Fraser综合征病因和临床诊治的研究进展

doi:10.12280/gjszjk.20250004

摘要/Abstract

摘要：

Fraser综合征（Fraser syndrome，FS）是一种罕见的常染色体隐性遗传病，主要由Fras1/Frem蛋白复合物相关基因突变导致，与上皮-间充质结合紊乱密切相关。FS具有显著的临床和遗传异质性，表现为多发性先天性畸形，以隐眼、并指（趾）、肾发育不全、生殖器异常、喉闭锁等为典型特征。产前超声检查以羊水过少、肾发育不全等为主要表现。FS主要在胎儿和婴儿期发病，致残率、致死率高。目前，已知与FS相关的基因包括FRAS1、FREM2和GRIP1。临床上FS的诊断需综合临床症状、影像学检查和基因检测结果。尽管目前FS尚缺乏特异性治疗方法，但针对性的多学科干预和支持性治疗可改善患者预后。本文综述FS的临床特征、病因及发病机制、诊断、治疗等方面的研究进展，以期为FS的临床诊治提供参考。

关键词: Fraser综合征, 遗传性疾病, 表型, 诊断, FRAS1基因, FREM2基因, GRIP1基因

Abstract:

Fraser syndrome (FS), a rare autosomal recessive genetic disease, is primarily caused by the mutation in genes associated with the Fras1/Frem protein complex, which is closely related to the disruption of epithelial-mesenchymal interactions. With significant clinical and genetic heterogeneity, FS is characterized by multiple congenital malformations, and typical features such as cryptophthalmos, syndactyly, renal agenesis, ambiguous genitalia, and laryngeal atresia. Prenatal ultrasound typically reveals oligohydramnios and renal agenesis. FS predominantly manifests during fetal and infant stages, with high rates of disability and mortality. To date, the genes associated with FS include FRAS1, FREM2, and GRIP1. Clinical diagnosis of FS requires a comprehensive evaluation of symptoms, imaging examinations, and genetic testing. Although there is currently no specific treatment for FS, the targeted multidisciplinary interventions and supportive care can improve patient outcomes. This review summarizes the advances in the clinical characteristics, etiology, pathogenesis, diagnosis, and treatment of FS, aiming to provide valuable insights for its clinical management.

Key words: Fraser syndrome, Genetic diseases, Phenotype, Diagnosis, FRAS1 gene, FREM2 gene, GRIP1 gene

刘静, 辛敏, 罗玉雷, 刘金秀. Fraser综合征病因和临床诊治的研究进展[J]. 国际生殖健康/计划生育杂志, 2025, 44(3): 247-252.

LIU Jing, XIN Min, LUO Yu-lei, LIU Jin-xiu. Research Progress on Etiological Mechanism, Diagnosis and Treatment of Fraser Syndrome[J]. Journal of International Reproductive Health/Family Planning, 2025, 44(3): 247-252.

