Brachial and subclavian arteries aneurysms due to tuberous sclerosis complex mechanisms - case report and literature review.

INTRODUCTION: Tuberous sclerosis complex (TSC) is a rare autosomal dominant condition characterized by cutaneous, cerebral, and other multiorgan involvement. Aneurysms due to TSC pathogenic mechanism are rarely present, mainly aortic, renal, or intracranial and very few associated with peripheral circulation. A TSC patient, aged 31 years, who developed brachial and subclavian arteries aneurysms is presented. The question of a random association of the aneurysms with TSC versus aneurysms within pathogenic released mammalian target of rapamycin (mTOR) pathway effect was raised. CASE PRESENTATION: Patient's file, available from the age of six months, was analyzed for demonstration of the TSC diagnosis. Patient was examined, and cerebral magnetic resonance imaging (MRI) was repeated. Surgery and angiographic reports and images were reviewed. Pathology of the aneurysmal wall available from surgery was reexamined and special stainings and immunohistochemistry markers were applied. Genetic characterization of the patient was performed. Definite TSC was diagnosed based on major criteria [ungual fibromas, shagreen patch, cortical tubers, subependymal nodules (SENs), subependymal giant cell astrocytoma (SEGA)], minor criteria (confetti skin lesions, dental enamel pits, gingival fibromas), genetic result showing heterozygous variant in exon 8 of TSC1 gene (c.733C>T-p.Arg245*). Pathology analysis revealed markedly thickened aneurysmal wall due to smooth muscle cells (SMCs) proliferation in media and neoformation vessels with similar characteristics in the aneurysmal wall. DISCUSSIONS AND CONCLUSIONS: This is a rare case with aneurysms related to TSC, with an exceptional peripheral localization. Pathology exam is the key investigation in demonstrating the TSC-related pathogenic mechanism. A literature review showed 73 TSC cases presenting aneurysms published until now.

Muscle involvement with pseudohypertrophy in systemic light chain amyloidosis: Case report.

RATIONALE: Muscle pseudohypertrophy is a rare manifestation of light chain amyloidosis (AL) amyloidosis. PATIENT CONCERNS: A 63-year-old woman presented with a 2-year history of progressive asthenia, macroglossia, dysphonia, cachexia, hypotension, paresthesia, and lower limb muscle hypertrophy. DIAGNOSIS: Free serum lambda light chains were increased, and fat pad biopsy demonstrated Congo red-positive deposits. Additionally, electromyography showed a myopathic pattern, whereas muscle biopsy revealed amyloid deposits. A diagnosis of λAL with cardiac, renal, nervous system, and skeletal muscle involvement was established. INTERVENTIONS AND OUTCOMES: The patient received 3 subsequent lines of therapy over the following 23 months, with very slow hematological remission followed by resolution of organ dysfunction. LESSONS: Despite its rarity, muscle involvement should be considered in patients diagnosed with AL amyloidosis associated with unexplained muscle hypertrophy or weakness associated with macroglossia or elevated troponin T levels in the absence of clear cardiac involvement.

Novel FHL1 mutation variant identified in a patient with nonobstructive hypertrophic cardiomyopathy and myopathy - a case report.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a genetic disorder mostly caused by sarcomeric gene mutations, but almost 10% of cases are attributed to inherited metabolic and neuromuscular disorders. First described in 2008 in an American-Italian family with scapuloperoneal myopathy, FHL1 gene encodes four-and-a-half LIM domains 1 proteins which are involved in sarcomere formation, assembly and biomechanical stress sensing both in cardiac and skeletal muscle, and its mutations are responsible for a large spectrum of neuromuscular disorders (mostly myopathies) and cardiac disease, represented by HCM, either isolated, or in conjunction with neurologic and skeletal muscle impairment. We thereby report a novel mutation variant in FHL1 structure, associated with HCM and type 6 Emery-Dreifuss muscular dystrophy (EDMD). CASE PRESENTATION: We describe the case of a 40 year old male patient, who was referred to our department for evaluation in the setting of NYHA II heart failure symptoms and was found to have HCM. The elevated muscular enzymes raised the suspicion of a neuromuscular disease. Rigid low spine and wasting of deltoidus, supraspinatus, infraspinatus and calf muscles were described by the neurological examination. Electromyography and muscle biopsy found evidence of chronic myopathy. Diagnosis work-up was completed by next-generation sequencing genetic testing which found a likely pathogenic mutation in the FHL1 gene (c.157-1G > A, hemizygous) involved in the development of X-linked EDMD type 6. CONCLUSION: This case report highlights the importance of multimodality diagnostic approach in a patient with a neuromuscular disorder and associated hypertrophic cardiomyopathy by identifying a novel mutation variant in FHL1 gene. Raising awareness of non-sarcomeric gene mutations which can lead to HCM is fundamental, because of diagnostic and clinical risk stratification challenges.

