Disruptive CHD8 mutations define a subtype of autism early in development.

Autism spectrum disorder (ASD) is a heterogeneous disease in which efforts to define subtypes behaviorally have met with limited success. Hypothesizing that genetically based subtype identification may prove more productive, we resequenced the ASD-associated gene CHD8 in 3,730 children with developmental delay or ASD. We identified a total of 15 independent mutations; no truncating events were identified in 8,792 controls, including 2,289 unaffected siblings. In addition to a high likelihood of an ASD diagnosis among patients bearing CHD8 mutations, characteristics enriched in this group included macrocephaly, distinct faces, and gastrointestinal complaints. chd8 disruption in zebrafish recapitulates features of the human phenotype, including increased head size as a result of expansion of the forebrain/midbrain and impairment of gastrointestinal motility due to a reduction in postmitotic enteric neurons. Our findings indicate that CHD8 disruptions define a distinct ASD subtype and reveal unexpected comorbidities between brain development and enteric innervation.

Outcome Analysis From a Multicenter Registry on Unibody Stent-Graft System for the Treatment of Spontaneous Infrarenal Acute Aortic Syndrome (MURUSSIAS Registry).

PURPOSE: This study reports the outcomes from a Multicenter Registry on unibody stent-graft system for the treatment of spontaneous infrarenal acute aortic syndrome (MURUSSIAS registry). MATERIALS AND METHODS: The retrospective MURUSSIAS registry included spontaneous infrarenal acute aortic dissection (IAAS) managed with the unibody stent-graft system (AFX endovascular AAA system; Endologix Inc., Irvine, California) outside the current instruction for use. IAAS considered aortic dissection (AD), intramural hematoma (IMH), and penetrating aortic ulcer (PAU). Indications to IAAS treatment were symptoms, associated dilated abdominal aorta (>3 cm), rapidly-growing (>0.5 cm/6 months) aorta, IAAS disease progression. Measured results were technical success, early (within 30 days) and midterm outcomes (after 30 days), including mortality, complications, symptoms recurrence, type I/III endoleak occurrence, stent-graft patency, survival, and freedom from reintervention. The mean follow-up was 22.12 ± 17 months. RESULTS: The MURUSSIAS registry included 83 patients from 7 participating centers. IAAS indication to treatment were symptoms in 42 (51%). In 14 (17%) patients, the infrarenal aortic length was <80 mm, and in 28 (34%), the aortic bifurcation diameter was <16 mm. Technical success was 100%. Mortality occurred early in 1 (1%) and at the midterm in 3 (4%) patients. Complications occurred early in 10 (12%) patients (1 severe, 3 moderates, and 6 mild) and at midterm in 2 (2%) (2 moderate). No symptoms' recurrence or type I/III endoleaks were registered. The 36-month estimated survival and freedom from reinterventions were 89% and 92%, respectively. CONCLUSIONS: The MURUSSIAS registry is the largest collection of spontaneous IAAS managed endovascularly using the AFX endovascular AAA system. The IAAS peculiar anatomic features were fitted with the used technique with excellent results. This treatment strategy might be considered in IAAS unless specifically-designed endovascular solutions will be available also in the emergent setting. Further studies are required to assess the longer-term performances and the stability of the reported technique. CLINICAL IMPACT: The lack of specifically designed devices for infrarenal acute aortic syndrome (IAAS) disease remains an issue principally for its specific anatomic features. The MURUSSIAS registry retrospectively examined the outcomes of spontaneous IAAS treated using the unibody stent-graft system in a spontaneous national study; and reports the largest available data on this topic. The use of the unibody stent-graft system showed to fit the anatomic peculiarities of IAAS with excellent outcomes. This IAAS treatment strategy should be considered unless specifically designed endovascular solutions will be available.

Stent-Graft Relining Using the Altura Endograft for Type Ia and IIIb Endoleaks after Kissing Iliac Arteries Stent.

