目的

      Treacher Collins综合征（Treacher Collins syndrome, TCS）是一种常染色体遗传疾病，可能与TCOF1（约占80%~90%）、POLR1D或POLR1C（约占9%）等基因突变有关，导致第一、二腮弓发育异常，约5万新生儿中有一名受累^[1-3]。TCS患者临床表现为不同程度的颅颌面骨骼发育不良，如颧骨、眶周及上、下颌骨等发育畸形，异常发育的颅颌面骨骼可导致上呼吸道形态异常，影响上呼吸道功能。因TCS发病率低、在我国境内散发，且临床表型多样，导致相关研究难以开展。既往的研究多为散发病例个案报道，较少研究分析其面中部骨骼形态、上呼吸道形态特征及年龄对其面中部骨骼和上呼吸道发育的影响。此外，目前TCS患者颅颌面骨畸形和上呼吸道梗阻的治疗主要基于专家经验组成的低水平证据^[4]。据研究报道，延长器牵引治疗技术是常用的、有效的颅颌面骨发育不全的治疗方法，可改善颅颌面骨骼的畸形程度，但目前没有相关研究探索延长器在面中部横向骨牵引治疗对上呼吸道形态的影响。

      因此本研究旨在利用基于CT的三维数字化分析技术研究TCS的面中部骨骼形态和上呼吸道形态，与正常人群分别进行比较，以加深对疾病的认识、为其治疗方式的选择提供形态学基础；行面中部骨骼和上呼吸道的发育特征的年龄亚组分析，旨在为TCS患者治疗时机的选择提供参考；并进行动物实验，首次建立鼻上颌骨截骨后行横向牵引的实验动物模型，首次探索延长器横向牵引面中部骨骼对上呼吸道形态的影响，拟为存在面中部骨骼横向发育不良的TCS患者的治疗提供一种可能的选择。

方法

      选取2013年1月~2020年7月就诊于中国医学科学院整形外科医院的TCS患者及正常人群，共33例符合纳入标准，其中TCS组14例，对照组19例。按照年龄将患者分成三个亚组： 2-6岁、7-18岁及18岁以上。比较TCS组和对照组之间面中部颅颌面骨测量参数的差异；比较两组间上呼吸道总容积及局部上呼吸道容积的差异；分析TCS患者颅底、上颌骨、鼻部和上呼吸道形态与年龄相关的变化规律，并评估年龄和上呼吸道容积之间的相关性。

      探索性动物实验：选择10月~1岁龄比格犬为实验动物行面中部截骨手术、内置式颌骨牵引器置入手术及面中部骨骼横向牵引治疗。比较牵引前后面中部颅颌面骨和上呼吸道的变化特点。

      所有纳入研究对象均采用Philips Brilliance 64螺旋CT机进行颅颌面部扫描，所得CT影像学数据以DICOM格式储存，并导入ProPlan CMF 3.0（Materialise公司，比利时）进行颅颌面骨（阈值为226~3071）和上呼吸道（阈值为−1024~−200）三维数字化重建。在重建的三维模型上手动标记颅颌面骨解剖标志点，测量面中部颅颌面骨解剖学参数及上呼吸道容积。

结果

      TCS 患者组面中部横向径线较对照组显著缩短，如上颌骨基底宽度（MaxW）、上颌复合体长度（MxUL）及鼻骨相关横径（P<0.05）；TCS 组患者面中部多处矢状径线长度缩短，其中颅底点-后鼻棘点的距离（Ba-PNS）缩短程度最严重约16% （P<0.05）。但两组间比较代表前面中部高度的鼻根点-前鼻棘点距离（N-ANS）时，差异无统计学意义（P>0.05）。TCS 组患者颅底角及SNB角（蝶鞍点-鼻根点-下齿槽座点之间的夹角）较对照组下降（P<0.05），但两组间 SNA 角（蝶鞍点鼻根点-上齿槽座点之间的夹角）差异无统计学意义（P>0.05）。

