Spring 2001

CONTENTS Page: 1. Letter from the Executive Director 1. NIPF changes name to IPIF 1. 83% of IP cases have same mutation in NEMO gene 2. IP in Male Individuals 3. Consortium Update 3. Honors 4. My Rendezvous with IP 5. Research Directions for the 21st Century 6. Support Groups 7. Amy Susan Paller, M.D. 7. Need for Contributions NIPF CHANGES NAME TO IPIF The National Incontinentia Pigmenti Foundation (NIPF) has changed its name to Incontinentia Pigmenti International Foundation (IPIF). In 1995 when NIPF was founded the word National was incorporated into the title. At the time it was thought that if NIPF were able to contact families, medical providers etc. all over the United States we would consider NIPF as wholly successful. However, after six years, it has become obvious that we did not realize our community would encompass literally the entire world, and certainly not in the space of only a few years. To brag a bit, our success has been overwhelming. The international nature of the IPIF is obvious. The International IP Research Consortium consisted of five laboratories, 4 of them in Europe, and for a brief time a sixth was in Scandinavia. IPIF maintains a database of several thousand patients, families and medical providers spread across almost every country in the world.

A number of changes have been made. A new logo has been designed. There is a new e-mail address: ipif@ipif.org, and please note that the web site address now ends with IPIF. New stationery has been printed as well as labels, envelopes and the brochure. All organizations, which currently list NIPF, have been notified. However, so as not to lose contact with anyone, we will maintain 2 telephone listings and we will not drop the old e-mail address. This is a big undertaking, but we felt a necessary one.   LETTER FROM THE EXECUTIVE DIRECTOR What a spectacular year 2000 was for Incontinentia Pigmenti! It was a year in which we reached many important goals. The most outstanding was the successful identification of the gene called NEMO that causes IP. New developments are constantly occurring, but it will be some time before we can match this achievement. When the foundation began in 1995, our goals were clear. However, we could never have imagined how rapidly we would accomplish such growth and success. I would like to repeat what I've said many times before: none of our goals could have been met without the help and dedication of our many supporters. Each year when we send out the newsletters some are returned addressee unknown. Those who move often forget to send us a change of address, or forget to send us their new e-mail address. As developments in IP are occurring at a rapid pace, we do not want anyone to miss current information, please let us know if you plan to move. Please remember that you can always log on to the web site for current information. The site has been translated into several languares and has been greatly expanded. It must be kept in mind, however, that this is no time for complacency. Each time we resolve one issue, another one appears. We are still very far from our ultimate goal. We must recognize that the problems we address are complex, and that the road ahead is a long one. It is easy to congratulate ourselves on what we have so far attained, but many more years of difficult research lie ahead of us. As a very famous man once said, "we are at the end of the beginning." Susanne Bross Emmerich

83% OF IP CASES HAVE SAME MUTATION IN NEMO GENE Mutations in genes come in many different guises. They may be small changes in the thousands of units (bases) that make up the NEMO gene, or they may be larger alterations that cut out part or all of the gene. It was a big surprise to the IP consortium to find that many IP women (83%) carry an identical change in the NEMO gene, where over half of the gene is missing. This 'common' mutation is readily detectable with a laboratory test that can be performed on a small blood sample. So accurate diagnosis of IP is now possible in 83% of cases. Testing for this mutation has now been set up in several diagnostic centers in Europe and the United States and contact details for these can be obtained from the IPIF web site. Although the same change in the NEMO gene is responsible for most cases of IP it is not always found. About 20% of women with IP don't have the common mutation. They may have a different change in the NEMO genetic code or have a different condition from IP altogether. . Finding these changes is less routine as it requires rigorous searching of the whole gene sequence. Presently this cannot be done in many diagnostic laboratories but it is still being undertaken by the collaborating laboratories of the IP consortium. For those in the 20% the following holds true: A diagnosis of IP can only be confirmed when a mutation in the gene is found. If nothing is found she may still have IP but it cannot be confirmed or ruled out. There does not seem to be a difference in the severity of IP symptoms between those in the 80% and those in the 20%. When a woman with IP becomes pregnant, and her mutation is unknown, then it may not be possible to determine if the fetus she is carrying has the mutated NEMO gene. Clearly, the more IP cases that can be confirmed by DNA testing the better, and so efforts are under way to make identification of rare NEMO mutations easier. Dr. Sue Kenwrick Cambridge Institute for Medical Research Cambridge, United Kingdom

 

