OBJECTIVE: To explore the prenatal and postnatal features and genetic characteristics of patients with Lymphedema-Distichiasis syndrome (LDS) due to variants of FOXC2 gene. METHODS: A retrospective analysis was carried out on the phenotypic information, fetal ultrasound image, and genetic testing of two Chinese pedigrees diagnosed at the Third Affiliated Hospital of Zhengzhou University. A literature review was also carried out by searching the China National Knowledge Infrastructure (CNKI), Wanfang Database, and PubMed databases dated from January 2010 to June 2024 using keywords "Lymphedema-Distichiasis syndrome " and "FOXC2 ". This study has been approved by the Medical Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Ethic No. 2021-046-01). RESULTS: Neither family was found to harbor chromosomal aneuploidy or pathogenic CNVs larger than 100 kb. The fetuses from pedigree 1 and pedigree 2 were respectively found to be heterozygous for a c.361C>T (p.R121C) variant and a c.168C>A (p.Y56*) variant of the FOXC2 gene. Both variants were paternally derived. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variants were classified as pathogenic and likely pathogenic, respectively. Literature search has identified 20 articles, and combined with our cases, a total of 117 patients were identified. Among them, 13 had shown prenatal phenotypes, primarily with increased nuchal translucency (NT) (12/13), urinary abnormalities (5/12), and fetal edema (4/13). Postnatal phenotypes were observed in 110 cases, mainly as distichiasis (87/110) and lymphedema (73/110). Only 6 cases had both prenatal and postnatal phenotypes. A total of 32 genetic variants were identified. CONCLUSION The primary prenatal manifestations of LDS include increased NT, fetal edema, pleural and abdominal effusion, and separation of renal collecting system. Postnatal phenotypes are primarily characterized by lymphedema, distichiasis, and spinal extradural arachnoid cysts. Discovery of the c.168C>A variant has expanded the spectrum of FOXC2 gene mutations in China.
Adult ; Female ; Humans ; Male ; Pregnancy ; China ; East Asian People/genetics* ; Eyelashes/abnormalities* ; Forkhead Transcription Factors/genetics* ; Genetic Testing ; Lymphedema/genetics* ; Pedigree ; Phenotype ; Retrospective Studies

OBJECTIVE: To analyze FOXC2 gene variant in a family affected with lymphodema-distichiasis syndrome (LDS). METHODS: Peripheral blood samples were collected for the extraction of DNA and protein. Whole-exome sequencing was carried out to detect variants in the proband. Suspected variant was validated by Sanger sequencing. Western blotting was used to detect changes in protein expression. RESULTS: The proband and his mother were both found to carry a heterozygous nonsense variant c.177C>G (p.Tyr59X) of the FOXC2 gene, which was previously unreported. Down-regulated expression of FOXC2 was detected by Western blotting. Prenatal ultrasonography of the fetus indicated increased nuchal thickness. Amniocentesis was performed at 21+1 weeks of pregnancy, genetic testing suggested that the fetus also carried the c.177C>G variant. CONCLUSION The patients' condition may be attributed to the heterozygous nonsense variant c.177C>G of the FOXC2 gene, which resulted in a significant decrease in FOXC2 expression. Increased nuchal thickness may also be related with decreased FOXC2 expression. Above finding has expanded the variant spectrum of the FOXC2 gene.
Codon, Nonsense ; Eyelashes ; abnormalities ; Female ; Forkhead Transcription Factors ; genetics ; metabolism ; Gene Expression ; Genetic Testing ; Genetic Variation ; Humans ; Lymphedema ; genetics ; Pedigree ; Pregnancy ; Prenatal Diagnosis

OBJECTIVE: To identify the genetic causes of a family with lymphedema-distichiasis syndrome (LDS). METHODS: The whole exome sequencing was performed in a aborted fetus as the proband, and a candidate gene was identified. Peripheral blood of 8 family members were collected. Genotypic-phenotypic analysis were carried out through PCR amplification and Sanger sequencing. RESULTS: The proband, and the mother, grandmother, uncle, granduncle of the proband all had distichiasis or varix of lower limb carried a CONCLUSIONS The
Aborted Fetus/physiopathology* ; Adult ; Eyelashes/pathology* ; Female ; Forkhead Transcription Factors/genetics* ; Frameshift Mutation ; Humans ; Lymphedema/pathology* ; Male ; Phenotype ; Pregnancy ; Whole Exome Sequencing

Child ; Chromosomes, Human, Y ; genetics ; Female ; Humans ; Lower Extremity ; pathology ; Lymphedema ; diagnosis ; genetics ; Noonan Syndrome ; diagnosis ; genetics

No abstract available.
DNA Mutational Analysis ; Female ; *Frameshift Mutation ; GATA2 Transcription Factor/*genetics ; Genetic Predisposition to Disease ; Hearing Loss, Sensorineural/diagnosis/genetics ; Humans ; Lymphedema/diagnosis/*genetics ; Myelodysplastic Syndromes/diagnosis/*genetics ; Phenotype ; Republic of Korea ; Young Adult

OBJECTIVETo identify the disease-causing gene in a four-generation Chinese family with 9 members affected with primary congenital lymphoedema (PCL, also known as Milroy disease).

