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GENETICS ASSESSMENT OF PRIMARY LYMPHOEDEMA
MICHELINI S. 1, BRUSON A. 2, CARDONE M. 1, SIROCCO F. 2, FIORENTINO A. 1, CECCHIN S. 2, SAINATO V. 1, BERTELLI M. 2
1 Ospedale San Giovanni Battista - ACISMOM, Rome (IT); 2 MAGI’SLAB - Rovereto (IT)
Introduction: Up to date, no one can say that all primary lymphedema are of genetic origin. We know the genetic familial forms (VEGFR and FOXC2) and some cases in which these two genetic mutations are also present in clinical 'sporadic' cases. But this does not mean that other causes, besides mutations genetically passed (so-called Mendelian), may induce alterations in the protein sequencing on the DNA of an embryo for various reasons (such as radiations, drugs – for example thalidomide in phocomelics - and perhaps many other causes or contributing factors).
Materials and methods: In our experience of a total of one thousand one hundred thirty four patients with primary lymphoedema, 7.6 percent presented the disease at the birth, in the 3.8 percent it appeared before the second decade of life and about 90 percent it appeared from the third decade of life.
Again in our casuistry of 220 probands, 3.9 percent of patients with primary lymphoedema submitted a positive family history, 6.0 percent belonged to syndromic lymphoedema and 90 percent appeared as sporadic forms.
Results: Among the enrolled probands with clinical diagnosis of primary lymphoedema, a positive family history was documented in 42 individuals, while regarding the remaining ones we do not have any news. By direct sequencing of exons 17-26 of the gene VEGFR3, including adjacent intronic regions and the only exon of the gene FOXC2, including intronic regions adjacent, have been indentified 12 different not common nucleotide change in 12 patients (nine are new alterations): six nucleotide alterations are located within the FLT4 gene (13% of cases) and the same number (13%) within the FOXC2 gene. These nucleotide changes were absent in 100 healthy subjects. In 8 of these 12 patients it was documented a positive family history. Other mutated genes discovered in probands were: KIF 11, GJC2, GATA2, HGF. The study is going on the families. In two cases we found a genetic mutation never described in literature: one in the codon 286 of gene VPR2 and the other in codon 5 of gene FLT4. The association between the mutation and the phenotype of lymphoedema is not clear and it will be further developed in other members of the same families, analyzing the problem.
Conclusions: This double clinical and genetic assessment allows us to decide the more appropriate management of patient and his/her family and could also provide the possibility of determining transmission risks; enabling application to prenatal diagnosis.
COMBINED PRIMARY LYMPHOEDEMA AND OTHER VASCULAR MALFORMATIONS
LEE BB, MD, LAREDO J, MD, AND NEVILLE R, MD
Department of Surgery George Washington University, Washington DC, USA
Introduction: Primary lymphedema represents the clinical manifestation of defective development of lymph-transporting system affecting lymph vessels and/or lymph nodes. It is therefore, one of the lymphatic malformations (LMs) involved to the “later” stage of lymphangiogenesis while lymphatic vessel trunks are formed.
Hence, the matured lymphatic vessels/nodes are directly involved as various extents of defective condition: hypoplasia, hyperplasia, and aplasia. And they were classified/named to “truncular” LM lesions.
However, when the developmental arrest should occur in the 'earlier' stage before the stage of vessel trunk formation , it maintains the primitive structure of reticular network and remains as a amorphous vascular cluster. They were named to “extratruncular” LM lesions. Traditionally, they were called as “lymphangioma” and more specifically to “cystic hygroma” for the head & neck cases.
Nevertheless, the most unique condition “extratruncular” LM lesions have as an embryonic tissue remnant is the mesenchymal cell characteristics to grow through the rest of life when the condition should meet with adequate stimulation (e.g. menarache, pregnancy, hormone, trauma, and surgery).
For such condition/milieu to cause the defective development in the later stage of lymphangiogenesis to result in “primary” lymphedema, there is always a good risk to have similar defective development in the earlier stage of the lymphangiogenesis to result in “lymphangioma”.
Logically, there is same risk of defective development not only in the lymphatic system through two different stages of the lymphangiogenesis but also in the venous, arterial and capillary systems.
Such condition of combined vascular malformations has been newly classified to Hemolymphatic malformation (HLM) consisted of various vascular malformations: venous malformation (VM), arterio-venous malformation (AVM), and/or capillary malformation (CM).
Through gone era of old concept based on name-based eponyms, this unique condition of VM, LM, and CM coexisting simultaneously, was called “Klippel-Trenaunay syndrome (KTS)” while another condition with additional AVM was called “Parkes Weber syndrome (PWS)” to differentiate these two different conditions.
Although the majority of LM lesion exists as an independent form of the vascular malformation, infrequently both truncular and extratruncular LM lesions coexist and also further with other vascular malformations to form a HLM.
Conclusion: Proper identification of two different embryological subtypes is mandated not only for proper management of primary lymphedema as one of the LMs but also for all other congenital vascular malformations (CVMs). Especially when primary lymphedema/truncular LM is identified as one of the many different vascular malformation components of KTS or PWS, proper evaluation of other coexisting CVMs is as important as the LM itself.
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THE EUROPEAN JOURNAL OF LYMPHOLOGY - Vol. XXVI - Nr. 72 - 2015