At the Sixth International Workshop on Multiple Endocrine Neoplasia (MEN) at Noordwijkerhout, the Netherlands, in June 1997, there were several presentations that dealt with the question of prenatal diagnosis for MEN and VHL.

Dr. Robert Gagel of the M.D. Anderson Cancer Research Center in Houston, Texas, spoke about clinical use of DNA analysis in MEN2, using genetic analysis to determine risk factors and develop strategies to minimize the impact of the condition.

In the course of his talk he described one example of preimplantation screening. A patient with MEN 2A (medullary thyroid carcinoma, pheochromocytoma and parathyroid disease) and a RET proto-oncogene mutation sought preimplantation screening. The patient and his wife had made a tentative decision to not have children because of morbidity related to thyroid cancer and pheochromocytoma in other family members. The identification of a specific RET mutation causative for MEN 2A in this family and the availability of expertise in preimplantation screening led them to request in vitro fertilization and experimental preimplantation screening to avoid having an affected child.

The procedure consists of

hyperstimulating the mother’s ovaries, removal of eggs thru vaginal wallplacing eggs in petri dish with in vitro fertilization, fertilize with father’s spermgrowing them 3 days to 8 cellsteasing away a single cell, analyzing that one cell
reimplanting only the blastomas with normal MEN genes into the mother’s uterus

Their experience in this case was:

7 normal embryos, 4 affected, 1 testing failure4 embryos were frozen for potential later use
3 were transferred to the mother’s uterus

They had a miscarriage on the first try. On the second independent attempt there was failure of implantation. The couple decided not to try preimplantation screening, but subsequently conceived by natural methods. The MEN2 status of the child is not yet known, but the couple are happy parents.

Economically, the possibility of eliminating the altered gene is very attractive. Even though the cost of the procedure is high, the cost will be recouped in a single generation.

$25-50K for preimplantation screening, with a success rate of 25-45%
cost of management of MEN2 over a lifetime can range from $50,000 to $100,000.

But the emotional cost is high, and there are many ethical arguments. Will the elimination of the mutant allele from the gene pool have some long-term unanticipated effect? Perhaps there is a genius gene on the same chromosome?

Dr. J. P. M. Geraedts of the Genetics department, University of Maastricht, the Netherlands, also spoke about in-vitro fertilization. The biggest problem, he said, is that we are still unable to make a positive selection – we can only make a negative one. It would be nice if we could determine which sperm carried the altered gene and sort them out before fertilization, but we can’t study the sperm without killing it. Through pre-implantation diagnosis we can choose not to implant the blastomas with the altered gene. With pre-natal diagnosis the pregnancy is already well established, and a choice to abort is problematic. His team has also found that there is a problem with false positive and false negative results, especially in dominant disorders. Dr. Maher expressed concern that not all VHL gene mutations detected in blood may be readily detected in a single cell.

The quandary is: Is an embryo a human being from the moment of conception, or does it gradually become a human being? Is pre-implantation testing more acceptable because it’s earlier, or is prenatal testing more acceptable because it is a completely natural conception without danger of damage to the embryo? You take away 1-2 cells, and what are the long-range effects? We don’t know. In each country the government is looking at this problem.

In the Netherlands in 1993 legislation was submitted for "severe lethal diseases with a high recurrence risk" by KEMO the Dutch agency that oversees such things. At present it has still not been implemented. "KEMO holds the view that the first clinical applications of PGT for the time being need to be restricted to severe conditions, for which no treatment is available, because of the burden, the uncertainties and the risks of this still experimental procedure." The Dutch authorities believe that the use of pre-natal testing and abortion to prevent the birth of a child with a cancer predisposition factor is not justified.

During the consensus conference, questions were posed to the attendees about their opinions about the use of DNA diagnosis in VHL.

Question: If a specific mutation is present in a definitely affected family member, at what age do you advise to have DNA analysis performed on his/her offspring?

prenatally 5%

at birth 17%

1-5 years 36%

5=10 years 15%

start of clinical exams 8%

at age when children can choose 18%

when symptoms are present 3%

In Dr. Neumann’s experience, parents want their children tested at 1-5 years, and we do have children with serious eye problems before age 5.

Another physician commented that it aligns with the time at which you begin clinical screening for this disease -- you simply complement regular screening with DNA testing.

Question: Would you advise IVF plus preimplantation testing (PGT)?

Never 42%

Yes for MEN1 and MEN2 as well as VHL 32%

Only for MEN1 and VHL (because MEN2 may be cured) 13%

Only for VHL 13%

The attendees were hotly divided on this question. One attendee from Israel said that in cases where the condition was not 100% penetrant (where everyone has severe problems), using such a method is ethically very questionable. Throughout Europe anything that appears to be "selective breeding" raises unhappy memories of Nazi policies. IVF/PGT is not allowed in Germany, and the physician cannot even recommend a doctor in another country who performs this procedure. Employees of the U.S. National Institutes of Health can not even comment on this topic.

As printed in the VHL Family Forum 6:1, March 1998. For permission to reprint, please contact VHL Family Alliance, info@vhl.org.