{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T17:43:28Z","timestamp":1792604608105,"version":"4.5.0"},"reference-count":30,"publisher":"BMJ","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"published-print":{"date-parts":[[2002,7]]},"abstract":"<jats:p>\n                  <jats:bold>Introduction:<\/jats:bold> Lymphoedema-distichiasis syndrome (LD) (OMIM 153400) is a rare, primary lymphoedema of pubertal onset, associated with distichiasis. Causative mutations have now been described in <jats:italic>FOXC2<\/jats:italic>, a forkhead transcription factor gene. Numerous clinical associations have been reported with this condition, including congenital heart disease, ptosis, varicose veins, cleft palate, and spinal extradural cysts.<\/jats:p>\n               <jats:p>\n                  <jats:bold>Subjects:<\/jats:bold> We report clinical findings in 74 affected subjects from 18 families and six isolated cases. All of them were shown to have mutations in <jats:italic>FOXC2<\/jats:italic> with the exception of one family who had two affected subjects with lymphoedema and distichiasis and linkage consistent with the 16q24 locus.<\/jats:p>\n               <jats:p>\n                  <jats:bold>Results:<\/jats:bold> The presence of lymphoedema was highly penetrant. Males had an earlier onset of lymphoedema and a significantly increased risk of complications. Lymphatic imaging confirmed the earlier suggestion that LD is associated with a normal or increased number of lymphatic vessels rather than the hypoplasia or aplasia seen in other forms of primary lymphoedema. Distichiasis was 94.2% penetrant, but not always symptomatic. Associated findings included ptosis (31%), congenital heart disease (6.8%), and cleft palate (4%). Other than distichiasis, the most commonly occurring anomaly was varicose veins of early onset (49%). This has not been previously reported and suggests a possible developmental role for <jats:italic>FOXC2<\/jats:italic> in both venous and lymphatic systems. This is the first gene that has been implicated in the aetiology of varicose veins.<\/jats:p>\n               <jats:p>\n                  <jats:bold>Conclusion:<\/jats:bold> Unlike previous publications, the thorough clinical characterisation of our patients permits more accurate prediction of various phenotypic abnormalities likely to manifest in subjects with <jats:italic>FOXC2<\/jats:italic> mutations.<\/jats:p>","DOI":"10.1136\/jmg.39.7.478","type":"journal-article","created":{"date-parts":[[2002,7,28]],"date-time":"2002-07-28T19:09:06Z","timestamp":1027883346000},"page":"478-483","source":"Crossref","is-referenced-by-count":235,"title":["Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with <i>FOXC2<\/i> mutations or linkage to 16q24"],"prefix":"10.1136","volume":"39","author":[{"given":"G","family":"Brice","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Mansour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Bell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J R O","family":"Collin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A H","family":"Child","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A F","family":"Brady","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Sarfarazi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K G","family":"Burnand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Jeffery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P","family":"Mortimer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V A","family":"Murday","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2002,7,1]]},"reference":[{"key":"2025101800543895000_39.7.478.1","first-page":"46","volume":"2","year":"1899","journal-title":"Ztschr Augenhkd"},{"key":"2025101800543895000_39.7.478.2","first-page":"505","volume":"56","year":"1892","journal-title":"NY Med J"},{"key":"2025101800543895000_39.7.478.3","first-page":"341","volume":"6","year":"1898","journal-title":"Presse Med"},{"key":"2025101800543895000_39.7.478.4","first-page":"248","volume":"62","year":"1965","journal-title":"Trans Am Ophthalmol Soc"},{"key":"2025101800543895000_39.7.478.5","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/7.13.2073"},{"key":"2025101800543895000_39.7.478.6","doi-asserted-by":"publisher","DOI":"10.1086\/303019"},{"key":"2025101800543895000_39.7.478.7","doi-asserted-by":"publisher","DOI":"10.1086\/302500"},{"key":"2025101800543895000_39.7.478.8","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.37.9.725"},{"key":"2025101800543895000_39.7.478.9","doi-asserted-by":"publisher","DOI":"10.1086\/316915"},{"key":"2025101800543895000_39.7.478.10","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.38.11.761"},{"key":"2025101800543895000_39.7.478.11","doi-asserted-by":"publisher","DOI":"10.1007\/s004390100528"},{"key":"2025101800543895000_39.7.478.12","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/10.11.1185"},{"key":"2025101800543895000_39.7.478.13","doi-asserted-by":"publisher","DOI":"10.1038\/84781"},{"key":"2025101800543895000_39.7.478.14","doi-asserted-by":"publisher","DOI":"10.1086\/302109"},{"key":"2025101800543895000_39.7.478.15","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.24.3.170"},{"key":"2025101800543895000_39.7.478.16","unstructured":"Widmer LK. 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