COQ7 defect causes prenatal onset of mitochondrial CoQ10 deficiency with cardiomyopathy and gastrointestinal obstruction.

COQ7 pathogenetic variants cause primary CoQ10 deficiency and a clinical phenotype of encephalopathy, peripheral neuropathy, or multisystemic disorder. Early diagnosis is essential for promptly starting CoQ10 supplementation. Here, we report novel compound heterozygous variants in the COQ7 gene responsible for a prenatal onset (20 weeks of gestation) of hypertrophic cardiomyopathy and intestinal dysmotility in a Bangladesh consanguineous family with two affected siblings. The main clinical findings were dysmorphisms, recurrent intestinal occlusions that required ileostomy, left ventricular non-compaction cardiomyopathy, ascending aorta dilation, arterial hypertension, renal dysfunction, diffuse skin desquamation, axial hypotonia, neurodevelopmental delay, and growth retardation. Exome sequencing revealed compound heterozygous rare variants in the COQ7 gene, c.613_617delGCCGGinsCAT (p.Ala205HisfsTer48) and c.403A>G (p.Met135Val). In silico analysis and functional in vitro studies confirmed the pathogenicity of the variants responsible for abolished activities of complexes I + III and II + III in muscle homogenate, severe decrease of CoQ10 levels, and reduced basal and maximal respiration in patients' fibroblasts. The first proband deceased at 14 months of age, whereas supplementation with a high dose of CoQ10 (30 mg/kg/day) since the first days of life modified the clinical course in the second child, showing a recovery of milestones acquirement at the last follow-up (18 months of age). Our study expands the clinical spectrum of primary CoQ10 deficiency due to COQ7 gene defects and highlights the essential role of multidisciplinary and combined approaches for a timely diagnosis.

Fabry disease: a rare disorder calling for personalized medicine.

Fabry Disease (FD) is a genetic disease caused by a deficiency in the activity of lysosomal galactosidase A (α-GalA), an enzyme responsible for the catabolism of globotriaosylceramide (Gb3). Since lysosomes are present throughout the body and play a crucial role in catabolism and recycling of cytosolic compounds, FD can affect multiple organs and result in various symptoms, including renal, cardiovascular, neurological, cutaneous, and ophthalmic manifestations. Due to the nonspecific symptoms and the rarity of FD, it is often diagnosed late in life. However, introducing targeted therapies such as enzyme replacement therapy (ERT) and chaperone therapy has significantly improved FD's natural history and prognosis by restoring α-GalA enzyme activity. Despite the advancements, there are limitations to the currently available therapies, which has prompted research into new potential treatments for FD, including alternative forms of enzyme replacement therapy, substrate reduction therapy, mRNA therapy, and genetic therapy. In this review, we analyze the epidemiology, pathophysiology, and treatment of FD, with particular emphasis on promising therapeutic opportunities that could shift the treatment of this rare disease from a standardized to a personalized approach soon.

Continued sac perfusion of popliteal artery aneurysms after ligation and bypass. Relevance of duplex ultrasound surveillance and treatment.

AIM: Conventional management of popliteal artery aneurysms (PAA) through a medial approach may be lon term ineffective. We report our long term rate of continued sac perfusion after ligation and bypass, combined to duplex ultrasound (DUS) surveillance protocol. PATIENTS AND METHODS: Follow-up data of 24 PAA (mean diameter 37.5 ± 8.8 mm) treated by ligation and bypass with eventual adjunctive procedures (direct sac embolization or resection) were collected. The endpoints of the study were the long term rate of continued sac perfusion and the freedom from any reintervention. RESULTS: Twentyfour PAA were treated in 20 patients. Long term follow-up was complete for 19 graft (79.1%). During a median follow-up of 71.2 months (4-168), persistent sac flow was found in 5 legs (26.3%), 4 to 36 months after surgery, without enlargement or rupture. The cumulative Kaplan-Meier survival free from PAA reperfusion at 1, 3, and 6 years was 91.5%, 77.5%, and 71.5%, respectively. Basing on DUS surveillance, late additional procedures were required in 5 patients (25%), to treat sac reperfusion or preserve graft patency. The cumulative Kaplan-Meier survival free from any reintervention at 1, 3, and 6 years was 91.5%, 72.8%, and 67%, respectively. CONCLUSIONS: Conventional management of PAA through a medial approach may be associated to progressive sac expansion. The DUS surveillance protocol remains strongly recommended to detect sac perfusion and suggest the timing of reintervention before rupture occurs. Adjunctive intraoperative procedures could improve the long term results, but further studies on large series are needed. KEY WORDS: Acrylic glue, Duplex ultrasound study, Femoropopliteal bypass, Popliteal artery aneurysm, Ultrasoundguided embolization.