METHODSLinkage analysis was performed with a few microsatellite markers flanking the candidate genetic loci for PCL, including 3 known genes associated with autosomal dominant PCL. For mutation analysis, VEGFR3 gene was sequenced with DNA from the proband. Direct DNA sequencing of exon 25 of the VEGFR3 gene was performed in all family members.

RESULTSThe disease gene in the family was mapped to chromosome 5q35.3 with a maximum Lod score of 2.07. Direct DNA sequencing of VEGFR3 gene revealed a heterozygous C to T transition at nucleotide 3341, resulting in p.Pro1114Leu mutation. The p.Pro1114Leu mutation co-segregated with all affected individuals in the family.

CONCLUSIONThis study identified a C3341T (p.Pro1114Leu) mutation in the VEGFR3 gene in a Chinese family with PCL, provided evidence that VEGFR3 mutation can cause PCL in Chinese.

Amino Acid Substitution ; Asian Continental Ancestry Group ; genetics ; Cataract ; genetics ; Genetic Loci ; Humans ; Lod Score ; Lymphedema ; genetics ; Microsatellite Repeats ; genetics ; Mutation ; Point Mutation ; Vascular Endothelial Growth Factor Receptor-3 ; genetics

OBJECTIVETo study the therapeutic effect of vascular endothelial growth factor C (VEGF-C) gene for chronic obstructive lymphedema in mouse tail model which may provide a new treatment for lymphedema.

METHODSRT-PCR and immunoabsorption were applied to detect VEGF-C gene expression in fibroblasts and secretion of VEGF-C protein in COS7 cells respectively after pCDNA3.1 (+) VEGF-C transfection. A mouse tail model of chronic obstructive lymphedema was created. Then the pcDNA3.1-VEGF-C plasmid was injected into the tail. The effect of modulating lymphangiogenesis was observed.

RESULTSCompared with control group, overexpression of VEGF-C enhanced lymphangiogenesis in vivo and mouse tail skin suffering chronic obstructive lymphedema was improved by VEGF-C gene significantly.

CONCLUSIONSVEGF-C can improve the lymphedema through enhancing lymphangiogenesis.

Animals ; COS Cells ; Cells, Cultured ; Cercopithecus aethiops ; Disease Models, Animal ; Female ; Gene Transfer Techniques ; Genetic Therapy ; Humans ; Lymphedema ; therapy ; Mice ; Mice, Inbred BALB C ; Plasmids ; Transfection ; Vascular Endothelial Growth Factor C ; genetics

OBJECTIVETo study the efficacy of gene therapy with human vascular endothelial growth factor-c (VEGF-C) on obstructive lymphedema.

METHODSTwo animal models of lymphedema were created: one in the right hind limb of adult New Zealand white rabbits and the other in SD mouse tail. Each model was randomly divided into two groups to receive intradermal injection of either VEGF-C gene (experimental group), or saline(control group). In rabbit model, the volume change of affected limb was measured. In mouse model, biopsy was performed after 3 weeks treatment to detect the expression of VEGF-C mRNA and proteins. The lymphagenesis was evaluated by immunohistochemical examination with lymphatic endothelium hyaluronan receptor antibody.

RESULTSThe volume of the affect rabbit limb decreased by (24.40 +/- 1.08) ml in experimental group, compared with (5.80 +/- 1.92) ml in control group (P = 0.0001). The expression of VEGF-C mRNA and protein increased markedly in experiment group, but not in controls. More lymphatic vessels with large caliber were seen in experiment group (P = 0.0004).

CONCLUSIONSVEGF-C gene therapy may alleviate or treat lymphedema by inducing lyphmangiogenesis.

Animals ; Disease Models, Animal ; Gene Transfer Techniques ; Genetic Therapy ; Humans ; Lymphedema ; therapy ; RNA, Messenger ; genetics ; Rabbits ; Rats ; Rats, Sprague-Dawley ; Vascular Endothelial Growth Factor C ; genetics