A 79 years old man, affected by serious comorbidities, occurred to the Emergency Room of our Hospital complaining abdominal pain. He was previously submitted to kissing iliac arteries stent for iliac aneurysms. An urgent CT scan showed a type Ia and a type IIIb endoleaks with left common iliac artery enlargement, occlusion of both hypogastric arteries and inferior mesenteric artery, and a severe stenosis of the right iliac external artery. We opted for a relining with a two-piece D-shaped Altura endograft for the aorta, with bilateral iliac components, landing at the level of the external iliac arteries. Postoperative course was uneventful with no endoleak or endograft migration on CT scan control at 6 months.

Endovascular Treatment of Juxtarenal Abdominal Aortic Aneurysms Recurring to the "Vent Technique".

BACKGROUND: Juxtarenal abdominal aortic aneurysms represent 15-20% of all abdominal aortic aneurysms (AAAs). The gold standard of treatment is represented by open surgical repair (OSR). Patients judged unfit for OSR could be submitted to fenestrated endovascular aortic repair (FEVAR) or the chimney technique. FEVAR requires 3-4 weeks for endograft production, a minimal length of 4 mm for proximal aortic neck and a large access vessels diameter, with high costs. The traditional chimney technique, feasible also in urgent cases, has a risk of type IA endoleak due to the space created between covered stents introduced into visceral arteries and the endograft. METHODS: In the present article, we report our experience about juxtarenal AAA (jAAA) treatment in 5 patients, recurring to uncovered bare metal stents associated with the ultralow profile Ovation endograft. RESULTS: No intraoperative complications or type IA endoleaks were recorded. Primary clinical success at 1 month was also 100%. During a mean follow-up period of 12.1 ± 3.6 months (range, 9-15 months), no complications related to aneurysm were recorded. CONCLUSIONS: The technique reported represents a valid endovascular option for jAAA treatment in patients at high risk for OSR. With respect to FEVAR, urgent patients should also be treated. With respect to traditional Ch-EVAR, the risk of type IA endoleak is reduced, with a lower rate of reoperation during follow-up. Preliminary clinical results are promising.

Successfully Kissing Stent of Innominate Artery and Left Common Carotid Artery Subsequent to Blunt Injury, in the Setting of a Bovine Aortic Arch.

Blunt injuries of the great vessels arising from the aortic arch are usually fatal. The innominate artery lesions represent the most common site of injury after the aortic isthmus distal to the left subclavian artery. Injuries are usually located at the origin of the vessel from the aortic arch, especially in patients with bovine aortic arch. Open traditional repair is a successful but invasive treatment, with long hospital stay and different possible complications. Although a bovine aortic arch presents an increased technical challenge, it is possible to achieve a complete and safe repair of the innominate artery injuries through a total endovascular treatment, with important reduction of risks and complications related to operation, compared to traditional open repair. We report the case of a 62-year-old man in our hospital with a posttraumatic pseudoaneurysm of the innominate artery in the setting of a bovine aortic arch, associated with a transection of the descending thoracic aorta. In the urgent setting, the patient was submitted to a kissing stent of innominate artery-left common carotid artery and deployment of thoracic endoprosthesis to exclude the aortic transection, with good final result.

Disruption of POGZ Is Associated with Intellectual Disability and Autism Spectrum Disorders.