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IP IN MALE INDIVIDUALS Mutations of the NEMO gene in IP patients typically abolish NF-kB activity, causing mutant cells to die and leading to the medical problems associated with IP. This cell death is also responsible for the death of male fetuses with an IP mutation; the male individuals lack a normal X-chromosome and cannot overcome the loss of NF-_kB activity. For many decades since its first description, IP was considered a "classic" male-lethal disorder because a vast majority of patients were females. The observation of multiple spontaneous abortions of male fetuses further made this an "indisputable" fact. In contradiction to this traditional concept about male lethality, we now understand that some male individuals can also suffer from IP. There are three mechanisms by which male IP patients survive the lethality that is usually associated with this disorder. A few reports of male individuals with IP exist in the scientific literature. Nearly all of these patients have a disorder called Klinefelter syndrome. Humans normally have 22 pairs of autosomal chromosomes and 2 sex chromosomes (XX in females or XY in males). In Klinefelter cases, the male individuals have an additional X chromosome, bringing the total chromosomal complement to 47. They are typically referred to as 47, XXY for 47 chromosomes, including two X chromosomes and one Y chromosome. One can imagine that if a Klinefelter boy has an IP mutation on one of his X-chromosomes, then the normal X-chromosome can rescue him from lethality that would otherwise result from the mutation. Hence, his situation is very similar to the condition in female IP patients. We recently demonstrated this phenomenon in a male individual with Klinefelter syndrome and IP. He has typical IP signs and has survived with the lethal NEMO deletion mutation found in 90% of IP patients. A second means by which male IP patients can survive is through having a mosaic mutation. What this means is that male individuals can be composed of two types of cell populations&endash;one group of cells that has an IP mutation and another group that does not. Very early in pregnancy, when a fetus is still a mass of few cells, a single cell may acquire a NEMO mutation. Since many cell generations arise from this single mutated parent cell, the resulting offspring cells will cause medical problems in tissues where they are present. Since most NEMO mutations are lethal to the cell, the mutant cells likely die during fetal development, allowing normal cells to proliferate and take their place. This is what happens in female IP individuals as well, except that the mutation is often inherited and the X-inactivation process leads to the mosaic characteristics of the IP female and prevents lethality.

The third mechanism that allows male individuals to survive with NEMO mutations was recently discovered by four scientific groups, including ours. Male patients of this type are providing clues to the many functions of NEMO, and are thus of particular interest. We were studying a couple of boys who had typical signs of IP but also had other medical problems not usually associated with IP. Remarkably, uncharacteristic of IP, all of these male patients had survived pregnancy and birth. The first male patient had osteopetrosis (bone expansions and fractures), lymphedema (swelling of limb extremities with lymph fluid), and immune dysfunction (which causes severe infections and often death). This patient died from tuberculosis at the age of 2.5 years. A second male patient had only severe immune dysfunction, in addition to IP signs, and he is still alive, although with multiple infections. The third male individual died from massive hemorrhaging (uncontrolled bleeding) 24 hours after birth. It is very important to understand that these male patients had affected female relatives, either siblings or parents, who exhibited typical IP signs but none of the unusual problems seen in the male individuals. Analysis of DNA from these male individuals showed that they had mutations near the end of the NEMO gene. Testing these mutations showed that they were not as severe as the NEMO mutations we had found before. Indeed it turned out that these unusual mutations reduced, but did not eliminate, NF-_kB activity. From these results, it became evident that mild mutations allow male patients to survive because NF-kB is still active in their mutant cells. Female patients with mild mutations do not show the range of medical problems seen in their affected male relatives because their additional, normal X-chromosome allows normal NF-kB activity and their mutant X-chromosome also does not eliminate NF-kB activity. Thus, the NF-kB activity in total is greater in tissues of female individuals than in those of male patients, and this likely explains the difference in medical problems between them. These findings constitute a benchmark achievement in IP research because they point out a historical error in diagnosis and genetic counseling for IP. In addition, male IP patients offer a unique opportunity to study this complicated disorder because they express all the possible medical signs that arise from defects in NEMO, some of which would otherwise be concealed by X-inactivation in female individuals and the lethality in male individuals with typical NEMO mutations. The mild mutations we have found in male IP patients have also illuminated other functions of the NF-kB molecule and revealed close links between IP and several other disorders.

