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URL of this page: https://medlineplus.gov/genetics/condition/fraser-syndrome/

Fraser syndrome

Description

Fraser syndrome is a rare disorder that affects development before birth. Characteristic features of this condition include:

  • Eyes that are covered by skin (cryptophthalmos)
  • Fusion of the skin between the fingers and toes (cutaneous syndactyly)
  • Abnormalities of the genitalia and the urinary tract (genitourinary anomalies)

Cryptophthalmos is the most common abnormality in people with Fraser syndrome. In most cases, both eyes are completely covered by skin. However, in some affected individuals, only one eye is covered, or one or both eyes are partially covered. Additional eye abnormalities may include:

  • Eyes that do not develop fully and are abnormally small (microphthalmia)
  • Eyes that are severely underdeveloped or absent (anophthalmia)

Because of these eye abnormalities, people with Fraser syndrome may have partial or complete vision loss.

Individuals with Fraser syndrome often have abnormalities in their reproductive and urinary tracts. These can include:

  • Absence of one or both kidneys (renal agenesis)
  • Abnormal development of the vagina
  • Undescended testes (cryptorchidism)
  • External genitalia that do not appear clearly male or female

Affected individuals may also have other kidney problems or abnormalities of other parts of the urinary tract, such as the bladder.

A variety of other signs and symptoms can be associated with Fraser syndrome:

  • Heart abnormalities 
  • Abnormalities of the voicebox (larynx) or other parts of the upper airway
  • Abnormalities of the ears or nose
  • An opening in the upper lip (cleft lip) with or without an opening in the roof of the mouth (cleft palate) 
  • An absence (atresia) or narrowing (stenosis) of the anus

Intellectual disabilities sometimes occur, although many people with Fraser syndrome have normal intelligence. The specific features and the severity of Fraser syndrome can vary widely. In severe cases, abnormalities of the airway or kidneys can be fatal before or shortly after birth.

Frequency

Fraser syndrome is a rare condition. It is believed to affect up to 1 in 250,000 newborns. More than 250 cases have been reported in the scientific literature.

Causes

Genetic changes that cause disease are called pathogenic variants. Pathogenic variants in the FRAS1, FREM2, or GRIP1 genes can cause Fraser syndrome. FRAS1 gene variants are the most common cause of Fraser syndrome. FREM2 and GRIP1 gene variants are each responsible for a small percentage of cases.

The proteins that are produced from the FRAS1 and FREM2 genes are part of a group of proteins called the FRAS/FREM complex. The protein that is produced from the GRIP1 gene ensures that the FRAS1 and FREM2 proteins get to the correct location to form the FRAS/FREM complex.

The FRAS/FREM complex is found in basement membranes, which are thin, sheet-like structures that separate and support the cells in many tissues. One of the roles of the FRAS/FREM complex is to anchor the basement membrane of the top layer of skin to the layer of skin below. The FRAS/FREM complex is also involved in the proper organization and development of certain organs and tissues, including the kidneys.

The pathogenic variants in the FRAS1, FREM2, or GRIP1 genes that cause Fraser syndrome interfere with the proper formation of the FRAS/FREM complex. This disrupts the connection between tissue layers, including the connection between the top layer of skin and the layer of skin underneath. Disrupting the interactions between tissue layers impairs cellular movement and communication during early development, which can lead to the cryptophthalmos and cutaneous syndactyly seen in affected individuals. 

Through a mechanism that is not well understood, the pathogenic variants that cause Fraser syndrome appear to interfere with the self-destruction of cells that are no longer needed (apoptosis), which may contribute to the additional abnormalities seen in people with Fraser syndrome.

In some people with Fraser syndrome, a pathogenic variant cannot be identified. In these cases, the cause of the disorder is unknown. 

Learn more about the genes associated with Fraser syndrome

Inheritance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a pathogenic variant to cause the disorder. Usually, the parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

Other Names for This Condition

  • Cryptophthalmos syndactyly syndrome
  • Cryptophthalmos syndrome
  • Cryptophthalmos with other malformations
  • Fraser-Francois syndrome
  • Meyer-Schwickerath syndrome
  • Ullrich-Feichtiger syndrome

