Three patients with hallucal polydactyly and WAGR syndrome, including discordant expression of Wilms tumor in MZ twins

Abstract

The WAGR contiguous gene deletion syndrome is a combination of Wilms tumor, Aniridia, Genito-urinary abnormalities, and growth and mental retardation which is invariably associated with an 11p13 deletion. We report two monozygotic twins and a third, unrelated patient with WAGR syndrome and additional clinical features not usually associated with WAGR. Both twins had developmental delay, growth deficiency, severe ocular involvement (nystagmus, aniridia, cataracts), atrial septal defect and two uncommon findings: agenesis of the corpus callosum and duplication of the halluces. One twin developed Wilms tumors aged 19 months while her sister remained tumor free by the age of 6.5 years. The singleton patient showed typical WAGR syndrome and preaxial hallucal polydactyly. Molecular cytogenetic studies refined the identification of the extent of the deleted segments, which were not identical in the two families. The two deletions included the PAX6 and WT1 genes as previously reported in typical WAGR patients. The unusual anomalies described in this report, may represent the expression of low penetrant traits associated with haploinsufficency of one or more of the genes present in the deletion (PAX6 is expressed in CNS) or may indicate epistatic influences of modifier genes on the expression of gene(s) present in the WAGR region.

A novel WT1 mutation in a 46,XY boy with congenital bilateral cryptorchidism, nystagmus and Wilms tumor

“…However, although nystagmus has been previously described in a few female WAGR patients with WT1 gene deletions [14,15,17], to our knowledge our patient represents the first case in which this congenital defect is observed in a carrier of an intragenic WT1 mutation. Whether the two events are causally related or merely coincidental remains to be determined.…”

“…In fact, different clinical manifestations, including severe obesity, nystagmus and polydactily, in addition to those defining the WAGR syndrome, have been variably observed in individuals with WT1 gene deletions [13][14][15][16][17]. Analogously, a few DDS patients with WT1 missense mutations exhibit additional phenotypes, such as pyloric stenosis and cortical atrophy [18,19], whereas congenital diaphragmatic hernia has been reported both in WAGR and in DDS patients [20][21][22][23].…”

PAX6 mutation in association with ptosis, cataract, iris hypoplasia, corneal opacification and diabetes: a new variant of familial aniridia?

“…There is a single case report in the literature of agenesis of the corpus callosum occurring in association with aniridia as part of the WAGR syndrome (Wilms tumour, aniridia, genitourinary anomalies and mental retardation, a contiguous gene deletion syndrome because of deletion of 11p13, the region containing the WT1 and PAX6 genes) which in contrast, our patient did not have. 24 The PAX6 mutation database also revealed cases of aniridia associated with agenesis of the anterior commissure. 12 There are no reports of lipomas associated with PAX6 mutations.…”

Non‐identical monozygotic twins, intermediate twin types, zygosity testing, and the non‐random nature of monozygotic twinning: A review

“…In a family with multiple endocrine neoplasia type 1 (MEN1), MZ twins inherited from their mother a novel mutation in the MEN1 gene; one twin had hyperparathyroidism and an insulinoma, whereas the other twin was asymptomatic [Concolino et al, 2008]. In a pair of female MZ twins with WAGR syndrome, one twin developed a Wilms' tumor at the age of 19 months, whereas the other twin was tumor-free to the age of 6 years [Brémond-Gignac et al, 2005]. A pair of MZ twins were discordant for retinoblastoma.…”