Intellectual disability (ID) and autism spectrum disorders (ASD) are genetically heterogeneous, and a significant number of genes have been associated with both conditions. A few mutations in POGZ have been reported in recent exome studies; however, these studies do not provide detailed clinical information. We collected the clinical and molecular data of 25 individuals with disruptive mutations in POGZ by diagnostic whole-exome, whole-genome, or targeted sequencing of 5,223 individuals with neurodevelopmental disorders (ID primarily) or by targeted resequencing of this locus in 12,041 individuals with ASD and/or ID. The rarity of disruptive mutations among unaffected individuals (2/49,401) highlights the significance (p = 4.19 × 10(-13); odds ratio = 35.8) and penetrance (65.9%) of this genetic subtype with respect to ASD and ID. By studying the entire cohort, we defined common phenotypic features of POGZ individuals, including variable levels of developmental delay (DD) and more severe speech and language delay in comparison to the severity of motor delay and coordination issues. We also identified significant associations with vision problems, microcephaly, hyperactivity, a tendency to obesity, and feeding difficulties. Some features might be explained by the high expression of POGZ, particularly in the cerebellum and pituitary, early in fetal brain development. We conducted parallel studies in Drosophila by inducing conditional knockdown of the POGZ ortholog row, further confirming that dosage of POGZ, specifically in neurons, is essential for normal learning in a habituation paradigm. Combined, the data underscore the pathogenicity of loss-of-function mutations in POGZ and define a POGZ-related phenotype enriched in specific features.

The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant.

OBJECTIVE: Cut homeodomain transcription factor CUX2 plays an important role in dendrite branching, spine development, and synapse formation in layer II to III neurons of the cerebral cortex. We identify a recurrent de novo CUX2 p.Glu590Lys as a novel genetic cause for developmental and epileptic encephalopathy (DEE). METHODS: The de novo p.Glu590Lys variant was identified by whole-exome sequencing (n = 5) or targeted gene panel (n = 4). We performed electroclinical and imaging phenotyping on all patients. RESULTS: The cohort comprised 7 males and 2 females. Mean age at study was 13 years (0.5-21.0). Median age at seizure onset was 6 months (2 months to 9 years). Seizure types at onset were myoclonic, atypical absence with myoclonic components, and focal seizures. Epileptiform activity on electroencephalogram was seen in 8 cases: generalized polyspike-wave (6) or multifocal discharges (2). Seizures were drug resistant in 7 or controlled with valproate (2). Six patients had a DEE: myoclonic DEE (3), Lennox-Gastaut syndrome (2), and West syndrome (1). Two had a static encephalopathy and genetic generalized epilepsy, including absence epilepsy in 1. One infant had multifocal epilepsy. Eight had severe cognitive impairment, with autistic features in 6. The p.Glu590Lys variant affects a highly conserved glutamine residue in the CUT domain predicted to interfere with CUX2 binding to DNA targets during neuronal development. INTERPRETATION: Patients with CUX2 p.Glu590Lys display a distinctive phenotypic spectrum, which is predominantly generalized epilepsy, with infantile-onset myoclonic DEE at the severe end and generalized epilepsy with severe static developmental encephalopathy at the milder end of the spectrum. Ann Neurol 2018;83:926-934.

Preliminary Results of Aorfix™ Stent Graft to Treat Infrarenal Abdominal Aortic Aneurysms with Severe Proximal Aortic Neck Angulation.

BACKGROUND: We report a preliminary experience about endovascular aortic repair (EVAR) of infrarenal abdominal aortic aneurysm (iAAA) with severe proximal aortic neck angulation (NA) using the Aorfix™ stent graft. METHODS: Data of consecutive patients with iAAA with severe proximal NA submitted to endovascular repair between September 2012 and December 2014 in 2 Italian centers of Vascular and Endovascular Surgery were retrospectively reviewed, and outcomes were analyzed using the software JMP 5.1.2. RESULTS: A total of 26 patients were treated. Median proximal NA was 87.5° (range 68-108°), and 3 patients were treated outside the instruction for use of Aorfix because of a proximal NA > 90°. Eleven patients (42.3%) had severe iliac tortuosity. The primary success rate was 92.3%, as 2 patients required intraoperative correction of a type Ia endoleak. Within 30 days, a right limb occlusion was successfully resolved with endovascular recanalization. The median follow-up period was 14 months (range 1-48 months): 1 patient died for neoplasm and 1 patient presented a type II endoleak from lumbar arteries at 3 months, which is still under surveillance. No other complications were reported during the follow-up period. CONCLUSIONS: Preliminary results with the Aorfix stent graft seemed to be promising in the aim of reducing endoleak and migration rates in presence of iAAA with severe proximal aortic NA.

