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本文由“小麻哥的日常”授权转载 分享一篇Apert 综合征的文献，对该病例有比较详细的描述，翻译供参考！ Introduction Apert syndrome is another genetically inherited syndrome characterized by craniosynostosis (premature fusion of coronal sutures) resulting skull and facial deformities and syndactyly. The syndrome was first described in 1906 by French physician Eugene Apert when he described nine people with similar facial and extremity characteristics.[1] 前言 Apert综合征是一种遗传性综合征，其特征是颅缝早闭(冠状缝过早融合)导致的颅骨和面部畸形及并指畸形。1906年，法国医生尤金·阿佩特首次描述了这种综合征，当时他描述了9名面部和四肢特征相似的人。 Etiology Apert syndrome is an autosomal dominant inherited craniosynostosis syndrome. It is due to gain-of-function missense mutations of fibroblast growth factor receptor (FGFR2)-2 on chromosome 10q.[2] 病因学 Apert综合征是一种常染色体显性遗传性颅缝早闭综合征。这是由于10q染色体上成纤维细胞生长因子受体（FGFR2）-2的功能获得性错义突变所致。 Epidemiology Apert syndrome is a rare disease and is estimated to occur in 1 in 65,000 to 200,000 births depending on the study cited.[3] Males and females are equally affected. The incidence of the disease significantly increases with paternal age and is felt to provide a selective advantage within the male spermatogonial cells.[4] The syndrome has complete penetrance but variable expressivity resulting in phenotypically unaffected to severe deformities within the same family. 流行病学 Apert综合征是一种罕见的疾病，根据已有的研究，估计每65,000到200,000个新生儿中就有1个会发生，男性和女性的发病率相同。该病的发病率随着父系年龄的增长而显著增加，并被认为在男性精原细胞内具有选择性优势。该综合征具有完全的外显率，但表现形式多变，导致同一家系内的表型不受畸形严重程度的影响。 Pathophysiology Two-thirds of cases of Apert syndrome are due to a specific cysteine to guanine mutation at position 755 of the Fibroblast Growth Factor Receptor 2 (FGFR2) gene resulting in a serine to tryptophan amino acid change on the paternally derived allele.[4][5] The incidence of the disease increases with the age of the father.[4] Unfortunately, there are only hypotheses as to why both the extremities and cranial sutures are affected, and some data from a single mouse model. In mice, the FGFR2 receptor loses its specificity and can bind other fibroblast growth factors thereby suppressing apoptosis of osteoblasts resulting in syndactyly and craniosynostosis. The underlying mechanism is still not clear even in this mouse model, but it is linked to a specific FGF.[6] 病理生理学 三分之二的Apert综合征病例是由于成纤维细胞生长因子受体2（FGFR2）基因755位的一种特定半胱氨酸到鸟嘌呤的突变，导致父系衍生等位基因上的丝氨酸到色氨酸氨基酸发生变化。疾病的发生率随着父亲的年龄而增加。不幸的是，只有关于为什么四肢和颅骨缝都会受到影响的假设，以及来自单个小鼠模型的一些数据。在小鼠中，FGFR2受体失去其特异性，可结合其他成纤维细胞生长因子，从而抑制成骨细胞的凋亡，从而导致并指畸形和颅骨缝早闭。即使在这个老鼠模型中，潜在的机制仍然不清楚，但它与特定的FGF有关。 History and Physical The family history of patients suspected of having Apert syndrome is crucial due to its autosomal dominant inheritance. A lack of family history does not rule out the diagnosis due to the possibility of de novo mutations; however, a positive family history makes the diagnosis much more likely. 病史和体征 由于常染色体显性遗传，怀疑患有Apert综合征的患者的家族史至关重要。缺乏家族史不排除因可能发生新发突变而诊断的可能性；然而，阳性家族史使诊断更有可能。 Patients with Apert syndrome have craniosynostosis, midface hypoplasia, and symmetric syndactyly of the hands and feet. The craniosynostosis is more severe than that found in Crouzon syndrome, and the additional finding of syndactyly helps confirm the diagnosis between multiple, similar syndromes in regards to their phenotype. However, features of hypertelorism (wide-set eyes), proptosis (bulging eyes), and down-slanting palpebral fissures are facial features found in several of the craniosynostoses that cannot be used to differentiate the syndromes but are helpful. 患有Apert综合征的患者有颅骨缝早闭、面部中部发育不全和对称的手足并指畸形。颅骨缝早闭比Crouzon综合征更严重，就表型而言，并指体征有助于鉴别多个相似综合征。然而，远视（宽眼）、眼球突出（眼球凸出）和下斜视眼睑裂是一些颅缝早闭症的面部特征，这些特征不能用来鉴别不同的综合征，但有帮助。 