Novel FREM1 mutations expand the phenotypic spectrum associated with manitoba‐oculo‐tricho‐anal (MOTA) syndrome and bifid nose renal agenesis anorectal malformations (BNAR) syndrome

Loss of function mutations in FREM1 have been demonstrated in Manitoba‐oculo‐tricho‐anal (MOTA) syndrome and Bifid Nose Renal Agenesis and Anorectal malformations (BNAR) syndrome, but the wider phenotypic spectrum that is associated with FREM1 mutations remains to be defined. We screened three probands with phenotypic features of MOTA syndrome. In one severely affected infant who was diagnosed with MOTA syndrome because of bilateral eyelid colobomas, a bifid nasal tip, hydrometrocolpos and vaginal atresia, we found two nonsense mutations that likely result in complete loss of FREM1 function. This infant also had renal dysplasia, a finding more consistent with BNAR syndrome. Another male who was homozygous for a novel stop mutation had an extensive eyelid colobomas, corneopalpebral synechiae, and unilateral renal agenesis. A third male child diagnosed with MOTA syndrome because of corneopalpebral synechiae and eyelid colobomas had a homozygous splice site mutation in FREM1. These cases illustrate that disruption of the FREM1 gene can produce a spectrum of clinical manifestations encompassing the previously described MOTA and BNAR syndromes, and that features of both syndromes may be seen in the same individual. The phenotype of FREM1‐related disorders is thus more pleiotropic than for MOTA and BNAR syndrome alone and more closely resembles the widespread clinical involvement seen with Fraser syndrome. Moreover, our first case demonstrates that vaginal atresia may be a feature of FREM1‐related disorders. © 2013 Wiley Periodicals, Inc.     

经导管介入治疗肺动静脉瘘7例

肺动静脉瘘(arteriovenous fistula,AVF)指肺动脉与肺静脉间存在异常交通,造成右向左分流、动脉血氧饱和度下降,临床罕见,发病率为0.02‰～0.03‰,患者如得不到及时、有效的救治,死亡率达11%[1]。我院于2001年6月—2011年8月对7例肺AVF患者实施介入治疗,现报道如下。     

Hemorrhage risk after partial endovascular NBCA and ONYX embolization for brain arteriovenous malformation

Abstract

Objective: To estimate for hemorrhage risk of partially endovascularly embolized brain arteriovenous malformation (BAVM).

Methods: We retrospectively reviewed 147 consecutive patients with BAVM-treated mainly with endovascular N-butyl cyanoacrylate (NBCA) and ONYX embolization. In Kaplan–Meier survival analysis, the index date was the dated of initial endovascular embolization; cases were censored at time of subsequent intracranial hemorrhage (ICH), or loss to follow-up, and multivariate proportional-hazards regression models included age of presentation (?30 years old), clinical presentations, and other potential confounders.

Results: We reviewed 147 patients with BAVM (58·8% male; mean age±SD at treatment: 27·5±11·1 years) treated with endovascular embolization. One hundred and forty-four NBCA and 76 ONYX embolizations were performed. Complete obliteration of BAVMs was achieved in 29 patients (19·7%). Thirty-two (21·8%) patients were treated with additional Gamma-knife radiosurgery. During 499·5 years of follow-up, 15 partially treated patients suffered a further hemorrhage, which caused four deaths. The crude annual risk of hemorrhage was 3·0% and the annual death rate was 0·8%. Among partially treated patients with hemorrhage at initial presentation, the risk of hemorrhage was 3·8%, while the risk of hemorrhage for patients without hemorrhage at initial presentation was 2·5%. The annual rate of subsequent hemorrhage was 2·6% for non-ICH and 4·2% for ICH in the partial NBCA embolization group compared with 2·4% for non-ICH and 2·4% for ICH in the partial ONYX embolization group.

Conclusions: The effect of partial AVM embolization with liquid embolic agents may still be unclear as for risk reduction of annual hemorrhage rate of cerebral AVM.     

The status of diabetic embryopathy

Diabetic embryopathy is a theoretical enigma and a clinical challenge. Both type 1 and type 2 diabetic pregnancy carry a significant risk for fetal maldevelopment, and the precise reasons for the diabetes-induced teratogenicity are not clearly identified. The experimental work in this field has revealed a partial, however complex, answer to the teratological question, and we will review some of the latest suggestions.     

Craniofacial osseointegration

In year 2007, 30 years have elapsed since the first patient was supplied with a craniofacial osseointegrated implant. The reason for implanting in this patient was a severe conductive hearing loss, which necessitated the use of a bone conduction hearing aid. By utilizing the possibility to transmit sound to the cochlea via direct bone conduction, a new era in audiology was established. Further applications of osseointegration in the craniofacial field is related to the rehabilitation of patients with defects from cancer therapy, malformations, traumatic amputations and burns. Specific fields of osseointegration in this respect are due to possible side effects from radiotherapy and chemotherapy that will affect osseointegration negatively. Other aspects are related to osseointegration in children. This review will focus on the knowledge gained during the first 30 years of craniofacial osseointegration.     