An Hybrid 2-Stage Technique to Treat a Post-Traumatic Internal Carotid-Jugular Fistula.

Penetrating wounds of the neck involving the carotid arteries can lead to 2 possible and important late sequelae: pseudoaneurysm formation and arteriovenous fistula (AVF), if an artery and the adjacent jugular vein are simultaneously lacerated. Traumatic AVF of the neck are rare complications and if untreated may cause congestive heart failure, cerebral ischemia, thromboembolism, or even rupture complications. Current treatment options for carotid-jugular AVF include operative repair, detachable balloon, coiling, or stenting. We present a hybrid 2-stage technique to treat an internal carotid-jugular vein fistula in a young woman, based first on carotid stenting to reduce the bleeding and reestablish an adequate cerebral perfusion, followed by stent removal and safe vessels surgical reconstruction through carotid-to-carotid bypass and vein repair.

The role of procalcitonin as a marker of diabetic foot ulcer infection.

Foot ulcers are frequent in diabetic patients and are responsible for 85% of amputations, especially in the presence of infection. The diagnosis of diabetic foot ulcer infection is essentially based on clinical evaluation, but laboratory parameters such as erythrocyte sedimentation rate (ESR), white blood count (WBC), C-reactive protein (CRP) and, more recently, procalcitonin (PCT) could aid the diagnosis, especially when clinical signs are misleading. Fifteen diabetic patients with infected foot ulcers were admitted to our department and were compared with an additional group of patients with non-infected diabetic foot ulcers (NIDFUs). Blood samples were collected from all patients in order to evaluate laboratory markers. In the current study, the diagnostic accuracy of PCT serum levels was evaluated in comparison with other inflammatory markers such as CRP, ESR and WBC as an indicator to make the distinction between infected diabetic foot ulcers (IDFUs) and NIDFUs. CRP, WBC, ESR and especially PCT measurements represent effective biomarkers in the diagnosis of foot infections in diabetic patients particularly when clinical signs are misleading.

Old and New Techniques as a Safe Hybrid Approach for Carotid Tandem Lesions.

BACKGROUND: Carotid revascularization is performed to prevent stroke. Carotid tandem lesions represent a challenge for treatment, and a hybrid approach may result effective. CASE REPORT: A high-risk 65-year-old woman presented with a "tandem lesion" of left common and internal carotid artery. She was deemed unfit for "simple" standard carotid endarterectomy (CEA). A "single-step" safe hybrid procedure was scheduled for the patient. A "Cormier" carotid vein graft bypass with a retrograde stenting was performed under local anesthesia. CONCLUSIONS: The "safe hybrid procedure" for tandem lesions of the common and internal carotid artery is effective and suitable in high-risk patients in a high-volume centers.

An Uncommon Case of Type III Endoleak Treated with a Custom-made Thoracic Stent Graft.

Endovascular aortic repair (EVAR) has been shown to be a valid and minimally invasive alternative to open abdominal aortic aneurysm repair. A major shortcoming for EVAR is the need to submit patients to regular follow-up to detect potential complications such as endoleak, limb occlusion, aneurysm expansion, aneurysm rupture, infection, structural failure, and migration. In this case report, we describe an uncommon case of late type III endoleak due to complete detachment of the stent-graft main body segment from its suprarenal uncovered fixation stent. It was treated with a custom-made Relay(®) NBS Plus (Bolton Medical, Barcelona, Spain) thoracic stent graft which also provided extra suprarenal fixation of the thoracic stent graft in the proximal neck. The postoperative period was uneventful and a computed tomography scan 1 year later revealed proper positioning of the stent graft and no signs of endoleak. The successful strategy chosen to correct this complication was at the same time original and infrequent, and also avoided potential complications related to open surgical repair and general anesthesia.

Recurrent duplications of 17q12 associated with variable phenotypes.

