Fraser and Ablepharon macrostomia phenotypes: Concurrence in one family and association with mutatedFRAS1

Abstract

To date, Fraser syndrome (FS) and Ablepharon macrostomia syndrome (AMS) have been considered distinct disorders, but they share strikingly similar patterns of congenital abnormalities, specifically craniofacial anomalies. While recent research has led to the identification of the genes FRAS1 and FREM2 as the cause of FS, the genetic basis of AMS continues to be enigmatic. We report on the concurrence of AMS-like and Fraser phenotypes in a Brazilian family. Both affected sibs were homozygous for a novel splice site mutation in the FRAS1 gene. Extensive studies on mRNA expression indicated that this mutation most likely leads to loss of function as most previously reported FRAS1 mutations associated with FS. We conclude that a phenotype resembling AMS is a rare clinical expression of FS with no obvious genotype-phenotype correlation. However, the molecular basis of "true" AMS which has been reported as a sporadic disorder in all cases but one, and so far with no relation to FS, is probably different and still needs to be further investigated.

fras1shapes endodermal pouch 1 and stabilizes zebrafish pharyngeal skeletal development

“…Similar to zebrafish fras1 mutants, human Fraser syndrome patients also show profound variation between siblings (Cavalcanti et al, 2007;Prasun et al, 2007), asymmetry within individual patients (Cavalcanti et al, 2007), and similar variation across distinct families (van Haelst et al, 2008). These observations of Fraser syndrome patients, combined with our observations of genetically similar fras1 mutant zebrafish raised in tightly controlled environments, indicate that stochastic processes influence Fraser syndrome variation.…”

“…Developmental instability may also influence symptomatic expressivity in human Fraser syndrome (Cavalcanti et al, 2007). It is likely that genetic variation also influences some of the observed phenotypic variation in patients with Fraser syndrome (Slavotinek and Tifft, 2002).…”

“…For instance, siblings can show life and death differences in symptomatic expressivity (Prasun et al, 2007). Other models focus on stochastic sources of variation in Fraser syndrome, noting that symptoms (cryptophthalmos) can vary between left and right sides of patients at frequencies predicted by chance (Cavalcanti et al, 2007).…”

Barber–Say syndrome and Ablepharon–Macrostomia syndrome: An overview

“…If uncertainties remained the feature was not scored for the patient involved. Several patients were excluded as likely a different disorder was present [Pellegrino et al, 1996;Amor and Savarirayan, 2001;Cavalcanti et al, 2007;Kallish et al, 2011;Larumbe et al, 2011;Suga et al, 2014], or we remained uncertain about the diagnosis (please see Differential Diagnosis for a more detailed discussion of these reports) [Sod et al, 1977;Dinulos and Pagon, 1999 (patient 2); Ng and Rajguru, 2006].…”

“…Since then, 19 patients were reported as having AMS [Hornblass and Reifler, 1985;Cesarino et al, 1988;Jackson et al, 1988;Markouizos et al, 1990;Price et al, 1991;Cruz et al, 1995;Pellegrino et al, 1996;Ferraz et al, 2000;Amor and Savarirayan, 2001;Stevens and Sargent, 2002;Brancati et al, 2004;Cavalcanti et al, 2007;Kallish et al, 2011;Rohena et al, 2011;Larumbe et al, 2011;Feinstein et al, 2015]. McCarthy and West [1988] suggested an autosomal recessive pattern of inheritance due to the resemblance of the phenotype with other entities with eyelid abnormalities that followed this pattern of inheritance.…”