Additional Information & Resources

Genetic Testing Information

Genetic and Rare Diseases Information Center

Patient Support and Advocacy Resources

Clinical Trials

Catalog of Genes and Diseases from OMIM

Scientific Articles on PubMed

References

  • Al-Hamed MH, Sayer JA, Alsahan N, Tulbah M, Kurdi W, Ambusaidi Q, Ali W, Imtiaz F. Novel loss of function variants in FRAS1 AND FREM2 underlie renal agenesis in consanguineous families. J Nephrol. 2021 Jun;34(3):893-900. doi: 10.1007/s40620-020-00795-0. Epub 2020 Jul 8. Citation on PubMed
  • Barisic I, Odak L, Loane M, Garne E, Wellesley D, Calzolari E, Dolk H, Addor MC, Arriola L, Bergman J, Bianca S, Boyd PA, Draper ES, Gatt M, Haeusler M, Khoshnood B, Latos-Bielenska A, McDonnell B, Pierini A, Rankin J, Rissmann A, Queisser-Luft A, Verellen-Dumoulin C, Stone D, Tenconi R. Fraser syndrome: epidemiological study in a European population. Am J Med Genet A. 2013 May;161A(5):1012-8. doi: 10.1002/ajmg.a.35839. Epub 2013 Mar 26. Citation on PubMed
  • Dumitru A, Costache M, Lazaroiu AM, Simion G, Secara D, Cirstoiu M, Emanoil A, Georgescu TA, Sajin M. Fraser Syndrome - a Case Report and Review of Literature. Maedica (Bucur). 2016 Mar;11(1):80-83. Citation on PubMed
  • Hoefele J, Wilhelm C, Schiesser M, Mack R, Heinrich U, Weber LT, Biskup S, Daumer-Haas C, Klein HG, Rost I. Expanding the mutation spectrum for Fraser syndrome: identification of a novel heterozygous deletion in FRAS1. Gene. 2013 May 15;520(2):194-7. doi: 10.1016/j.gene.2013.02.031. Epub 2013 Mar 6. Citation on PubMed
  • Ikeda S, Akamatsu C, Ijuin A, Nagashima A, Sasaki M, Mochizuki A, Nagase H, Enomoto Y, Kuroda Y, Kurosawa K, Ishikawa H. Prenatal diagnosis of Fraser syndrome caused by novel variants of FREM2. Hum Genome Var. 2020 Oct 2;7:32. doi: 10.1038/s41439-020-00119-5. eCollection 2020. Citation on PubMed
  • Martinez-Frias ML, Bermejo Sanchez E, Felix V, Calvo Celada R, Ayala Garces A, Hernandez Ramon F. [Fraser syndrome: frequency in our environment and clinical-epidemiological aspects of a consecutive series of cases]. An Esp Pediatr. 1998 Jun;48(6):634-8. Spanish. Citation on PubMed
  • McGregor L, Makela V, Darling SM, Vrontou S, Chalepakis G, Roberts C, Smart N, Rutland P, Prescott N, Hopkins J, Bentley E, Shaw A, Roberts E, Mueller R, Jadeja S, Philip N, Nelson J, Francannet C, Perez-Aytes A, Megarbane A, Kerr B, Wainwright B, Woolf AS, Winter RM, Scambler PJ. Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein. Nat Genet. 2003 Jun;34(2):203-8. doi: 10.1038/ng1142. Citation on PubMed
  • Petrou P, Makrygiannis AK, Chalepakis G. The Fras1/Frem family of extracellular matrix proteins: structure, function, and association with Fraser syndrome and the mouse bleb phenotype. Connect Tissue Res. 2008;49(3):277-82. doi: 10.1080/03008200802148025. Citation on PubMed
  • Simikyan RG, Zhang X, Strelkova O, Li N, Zhu M, Eckhard A, Baranov PY, Wu X, Richey L, Indzhykulian AA. Frem2 Knockout Mice Exhibit Fraser Syndrome Phenotypes and Neonatal Lethality Due to Bilateral Renal Agenesis. bioRxiv [Preprint]. 2025 Aug 5:2024.10.28.620501. doi: 10.1101/2024.10.28.620501. Citation on PubMed
  • Slavotinek AM, Tifft CJ. Fraser syndrome and cryptophthalmos: review of the diagnostic criteria and evidence for phenotypic modules in complex malformation syndromes. J Med Genet. 2002 Sep;39(9):623-33. doi: 10.1136/jmg.39.9.623. Citation on PubMed or Free article on PubMed Central
  • Thi Pham XT, Nguyen PN, Hoang XS. Fraser Syndrome: A Narrative Review Based on a Case from Vietnam and the Past 20 Years of Research. Diagnostics (Basel). 2025 Jun 25;15(13):1606. doi: 10.3390/diagnostics15131606. Citation on PubMed
  • van Haelst MM, Maiburg M, Baujat G, Jadeja S, Monti E, Bland E, Pearce K; Fraser Syndrome Collaboration Group; Hennekam RC, Scambler PJ. Molecular study of 33 families with Fraser syndrome new data and mutation review. Am J Med Genet A. 2008 Sep 1;146A(17):2252-7. doi: 10.1002/ajmg.a.32440. Citation on PubMed
  • van Haelst MM, Scambler PJ; Fraser Syndrome Collaboration Group; Hennekam RC. Fraser syndrome: a clinical study of 59 cases and evaluation of diagnostic criteria. Am J Med Genet A. 2007 Dec 15;143A(24):3194-203. doi: 10.1002/ajmg.a.31951. Citation on PubMed
  • Vogel MJ, van Zon P, Brueton L, Gijzen M, van Tuil MC, Cox P, Schanze D, Kariminejad A, Ghaderi-Sohi S, Blair E, Zenker M, Scambler PJ, Ploos van Amstel HK, van Haelst MM. Mutations in GRIP1 cause Fraser syndrome. J Med Genet. 2012 May;49(5):303-6. doi: 10.1136/jmedgenet-2011-100590. Epub 2012 Apr 17. Citation on PubMed

The information on this site should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health.