Other disorders are now recognized as being related to IP because of the medical problems seen in male IP individuals. Once again, the reason that female IP patients do not demonstrate defects seen in any of the IP-related disorders or in male IP individuals is because they have two X-chromosomes and the X-inactivation process likely helps prevent complete expression of the physical signs. In the near future, these disorders together are likely to provide substantial insight into the mechanisms by which IP arises. With these developments, it has become obvious that the diagnostic methods for IP should be revised to include criteria for male cases. Since male individuals with IP demonstrate different medical problems depending on their mutation, we propose that they be categorized under a novel classification, called VOIMIE syndrome (for vascular anomalies, osteopetrosis, and immune dysfunction in male individuals with IP- or ED-like signs). Swaroop Aradhya, Ph.D. David L. Nelson, Ph.D. Department of Molecular and Human Genetics Baylor College of Medicine, Houston, Texas

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CONSORTIUM UPDATE The International IP Research Consortium has been a remarkable success. As noted in previous newsletters, not only have the members identified the gene, which causes IP; they also formed very close working relationships and mutual respect for each other's abilities. As is also quite rare in such circumstances a real affection developed among the participants. There was no existence of competitiveness or ego clashes and they all considered the meetings not only informative but also fun. Two events have led to a major change within the group. The first is that the goal of identifying the gene, which causes IP, has been successfully attained. The purpose for which the Consortium was created has been accomplished, and now the focus is a different one. It is to study the gene. The first change is the addition of new members to the consortium. Last year Alain Israel and Gilles Courtois of the Institut Pasteur joined us. They are involved in the second phase of IP, which is to study what happens within the body when the gene, called NEMO, mutates and causes IP. They are doing this by having created a mouse which has IP. Their other goal is to eventually be able to predict, either in utero or shortly after birth, the extent of the IP symptoms an individual will develop. Hopefully, after additional extensive research, one will be able to alter the outcome. By producing a mouse model with IP, and the various mutations, the members of the consortium can also study different possible treatment modalities. The most recent member to have joined the Consortium is Jean-Laurent Casanova of Laboratoire de Genetique Humaine des Maladies Infectieuses, Faculte de Medecine, Necker-Enfants Malades, Paris. He is renowned for having been the only member of the scientific community to successfully replace a mutated gene with a healthy version. He virtually eliminated the consequences of a very serious disorder commonly referred to as bubble babies--children who are born without an immune system. Four years ago he replaced the defective gene with a normal version and the children in the study group have been healthy for these last four years. We are hopeful that he can one day do the same for IP. The second change is the natural attrition of members of the Consortium that occurs over a period of time. Nina Heiss of Germany, left for two reasons. The laboratory, in which she worked only searches for genes, it does not study them. Therefore her work within the consortium had come to an end. The other reason Nina left is that she accepted a position in a pharmaceutical company. This means a great deal more can provide. Another of our leading researchers in Italy, Teresa Esposito, received a promotion and was transferred from Naples to Sardinia. Soon we will lose Swaroop Aradhya in the US. Swaroop's thesis for his Ph.D. at Baylor College of Medicine was the identification of the gene, which causes IP. As wonderful as the discovery was it meant that the consortium will no longer have the privilege of working with Swaroop. After obtaining his Ph.D. he will move on to another laboratory, as yet to be selected.

One of the saddest events was the loss of funding for IP research in England. Just as we all celebrated the identification of NEMO, the lab in Cambridge was required to reapply for its funding. This is a process that must be gone through every two years. To everyone's astonishment, the grant was refused. Even more surprising was that the organization that refused to renew the grant had just run an article in their journal lauding the success in identifying the gene that causes IP. Funders work in mysterious ways. We therefore have to say goodbye to Sue Kenwrick, Hayley Woffendin and Tracy Jakins, all of whom have been key to our success. I've taken the liberty of reprinting two of the farewell letters that were received. They express what it meant to the authors to be part of this consortium. Dear Susanne, I feel really sad that I have to leave this project and all the wonderful people that I've worked with. To be involved in such a successful project has been a dream. When we met 4 years ago in Paris and said we would do all we could to find the IP gene we had no idea whether we would do so in1 year or 15. Without your enthusiasm and support I doubt whether we would have been so successful and it certainly wouldn't have happened so quickly. At times it must have been quite tedious for you to sit through data presentations, but your presence really spurred me on. With you there I was always reminded of the larger picture of why we were doing all the painstaking work. It is quite incredible what you've achieved. You've met enough scientists to know that having a successful collaboration is very rare! May your hard work continue to give hope to so many people? With love, Hayley   Dear Susanne: I just had my thesis defense on Thursday (May 10). It was a hectic month before that, preparing a 250-page thesis. I'm relieved that it is over now so I can catch my breath, but also sad in a way because IP has been such a rewarding project to work on. It was an emotional moment when I had to thank everyone who has been helpful to me, particularly the Consortium. Best wishes, Swaroop

