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Primary lymphoedema is a genetic disorder with numerous phenotypic subgroups. The most common form is the non-syndromic Meige disease, which is primarily of pubertal or later onset, with oedema clinically indistinguishable from that found in the lymphoedema-distichiasis syndrome. There are also other very rare forms of lymphoedema such as yellow nail syndrome and lymphoedema with ptosis, which are clinically similar to Meige disease. The only causative genes so far identified for the non-congenital primary lymphoedemas are the transcription factor FOXC2, where mutations are known to produce lymphoedema with distichiasis, and SOX18 in the very rare condition hypotrichosis-lymphoedema-telangiectasia. This study has examined FOXC2 gene by sequence analysis in 23 affected individuals with Meige disease. A novel truncating mutation (c.563-584del) was identified in one family and found to segregate with the disease in eight affected relatives over three generations. This deletion creates a frameshift that predicts a premature stop at nucleotide 599 and truncating the normal protein by 38%. Although the affected patient initially selected for mutation screening from this family had lymphoedema without distichiasis, all but one of his affected relatives who carried the FOXC2 mutation did have accessory eyelashes originating from their meibomian glands. This is further confirmation that of the primary lymphoedemas, only lymphoedema with distichiasis is caused by FOXC2 mutations. All forms of post-pubertal lymphoedema need careful phenotyping for distichiasis, which may prove difficult to confirm unless several family members are examined, and cannot ever be assumed to be absent from self-report.
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PMID:Primary non-syndromic lymphoedema (Meige disease) is not caused by mutations in FOXC2. 1819 97

Lymphedema-distichiasis syndrome (LD, OMIM 153400) is an autosomal dominant disorder with variable expression. It is caused by mutations in the FOXC2-gene, which codes for a forkhead transcription factor involved in the development of the lymphatic and vascular system. LD is characterized by late childhood or pubertal onset lymphedema of the limbs and distichiasis (double row of eyelashes). While the latter is the most common expression of LD, venous insufficiency occurs in half of the patients. Other associations have been reported, including congenital heart disease, ptosis, cleft lip/palate and spinal extradural cysts. Here we describe a family with classical lymphedema-distichiasis syndrome caused by a duplication in the FOXC2-gene.
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PMID:Lymphedema-distichiasis syndrome: a distinct type of primary lymphedema caused by mutations in the FOXC2 gene. 1898 89

Lymphedema-distichiasis syndrome is a rare primary lymphedema inherited as an autosomal dominant disorder. The characteristic features consist of late onset-lymphedema and distichiasis together with other occasionally seen features including varicose vein, cleft palate, ptosis, and congenital heart diseases. FOXC2 is the gene found to be associated with this syndrome. We report here the first Thai patient who has characteristic features of this syndrome and the infrequently described features including ankyloglossia, and Robin sequence which consists of glossoptosis, cleft palate, and micrognathia. Mutation analysis of FOXC2 revealed c. 595-596 insC.
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PMID:c. 595-596 insC of FOXC2 underlies lymphedema, distichiasis, ptosis, ankyloglossia, and Robin sequence in a Thai patient. 2018 99

Distichiasis presents as double rows of eyelashes arising from aberrant differentiation of the meibomian glands of the eyelids, and it may be sporadic or hereditary. FOXC2 gene mutations in hereditary distichiasis are rarely reported. Here, we examined two generations of a Chinese family with hereditary distichiasis but without lymphedema or other features of LD syndrome. The FOXC2 gene was amplified and sequenced in all family members. Subcellular localization and luciferase assays were performed to assess the activity of the mutant FOXC2 protein. Clinical examinations showed distichiasis, lower eyelid ectropion, congenital ptosis and photophobia in all affected individuals. Sequence analysis revealed a novel frameshift mutation, c.964_965insG, in the coding region of the FOXC2 gene. This mutation caused protein truncation due to the presence of a premature stop codon. A fluorescence assay showed that this mutation did not change the nuclear localization of the protein. However, it impaired DNA-binding activity and decreased transcriptional activation. This is the first report of a FOXC2 mutation in hereditary distichiasis in the Chinese population. The findings of our study expand the FOXC2 mutation spectrum and contribute to the understanding of the genotype-phenotype correlation of this disease.
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PMID:Novel FOXC2 Mutation in Hereditary Distichiasis Impairs DNA-Binding Activity and Transcriptional Activation. 2757 Apr 85

Lymphedema distichiasis syndrome (LDS) is a rare, autosomal dominant genetic condition, characterized by lower limb lymphedema and distichiasis. Other associated features that have been reported include varicose veins, cleft palate, congenital heart defects, and ptosis. We update a previously reported family with a pathogenic variant in FOXC2 (c.412-413insT) where five affected individuals from the youngest generation had congenital renal anomalies detected on prenatal ultrasound scan. These included four fetuses with hydronephrosis and one with bilateral renal agenesis. A further child with LDS had prominence of the left renal pelvis on postnatal renal ultrasound. We also describe a second family in whom the proband and his affected son had congenital renal anomalies; left ectopic kidney, right duplex kidney, and bilateral duplex collecting systems with partial duplex kidney with mild degree of malrotation, respectively. Foxc2 is expressed in the developing kidney and therefore congenital renal anomalies may well be associated, potentially as a low penetrance feature. We propose that all individuals diagnosed with LDS should have a baseline renal ultrasound scan at diagnosis. It would also be important to consider the possibility of renal anomalies during prenatal ultrasound of at risk pregnancies, and that the presence of hydronephrosis may be an indication that the baby is affected with LDS.
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PMID:Renal anomalies and lymphedema distichiasis syndrome. A rare association? 2854 99