syndrome (PRES). Syndrome was associated with arterial hypertension (AHT). The syndrome fully recovered both by imaging and clinical signs after normalization of arterial pressure during hospitalization. Immediately after hospital discharge, the patient developed a complex psychiatric syndrome and choreic movements that represented conversion to the symptomatic phase of HD. A one-year later follow up clearly showed the patient had developed the symptomatic stage of HD by presenting both psychiatric symptoms and choreic movements. Onset of AHT may represent an early premonitory signal of HD becoming manifested. Induction of PRES might be associated with BBB impairment in HD.

Molecular alterations found in gliomas are now considered entity-defining features. The World Health Organization (WHO) classification system currently classifies the vast majority of gliomas utilizing an integrated genotype-phenotype approach. We present a case of diffuse astrocytoma with a mosaic isocitrate dehydrogenase (IDH)1-R132H-mutant immunophenotype and low subclonal allele frequency. A 35-year-old patient with a history of IDH1-R132H mutated diffuse astrocytoma in 20014 presented to the hospital again in 2019. MRI examination showed a non-enhancing abnormal signal in the periphery of her previous surgical cavity. Histopathological examination revealed that the tumor was hypercellular and without high grade histopathological features. The neoplastic cells were immunohistologically positive for GFAP, Olig2, and ATRX. However, only some scattered tumor cells were positive for IDH1-R132H. Cytogenetic studies revealed a lack of chromosomal 1p/19q co-deletion. Further next-generation sequencing (NGS) demonstrated a low-level IDH1-R132H mutation and allele frequency. Based on these findings, the diagnosis of diffuse astrocytoma with mosaic IDH1-R132H-mutant immunophenotype and low subclonal allele frequency (WHO grade II) was generated. This case indicates that gliomas may have heterogeneous molecular profile and the intra-tumoral molecular heterogeneity highlights the need to further characterize the molecular profile for glioma classification and clinical management.