The ability to identify the clinical nature of the recurrent duplication of chromosome 17q12 has been limited by its rarity and the diverse range of phenotypes associated with this genomic change. In order to further define the clinical features of affected patients, detailed clinical information was collected in the largest series to date (30 patients and 2 of their siblings) through a multi-institutional collaborative effort. The majority of patients presented with developmental delays varying from mild to severe. Though dysmorphic features were commonly reported, patients do not have consistent and recognizable features. Cardiac, ophthalmologic, growth, behavioral, and other abnormalities were each present in a subset of patients. The newly associated features potentially resulting from 17q12 duplication include height and weight above the 95th percentile, cataracts, microphthalmia, coloboma, astigmatism, tracheomalacia, cutaneous mosaicism, pectus excavatum, scoliosis, hypermobility, hypospadias, diverticulum of Kommerell, pyloric stenosis, and pseudohypoparathryoidism. The majority of duplications were inherited with some carrier parents reporting learning disabilities or microcephaly. We identified additional, potentially contributory copy number changes in a subset of patients, including one patient each with 16p11.2 deletion and 15q13.3 deletion. Our data further define and expand the clinical spectrum associated with duplications of 17q12 and provide support for the role of genomic modifiers contributing to phenotypic variability.

Definition of minimal duplicated region encompassing the XIAP and STAG2 genes in the Xq25 microduplication syndrome.

Typical Xq25 duplications are large and associated with heterogeneous phenotypes. Recently, small duplications involving this genomic region and encompassing the GRIA3 and STAG2 genes have been reported. These Xq25 microduplications are associated with a recognizable syndrome including intellectual disability and distinctive facial appearance. We report on Xq25 microduplications in two unrelated families identified by array comparative genomic hybridization. In both families, the genomic imbalances segregated with the disease in male individuals, while the phenotypes of the heterozygous females appeared to be modulated by their X-inactivation pattern. These rearrangements of about 600 kb involved only three genes: THOC2, XIAP, and STAG2. Further characterization by FISH analyses showed tandem duplication in the Xq25 locus of these genes. These data refine the Xq25 candidate region, identifying a minimal duplicated region of about 270 kb encompassing the XIAP and STAG2 genes. We discuss the function of the genes in the rearrangements and their involvement in the pathogenesis of this disorder.

A Case of Late Type Ia Endoleak After Endovascular Aneurysm Sealing Using the Nellix System: Proximal Extension with Triple Chimney and Gutter Endoleak Embolization.

An 87-year-old man, who submitted to endovascular aneurysm sealing (EVAS) on 2017, presented a type Ia endoleak 2 years later, with enlargement of the aneurysmal sac. We planned an endovascular procedure of correction consisting of a proximal extension through two covered stent grafts deployed into the previous Nellix stent grafts, with associated triple chimney. However, 3 months later, he had a further 5 mm aneurysmal sac enlargement. He was submitted to angiography with coil embolization of gutters, obtaining a successfully result. At 1 and 3 months, he is free from endoleak, with a stable aneurysmal diameter.

A Case of Multilevel Aortic Disease Treated Using Cardiatis Multilayer Flow Modulator.

A recent systematic review and meta-analysis shows that synchronous and metachronous thoracic and abdominal aortic aneurysms are present in 19.2% of cases. The management remains controversial: elective simultaneous TEVAR and EVAR could increase morbidity due to increased aortic coverage during a single procedure, longer operative times, increased blood loss, and greater contrast exposure. Conversely, simultaneous thoracic endovascular aortic repair (TEVAR) and endovascular aneurysms repair (EVAR) prevent the need for two interventions, reduces future access site complications, and obviates interval aortic complications. We present a case of a multilevel aortic disease treated in three stages: EVAR, TEVAR, and exclusion of an increasing aortic visceral penetrating aortic ulcer through a multilayer flow modulator endograft with an optimal result.

The role of cord blood platelet gel in the management of a diabetic foot with tendon exposure.