A rare case of mitochondriopathy with autosomal dominant progressive external ophthalmoplegia diagnosed through skeletal muscle biopsy.

Mitochondriopathies are a heterogeneous group of genetic diseases of all ages, with a very diverse clinical presentation related to genetic heteroplasmy. The clinical symptoms display a large variability and generally, the more severe phenotypes have an early onset, even from the neonatal period, while milder ones are manifested later in the adulthood. Most publications have already demonstrated deletions or point mutations in mitochondrial deoxyribonucleic acid (DNA), but in recent years, the field of investigation has expanded to syndromes caused by mutations in the nuclear DNA (nDNA), with a Mendelian inheritance. We present the case of a male patient with a mitochondriopathy with phenotype of chronic progressive external ophthalmoplegia (PEO), due to an autosomal dominant mutation in nDNA, in the DNA polymerase subunit gamma (POLG) gene, the pathogenic variant c.2864A>G (p.Tyr955Cys), morphologically investigated and diagnosed using a skeletal muscle biopsy. The aim of this presentation is to emphasize the diagnostic value of the muscle biopsy both in cases of clinical suspicion and in more challenging cases of mitochondrial diseases with atypical or unusual features. Although genetic testing may be the initial test of choice in cases with suggestive clinical presentation, muscle biopsy is an alternative diagnostic aid with high value even in our molecular era. We present pathological and ultrastructural data to confirm the diagnosis.

The role of skin and muscle biopsy in the diagnosis of main connective tissue diseases.

Systemic involvement in autoimmune diseases is often unclear and organ changes are confounding, thus making it difficult to have an early accurate diagnosis. In those situations, both clinical and paraclinical findings might orientate the diagnosis, but only histological or immunohistochemistry changes might be accurate enough. The skin histological changes are relevant and sometimes might have a tremendous role in the accurate diagnosis of autoimmune rheumatic diseases, due to the correlation with the clinical systemic manifestations of the diseases and through the accessibility of biopsy. In the same time, muscle biopsy can provide important support for physicians improving diagnosis and optimizing management of connective tissue diseases.

Therapeutic potential of certain drug combinations on paclitaxel-induced peripheral neuropathy in rats.

BACKGROUND AND AIMS: Experimental research and clinical data support the potential combination therapy for the treatment of neuropathic pain. We aimed to investigate the analgesic effect of the following associations: gabapentin + etifoxine; tramadol + etifoxine; gabapentin + tramadol, in an experimental model of peripheral neuropathy induced by paclitaxel. MATERIALS AND METHODS: Neuropathy was induced in male Wistar rats by the daily administration of 2 mg÷kg body weight (bw) paclitaxel intraperitoneally, four days in a row. Analgesics were given concomitantly with paclitaxel, in the following doses: tramadol 15 mg÷kg bw, etifoxine 100 mg÷kg bw, gabapentin 300 mg÷kg bw. Tactile allodynia and mechanical hyperalgesia were assessed using the Dynamic Plantar Aesthesiometer apparatus (Ugo Basile). After 18 days of treatment, the brain and liver tissue susceptibility to lipid peroxidation was evaluated and the sciatic nerve histological examination of the effect on myelin fibers was performed. RESULTS AND CONCLUSIONS: Experimental data have shown a strong analgesic effect of these three tested combinations expressed mainly by the statistically significant increased maximum response time, both in the assessment of allodynia and hyperalgesia. The gabapentin + tramadol combination lead to the maximum analgesic effect, immediately after the discontinuation of paclitaxel (44.94%, p<0.0001) and throughout the study. The treatment associated with tramadol caused a reduction in lipid peroxidation in the brain as compared to paclitaxel group. Combination therapy showed reduced damage to myelinated fiber density in the sciatic nerve. The drug combinations used in the experiment showed therapeutic potential in the fight against neuropathic pain induced by the administration of taxanes.

