Wednesday 15 December 2004
Fraser syndrome is an autosomal recessive malformative syndrome. It occurs in 1:10,000 births.
Commonest anomalies in humans are cryptophthalmos, cutaneous syndactyly of digits, abnormal ears and genitalia, renal agenesis, and congenital heart defects. Almost half of affected infants are stillborn or die in infancy, and mental retardation is common.
Cryptophthalmos may be partial or complete, unilateral or bilateral, apparently nonsyndromal or syndromal. Cryptophthalmos is a developmental field defect on the basis of heterogeneity (autosomal dominant and recessive forms) and phylogeneity (occurrence also in the pheasant, rabbit, pigeon, dog, and mouse).
Fraser syndrome is a recessive, multisystem disorder presenting with cryptophthalmos, syndactyly and renal defects and associated with loss-of-function mutations of the extracellular matrix protein FRAS1.
- unusual hairline (hair growth on temples extending to lateral eyebrow)
- middle ear malformations
- external ear malformations
- absent or malformed lacrimal ducts
- hypoplastic, notched nares
- broad, low nasal bridge
- midline nasal cleavage
- cleft lip / cleft palate
- teeth crowding
- laryngeal stenosis
- laryngeal atresia
widely spaced nipples
- small penis
- clitoral enlargement
- vaginal atresia
- bicornuate uterus
- anterior urethral atresia (10051174)
- gonadal dysgenesis (3086530)
- gonadoblastoma in situ (3086530)
diastasis of symphysis pubis
- mental retardation
germline mutations in
- FRAS1 gene (MIM.607830)
- FREM2 gene (MIM.608945)
In humans this autosomal recessive disorder maps to 4q21, is homologous to the bleb (bl/bl) mouse, and is due to mutations in the FRAS1 gene that codes for a 4007 amino acid protein 85% identical to the Fras1 gene of the bleb mouse. Fras1 mutant mice have a blebbed phenotype characterized by intrauterine epithelial fragility generating serous and, later, hemorrhagic blisters. (15838507)
The myelencephalic blebs (my) strain has a similar phenotype and has been mapped to Frem2, a gene related to Fras1 and Frem1, and showed that a Frem2 gene-trap mutation was allelic to my. Expression of Frem2 in adult kidneys correlated with cyst formation in my homozygotes, indicating that the gene is required for maintaining the differentiated state of renal epithelia. (15838507)
Two individuals with Fraser syndrome were homozygous with respect to the same missense mutation of FREM2, confirming genetic heterogeneity. This only missense mutation reported in any blebbing mutant or individual with Fraser syndrome, suggests that calcium binding in the CALXbeta-cadherin motif is important for normal functioning of FREM2. (15838507)
Comstock JM, Putnam AR, Opitz JM, Pysher TJ, Szakacs J. Prenatal death in fraser syndrome. Fetal Pediatr Pathol. 2005 Jul-Aug;24(4):223-38. PMID: 16396829
Slavotinek, A.; Li, C.; Sherr, E. H.; Chudley, A. E. : Mutation analysis of the FRAS1 gene demonstrates new mutations in a propositus with Fraser syndrome. Am. J. Med. Genet. 140A: 1909-1914, 2006.
Jadeja S, Smyth I, Pitera JE, Taylor MS, van Haelst M, Bentley E, McGregor L, Hopkins J, Chalepakis G, Philip N, Perez Aytes A, Watt FM, Darling SM, Jackson I, Woolf AS, Scambler PJ. Identification of a new gene mutated in Fraser syndrome and mouse myelencephalic blebs. Nat Genet. 2005 May;37(5):520-5. PMID: 15838507
Vrontou, S.; Petrou, P.; Meyer, B. I.; Galanopoulos, V. K.; Imai, K.; Yanagi, M.; Chowdhury, K.; Scambler, P. J.; Chalepakis, G. : Fras1 deficiency results in cryptophthalmos, renal agenesis and blebbed phenotype in mice. Nature Genet. 34: 209-214, 2003. PubMed ID : 12766770
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. PMID: 12766769