图/表 1

参考文献 34

[1]	Das D, Modaboyina S, Raj S, et al. Clinical features and orbital anomalies in Fraser syndrome and a review of management options[J]. Indian J Ophthalmol, 2022, 70(7):2559-2563. doi: 10.4103/ijo.IJO_2627_21. pmid: 35791156
[2]	Bouaoud J, Olivetto M, Testelin S, et al. Fraser syndrome: review of the literature illustrated by a historical adult case[J]. Int J Oral Maxillofac Surg, 2020, 49(10):1245-1253. doi: 10.1016/j.ijom.2020.01.007.
[3]	Ikeda S, Akamatsu C, Ijuin A, et al. Prenatal diagnosis of Fraser syndrome caused by novel variants of FREM2[J]. Hum Genome Var, 2020, 7:32. doi: 10.1038/s41439-020-00119-5. pmid: 33082983
[4]	Turgut GT, Sarac Sivrikoz T, Komurcu-Bayrak E, et al. FREM2-related Fraser syndrome with popliteal pterygium and structural central nervous system anomalies[J]. Eur J Med Genet, 2023, 66(3):104712. doi: 10.1016/j.ejmg.2023.104712.
[5]	Boussion S, Lyonnet S, Van Der Zwaag B, et al. Fraser syndrome without cryptophthalmos: Two cases[J]. Eur J Med Genet, 2020, 63(4):103839. doi: 10.1016/j.ejmg.2020.103839.
[6]	Midro AT, Stasiewicz-Jarocka B, Borys J, et al. Two unrelated families with variable expression of Fraser syndrome due to the same pathogenic variant in the FRAS1 gene[J]. Am J Med Genet A, 2020, 182(4):773-779. doi: 10.1002/ajmg.a.61495. pmid: 31999076
[7]	Brimo Alsaman MZ, Agha S, Sallah H, et al. Bilateral anophthalmia and intrahepatic biliary atresia, two unusual components of Fraser syndrome: a case report[J]. BMC Pregnancy Childbirth, 2020, 20(1):358. doi: 10.1186/s12884-020-03048-x.
[8]	Mbonda A, Endomba FT, Kanmounye US, et al. Diagnosis of Fraser syndrome missed out until the age of six months old in a low-resource setting: a case report[J]. BMC Pediatr, 2019, 19(1):292. doi: 10.1186/s12887-019-1673-6. pmid: 31438902
[9]	Zhou Y, Yang X, Liu Z, et al. Excluding embryos with two novel mutations in FREM2 gene by the next-generation sequencing-based single nucleotide polymorphism haplotyping[J]. Aging(Albany NY), 2021, 13(22):24786-24794. doi: 10.18632/aging.203715.
[10]	Zhang X, Wang D, Dongye M, et al. Loss-of-function mutations in FREM2 disrupt eye morphogenesis[J]. Exp Eye Res, 2019, 181:302-312. doi: 10.1016/j.exer.2019.02.013. pmid: 30802441
[11]	陈弘大, 李闪, 高劲松, 等. FREM2基因变异致隐眼畸形1例胎儿的遗传学分析[J]. 中华医学遗传学杂志, 2024, 41(5):606-611. doi: 10.3760/cma.j.cn511374-20230915-00135.
[12]	李雅娟, 张丁宁, 郑军. 新生儿Fraser综合征1例[J]. 医学理论与实践, 2024, 37(11):1908-1909. doi: 10.19381/j.issn.1001-7585.2024.11.040.
[13]	Fraser GR. Our genetical ′load′. A review of some aspects of genetical variation[J]. Ann Hum Genet, 1962, 25(4):387-415. doi: 10.1111/j.1469-1809.1962.tb01774.x.
[14]	Mangla M, Kaliappan A, Srirambhatla A, et al. Fraser syndrome with limb reduction defect: a rare and unique anatomic variation[J]. Surg Radiol Anat, 2024, 46(4):501-506. doi: 10.1007/s00276-024-03299-9. pmid: 38310170
[15]	Amornvit P, Rokaya D, Sapkota D, et al. Oral and Craniofacial Anomalies of Fraser Syndrome: Prosthetic Management[J]. Kathmandu Univ Med J(KUMJ), 2022, 20(79):391-395.
[16]	Al-Hamed MH, Sayer JA, Alsahan N, et al. Novel loss of function variants in FRAS1 AND FREM2 underlie renal agenesis in consanguineous families[J]. J Nephrol, 2021, 34(3):893-900. doi: 10.1007/s40620-020-00795-0.
[17]	Kantaputra PN, Wangtiraumnuay N, Ngamphiw C, et al. Crypt-ophthalmos, dental anomalies, oral vestibule defect, and a novel FREM2 mutation[J]. J Hum Genet, 2022, 67(2):115-118. doi: 10.1038/s10038-021-00972-4.
