Tan Weizhen, Lin Angela, Keppler-Noreuil Kim
Clinical Instructor, Harvard Medical School, Division of Pediatric Nephrology, MassGeneral Hospital for Children, Boston, Massachusetts
Professor of Pediatrics, Harvard Medical School, Medical Genetics, MassGeneral Hospital for Children, Boston, Massachusetts
Cranioectodermal dysplasia (CED) is a ciliopathy with skeletal involvement (narrow thorax, shortened proximal limbs, syndactyly, polydactyly, brachydactyly), ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails), joint laxity, growth deficiency, and characteristic facial features (frontal bossing, low-set simple ears, high forehead, telecanthus, epicanthal folds, full cheeks, everted lower lip). Most affected children develop nephronophthisis that often leads to end-stage kidney disease in infancy or childhood, a major cause of morbidity and mortality. Hepatic fibrosis and retinal dystrophy are also observed. Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary manifestation that distinguishes CED from most other ciliopathies. Brain malformations and developmental delay may also occur.
DIAGNOSIS/TESTING: The diagnosis of CED is established in a proband with characteristic clinical and radiographic features (including two frequent features and two other abnormalities, with at least one ectodermal defect – i.e., involvement of the teeth, hair, or nails) and/or by identification of biallelic pathogenic variants in one of the six genes currently known to be associated with CED: , , , , , or .
As needed, surgery to correct sagittal craniosynostosis usually before age one year. Surgical correction may be needed for polydactyly of the hands and feet. Orthopedic care for hip dysplasia. Human growth hormone therapy could be considered in those who meet standard treatment criteria. Standard treatment for dental anomalies, nephronophthisis, liver disease, cardiac anomalies, and/or inguinal and umbilical hernias. For those with progressive visual impairment: low-vision aids and appropriate educational programs. Mechanical ventilation may be required in newborns with pulmonary hypoplasia. For those with developmental delay, speech and physical therapy and appropriate educational programs. In infancy and childhood: monitor tooth development; morning urine osmolarity testing, urine collection assay for polyuria, blood pressure, serum creatinine and blood urea assessment, and renal ultrasound as recommended by nephrologist; hepatic transaminases and measurement of synthetic liver function as recommended by hepatologist. Annual ophthalmologic examinations starting at age four years to detect early signs of retinal degeneration. Cardiac examinations, EKG, and echocardiography per cardiologist. Review of developmental progress at each primary care visit, and formal evaluation with neuropsychological testing if delays noted.
CED is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CED-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible once the CED-causing pathogenic variants have been identified in an affected family member. Second-trimester ultrasound examination may detect renal cysts, shortening of the limbs, and/or polydactyly.
颅面外胚层发育不良（CED）是一种伴有骨骼受累（胸廓狭窄、近端肢体缩短、并指、多指、短指）、外胚层特征（牙齿发育不全且间距宽、牙齿缺失、头发稀疏、皮肤松弛、指甲异常）、关节松弛、生长发育迟缓以及特征性面部特征（额部隆起、低位简单耳、高额、内眦间距增宽、内眦赘皮、脸颊丰满、下唇外翻）的纤毛病。大多数患病儿童会发展为肾单位肾痨，这常常在婴儿期或儿童期导致终末期肾病，是发病和死亡的主要原因。还观察到肝纤维化和视网膜营养不良。长头畸形通常继发于矢状缝早闭，是将CED与大多数其他纤毛病区分开来的主要表现。也可能出现脑畸形和发育迟缓。
诊断/检测：CED的诊断通过先证者具有特征性临床和影像学特征（包括两个常见特征和另外两个异常，且至少有一个外胚层缺陷——即牙齿、头发或指甲受累）和/或通过在目前已知与CED相关的六个基因之一中鉴定双等位基因致病变异来确立： 、 、 、 、 或 。
根据需要，通常在一岁前进行手术矫正矢状缝早闭。手脚多指可能需要手术矫正。对髋关节发育不良进行骨科护理。符合标准治疗标准的患者可考虑使用人生长激素治疗。对牙齿异常、肾单位肾痨、肝病、心脏异常和/或腹股沟及脐疝进行标准治疗。对于有进行性视力损害的患者：使用低视力辅助器具并开展适当的教育项目。肺发育不全的新生儿可能需要机械通气。对于有发育迟缓的患者，进行言语和物理治疗以及适当的教育项目。在婴儿期和儿童期：监测牙齿发育；按照肾病学家的建议进行晨尿渗透压检测、多尿的尿液收集分析、血压、血清肌酐和血尿素评估以及肾脏超声检查；按照肝病学家的建议进行肝转氨酶检测和肝脏合成功能测定。从四岁开始每年进行眼科检查以检测视网膜变性的早期迹象。按照心脏病专家的建议进行心脏检查、心电图和超声心动图检查。每次初级保健就诊时复查发育进展，如果发现发育迟缓则进行神经心理测试的正式评估。
CED以常染色体隐性方式遗传。如果已知父母双方都是导致CED的致病变异的杂合子，受影响个体的每个同胞在受孕时有25%的几率受到影响，50%的几率是无症状携带者，25%的几率不受影响且不是携带者。一旦在受影响的家庭成员中鉴定出导致CED的致病变异，就可以对有风险的亲属进行携带者检测、对风险增加的妊娠进行产前检测以及进行植入前基因检测。孕中期超声检查可能检测到肾囊肿、肢体缩短和/或多指。
