Fraser syndrome without cryptophthalmos: Two cases.

Fraser syndrome (MIM#219000) is an autosomal recessive disorder, characterized by the association of cryptophthtalmos, syndactyly of the four extremities, urinary tract abnormalities and laryngo-tracheal anomalies. This condition is due to homozygous or compound heterozygous mutations in the FRAS/FREM complex genes: FRAS1, FREM2 and GRIP1. Here we report two atypical cases of Fraser syndrome due to mutations in the FRAS1 gene without cryptophthalmos. The first proband had syndactyly of three extremities, bilateral nostril coloboma, dysplastic ears with bilateral conductive hearing loss, blepharophimosis and lacrimal duct abnormalities. FRAS1 sequencing identified two pathogenic compound heterozygous variants: a nonsense variant in exon 70 and a missense variant in exon 24. The second proband had membranous syndactyly of the four extremities, left renal agenesis, laryngeal and ano-rectal malformations, dysplastic ears and bilateral conductive hearing loss. FRAS1 sequencing identified a pathogenic homozygous variant in the last exon of the gene. This first description of molecularly confirmed cases with Fraser syndrome without cryptophthalmos could contribute to further delineation of the clinical spectrum of Fraser syndrome, especially for possible phenotypically milder cases. Larger cohorts are required to try to refer the hypothesis of genotype-phenotype correlation.

Genetics of patella hypoplasia/agenesis.

The patella is a sesamoid bone, crucial for knee stability. When absent or hypoplastic, recurrent knee subluxations, patellofemoral dysfunction and early gonarthrosis may occur. Patella hypoplasia/agenesis may be isolated or observed in syndromic conditions, either as the main clinical feature (Nail-patella syndrome, small patella syndrome), as a clue feature which can help diagnosis assessment, or as a background feature that may be disregarded. Even in the latter, the identification of patella anomalies is important for an appropriate patient management. We review the clinical characteristics of these rare diseases, provide guidance to facilitate the diagnosis and discuss how the genes involved could affect patella development.