Diabetic foot infection is frequent in diabetic patients and is due to neuropathy, trauma or peripheral arterial disease. The presence of an abscess requires urgent drainage and specific antibiotic therapy. Patients with critical limb ischemia need revascularization and, subsequently the intervention of a plastic surgeon is often required in cases of exposure of tendons and ligaments. During the COVID-19 pandemic, a patient was refered to our department with an abscess on the dorsum of the left foot. After urgent drainage with tendon exposure, he started specific antibiotic therapy and underwent tibial vessels angioplasty. After infection healing cord blood platelet gel was applied, accelerating the healing process, with injection of its liquid part into the exposed tendons, thus retaining the vital functions of the tendons.

Early and mid-term results of endovascular treatment of thoracic aorta diseases: a single-center experience.

We conducted an analysis to assess early and mid-term outcomes of patients after thoracic endovascular aortic repair (TEVAR) for type B thoracic aorta dissection, descending thoracic aneurysm, or traumatic aortic transection. From January 2016 through December 2018, twenty-seven patients (23 male, 4 female, mean age of 57 years) affected by type B dissection (n = 13 [48.2%]), thoracic aneurysm (n = 9 [33.3%]), and post-traumatic aortic isthmus rupture (n = 5 [18.5%]) were treated using TEVAR with and without left subclavian artery revascularization. All procedures were performed in a hybrid operating room using general (n = 12) or regional (n = 15) anesthesia. A combined brachial artery and bilateral femoral artery access was used in all patients. To achieve adequate proximal thoracic aorta landing zone length, coverage of the left subclavian artery with proximal endovascular plug occlusion was performed in 17 patients (62.9%); including 4 patients undergoing carotid-subclavian artery bypass before TEVAR stent-graft deployment. Primary procedural success rate was 96.3%; 1 patient had a Type Ib endoleak that was treated by distal stent graft extension. Four adverse outcomes occurred in the immediate postoperative period, including 2 cases of left upper arm acute ischemia (7.4%), ischemic stroke (3.7%), and asymptomatic iliac artery dissection (3.7%). During a mean follow-up of 18 months, no graft-related deaths or endoleak occurred. One patient developed symptomatic subclavian steal syndrome 1 month after operation and underwent a left carotid-subclavian artery bypass with symptom resolution. One patient died 6 months after TEVAR due to neoplasm. Our experience indicates TEVAR is a safe and less invasive alternative to open surgery for a spectrum of thoracic aorta diseases, especially for urgent conditions and in patients with high-risk surgical comorbidities.

Use of cord blood platelet gel to enhance healing of deep surgical site dehiscences after peripheral bypass.

Surgical site dehiscence after lower limb revascularization through bypass represents a serious postoperative complication, especially in diabetic and obese patients, with subsequent risk of early graft failure, infection, sepsis, hemorrhage, major amputation and sometimes death. To prevent bypass exposure and subsequent complications, physicians recur to reoperation, antibiotic therapy, advanced dressing and vacuum-assisted closure therapy. To improve the process of wound healing, cord blood platelet gel can be used to fill deep and large wounds. Growth factors released from platelets in the cord blood platelet gel stimulate the process of healing and allow patients to be followed up in Outpatient Surgery, thus reducing hospital stay and costs, while providing excellent results.

Percutaneous drug-eluting balloon angioplasty to treat dialysis access stenosis.

A common complication of arteriovenous fistula for hemodialysis is development of conduit stenosis, which compromises function and can result in access thrombosis. Possible treatment options include open repair and endovascular therapy, with the latter preferred due to lower morbidity and similar outcomes. Recurrence of conduit stenosis is common and, based on the pathophysiology of this lesion, the application of drug-coated balloon angioplasty is attractive. In this report, the application of drug-eluting balloon angioplasty for dialysis access stenosis in 18 consecutive patients is detailed and primary patency rates of 82% at 1 year and 68% at 2 years were calculated.