Discovery of a new mutation in the desmin gene in a young patient with cardiomyopathy and muscular weakness.

A 25-year-old woman with a five years history of syncope, mild left ventricular hypertrophy and moderately enlarged atria, was diagnosed with third degree atrioventricular heart block alternating with atrioventricular heart block 2:1, and received a dual chamber pacemaker. After three years of evolution, she developed atrial fibrillation, marked biatrial enlargement, severely depressed longitudinal myocardial velocities, associated with mild girdle weakness and slight increase in creatine kinase level. The diagnosis of restrictive cardiomyopathy with mild skeletal myopathy imposed the screening for a common etiology. Skeletal muscle biopsy revealed the morphological picture of myofibrillar myopathy with sarcoplasmic aggregates, immunoreactive for desmin and other ectopic proteins on immunohistochemistry, appearing as granulofilamentous material at ultrastructural level. Western blot analysis confirmed the desmin overexpression. Genetic testing identified a heterozygous missense variant DES rs869025381, c.1297C>A, p.(Pro433Thr), not previously reported. This is not only the first confirmed Romanian patient with myofibrillar myopathy with clinical features of severe restrictive cardiomyopathy associated with mild skeletal myopathy, but also a case which adds up to the known mutational spectrum in desminopathy.

Vascular endothelial growth factor - key mediator of angiogenesis and promising therapeutical target in ulcerative colitis.

Ulcerative colitis (UC) is an inflammatory bowel disease, triggered by an inappropriate immune response of colonic mucosa. Angiogenesis is an important part of inflammatory process, enhancing inflammation in a vicious circle that aggravates mucosal damage and remodeling. The most important pathway for angiogenesis in ulcerative colitis involves vascular endothelial growth factor (VEGF) and endoglin (CD105) and can be used as target for adjuvant therapy in order to improve patients' outcome. We present a retrospective cohort study evaluating mucosal expression of VEGF and CD105 and their correlation with patients' evolution and risk of relapse. In our study, patients with UC have correlated increases of VEGF expression and microvessel density (evaluated with CD105 staining), sustaining the hypothesis that angiogenesis is not just a passive process driven by inflammation, but an active player of mucosal lesions in ulcerative colitis.

Proliferation activity in bladder tumors does not correlate with the pathological grading.

Worldwide, bladder cancer is the seventh most frequent cancer in men and the 17th most frequent cancer in women, respectively. In men, this type of cancer is the second most frequent type of cancer localized in the genitourinary system, after prostate cancer. The incidence of bladder cancer is ever growing and the etiopathogenic factors of bladder cancer are numerous and still not fully understood. Smoking is the most common risk factor incriminated in the onset of urinary tract cancer, the incidence of bladder cancer being directly connected to the smoking duration and the tobacco amount intake. Regarding the histopathological types, more than 90% of bladder cancer is represented by transitional cell carcinomas. Histopathology assessment of bladder cancer is a constant challenge regarding the connection between tumor grading, depth of invasion, extension and clinical prognosis. We evaluated here a number of 32 confirmed bladder tumors and we aimed to find common patterns of expression for markers like cytokeratin 7 (CK7), CK20, vascular endothelial growth factor (VEGF), CD34, matrix metalloproteinases (MMPs) 2, 8 and 9, as well as for the Ki67 proliferation index. Our study showed that both CK7 and CK20 were present in different tumor areas and tumor gradings, MMP9 was more constantly expressed compared to the more variable expression of MMPs 2 and 8, vascular densities did not seem to increase in high-grade invasive tumors compared to low-grade tumors. Interestingly, while high Ki67 proliferating indexes were present especially in high-grade superficially tumors, compared to low-grade papillary tumors; this correlation was inversed for the advancing edges of the tumor. This common feature of invasive urothelial tumors will thus require further studies in order to elucidate the cellular signaling pathways by which these tumors increase their overall invasiveness.

Correlations Between the Density of Tryptase Positive Mast Cells (DMCT) and that of New Blood Vessels (CD105+) in Patients with Gastric Cancer.

