The following questions are all related and I will combine my answers into one response.
Q1: A young woman who is undergoing treatment for lymphedema of her lower limbs would like to start a family. She asks today: “What are my chances of having a baby with lymphedema?”
Q2: A young family has been seeing you for lymphedema therapy for their 3 year old child. They are planning a second child and want to know their risk of having a second child with lymphedema.
Q3: Are there any tests currently available to identify genetic mutations associated with LE?
A: These types of questions can be very difficult to answer and the responses to individual patients are likely to be somewhat different, depending on the particular situation and the information available. The first thing to think about is the type of lymphedema the patient presents. In Question 1, the young woman could have either primary or secondary lymphedema of her legs. Obtaining a good history, particularly with inquiries about any other family members with lymphedema, performing a thorough clinical evaluation, and obtaining lymphatic imaging usually will provide adequate information. If the lymphedema is secondary, there will be no genetic basis for passing on lymphedema to her offspring. However, she still could have a yet unknown genetic risk for lymphedema, e.g. inadequate levels of lymphatic pro-growth factors that could be passed on to her offspring and may predispose them to secondary LE.
If the lymphedema is primary, then
we can look at Questions 1 and 2 together.
The next determination to make
is whether the lymphedema is due to a
genetic defect that has been inherited
from the parents or, alternatively, is
due to a new mutation. Crucial to any
answers will be the family pedigree. If
the LE can be seen in at least one
member from each generation, then
the trait is most likely due to a dominant
mutation. This means that only
one mutated gene needs to be present
for LE to appear. If this is the
case, then the odds are 50% that the new offspring will be affected (due to a 50% chance of inheriting the mutated gene from the affected parent).
If the inheritance pattern does not
seem to follow dominant inheritance or
there are no other family members with
LE, the situation needs to be explored
further. In the case of Question 2, the
first child could have acquired LE if
both the parents carried one recessive
gene. If this is the case, then there
would be a 25% chance that the second
child could present with LE (50%
chance of mutated gene in parent 1 x
50% chance of mutated gene in parent
2). Alternatively, both the first child
from Question 2 and the patient from
Question 1 could have been born with
a new mutation that caused the LE
(note that structural or functional defects also can cause LE and one cannot assume that all primary lymphedemas have been inherited).
One must also be aware of reduced
penetrance (basically the ability of a
gene to show its effect) which could
cause an individual—a parent in this
case who carries the mutation—to not
present with lymphedema. If it seems
to be a new mutation, there is no easy
answer. This is because we don’t know
if the new mutation is dominant (with a
high chance of passing the gene on—
Question 1), or if it is a new recessive
mutation in one of the parents (Question
2). There are three confirmed
genes linked to lymphedema at the
present time. Mutations in VEGFR-3 have been found in a subpopulation of congenital lymphedema families and it is a dominant mutation. FOXC2 mutations have been reported in almost all families with lymphedema-distichiasis, and this also follows a pattern of dominant inheritance. The third, SOX18, has been limited to a few families worldwide and it follows a recessive pattern. The best way to search for these mutations is to sequence the genetic material at the gene locus. As many of you are aware, sequencing occurs in a multitude of laboratories around the world every day. However, there are only a handful of laboratories that focus on the lymphatic-related genes. Even though they can perform these analyses, these laboratories are restricted to research and there are no commercial tests or approved kits currently in place for the clinic.
There are likely many new lymphatic
system-related genes yet to be discovered,
and these will be inherited in
dominant and reces-sive (and possibly
even more complex) patterns. In the
future, genetic testing also will become
quicker, easier and more available
clinically. Until we reach that point in time, the many questions and uncertainties that remain will make answering the questions posed somewhat vexing and leave both the clinician and patient searching for more information on the unknowns.
Michael Bernas, MS
Associate Scientific Investigator
Department of Surgery
University of Arizona
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