In regards to the hand, a short, radially deviated thumb, complex syndactyly of the index, long, and ring finger, syndactyly of the fourth webspace, and symphalangism (congenital stiffness of the fingers due to failure of the bone to fully separate as typically happens during fetal growth) are characteristic findings of the hand. There are three specific subtypes of hand findings in Apert syndrome based on the overall shape of the hand. They are spade (side-to-side fusion with flat palm), mitten (fusion of fingers resulting in concave palm), and rosebud (tight fusion of all digits). There are other craniofacial deformities found in Apert syndrome and other craniosynostoses such as acrocephaly (cone-shaped calvarium), proptosis, prominent forehead, hypertelorism, down slanting palpebral fissures and a flattened nasal bridge. Oral findings included dental crowding, high-arched palate, narrow palate, and pseudo-clefts. Internal organs and other skeletal anomalies such as cervical fusions can be seen. Mild to moderate intellectual disability is also possible. 就手而言，拇指短而径向偏离、食指、中指和无名指的复杂并指、第四蹼间隙的并指畸形和共指畸形（胎儿生长过程中由于骨骼不能完全分离而导致手指先天性僵硬）是手的特征性表现。根据手的整体形状，Apert综合征的手部表现有三种特殊亚型。它们是铁锹（与手掌平边融合）、连指手套（手指融合导致手掌凹陷）和玫瑰花蕾（所有手指紧密融合）。在Apert综合征和其他颅骨缝早闭症中还发现了其他颅面畸形，如尖颅（锥形颅骨）、突眼、前额突出、斜视、睑裂向下倾斜和鼻梁扁平。口腔发现包括牙齿拥挤，高腭弓，窄腭和隐性唇裂。可以看到内脏和其他骨骼异常，如颈椎融合。轻度至中度智障也有可能。 Evaluation The evaluation for Apert syndrome in the setting of known family history is a clinical one as the characteristic physical examination findings confirm the diagnosis. In cases where the clinical presentation is not clear and no family history to support the diagnosis, additional tests such as advanced imaging techniques can help. Magnetic resonance imaging (MRI) and computed tomographic (CT) imaging of the brain are used to detect craniosynostosis or other skeletal abnormalities (perisutural sclerosis, reduced serration, and bony bridging and/or the absence of the suture altogether). These same imaging techniques can be helpful in detecting complications related to the syndrome such as increased intracranial pressure. 评估 在已知家族史的背景下对Apert综合征的评估是一种临床评估，因为其特征性的体检结果证实了诊断。在临床表现不清楚且无家族史支持诊断的情况下，额外的检查如先进的影像学技术可以帮助诊断。大脑的磁共振成像（MRI）和计算机断层扫描（CT）成像用于检测颅骨缝早闭或其他骨骼异常（缝周硬化、锯齿减少、骨桥和/或完全没有缝合线）。这些相同的成像技术有助于发现与该综合征相关的并发症，如颅内压增高。 Much like that discussed with Crouzon syndrome in which there is an unclear diagnosis, or the syndrome has atypical features, genetic and molecular testing can be pursued. Unfortunately, the underlying mechanism of multiple craniosynostosis syndromes is related to FGFR mutations and abnormal signaling. Prenatal genetic testing, MRI, and ultrasounds can be utilized to confirm the diagnosis before the birth of the child.[7] The use of amniocentesis and/or chorionic villus sampling can be performed, but the combination of safer imaging techniques will likely render the higher risk procedures obsolete except in the most difficult cases. 就像Crouzon综合征所讨论的那样，没有明确的诊断，或者该综合征具有非典型特征，可以进行基因和分子检测。不幸的是，多发性颅缝综合征的潜在机制与FGFR突变和异常信号有关。产前基因检测、核磁共振成像和超声波可用于在孩子出生前确认诊断。[7]可以使用羊膜穿刺术和/或绒毛取样，但结合更安全的成像技术可能会避免使用这些高风险方法，除非是最困难的病例。 As described above, the history, physical, and imaging findings are used to confirm the specific craniosynostosis but can be difficult due to significant overlap amongst the syndromes (Pfeiffer, Apert, Saether-Chotzen, Carpenter, and Jackson-Weiss syndromes). 如上所述，病史、体格检查和影像学检查结果可用于确认特定的颅骨缝早闭症，但由于综合征之间存在显著重叠（Pfeiffer、Apert、Saether-Chotzen、Carpenter和Jackson-Weiss综合征）而使诊断变得困难。 Treatment / Management Like other craniosynostoses, management is a team-based approach requiring multiple subspecialists such as pediatricians, neurosurgeons, plastic surgeons, craniofacial surgeons, ophthalmologists, and dentists. Surgery is required to prevent complete coronal suture closure and protect brain development. 治疗/管理 与其他颅骨缝早闭症一样，采取团队协作治疗，需要多个亚专科医生，如儿科医生、神经外科医生、整形外科医生、颅面部外科医生、眼科医生和牙医。手术是为了防止冠状缝完全闭合和保护大脑发育。 A detailed description of the surgical management of Apert syndrome can be found in the guidelines from the “Working Group on Craniosynostosis.[8]” Much like Crouzon syndrome, earlier surgical decisions (before the age of 1) are felt to provide better long-term outcomes.