Mast cells proteases, tryptase and chymase are directly involved in the growth and progression of solid tumors due to their important role in tumor angiogenesis. We examined the density of tryptase positive mast cells and the mean density of new blood vessels in gastric malignant tumors of patients with and without Helicobacter pylori infection, using immunohistochemical staining for tryptase (for mast cells) and CD 105 (for new vessels). Tryptase and CD 105 expression was detected in gastrectomy specimens. In this study, mast cell density correlates with angiogenesis and the growth and progression of gastric cancer. It also shows that the participation of Helicobacter pylori infection in the growth and progress of gastric neoplasia is due to an increase of peritumoral angiogenesis, with subsequent local and distant tumor spread and perivascular growth, but without perineural and nodal involvement.

Carcinoma in situ of the urinary bladder - from pathology to narrow band imaging.

OBJECTIVES: A retrospective clinical analysis was performed over a time period of 10 months while aiming to establish the impact of narrow band imaging (NBI) cystoscopy and transurethral resection of bladder tumors (TURBT) in cases of carcinoma in situ (CIS). MATERIALS AND METHODS: CIS tumor cells are characterized by a high cytological grade, a certain degree of cyto-nuclear pleomorphism, large, irregular, hyperchromatic nuclei, high nuclear/cytoplasmatic ratio and mitotic figures. One hundred thirty-nine patients were consecutively diagnosed with non-muscle invasive bladder cancer (NMIBC) based on standard white light cystoscopy (WLC) and NBI vision. Urinary cytology was performed in cases of flat lesions suspected by either type of cystoscopy before the TURBT staging. Conventional endoscopic resection was performed for all white light (WL) visible lesions and NBI-guided TURBT exclusively for the observed tumors. RESULTS: At subsequent pathological analysis, 13 CIS patients were confirmed. NBI cystoscopy emphasized a superior diagnostic accuracy as compared to WLC concerning the cases' (92.3% versus 69.2%) as well as lesions' (93.75% versus 71.9%) detection rates. NBI-TURBT provided a higher proportion of additional tumors' cases (53.8% versus 15.4%) when compared to classical resection but was marked by an increased frequency of false-positive results (18.9% versus 11.5%). Urinary cytology displayed an 84.6% sensitivity rate. CONCLUSIONS: NBI cystoscopy and resection substantially ameliorated the CIS-related diagnostic accuracy within a parallel to the standard endoscopic approach at the cost of a reduced specificity. NBI-TURBT was able to find more CIS patients as well as lesions, thus improving the sensitivity of standard resection and urinary cytology.

Rett-like onset in late-infantile neuronal ceroid lipofuscinosis (CLN7) caused by compound heterozygous mutation in the MFSD8 gene and review of the literature data on clinical onset signs.

BACKGROUND: We present clinical and molecular findings of a patient with ceroid-lipofuscinosis CLN7, with a compound heterozygous mutation of the MFSD8 gene, with Rett syndrome clinical signs onset and a later development of full picture of vLINCL. CASE PRESENTATION: A 7 years-old female patient with normal development until the age 12 months, developed Rett like clinical picture (psychomotor regression, microcephaly, stereotypic hands movements in the midline, hyperventilation episodes) present at the onset of her condition (age 18 months), features still present at the initial evaluation in our clinic at age 5 years. RESULTS: MECP2 (methyl CpG binding protein 2) gene mutation was negative. At age 6 years she was readmitted for severe ataxia and blindness, seizures, and severe developmental regression leading to NCL (neuronal ceroid lipofuscinosis) suspicion. EEG showed slow background with IRDA (intermittent rhythmic delta activity). A conjunctive biopsy showed abnormal curvilinear and fingerprint lysosomal deposits, and genetic analysis revealed two heterozygous mutations of MFSD8 gene (c.881C > A p.Thr294Lys and c.754 + 2T > A) each inherited from carrier parents and a heterozygous variant (c.470A>C p.Asp157Ala) of CLN5 gene. CONCLUSION: NCL should be suspected and MFSD8 genetic testing should also be considered in patients with Rett like phenotype at onset and negative MECP2 mutation. Such cases should be carefully and frequently re-evaluated in order to avoid delayed diagnosis and offer proper genetic advice to the family. In our knowledge, this might be the first case of CLN7 disease with Rett like onset described in the literature, which developed typical vLINCL clinical phenotype after age 5.5 years. A short review of the literature showing NCL onset modalities is presented.