Proteus syndrome review: molecular,clinical, and pathologic features

Proteus syndrome is caused by an activating AKT1 mutation (c.49G>A, p.Glu17Lys). Many variable features are possible in this mosaic disorder, including: (i) disproportionate, asymmetric, and distorting overgrowth; (ii) bone abnormalities different from those observed in other disorders; (iii) a characteristic cerebriform connective tissue nevus made up of highly collagenized connective tissue; (iv) epidermal nevi in early life, consisting of acanthosis and hyperkeratosis; (v) vascular malformations of the capillary, venous, or lymphatic types; (vi) dysregulated adipose tissue including lipomas, lipohypoplasia, fatty overgrowth, and localized fat deposits; (vii) other unusual features, including bullous lung alterations; specific neoplasms; a facial phenotype associated with intellectual disability and/or seizures, and/or brain malformations; and (viii) deep vein thrombosis, resulting in premature death. Concluding remarks address diagnostic criteria, natural history, management, psychosocial issues, and differential diagnosis.     

Polymicrogyria with dysmorphic basal ganglia? Think tubulin!

Dominant mutations in TUBB2B have been reported in patients with polymicrogyria. We further explore the phenotype associated with mutations in TUBB2B. Twenty patients with polymicrogyria (five unilateral) were tested for mutations in TUBB2B by Sanger sequencing. We identified two novel de novo mutations, c.743C>T (p.Ala248Val) and c.1139G>T (p.Arg380Leu) in exon 4 of TUBB2B in three unrelated families. Brain magnetic resonance images showed polymicrogyria involving predominantly the perisylvian regions. In addition, there was a dysmorphic appearance of the basal ganglia, thin corpus callosum, enlargement of the ventricles, thinning of the white matter and hypoplasia of pons and cerebellar vermis. This combination of associated features was absent in all 17 patients with polymicrogyria in whom no mutation was identified. This report underlines that the association of polymicrogyria with thin or absent corpus callosum, dysmorphic basal ganglia, brainstem and vermis hypoplasia is highly likely to result from mutations in TUBB2B and provides further insight in how mutations in TUBB2B affect protein function.     

The defects in development and apoptosis of cardiomyocytes in mice lacking the transcriptional factor Pax-8

Backgroud

Cardiac-specific deletion of ALK3 is lethal in mid-gestation with ventricular septum malformations (VSM). This study was designed to define the Pax-8's role in heart development and cardiomyocyte apoptosis.

Methods

Pathologic changes in the hearts of Pax-8 or ALK3 knockout and wild type control mice were determined by light and electron microscopy. Analysis of cardiomyocyte apoptosis was performed by TUNEL. The effect of Pax-8 gene deficiency on caspase-3 activity was examined after transfecting Pax-8 siRNA into cultured myoblast cell line.

Results

Mice with ALK3 or Pax-8 gene knockout but not wild type control animals showed the development of VSM. Increased cardiomyocyte apoptosis was found in homozygotes. Echocardiography showed that Pax-8 homozygote mice developed malfunction of the heart. Furthermore, the caspase-3 activity was significantly higher in the cells treated with Pax-8 siRNA as compared to those treated with negative control siRNA in H9C2 (2-1) cell line.

Conclusions

The Pax-8 gene may play a crucial role in heart development and regulating cardiocyte apoptosis. Knockout of Pax-8 may exert a similar effect on myocardial morphology and apoptosis as those seen in ALK3 knockouts. Furthermore, the ventricular septum malformations could be partially attributed to accelerated cardiomyocyte apoptosis.     

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.     

显微外科手术联合不同方法治疗高级别颅内动静脉畸形

目的探讨对高级别颅内动静脉畸形（AVM）患者的治疗方法和疗效。方法回顾性分析23例高级别AVM患者开颅手术治疗的临床资料。男15例,女8例;平均（18±6）岁。Spetzler-Martin分级：Ⅳ级13例,Ⅴ级10例。畸形团的长径为3.5～15.0 cm,平均（7.5±2.0）cm。所有病例均接受了显微外科手术治疗。其中2例入院前1年和8年在外院接受栓塞治疗,3例近期接受术前栓塞,对18例直接实施显微外科手术。对切除后部分残留畸形团的5例行伽玛刀治疗。以格拉斯哥预后评分（GOS）评价疗效。结果①术前近期栓塞＋手术切除的3例术后恢复良好,术后GOS4分的1例,5分2例;远期栓塞＋手术2例和直接手术18例,在切除术后,1例昏迷及四肢瘫痪,1例死亡。GOS 5分的12例,4分5例,3分1例,2分1例,1分1例。②对17例患者术后行DSA复查,1例行MRA复查。显示11例获得全切,6例近全切除,1例部分切除。病死率为4%（1/23）,重残率为4.5%（1/22）。③随访1～95个月,GOS 5分14例,4分6例,3分2例。结论对高级别颅内动静脉畸形行手术切除是主要的治疗方法,并且疗效肯定,而适当的术前栓塞是手术成功的重要辅助手段。     