Modifiers of Autosomal Dominant Polycystic Kidney Disease Severity: The Role of PKD1 Hypomorphic Alleles.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of kidney failure in adult life. Rarely, ADPKD can be diagnosed in utero or in infancy, and the genetic mechanism underlying such severe presentation has been shown to be related to reduced gene dosage. Biallelic PKD1 variants are often identified in early onset ADPKD, with one main pathogenic variant and a modifier hypomorphic variant showing an in trans configuration. We describe two unrelated individuals with early onset cystic kidney disease and unaffected parents, where a combination of next-generation sequencing of cystic genes including PKHD1, HNF1B and PKD1 allowed the identification of biallelic PKD1 variants. Furthermore, we review the medical literature in order to report likely PKD1 hypomorphic variants reported to date and estimate a minimal allele frequency of 1/130 for this category of variants taken as a group. This figure could help to orient genetic counseling, although the interpretation and the real clinical impact of rare PKD1 missense variants, especially if previously unreported, remain challenging.

Surgical approach to the suprarenal abdominal aorta.

AIM: The surgical approach to the pararenal aorta can be performed through a midline laparotomy or retroperitoneal approach. The current paper reports the techniques for the suprarenal aortic approach, through the review of technical literature on this topic. METHODS: Forty-six out of 82 technical papers regarding the surgical approach to the suprarenal aorta were reviewed, focusing on relevant technical details, such as the position of patient, type of incision, aortic approach and anatomical limitations. RESULTS: The left retroperitoneal abdominal approach offers numerous advantages, mainly observing some modifications of the original technique (9th intercostal space incision, short radial frenotomy, section of the inferior mesenteric artery). The traditional transperitoneal access, through a midline or bilateral subcostal incision with retroperitoneal medial visceral rotation, is best indicated when an unrestricted approach to the right iliac arteries is needed, but it can be more challenging in patients with "hostile abdomen", for which a retroperitoneal route is probably more appropriate. A more aggressive surgical approach through a 7th-9th space thoracolaparotomy, combined with semicircunferential frenotomy, should be strongly recommended to provide a safe suprarenal aortic aneurysm repair in high risk patients, who often require adjunctive procedures, such as selective visceral perfusion and left heart bypass. CONCLUSIONS: Many technical options can be used to approach the suprarenal aorta, but none can be "radicalized". The surgical strategy must be individualized according to the anatomo-clinical characteristics of the patient and aneurysm morphology as well. KEY WORDS: Abdominal aorta, Aortic aneurysm, Surgical approach.

Hybrid treatment of large extracranial carotid artery aneurysm.

An extracranial carotid artery aneurysm (ECAA) is a rare condition. The major complications are rupture and thromboembolism. Therefore, treatment is generally recommended. We report the case of a young woman affected by an ECAA, with a cervical pulsatile mass. A multidisciplinary evaluation was performed to ensure the best treatment in terms of safety and efficacy, and the patient underwent hybrid treatment. The 6-month computed tomography angiogram revealed patency of the carotid artery stents and the venous graft, in the absence of any relevant complications. An ECAA is a serious clinical condition. The treatment is challenging, and a multidisciplinary evaluation and precise planning are recommended.

SRSF1 haploinsufficiency is responsible for a syndromic developmental disorder associated with intellectual disability.

SRSF1 (also known as ASF/SF2) is a non-small nuclear ribonucleoprotein (non-snRNP) that belongs to the arginine/serine (R/S) domain family. It recognizes and binds to mRNA, regulating both constitutive and alternative splicing. The complete loss of this proto-oncogene in mice is embryonically lethal. Through international data sharing, we identified 17 individuals (10 females and 7 males) with a neurodevelopmental disorder (NDD) with heterozygous germline SRSF1 variants, mostly de novo, including three frameshift variants, three nonsense variants, seven missense variants, and two microdeletions within region 17q22 encompassing SRSF1. Only in one family, the de novo origin could not be established. All individuals featured a recurrent phenotype including developmental delay and intellectual disability (DD/ID), hypotonia, neurobehavioral problems, with variable skeletal (66.7%) and cardiac (46%) anomalies. To investigate the functional consequences of SRSF1 variants, we performed in silico structural modeling, developed an in vivo splicing assay in Drosophila, and carried out episignature analysis in blood-derived DNA from affected individuals. We found that all loss-of-function and 5 out of 7 missense variants were pathogenic, leading to a loss of SRSF1 splicing activity in Drosophila, correlating with a detectable and specific DNA methylation episignature. In addition, our orthogonal in silico, in vivo, and epigenetics analyses enabled the separation of clearly pathogenic missense variants from those with uncertain significance. Overall, these results indicated that haploinsufficiency of SRSF1 is responsible for a syndromic NDD with ID due to a partial loss of SRSF1-mediated splicing activity.