HONORS The first honor that was bestowed upon one of our IP Consortium members came at the annual meeting of The American Society of Human Genetics. This is the largest and most prestigious professional membership organization for human geneticists. In the year 2000 IPIF took its own booth. Literature was handed out, as well as printed copies of the web site, newsletters and brochures. Knowledge of and interest in IP has significantly increased over the years. At the closing of each meeting it presents three awards in the category of the Student Awards Program. Four awards for outstanding clinical and basic research are presented to students. We are extremely proud that in the year 2000 it was won by a member of the International IP Research Consortium, Swaroop Aradhya of Baylor College of Medicine. Swaroop has been a Ph.D. candidate whose thesis was identifying the gene which causes IP. This honor is much sought after and difficult to attain. Swaroop now has his Ph.D. The second member of our consortium of whom we are especially proud is Asmae Smahi at the Necker Hopital for les Enfants Malades in Paris, France. A competition was held at the National Institut for Health and Medical Research(INSERM). Asmae won third place in a field of 60 entrants. She presented the results of her past work on IP in the context of the IP Consortium. Her future project focuses on the NEMO gene, IP, and related diseases. She has now been recruited as a permanent researcher. Her work will be carried out in the lab in which she has spent the last 12 years. Asmae Smahi               Swaroop Aradhya accepting the ASHG award.

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MY RENDEZVOUS WITH IP By Swaroop Aradhya I recall writing my personal statement for college applications in the spring of 1990. The Human Genome Project had just been launched amidst substantial debate. It was a grand program, promising immense benefits for medicine, and even towards understanding ourselves as a species. However, there were plenty of people who disagreed, feeling that human meddling with what must certainly be a divine design could be catastrophic; I was in this latter group, and only 18 years old. I was completing my senior year at Kodaikanal International School, in the lush, foggy hills of south India. My personal statement about the potential negative consequences of the Human Genome Project must have found some interested readers at Grinnell College, Iowa. My undergraduate education at Grinnell was quite enriching, with a strong emphasis on analytical thought. I was always interested in biology, but it was at Grinnell that I experienced biological research first-hand. I also spent a summer, during my undergraduate years, as a Pew Undergraduate Research Scholar at the University of Chicago's Ben May Center for Cancer Research. Following graduation from Grinnell, I applied for research positions at the National Institutes of Health in Bethesda, Maryland. The well-known cytogeneticist, David Ledbetter, recognized for discovering the genetic cause for Prader-Willi and Angelman syndromes, offered me a position. What a fabulous two years that turned out to be. I got a real taste of biomedical research, especially human genetics. With this experience in my record, I applied to the best human genetics graduate programs in the country, with Baylor College of Medicine (in Houston) at the top of the list. I arrived in Houston in August of 1996 and plunged into a year of intense classes and lab rotations. David Nelson's laboratory, known for its contribution to the Human Genome Project and especially famous for the discovery of the genetic basis for Fragile X syndrome, was my first choice for lab rotations. In March 1997, I joined David's lab but was not sure which of several projects to choose in the lab. The majority of graduate students and postdoctoral fellows were working on Fragile X syndrome, and a couple was working on primate evolution. Nobody was working on Incontinentia Pigmenti (IP). From the perspective of graduate student training, a project aimed at identifying a disease-causing gene is risky because nobody can predict how long it will take. I thought IP was interesting for several reasons. The physical signs (or "phenotype") were so complicated &endash; so, the biology could be exciting. It was also known as a classic male-lethal disease of which there were not many, so it would be intriguing to find out why it was lethal and how the disease manifested itself in female individuals. The region where the IP gene was thought to exist was rather large to examine for mutations that cause the disease. Of the 3 million bases in the IP region, 1.6 million bases still had to be sequenced and an Italian collaborator within the recently formed International IP Consortium was preparing to put this