Onyx胶或联合其他栓塞材料治疗颅内动静脉畸形

目的探讨Onyx栓塞颅内动静脉畸形（AVM）的不同治疗策略、疗效及并发症。方法回顾性分析2009年1月—2011年12月广东省人民医院神经外科应用Onyx栓塞183例AVM患者的临床资料。其中Speztler-Martin（S-M）分级Ⅰ级28例,Ⅱ级53例,Ⅲ级54例,Ⅳ级31例,Ⅴ级17例。单纯Onyx胶栓塞113例,球囊辅助栓塞2例,联合弹簧圈栓塞5例,联合Glub-ran胶栓塞63例。分析患者的疗效及并发症等。结果①S-MⅠ～Ⅱ级完全栓塞治愈率为67.9%（55/81）,Ⅲ级为14.8%（8/54）,Ⅳ级为6.5%（2/31）,Ⅴ级为0,总体完全栓塞治愈率为35.5%（65/183）。②并发症发生情况：术中微导管断管2例,术中出血2例（其中1例为术中断管者）,术后出血2例（死亡1例）,新发神经功能障碍或原症状加重7例,总体并发症发生率为6.6%。③对143例进行了1～18个月的随访,其中再次出血3例（2.1%,S-MⅠ～Ⅲ级各1例）。4例次全栓塞的病例完全自愈,无一例复发或再生。7例有新发神经功能障碍或原症状加重者中,6例于术后3～6个月完全恢复或症状明显改善,1例改善不明显。结论个体化应用Onyx栓塞颅内AVM,可降低血管内治疗相关的并发症,提高完全栓塞治愈率。     

脉冲染料激光治疗皮肤微静脉畸形疗效分析

目的：观察595nm脉冲染料激光治疗皮肤微静脉畸形的疗效和不良反应,分析疗效相关因素,初步探讨皮肤镜技术在皮肤微静脉畸形治疗和随访中的作用。方法：应用595rim脉冲染料激光治疗皮肤微静脉畸形患者226例,观察治疗效果、不良反应,比较疗效与患者性别、年龄及病变类型等因素间的相关性,运用皮肤镜技术对疗效及不良反应进行评价分析及随访。结果：脉冲染料激光治疗皮肤微静脉畸形的总体有效率为51．8％,发生副反应7例（3．09％）,其疗效与患者年龄、病灶类型等因素相关（P〈0．05）,与性别无明显相关性;皮肤镜技术可明确区分病灶残留与色素沉着,指导后续治疗。结论：595nm脉冲染料激光治疗皮肤微静脉畸形安全性高,疗效良好,副反应低,皮肤镜技术可用于皮肤微静脉畸形激光治疗疗效的客观评价及随访。     

腹腔镜技术在肠道血管畸形急性出血中的应用体会

目的:探讨腹腔镜技术诊治肠道血管畸形急性出血的临床价值。方法:回顾分析为13例保守治疗无效的小肠血管畸形急性出血患者行腹腔镜辅助手术的临床资料。结果:13例患者术前选择性行肠系膜数字减影血管造影(digital sub-traction angiography,DSA)。造影定位下行腹腔镜辅助小肠部分切除吻合术10例,回盲部切除末端回肠造口术1例;术中造影无法明确,内镜协助探查明确出血部位,腹腔镜辅助下行小肠切除吻合1例;导管造影及内镜协助探查均无法明确出血部位,行小肠双口造瘘观察1例。12例痊愈出院,1例死亡。结论:DSA及术中造影是诊断小肠出血并准确定位的有效方法,为外科手术提供了正确的定位。DSA及术中造影准确定位后行腹腔镜辅助手术切除病变肠段安全、有效。     

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.     

儿童脑动静脉畸形出血早期诊断和显微外科治疗

目的 探讨儿童脑动静脉畸形(AVM)破裂出血急性期的诊断方法和显微外科治疗的时机与手术技术.方法 对2002年6月至2011年6月间收治的32例儿童AVM出血患者进行回顾性分析.除CTA和MRA检查外,本组行早期全脑DSA检查24例,另外入院时因出血量大发生脑疝者8例,立即行血肿清除术,其中3例病情稳定后再行DSA检查.明确诊断后根据Spetzler-Martin分级选择治疗方案.24例Spetzler-Martin分级Ⅰ～Ⅲ级AVM患者行急性期(3d内)显微外科治疗,其中栓塞后再手术2例.结果 8例急诊行显微手术血肿清除术者,术后死亡2例,镜下AVM完全切除2例,部分切除1例.病情稳定后行DSA检查证实AVM者3例,继而再行显微手术切除.24例急性期显微手术AVM切除者,术中显微镜下AVM血管团和颅内血肿完全清除.术后获DSA或CTA复查18例,均未见病灶残留.随访3-12个月.根据GOS评定:24例Sptetzler-Martin分级Ⅰ～Ⅲ级AVM患者恢复良好者21例,轻残2例,重残1例,无死亡病例.结论 DSA是儿童AVM出血早期诊断主要的检查手段.急性期显微手术可降低出血病死率和改善预后.