DNAJB11 Mutation in ADPKD Patients: Clinical Characteristics in a Monocentric Cohort.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a late-onset cilia-related disorder, characterized by progressive cystic enlargement of the kidneys. It is genetically heterogeneous with PKD1 and PKD2 pathogenic variants identified in approximately 78% and 15% of families, respectively. More recently, additional ADPKD genes, such as DNAJB11, have been identified and included in the diagnostic routine test for renal cystic diseases. However, despite recent progress in ADPKD molecular approach, approximately ~7% of ADPKD-affected families remain genetically unresolved. We collected a cohort of 4 families from our center, harboring heterozygous variants in the DNAJB11 gene along with clinical and imaging findings consistent with previously reported features in DNAJB11 mutated patients. Mutations were identified as likely pathogenetic (LP) in three families and as variants of uncertain significance (VUS) in the remaining one. One patient underwent to kidney biopsy and showed a prevalence of interstitial fibrosis that could be observed in ~60% of the sample. The presence in the four families from our cohort of ADPKD characteristics together with ADTKD features, such as hyperuricemia, diabetes, and chronic interstitial fibrosis, supports the definition of DNAJB11 phenotype as an overlap disease between these two entities, as originally suggested by the literature.

Diagnostic Pitfalls of Chylothorax After Dasatinib Treatment of Chronic Myeloid Leukemia.

BACKGROUND Chronic myeloid leukemia (CML) is a myeloproliferative malignancy generally treated with Dasatinib, a tyrosin-kinase inhibitor. Pleural effusions are a known adverse effect, but only 0.8% of patients develop pleural effusions after 6 years of use. Recent case reports have implicated Dasatinib as a rare cause of chylothorax. CASE REPORT We describe a woman in her 30's with a history of chronic myeloid leukemia, who had been taking Dasatinib for 10 years and presented to the Emergency Department after a chest X-ray revealed bilateral pleural effusions in the setting of worsening dyspnea on exertion for 6 months. She had previously received radiotherapy at age 11 prior to an allogenic bone marrow transplant nearly 30 years prior. Thoracentesis removed 900 cc of chylous fluid, and flow cytometry and cultures found no evidence of infection or malignancy. Dasatinib was discontinued, and she was treated with diuretics, steroids, and a low-fat diet. The effusions reaccumulated twice in the following month and required 2 additional thoracenteses and courses of steroids. Months later, the bilateral chylous effusions recurred, and MR lymphangiogram demonstrated 2 thoracic duct tears. CONCLUSIONS While previous reports have indicated that Dasatinib can rarely cause chylous pleural effusions, it is unlikely after 5 years of use, and other etiologies must be considered by clinicians. Initial misattribution to Dasatinib alone can delay further necessary investigations, including lymphangiography. In our patient, it is more likely that other factors contributed to her chylothorax, including her previous radiotherapy 30 years prior, given her recurrence of chylous effusions following cessation of the medication.

Surgical treatment of a chronic thoracoabdominal dissection with false lumen thrombosis and true lumen compression determining multivisceral ischemia.

INTRODUCTION: The treatment of a chronic type B aortic dissection can be challenging and need a precise and multidisciplinary planning. MATERIALS AND RESULTS: A 62-year-old man presented to our hospital with acute aortic thrombosis on chronic thoracoabdominal dissection with bowel and kidney ischemia. He was submitted to urgent open surgical treatment with replacement of thoracoabdominal aorta and reimplantation of celiac trunk, superior mesenteric artery and right renal artery. During the intervention the visceral perfusion was provided with a modified Gott shunt; while the lower limb perfusion was provided by an existing right axillo-femoral and femoro-femoral bypass. The patient had a favorable course and did not report any complications. CONCLUSION: The ideal management strategy of complex post-dissection conditions has to be tailored on the single patient's features to provide the maximal efficacy and safety. If the endovascular treatment is not viable, open surgery represents a valid option.