EML4::ALK fusions in complex lymphatic malformations

Gorham–Stout disease (GSD) and generalized lymphatic anomaly (GLA) are subtypes of complex lymphatic malformations (CLMs) with osseous involvement that cause significant complications, including pain and pathologic fractures. As with other vascular anomalies, somatic mosaic mutations in oncogenes are often present, and the mTOR inhibitor sirolimus alleviates symptoms in some, but not all, patients. We describe two patients, one with GSD and one with GLA, found to have EML4::ALK fusions. This report of a targetable, oncogenic fusion in vascular malformations expands our understanding of the genetic basis for CLMs and suggests additional targeted therapies could be effective.     

Embolization using hydrogel-coated coils for pulmonary arteriovenous malformations

PurposeTo prospectively evaluate the efficacy and safety of embolization using hydrogel-coated coils for the treatment of pulmonary arteriovenous malformations (PAVMs).Materials and methodsThe outcomes of 21 PAVMs in 19 patients (3 men and 16 women; mean age, 58.8 ± 15.2 [SD] years; age range 14–78 years) treated by venous sac embolization (VSE) with additional feeding artery embolization were prospectively evaluated. For VSE, using one or more 0.018-inch hydrogel-coated coils was mandatory. Recanalization and/or reperfusion were evaluated by pulmonary arteriography 1 year after embolization.ResultsThe mean feeding artery and venous sac sizes were 4.0 mm and 8.5 mm, respectively. Embolization was successfully completed in 20/21 PAVMs, yielding a technical success rate of 95%. The feeding artery was also embolized in 17/20 successful PAVMs (85%). A technical failure occurred in one PAVM, where embolization was abandoned because of migration of one bare coil to the left ventricle. The mean numbers of hydrogel-coated coils and bare platinum detachable coils used for VSE were 3.3 ± 2.1 (SD) (range, 1–8) and 4.4 ± 3.9 (SD) (range, 1–17), respectively. The mean percentages of hydrogel-coated coils in number, length, and estimated volume were 42.9%, 33.3%, and 72.7% respectively. One patient with one PAVM was lost to follow-up after 3 months. Neither recanalization nor reperfusion was noted in the remaining 19 PAVMs (success rate, 19/19 [100%]). One grade 4 (coil migration) adverse event occurred, and it was treated without any sequelae.ConclusionVSE using hydrogel-coated coils with additional feeding artery embolization is a safe and effective treatment for PAVM.     

Complete versus partial excision of infected arteriovenous grafts: Does remnant graft material impact outcomes?

ObjectiveInfected arteriovenous grafts necessitate intervention to obtain source control. However, excising the graft material can be challenging and can lead to complications. Leaving a cuff of graft at the sites of anastomosis allows for the avoidance of potential risks. However, it is unclear whether doing so places patients at risk of recurrent graft infection. The purpose of the present study was to investigate the effect of complete vs partial excision of infected arteriovenous prosthetic dialysis access grafts.MethodsThe data from all patients who had undergone surgical intervention for infected arteriovenous grafts at a single institution were retrospectively reviewed. The patients were grouped according to intervention type: complete excision and partial excision of arteriovenous prosthetic grafts. Partial excisions were further substratified based on whether flow had been restored through the arteriovenous access. The primary outcome was freedom from subsequent intervention for infection, defined as the number of days from excision to subsequent reoperation for reinfection. Freedom from infection was analyzed using the Kaplan-Meier method.ResultsA total of 117 patients had undergone surgical intervention for 122 infected arteriovenous grafts from 2003 to 2016. Of these 117 patients, 79 (64.8%) had undergone partial excision of infected arteriovenous grafts, and 43 (35.2%) had undergone complete excision with vascular repair. Within the partial excision cohort, 71 infected arteriovenous grafts (58.2%) were not flow restored and 8 (6.6%) were flow restored using either prosthetic or autogenous interpositions. The median follow-up time was 2.4 years (interquartile range, 0.6-4.5 years). The most common causative organisms included methicillin-resistant Staphylococcus aureus (n = 34; 27.9%), methicillin-sensitive S. aureus (n = 17; 13.9%), and S. epidermidis (n = 15; 12.3%). The recurrent infection rate in the partial excision group was 16.5% (n = 13) compared with 2.3% (n = 1) in the complete excision group. In the flow-restored subcohorts, those with restoration using prosthetic interposition grafts had the greatest reinfection rate at 57.1% (n = 4), and those with restoration using autogenous conduits did not experience reinfection (P = .033).ConclusionsIncomplete excision of infected arteriovenous prosthetic grafts was associated with a higher rate of reinfection compared with complete graft excision. Complete excision presents technical challenges but could provide superior source control in managing infected dialysis access. Complete excision with vascular reconstruction should be performed when possible to avoid leaving remnant prosthetic material.