      TCS患者组的上呼吸道总容积、鼻呼吸道容积和鼻腔容积与对照组相比均显著下降（分别为P=0.037、P=0.013和P=0.012）。但与预期相反的是，TCS患者的鼻咽容积和口咽容积与对照组相比均略有下降，但差异未达统计学意义（P>0.05）。MaxW、MxUL、ANS-PNS长度与总上呼吸道容积、鼻呼吸道容积、鼻腔容积呈正相关（r>0.6，P<0.05）。总上呼吸道、鼻呼吸道和鼻腔的容积与鼻内部生长受限相关，表现为 Ba-ANS、Ba-PNS、Ro-ANS、N-ANS、N-PNS、S-ANS、S-PNS的减小。大多数颅颌面骨测量参数在7-18岁年龄亚组中观察到的组间差异最为显著。两组间上呼吸道总容积和局部上呼吸道容积的出现统计学差异的年龄滞后，出现在大于18岁年龄亚组。

      实验动物行面中部截骨手术、内置式颌骨牵引器置入手术及面中部骨骼横向牵引治疗后，面中部冠状位多个测量值较牵引前略有增长，如牵引后INML-INMR较牵引前增长约12.9%，差异具有统计学意义（P=0.002）。牵引后其鼻呼吸道容积平均为（34679.85±5392.44）mm³，与牵引前（31435.32±5668.5）mm³相比增加了10.3%，差异具有统计学意义（P=0.026）。

结论

      TCS患者存在不同程度的面中部骨骼发育不良，导致上呼吸道形态改变、容积下降，可导致上呼吸道功能受损。TCS患者面中部横径、前后径及多个颅颌面骨角度均较对照组明显下降，表现为鼻骨及上颌骨显著横向发育不良，但高度发育未见明显受限。TCS患者上呼吸道容积较对照组显著下降，以鼻腔容积下降最为显著。TCS患者与对照组之间最明显颅颌面骨测量参数的差异发生在7至18岁之间。两组间上呼吸道总容积和局部上呼吸道容积的出现统计学差异的年龄滞后，出现在大于18岁年龄亚组。因此，7-18岁采取干预措施，患者可能会在上呼吸道梗阻发生之前从手术中获益。

Objectives

      Treacher Collins syndrome (TCS) is an autosomal genetic disorder that may be associated with mutations in the TCOF1 (about 80%-90% of cases), POLR1D or POLR1C (about 9% of cases) genes, resulting in abnormal development of the first and second parotid arches, with an incidence of approximately 1 in 50,000 live births^[1-3]. Patients with TCS clinically present with varying degrees of craniomaxillofacial skeletal dysplasia, such as zygomatic, maxillary and mandibular developmental malformations, and the abnormally developed craniomaxillofacial skeletons can lead to abnormal upper airway morphology and affect the upper airway function. The low incidence of TCS, its dissemination in China, and the diversity of its clinical phenotype make it challenging to investigate. Most of the previous studies have been reported in isolated cases, and few studies have analyzed the morphological characteristics of the midface skeleton and upper airway development and the effect of age on their development. Currently, the treatment of upper airway obstruction in patients with TCS is mainly based on low level evidence consisting of expert experience^[4]. It has been reported that extender distraction osteogenesis (DO) therapy is a commonly used and effective treatment for craniomaxillofacial dysplasia to improve craniomaxillofacial developmental deformities. However, there were no relevant studies exploring the effects of DO therapy in the midface laterally on the upper airway. 

      Therefore, the aims of this study were to investigate the midface bones and upper airway morphology in patients with TCS using CT-based three-dimensional digital analysis technology, and compare them with the normal population in order to deepen the understanding of the disease and provide a morphological basis for the selection of treatment modalities; conduct age subgroup analysis of the developmental characteristics of the midface bones and upper airway, intended to provide reference for the selection of treatment timing in TCS patient and animal experiments were conducted to explore the effect of lateral distraction osteogenesis on the morphology of the upper airway for the first time.

Methods

      TCS patients and normal population attending the Plastic Surgery Hospital of the Chinese Academy of Medical Sciences from January 2013 to July 2020 were selected, and a total of 33 cases met the inclusion criteria, including 14 cases in the TCS group and 19 cases in the control group. Patients were divided into three age subgroups: 2-6 years, 7-18 years, and 18 years or older. The differences in craniomaxillofacial measurement parameters in the midface, total upper airway volume and segment upper airway volumes were compared between the TCS and control groups; the age-related changes in the morphology of the skull base, maxilla, nose and upper airway in TCS patients were analyzed, and the correlation between age and upper airway volume was assessed.

