Segregation analyses and a genome-wide linkage search confirm genetic heterogeneity and suggest oligogenic inheritance in some Milroy congenital primary lymphedema families

Respiratory Sciences Center, University of Arizona College of Medicine, Tucson, AZ 85724, USA.
American Journal of Medical Genetics (Impact Factor: 3.23). 03/2001; 98(4):303-12. DOI: 10.1002/1096-8628(20010201)98:43.0.CO;2-9
Source: PubMed


We previously described six families with Milroy congenital lymphedema, only one of which showed possible linkage to a candidate locus on chromosome 5 [Witte et al., 1998]. We have now performed a complex segregation analysis of these families, and performed linkage analyses with the other 387 markers used in our genome-wide search. Our results confirm that Milroy lymphedema is generally inherited as a dominant condition. However, this mode of inheritance, as elucidated from the segregation analyses, did not account for all observed familial correlations. The segregation analysis also suggested that shared environmental or additional genetic factors are important in explaining the observed familial aggregation. The finding of linkage to multiple locations in the largest family studied by multipoint parametric mapping (one of which was confirmed by sib-pair non-parametric mapping), suggests that Milroy congenital lymphedema may be oligogenic in this family.

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    • "Multiple gene loci may be involved in the causation of PCL [10]. In particular, the vascular endothelial growth factor receptor-3 (VEGFR3) gene has been implicated in the pathogenesis of PCL. "
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    ABSTRACT: . Primary congenital lymphedema is a rare disorder associated with insufficient development of lymphatic vessels. Usually most patients present with lower extremity edema seen sonographically. Rarely primary congenital lymphedema may be associated with severe lymphatic dysfunction resulting in hydrops fetalis. Case . A 27-year-old primigravida with a family history of leg swelling throughout multiple generations was diagnosed early in the third trimester with hydrops fetalis. Delivery was undertaken at 32 weeks for nonreassuring fetal status and the infant expired at approximately 45 minutes of life. Primary congenital lymphedema was confirmed via molecular testing of the vascular endothelial growth factor receptor-3 gene. Discussion . The diagnosis of PCL is suspected prenatally when ultrasound findings coincide with a positive family history of chronic lower limb lymphedema. Isolated PCL is rarely associated with significant complications. Rarely, however, widespread lymphatic dysplasia may occur, possibly resulting in nonimmune hydrops fetalis.
    02/2013; 2013(4):186173. DOI:10.1155/2013/186173
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    • "Causative mutations have been described in the kinase domains alone, but only a few of the papers looked at the whole gene [Connell et al., 2009; Evans et al., 2003]. FLT4 mutations do not account for all cases of MD, and some reports have suggested that there may be considerable genetic heterogeneity [Holberg et al., 2001]. Connell et al. (2009) reported that with rigorous phenotyping about 70% of MD cases were positive for an FLT4 mutation. "
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    ABSTRACT: Milroy disease (MD) is an autosomal dominantly inherited primary lymphedema. In 1998, the gene locus for MD was mapped to 5q35.3 and variants in the VEGFR3 (FLT4) gene, encoding vascular endothelial growth factor receptor 3 (VEGFR3), were identified as being responsible for the majority of MD cases. Several reports have since been published detailing pathogenic FLT4 mutations. To date, a total of 58 different variants in FLT4, 20 of which are unpublished, have been observed in 95 families with MD. A review of published mutations is presented in this update. Furthermore, the unpublished variants are presented including clinical data. Comparison of clinical features in patients and their families with the same mutations reveals incomplete penetrance and variable expression, making genotype-phenotype correlations difficult. Most mutations are missense, but a few deletions and one splicing variant have also been reported. Several animal models have confirmed the role of VEGFR3 in lymphangiogenesis and studies show mutant VEGFR3 receptors are not phosphorylated. Here, an MD patient with the same p.Ile1053Phe change as seen in the Chy mouse is presented for the first time. This finding confirms that this mouse lineage is an excellent model for MD. All the data reviewed here has been submitted to a database based on the Leiden Open (source) Variation Database (LOVD) and is accessible online at
    Human Mutation 01/2013; 34(1). DOI:10.1002/humu.22223 · 5.14 Impact Factor
    • "It affects the lower extremities although the upper extremities and even the trunk or face may be involved. Cases may be sporadic or familial, and inheritance is classically autosomal dominant although recessive inheritance has been described.3 Lymphedema praecox (Meige disease) which is the most common form of primary Lymphedema, usually occurs in females and develops after puberty, during pregnancy or prior to the age of 35.14 On the other hand, secondary lymphedema is acquired obstruction of the lymphatics which results from tumor, surgery, post-irradiation fibrosis, post-inflammatory scarring, filariasis, trauma, thyroid disease, obesity and chronic venous insufficiency.15 "
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    ABSTRACT: A 15-year-old girl with right lower extremity lymphedema praecox was treated through Low Level Laser Therapy (LLLT), by means of a GaAs and GaAlAs diodes laser-therapy device. Treatment sessions were totally 24, each cycle containing 12 every other day 15-minute sessions, and one month free between the cycles. The treatment was achieved to decrease the edema and no significant increase in circumference of involved leg was found following three months after the course of treatment. Although LLLT can be considered a beneficial treatment for Lymphedema Praecox, any definite statement around its effectiveness needs more studies on more cases.
    Journal of research in medical sciences 06/2011; 16(6):848-51. · 0.65 Impact Factor
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