| Cryptophthalmos may be partial or complete, unilateral or bilateral, apparently nonsyndromal or syndromal. A recent study of 2 stillborn infants at the University of utah prompted an analysis of the developmental aspects of the syndromal form (fraser syndrome). We conclude that, per se, 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). 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. 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. The pathogenesis evidently involves abnormal epithelial integrity during prenatal life. Older (mostly German) publications, some dating to the 19th century, provide a fascinating historical insight into the process of syndrome delineation. ( info) |
| frasier syndrome is characterized by slowly progressive nephropathy, male pseudohermaphroditism, streak gonad, and high risk of gonadoblastoma development. Here we report a case of a 46,XY phenotypic female with frasier syndrome, who was under hemodialysis. While her serum estradiol level was gradually increasing annually, gonadotropin level was constantly extremely high, and her appearance was still prepubertal. She was heterozygous for a novel guanine>adenine point mutation at position 1 of the splice donor site within intron 9 (IVS 9 1G>A) of the Wilms' tumor 1 gene. The possibility of this disease should be taken into consideration whenever we encounter a patient with steroid-resistant nephrotic syndrome and delayed puberty. ( info) |
3/4. Mutation analysis of the FRAS1 gene demonstrates new mutations in a propositus with fraser syndrome. fraser syndrome (OMIM 219000) is a rare, autosomal recessive condition with classical features of cryptophthalmos, syndactyly, ambiguous genitalia, laryngeal, and genitourinary malformations, oral clefting and mental retardation. Mutations causing loss of function of the FRAS1 gene have been demonstrated in five patients with fraser syndrome. However, no phenotype-genotype correlation was established and there was evidence for genetic heterogeneity. fraser syndrome is rare and the FRAS1 gene has 75 exons, complicating mutation screening in affected patients. We have screened two patients who fulfilled the diagnostic criteria for fraser syndrome and three patients with related phenotypes (two patients with manitoba oculotrichoanal syndrome and one patient with unilateral cryptophthalmos and labial fusion) for mutations in FRAS1 to increase the molecular genetic data in patients with fraser syndrome and related conditions. We report two new mutations in a patient with fraser syndrome, a frameshift mutation and a deletion of two amino acids that we consider pathogenic as both alter the NG2-like domain of the protein. Although we are still unable to clarify a phenotype-genotype relationship in fraser syndrome, our data add to the list of mutations associated with this syndrome. ( info) |
4/4. Prophylactic bilateral salpingo-oopherectomy in a 17-year-old with frasier syndrome reveals gonadoblastoma and seminoma: a case report. Mutations in the Wilms' tumor gene are present in children with frasier syndrome, denys-drash syndrome, wagr syndrome, and some cases of Wilms' tumor. The Wilms' tumor gene product, WT1, is necessary for normal urogenital development. Frasier syndrome is an association between focal segmental glomerulosclerosis, beginning in the second and third decade, male to female sex reversal, and dysgenetic gonads. We report a case of frasier syndrome in a 17-year-old adolescent girl with renal failure, kidney transplant, and dysgenetic gonads, with development of gonadoblastoma and dysgerminoma (seminoma). The diagnosis of frasier syndrome was based on nephrotic syndrome with diffuse mesangial sclerosis leading to chronic renal failure, dysgenetic gonads, 46 XY karyotype in a phenotypic female, and a mutation in the Wilms' tumor gene. Prophylactic laparoscopic bilateral salpingo-oopherectomy revealed gonadoblastoma and seminoma in opposite atrophic ovaries as well as a hypoplastic uterus. Early prophylactic resection of dysgenetic gonads is indicated in children with frasier syndrome to prevent the development of germ cell malignancy. ( info) |