Spinal extradural arachnoid cysts in lymphedema-distichiasis syndrome

Abstract

Purpose: Lymphedema-distichiasis syndrome is characterized by the presence of lower limb lymphedema and supernumerary eyelashes arising from the Meibomian glands. Spinal extradural arachnoid cysts have been observed in some families but their true frequency is unknown. The aim of this study is to determine the frequency of spinal extradural arachnoid cysts in lymphedema distichiasis syndrome. Methods: We collected clinical information from all 45 living members of a complete family of 48 members and performed molecular analysis of the FOXC2 gene in 30 individuals. We obtained spinal magnetic resonance imaging from all family members with a FOXC2 gene mutation. Results: Twelve family members carried a mutation in the FOXC2 gene and had clinical features of lymphedema-distichiasis syndrome. Of these, 58% (seven individuals) had extradural arachnoid cysts. Discussion: We suggest that a follow-up protocol for lymphedema-distichiasis syndrome families should include spinal magnetic resonance imaging for all affected members so that the timing of surgery for removal of these cysts can be optimized. Genet ymphedema-distichiasis is a rare familial syndrome with autosomal dominant inheritance (OMIM 153400). It is caused by mutations in the FOXC2 gene, a forkhead family transcription factor. 1 Lower limb lymphedema and distichiasis (supernumerary eyelashes arising from the Meibomian glands) characterize the syndrome. Other associated features are congenital cardiac defects, cleft palate, ptosis, and spinal extradural arachnoid cysts (SEDACs). The penetrance of the genetic defect is complete by adulthood 2 but expression is variable. The frequency of SEDACs in families with lymphedema-distichiasis syndrome (LDS) has not been established, although a family was described in which 70% of members had SEDACs. 3 We report on a family of 48 members over three generations in which 12 had LDS. We present data regarding prevalence of the FOXC2 mutation and the various clinical features in 30 individuals. SUBJECTS AND METHODSA 12-year-old asymptomatic girl attended our pediatric neurology clinic because her parents were worried that she might have spinal cysts because there was paternal family history of this malformation. Particularly, the girl's 13-year-old cousin had recently been found to have SEDACs compressing her spine, after presenting with a gait disturbance. Our patient's grandmother had been operated on twice for SEDACs. The parents wished to ascertain whether their child suffered from a genetic defect so that any necessary measures could be taken to prevent neurological damage. We obtained a magnetic resonance imaging (MRI) scan of her spine, which showed multiple SEDACs that were not compressing the spine (Fig. 1). Physical examination revealed no neurological deficits, but we noted mild lower limb lymphedema and distichiasis. There was a paternal family history of lymphedema. In view of the suspected diagnosis of LDS, we performed molecular analysis of the FOXC2 gene in the girl. A mutation was found, and we proposed a...

Identification of HOXD4 Mutations in Spinal Extradural Arachnoid Cyst

“…[ 10 ] The dural defect of SEDAC is considered to be due to abnormal dura mater development. FOXC2 , the disease gene for syndromic SEDAC[ 5 , 6 ] also encodes a homeobox transcription factor and expressed in the developing mesodermal mesenchyme which forms the dura mater. [ 13 – 15 ] Dura mater development would be impaired by FOXC2 loss of function mutations.…”

“…Genetic etiology of SEDAC has been suggested. [ 5 , 6 ] We previously investigated 2 familial SEDAC pedigrees associated with lymphedema-distichiasis syndrome (LDS) (OMIM 153400) and identified heterozygous loss of function mutations in FOXC2 (forkhead box C2). [ 6 ] In the study, we also investigated seven sporadic SEDAC patients, but found no FOXC2 mutation.…”

A novel FOXC2 mutation in spinal extradural arachnoid cyst

“…Most cases of SEDAC are sporadic; however, a few cases of familial SEDAC have been described. 4–7 Their studies showed that familial SEDAC was a part of phenotypes of lymphedema-distichiasis syndrome (LDS; OMIM 153400). LDS is an autosomal dominant disorder with variable expressivity.…”

“…Its minor phenotypes include ptosis, cleft palate, renal abnormalities, congenital heart disease, vertebral anomalies and SEDAC. 6 , 8–11 LDS was caused by FOXC2 (forkhead box C2) mutations. 6 , 12–16 We previously investigated two pedigrees with familial SEDAC and revealed that both families are related to LDS with variable expression of each phenotype.…”

“… 6 , 8–11 LDS was caused by FOXC2 (forkhead box C2) mutations. 6 , 12–16 We previously investigated two pedigrees with familial SEDAC and revealed that both families are related to LDS with variable expression of each phenotype. Subsequently, we identified novel FOXC2 mutations in each pedigree, giving solid evidence in the relationship between familial SEDAC and FOXC2 .…”