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• Phenotypic non-penetrance in Milroy-like disease associated with a mutation in the vascular endothelial growth factor-C gene (VEGFC)
  Henri J. Boersma, Martijn V. Heitink, Jiddeke M. van de Kamp and Michel van Geel
  Published on: 17 May 2017

• Published on: 17 May 2017

  Phenotypic non-penetrance in Milroy-like disease associated with a mutation in the vascular endothelial growth factor-C gene (VEGFC)

  • Henri J. Boersma, MD, PhD candidate Department of Dermatology, Maastricht University Medical Centre, Maastricht, Netherlands
  • Other Contributors:
    • Martijn V. Heitink, Dermatologist
    • Jiddeke M. van de Kamp, Clinical Geneticist
    • Michel van Geel, Clinical Laboratory Geneticist

  Phenotypic non-penetrance in Milroy-like disease associated with a mutation in the vascular endothelial growth factor-C gene (VEGFC)

  Boersma, H.J.1, M.V. Heitink2, J.M. van de Kamp3, van Geel, M 1,4

  1 Department of Dermatology, Maastricht University Medical Centre+, Maastricht, The Netherlands
  2 Department of Dermatology, VieCuri, Venlo, The Netherlands
  3 Department of Clinical Genetics, VU Medical Centre, Amsterdam, The Netherlands
  4 Department of Clinical Genetics, Maastricht University Medical Centre+, Maastricht, The Netherlands

  With great interest, we read the article by Balboa-Beltran et al [1], where they presented a three-generation family with a phenotype of typical Milroy disease without mutations in FLT4 but instead in VEGFC. Milroy disease is an autosomal dominant, congenital form of primary lymphoedema with reduced penetrance. In approximately 70% of Milroy disease patients, mutations in FLT4 are identified [2]. Connell et al. presented research wherein FLT4 pathogenic variants were detected in 75% of clearly affected patients having a positive family history and in 68% of typical Milroy patients but without a family history [3], suggesting that other genes may be involved. Balboa-Beltran et al [1], detected a novel nonsense mutation (p.(Arg210*)) in VEGFC by exome sequencing causing Milroy-like disease. They found that all carriers of this VEGFC mutation exhibited the clinical diagnostic criteria of Milroy disease, inclu...

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  Phenotypic non-penetrance in Milroy-like disease associated with a mutation in the vascular endothelial growth factor-C gene (VEGFC)

  Boersma, H.J.1, M.V. Heitink2, J.M. van de Kamp3, van Geel, M 1,4

  1 Department of Dermatology, Maastricht University Medical Centre+, Maastricht, The Netherlands
  2 Department of Dermatology, VieCuri, Venlo, The Netherlands
  3 Department of Clinical Genetics, VU Medical Centre, Amsterdam, The Netherlands
  4 Department of Clinical Genetics, Maastricht University Medical Centre+, Maastricht, The Netherlands

  With great interest, we read the article by Balboa-Beltran et al [1], where they presented a three-generation family with a phenotype of typical Milroy disease without mutations in FLT4 but instead in VEGFC. Milroy disease is an autosomal dominant, congenital form of primary lymphoedema with reduced penetrance. In approximately 70% of Milroy disease patients, mutations in FLT4 are identified [2]. Connell et al. presented research wherein FLT4 pathogenic variants were detected in 75% of clearly affected patients having a positive family history and in 68% of typical Milroy patients but without a family history [3], suggesting that other genes may be involved. Balboa-Beltran et al [1], detected a novel nonsense mutation (p.(Arg210*)) in VEGFC by exome sequencing causing Milroy-like disease. They found that all carriers of this VEGFC mutation exhibited the clinical diagnostic criteria of Milroy disease, including lower-limb swelling at birth or soon thereafter and upslanting toenails. In their article, the mutation segregated with the phenotype in the family according to a dominant inheritance model with full penetrance. In an article by Gordon et al [4] it was already demonstrated that mutations in VEGFC can cause a Milroy disease-like phenotype similar to that found in patients with mutations in the FLT4 gene. We would like to add to this knowledge by presenting a new case, seen in our Dutch academic hospital.

  In 2013, a young, male patient (1 year) exhibited lymphoedema in his right foot without a dilated vena saphena magna. At birth he presented with bilateral foot and lower leg lymphoedema, diminishing on the left after 3 months. The symptoms were suggestive of Milroy’s disease. To determine whether these symptoms were caused by a mutation, we performed Sanger sequence analysis for FLT4 and VEGFC and found the same heterozygous nonsense VEGFC mutation as described by Balboa-Beltran et al [1]. To determine if the mutation occurred de novo or segregated in the family, both parents were tested. The mutation was also found in his asymptomatic 28-year-old father. The patient’s paternal grandmother, also having the mutation, mentioned that she exhibited heavy peripheral oedema when she was pregnant. The paternal great-grandmother (not tested) supposedly developed extreme peripheral oedema after a uterus-extirpation in the past and we were informed that the paternal grandmother’s sister had large ankles at adult age. However, no conclusions may be drawn from the latter family members, since mutation analysis was not performed. This family suggests, in contrast to the article of Balboa-Beltran et al [1], that non-penetrance of this nonsense mutation in VEGFC is evident, in line with the patient’s initial absence of disease history within the family. Similar variable penetrance, is reported in Milroy disease associated with mutations in FLT4, where 10%-15% of individuals with an FLT4 pathogenic variant were shown to be clinically unaffected [2].

  References:
  1 Balboa-Beltran E, Fernandez-Seara MJ, Perez-Munuzuri A, et al. A novel stop mutation in the vascular endothelial growth factor-C gene (VEGFC) results in Milroy-like disease. J Med Genet 2014;51(7):475-8.
  2 Brice G, Child A, Evans A, et al. Milroy disease and the VEGFR-3 mutation phenotype. J Med Genet 2005;42(2):98-102.
  3 Connell FC, Ostergaard P, Carver C, et al. Analysis of the coding regions of VEGFR3 and VEGFC in Milroy disease and other primary lymphoedemas. Human Genet, 2009; 124(6), 625–631.
  4 Gordon K, Schulte D, Brice G, et al. Mutation in vascular endothelial growth factor-C, a ligand for vascular endothelial growth factor receptor-3, is associated with autosomal dominant milroy-like primary lymphedema. Circ Res 2013;112(6):956-60.

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  Conflict of Interest:
  None declared.

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