A New Mini-Invasive Approach for a Catastrophic Disease: Staged Endovascular and Endoscopic Treatment of Aorto-Esophageal Fistulas.

Aorto-esophageal fistula (AEF) is an uncommon but usually fatal disorder. Surgery with resection of an aneurysm and esophagus, in situ reconstruction of the descending aorta and omental flap installation offers the gold standard for the reduction of infections, but it is burdened by high intraoperative and perioperative mortality rates. We report our experience with a combined minimally invasive approach for the multi-stage treatment of three cases of aorto-esophageal fistula caused by thoracic aneurysm rupture. In all of the patients, the aneurysm was treated with thoracic endovascular aortic repair and the esophageal lesion was treated with esophageal endoprosthesis placement. According to our experience, the combined strategy of thoracic endovascular aortic repair (TEVAR) and esophageal less invasive endoscopic treatments represents an alternative solution in frail patients with high surgical risk.

De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations.

PURPOSE: ZMYND8 encodes a multidomain protein that serves as a central interactive hub for coordinating critical roles in transcription regulation, chromatin remodeling, regulation of super-enhancers, DNA damage response and tumor suppression. We delineate a novel neurocognitive disorder caused by variants in the ZMYND8 gene. METHODS: An international collaboration, exome sequencing, molecular modeling, yeast two-hybrid assays, analysis of available transcriptomic data and a knockdown Drosophila model were used to characterize the ZMYND8 variants. RESULTS: ZMYND8 variants were identified in 11 unrelated individuals; 10 occurred de novo and one suspected de novo; 2 were truncating, 9 were missense, of which one was recurrent. The disorder is characterized by intellectual disability with variable cardiovascular, ophthalmologic and minor skeletal anomalies. Missense variants in the PWWP domain of ZMYND8 abolish the interaction with Drebrin and missense variants in the MYND domain disrupt the interaction with GATAD2A. ZMYND8 is broadly expressed across cell types in all brain regions and shows highest expression in the early stages of brain development. Neuronal knockdown of the DrosophilaZMYND8 ortholog results in decreased habituation learning, consistent with a role in cognitive function. CONCLUSION: We present genomic and functional evidence for disruption of ZMYND8 as a novel etiology of syndromic intellectual disability.

Safety considerations with the current treatments for peripheral T-cell lymphoma.

INTRODUCTION: Peripheral T-Cell Lymphomas (PTCL) constitute a heterogeneous group of aggressive T - and natural killer (NK)-cell disorders and are associated with a poor prognosis. Frontline treatments often consist of anthracycline-based combination chemotherapy with the exception of NK-T cell lymphomas, where such combinations are ineffective due to the presence of P-glycoprotein which leads to multidrug resistance. Infectious and immune mediated side effects might be more pronounced in or unique to T-cell lymphomas due to the selection of agents which target multiple T-cell subtypes and also an immunocompromised state induced by the lymphomas themselves. AREAS COVERED: This review provides a comprehensive overview of safety considerations of treatment regimens used for peripheral T-cell lymphomas. We cover regimens used in both frontline and relapsed settings including combination chemotherapy, single agent chemotherapies and immunotherapies. EXPERT OPINION: Treatment of T-cell lymphomas often requires sequencing of several therapies due to lower efficacy of available treatment regimens in curing the disease compared to that seen in B-cell non-Hodgkin lymphomas. In addition, certain complications are more common in T-cell lymphomas due to their unique immunobiology. An understanding of these salient aspects is important for all providers who treat patients with this challenging disease group.

Expanding Phenotype of Poirier-Bienvenu Syndrome: New Evidence from an Italian Multicentrical Cohort of Patients.

BACKGROUND: Poirier-Bienvenu Neurodevelopmental Syndrome (POBINDS) is a rare disease linked to mutations of the CSNK2B gene, which encodes for a subunit of caseinkinase CK2 involved in neuronal growth and synaptic transmission. Its main features include early-onset epilepsy and intellectual disability. Despite the lack of cases described, it appears that POBINDS could manifest with a wide range of phenotypes, possibly related to the different mutations of CSNK2B. METHODS: Our multicentric, retrospective study recruited nine patients with POBINDS, detected using next-generation sequencing panels and whole-exome sequencing. Clinical, laboratory, and neuroimaging data were reported for each patient in order to assess the severity of phenotype, and eventually, a correlation with the type of CSNK2B mutation. RESULTS: We reported nine unrelated patients with heterozygous de novo mutations of the CSNK2B gene. All cases presented epilepsy, and eight patients were associated with a different degree of intellectual disability. Other features detected included endocrinological and vascular abnormalities and dysmorphisms. Genetic analysis revealed six new variants of CSNK2B that have not been reported previously. CONCLUSION: Although it was not possible to assess a genotype-phenotype correlation in our patients, our research further expands the phenotype spectrum of POBINDS patients, identifying new mutations occurring in the CSNK2B gene.