       Exploratory animal experiment: 10-month to 1-year-old Beagle dogs were selected as experimental animals for midface osteotomy and midface transverse distraction osteogenesis treatment. Changes in the midface bones and upper airway before and after distraction were compared.

      ProPlan CMF software (version 3.0; Materialize, Leuven, Belgium) was used to measure CT parameters, including the linear, angular cephalometric parameters, and upper airway volumes.

Results

      Cephalometric and morphological analysis of the midface revealed that, multiple transverse distances of TCS patients were significantly decreased when compared with the control group, such as the width of the maxillary base, the length of the maxillary complex, and some distances related to the nasal morphology (P<0.05); but the distance between bilateral orbitales increased in TCS group (P<0.05). Several anteroposterior distances in TCS group were decreased significantly when compared to control group and the distance between the skull base point and the posterior nasal spine was the most shortened (P<0.05). But there was no significant difference of the distance between nasion and anterior nasal spine, which represents anterior midface height between groups (P>0.05). The skull base angle and SNB angle (the angle between the sella point-nose root point-inferior alveolar seat point) of the TCS group both decreased when compared with the control group (P<0.05), but there was no significant difference in SNA angle (the angle between the sella point-nose root point-upper alveolar seat point) between the two groups (P>0.05).

      Total upper airway volume, nasal airway volume and nasal cavity volume were significantly decreased in the TCS patients group compared to the control group (P=0.037, P=0.013 and P=0.012, respectively). However, contrary to expectations, nasopharyngeal and oropharyngeal volumes were slightly decreased in TCS patients compared to controls, but the difference did not reach statistical significance (P>0.05). In addition, MaxW, MxUL, and ANS-PNS lengths were positively correlated with total upper airway volume, nasal airway volume, and nasal cavity volume (r>0.6, P<0.05). Total upper airway, nasal airway, and nasal cavity volumes were correlated with restricted internal nasal growth, as evidenced by reduced Ba-ANS, Ba-PNS, Ro-ANS, N-ANS, N-PNS, S-ANS, and S-PNS. The most significant intergroup differences in most craniomaxillofacial measurement parameters were observed in the 7-18 years age subgroup. In the subgroup older than 18 years, a statistical difference in upper airway volumes were observed between the two groups.

      Exploratory animal experiment: After midface bones osteotomy and midfacial transverse distraction treatment, several measurements of midface in experimental animals increased slightly compared with pre-distraction, such as INML-INMR increased about 12.9% after distraction(P=0.002). The mean nasal airway volume in the experimental animals after distraction was (34,679.85±5,392.44) mm³, which increased by 10.3% when compared with (31,435.32±5,668.5) mm³before distraction, with a statistically significant difference (P=0.026).

Conclusions

      Patients with TCS are often associated with varying degrees of midfacial skeletal dysplasia, resulting in morphological changes and decreased volume of the upper airway, which can lead to impaired upper airway function. The transverse diameter, anterior-posterior diameter and several craniofacial angles of the midface of TCS patients were significantly decreased compared with those of the control group, which showed significant lateral hypoplasia of the nasal bone and maxilla, but no significant restriction of midface height development. The most obvious differences between TCS patients and control subjects occurred between 7 and 18years of age. Therefore, patients may benefit from surgery before upper airway obstruction occurs

      Animal experiments were conducted the first time to explore the effect of transverse distraction of the mid-facial skeleton with a distracter on the morphology of the upper airway, and the results showed that transverse distraction treatment of the midface is a feasible surgical method to increase the volume of the upper airway in experimental animals. However, the design of the extender and fixation screw should be improved in the future, and more experiments should be performed with the improved extender to demonstrate the feasibility of transverse distraction therapy. We aimed to provide a possible treatment option for patients with craniomaxillofacial dysplasia in the presence of midfacial skeletal transversal dysplasia.