[9] Unfortunately, this is based on anecdotal evidence and not a randomized, controlled trial. Similarly, there is no standard of care for the treatment of syndactyly, but multiple revisions are likely as the child grows. 关于Apert综合征的外科治疗的详细描述可以在“颅骨缝早闭症工作组”的指南中找到。与Crouzon综合征相似，早期手术（1岁之前）被认为可以提供更好的长期预后。不幸的是，这是基于散发证据，而不是随机对照试验。同样，对于并指畸形的治疗也没有标准，但随着孩子的成长，可能会进行多次修改。 Long-term follow up is essential to reduce the risk of developing complications related to craniosynostoses such as strabismus, sleep apnea, and elevated intracranial pressure. Unfortunately, these issues are not completely resolved with surgical correction of the facial and cranial defects as 54% of patients had vision loss in at least one eye-related to amblyopia that developed after craniofacial surgery for Apert syndrome in one retrospective study from Australia. Fortunately, in this same study, the incidence of optic atrophy was low at 5% presumably due to the widespread adoption of early craniofacial surgery for craniosynostosis syndromes.[10] The incidence of strabismus is extremely common as well with two-thirds of patients developing the entity at some point.[11] Severe to profound hearing loss is also much more common in syndromic craniosynostoses than nonsyndromic variants.[12] Thus, a team-based approach with multiple subspecialists involved to monitor for the development of vision and life-threatening complications related to Apert and to make difficult decisions and if and when to perform surgery. 长期随访对于降低与颅骨缝早闭相关并发症发生的风险至关重要，如斜视、睡眠呼吸暂停和颅内压升高。不幸的是，在澳大利亚的一项回顾性研究发现颅颌面畸形矫正手术不能完全解决这些问题，54%的患者在因Apert综合征而进行的颅面手术后出现至少一只眼睛弱视加重而丧失视力。幸运的是，在这项研究中，视神经萎缩的发生率较低，仅为5%，这可能是由于广泛采用早期颅面外科手术治疗颅缝早闭综合征所致。斜视的发病率极为常见，三分之二的患者在某些时候出现了视神经萎缩。与非综合征患者相比，颅缝早闭综合征中听力丧失也更为常见。]因此，基于团队协作，由多个亚专科医生参与监测视力和危及生命的并发症发展，并做出是否和何时进行手术的决定。 While only available in laboratories at this point, chemical inhibitors of the FGFR signaling pathway restore normal FGFR signaling and rescue the associated skeletal defects. 虽然目前只有在实验室可用，FGFR信号通路的化学抑制剂可以恢复正常的FGFR信号并挽救相关的骨骼缺陷。 Differential Diagnosis The differential diagnoses of Apert syndrome include: Achondroplasia Antley- Bixler syndrome Beare- Stevenson syndrome Conditions arising due to mutations of the Fibroblast Growth Factor Receptors Crouzon syndrome Cutis Gyrata Pfeiffer syndrome Thanatophoric dysplasia 鉴别诊断 Apert综合征的鉴别诊断包括： Beare- Stevenson综合征 Beare-Stevenson综合征 成纤维细胞生长因子受体突变引起的疾病 Crouzon 综合征 角质皮肤症 Pfeiffer综合征 Thanatophoric发育不良 Prognosis The prognosis depends on when surgery was performed and what pathologies required surgical intervention. 预后 预后取决于手术时间和需要手术干预的病理类型。 Complications The main complications likely to occur in patients with Apert syndrome include: Increased intracranial pressure that can cause papilledema and cognitive impairment Exposure keratopathy and corneal scarring Respiratory complications Spinal cord injury and neurologic deficits in patients with cervical spine anomalies Aspiration pneumonia and further chronic lung disease 并发症 Apert综合征患者可能发生的主要并发症包括： 颅内压升高可导致视乳头水肿和认知障碍 暴露性角膜病变与角膜瘢痕 呼吸道并发症 颈椎异常患者的脊髓损伤与神经功能缺损 吸入性肺炎和进一步的慢性肺病 Consultations Ophthalmology (pediatric, oculoplastics) Plastic surgery Maxillofacial surgery Neurosurgery Otorhinolaryngology 会诊 眼科学（儿科，眼科学） 整形外科 颌面外科 神经外科 耳鼻咽喉科 Deterrence and Patient Education Apert syndrome is having an autosomal dominant inheritance and advanced paternal age is found to be associated with the de novo occurrence of Apert syndrome. There is a 50% chance of the genetic trait being passed to each child. If a pathologic variant person is present in the family, prenatal testing for pregnancies at increased risk should be ideally performed. 制止和患者教育 Apert综合征具有常染色体显性遗传，父系高龄与Apert综合征的再次发生有关。有50%的几率遗传给每个孩子。如果家中存在病理变异者，最好对高危妊娠进行产前检查。 免责声明： 本微信公众平台所刊载原创或转载内容不代表米勒之声的观点或立场。文中所涉及药物使用、疾病诊疗等内容仅供参考。  |
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