Phenogenomic heterogeneity of post-transplant plasmablastic lymphomas.

Plasmablastic lymphoma (PBL) is a rare and clinically aggressive neoplasm that typically occurs in immunocompromised individuals, including those with HIV infection and solid organ allograft recipients. Most prior studies have focused on delineating the clinicopathologic features and genetic attributes of HIV-related PBLs, where MYC deregulation and EBV infection, and more recently, mutations in JAK/STAT, MAP kinase, and NOTCH pathway genes have been implicated in disease pathogenesis. The phenotypic spectrum of post-transplant (PT)-PBLs is not well characterized and data on underlying genetic alterations are limited. Hence, we performed comprehensive histopathologic and immunophenotypic evaluation and targeted sequencing of 18 samples from 11 patients (8 males, 3 females, age range 12-76 years) with PT-PBL; 8 de novo and 3 preceded by other types of PTLDs. PT-PBLs displayed morphologic and immunophenotypic heterogeneity and some features overlapped those of plasmablastic myeloma. Six (55%) cases were EBV+ and 5 (45%) showed MYC rearrangement by fluorescence in situ hybridization. Recurrent mutations in epigenetic regulators (KMT2/MLL family, TET2) and DNA damage repair and response (TP53, mismatch repair genes, FANCA, ATRX), MAP kinase (KRAS, NRAS, HRAS, BRAF), JAK/STAT (STAT3, STAT6, SOCS1), NOTCH (NOTCH1, NOTCH3, SPEN), and immune surveillance (FAS, CD58) pathway genes were observed, with EBV+ and EBV- cases exhibiting similarities and differences in their mutational profiles. Clinical outcomes also varied, with survival ranging from 0-15.9 years postdiagnosis. Besides uncovering the biological heterogeneity of PT-PBL, our study highlights similarities and distinctions between PT-PBLs and PBLs occurring in other settings and reveals potentially targetable oncogenic pathways in disease subsets.

Targeting the T-Cell Lymphoma Epigenome Induces Cell Death, Cancer Testes Antigens, Immune-Modulatory Signaling Pathways.

The peripheral T-cell lymphomas (PTCL) could be considered the prototypical epigenetic disease. As a disease, they are uniquely sensitive to histone deacetylase (HDAC) and DNA methyltransferase (DNMT) inhibitors, both alone and in combination, are characterized by a host of mutations in epigenetic genes, and can develop spontaneously in genetically engineered murine models predicated on established recurring mutations in (RHOAG17V) and TET2, an epigenetic gene governing DNA methylation. Given the clinical benefit of HDAC inhibitors (HDACi) and hypomethlyation agents alone and in combination in PTCL, we sought to explore a mechanistic basis for these agents in PTCL. Herein, we reveal profound class synergy between HDAC and DNMT inhibitors in PTCL, and that the combination induces degrees of gene expression that are substantially different and more extensive than that observed for the single agents. A prominent signature of the combination relates to the transcriptional induction of cancer testis antigens and genes involved in the immune response. Interestingly, TBX21 and STAT4, master regulators of TH1 differentiation, were among the genes upregulated by the combination, suggesting the induction of a TH1-like phenotype. Moreover, suppression of genes involved in cholesterol metabolism and the matrisome were also identified. We believe that these data provide a strong rationale for clinical studies, and future combinations leveraging an immunoepigenetic platform.

How we treat advanced stage cutaneous T-cell lymphoma - mycosis fungoides and Sézary syndrome.

T-cell lymphomas (TCLs) constitute a rare subset of non-Hodgkin lymphomas, with mycosis fungoides/Sézary syndrome (MF/SS) being the most common subtype of cutaneous TCLs (CTCLs). Considered an incurable but treatable disease, MF/SS management presents several challenges including diagnostic delays, debilitating effect on patients' quality of life, need for several lines of therapies, multidisciplinary care and cumulative drug toxicities limiting duration of use. The present review intends to provide an overview of the recent advances in our understanding of the biology of CTCL and how these are being leveraged to provide additional treatment options for management of advanced and recurrent disease. In addition, the discussion of the different modalities of treatment is summarised to further outline the importance of multidisciplinary care and early referral to CTCL centres.