[18]	Rumping L, Hennekam R, Alders M, et al. "Hypothesis: Patient with possible disturbance in programmed cell death": further insights in pathogenicity and clinical features of Fraser syndrome[J]. Eur J Hum Genet, 2023, 31(1):16-17. doi: 10.1038/s41431-022-01175-x.
[19]	Koprulu M, Kumare A, Bibi A, et al. The first adolescent case of Fraser syndrome 3, with a novel nonsense variant in GRIP1[J]. Am J Med Genet A, 2021, 185(6):1858-1863. doi: 10.1002/ajmg.a.62163.
[20]	van Haelst MM, Scambler PJ, Hennekam RC. Fraser syndrome: a clinical study of 59 cases and evaluation of diagnostic criteria[J]. Am J Med Genet A, 2007, 143A(24):3194-3203. doi: 10.1002/ajmg.a.31951. pmid: 18000968
[21]	Ramadugu R, Kuppili S, Suvvari TK, et al. A Rare Case of Complete Cryptophthalmos and Suspected Fraser′s Syndrome in a Female Neonate[J]. Clin Med Insights Case Rep, 2023,16:11795476231189042. doi: 10.1177/11795476231189042.
[22]	Kunz F, Kayserili H, Midro A, et al. Characteristic dental pattern with hypodontia and short roots in Fraser syndrome[J]. Am J Med Genet A, 2020, 182(7):1681-1689. doi: 10.1002/ajmg.a.61610. pmid: 32488952
[23]	Mwipopo E, Massomo MM, Moshiro R, et al. Bilateral cryptophthalmos with overlapping features of Manitoba oculo-tricho-anal (MOTA) syndrome and Fraser syndrome 2[J]. BMJ Case Rep, 2023, 16(6):e252618. doi: 10.1136/bcr-2022-252618.
[24]	Tessier A, Sarreau M, Pelluard F, et al. Fraser syndrome: features suggestive of prenatal diagnosis in a review of 38 cases[J]. Prenat Diagn, 2016, 36(13):1270-1275. doi: 10.1002/pd.4971.
[25]	Madan J, Shetty M, Ramamurthy BS, et al. A multidisciplinary approach for prenatal diagnosis of FRASER SYNDROME-report of a novel variant in FRAS1[J]. Taiwan J Obstet Gynecol, 2022, 61(1):129-131. doi: 10.1016/j.tjog.2021.11.020. pmid: 35181022
[26]	Panigrahi S, Mohapatra K, Pradhan M, et al. A Rare Case of Fraser Syndrome with Partial Vaginal Agenesis and Its Successful Reconstructive Cosmetic Management: A Case Report[J]. J Obstet Gynaecol India, 2022, 72(4):349-352. doi: 10.1007/s13224-021-01462-5.
[27]	Bathla S, Karim W, Kumar A, et al. Fraser Syndrome: A Stumbling Block for the Anaesthesiologist[J]. Indian J Otolaryngol Head Neck Surg, 2022, 74(Suppl 3):5225-5227. doi: 10.1007/s12070-020-01843-8.
[28]	Landau-Prat D, Kim DH, Bautista S, et al. Cryptophthalmos: associated syndromes and genetic disorders[J]. Ophthalmic Genet, 2023, 44(6):547-552. doi: 10.1080/13816810.2023.2237568.
[29]	Ou TY, Tsai MC, Kuo PL, et al. Whole exome sequencing identifies a novel FRAS1 mutation and aids in vitro fertilization with preimplantation genetic diagnosis in Fraser syndrome[J]. Taiwan J Obstet Gynecol, 2022, 61(3):521-524. doi: 10.1016/j.tjog.2022.03.022.
[30]	Yu QX, Zhen L, Xiao ZQ, et al. Exome Sequencing in Fetuses With Bilateral Renal Agenesis Identified on Second Trimester Ultrasound: A Single Referral Center Experience[J]. Prenat Diagn, 2025, 45(2):218-222. doi: 10.1002/pd.6705.
[31]	张夏茵, 王婧荟, 龙尔平, 等. 先天性隐眼遗传致病基因研究现状[J]. 转化医学电子杂志, 2017, 4(8):1-5.
[32]	Esho T, Kobbe B, Tufa SF, et al. The Fraser Complex Proteins (Frem1, Frem2, and Fras1) Can Form Anchoring Cords in the Absence of AMACO at the Dermal-Epidermal Junction of Mouse Skin[J]. Int J Mol Sci, 2023, 24(7):6782. doi: 10.3390/ijms24076782.
[33]	Kantaputra PN, Tripuwabhrut K, Anthonappa RP, et al. Heterozygous Variants in FREM2 Are Associated with Mesiodens, Supernumerary Teeth, Oral Exostoses, and Odontomas[J]. Diagnostics(Basel), 2023, 13(7):1214. doi: 10.3390/diagnostics13071214.
[34]	Maeda-Usui A, Sato T, Nakano S, et al. Potential benefit of rapid genetic testing for Pallister-Hall syndrome[J]. Clin Pediatr Endocrinol, 2023, 32(2):119-122. doi: 10.1297/cpe.2022-0065.