region through large-scale high throughput sequencing. So even though the region was large, I thought it would be worth the risk to be able to be part of the effort to identify what could be a very important gene, especially since we were going to work with an international team of experts. Hence, the search was launched in Houston and would contribute to the collective efforts of the Consortium. The first thing I did was to build a large overlapping array of DNA fragments (about 150,000 bases per fragment, or "clone") that were isolated from the IP region at the very bottom of the X chromosome. These clones were sent to Italy for sequencing to contribute to the Human Genome Project. This information would help us find out what genes existed in this region so that we could begin to scan them for mutations in our patients. This sequence was the key to rapid identification of the IP gene. My first meeting with the IP Consortium was in June 1998 in Heidelberg. I can still remember the jet lag! I met all the postdoctoral fellows and senior scientists that had come together to discuss progress and future plans. We decided that while the Italians were generating sequence, we could search for DNA rearrangements on the X chromosomes of IP patients. However, no abnormalities were identified. We had another meeting in Paris in December 1998, but the mood was one of disappointment, even after all the hard work we had put in. The next six months progressed very slowly with little interaction between consortium members, mostly because we were dejected by the continuous accumulation of negative results. In June 1999, at our meeting in Cambridge, U.K., there was a spark of excitement, a type of rejuvenation among consortium members. We decided to systematically screen every known gene in the IP region because it was such a complicated disease that genes with different functions could explain the phenotype. Immediately after returning from Cambridge, we screened 11 genes but only found variations that turned out to be nonpathogenic DNA alterations, commonly found among normal individuals. There was still room for excitement. Another research group had mapped a new gene called NEMO to the IP region. This gene regulates a basic cellular pathway we thought could be involved in the development of the various Physio- logical systems affected in IP. However, there was no sequence information for the NEMO gene, so the Italian collaborators scrambled to generate this information. This was an exciting time; we felt that NEMO had to be the IP gene. As sequence came off the hot stove, we dug into it right away and started examining its important regions in patients to look for alterations that might explain the IP disorder. Exciting is an understatement &endash; after two years of struggling to find the gene and smiling in the face of disappointments, this was a rush to experience in its entirety. Mutations started surfacing and, as consortium members e-mailed back and forth every day with new results, we knew we had it. As with all scientific discoveries, ours had to be kept secret for many reasons, the most important reason being that

we had to protect if for publication. Had the news leaked and someone else published this result before us, we would have had our worst blow and could have even lost research funding. A couple of nervous months later, we published our story&endash;on May 25th&endash;in Nature, describing the mutations that lead to IP by causing enhanced death of cells due to a defect in a fundamental signaling pathway. This was a tremendous finding. In addition to helping explain how IP occurs, the mutations gave us significant insight into a cellular pathway that is important for normal development, from pregnancy through adulthood. This is what I wanted to be part of. Moreover, I was given an extra bonus&endash;the pleasure and privilege of working with such a stellar team of scientists. Celebration was long overdue. Before the publication of the Nature article, we gathered in Paris in February 2000 to polish up the publication for submission and decide on the future of the Consortium. It was a memorable meeting that contrasted with previous meetings, at which we had been serious, professional, and often, disappointed with the project. This meeting was energetic, exciting, and completely joyful. We celebrated for two days, reminiscing about the previous years and contemplating the near future. This was only the beginning &endash; now we were ready to find out what IP was all about. Upon returning to Houston and following the publication of the article, we had another stroke of good luck. There was substantial debate in the scientific community about IP in male individuals because this disorder was known to be male-lethal. We had enrolled a couple of "male IP" patients, thinking that they may have mutations different from typical IP patients. These male cases had mutations in the last part of the gene, and they appeared to be milder than other mutations in terms of their effect on the cells carrying the mutation. Hence, these male individuals were able to survive. This was a significant finding because it emphasized that male individuals can have IP and numerous male cases with IP may have been misdiagnosed with another similar disease. In addition, male patients offer an unprecedented opportunity to study the occurrence of IP at the physiological level since they have only one X chromosome and therefore always express the mutation. This has been my rendezvous with IP. Without the involvement of hundreds of patients in the United States and in Europe, we could not have accomplished this task. It has been a story of fun, stress, anxiety, disappointment, and exhilaration. But all is well that ends well. It has been a long road from that personal statement written in 1990, arguing about the negative consequences of fiddling with the human genome, to making my own contribution to the Human Genome Project. I must now move on to my next career phase&endash;postdoctoral training. I will immerse myself in understanding the genetic basis for another interesting human disorder and learn new things about "what must certainly be of divine design"&endash;our genome.

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RESEARCH DIRECTIONS FOR THE 21st CENTURY (Reprinted from NORD newsletter) A great many stories have appeared in magazines, newspapers and on television about progress in the field of genetics. The information is often confusing and contradictory. I will attempt to clarify what is a very important issue. Gene Mapping The Human Genome Project, launched during the final decade of the 20th century, has provided extraordinary scientific information that will keep researchers busy for many years to come. One of the most important lessons of the massive project to map every gene in the human body has been confirmation of the fact that study of a rare disease often leads to breakthroughs in the understanding and treatment of common diseases. Understanding of what a specific gene does will lead to a better scientific understanding of the mechanisms of a particular disorder. The Human Genome Project has been dubbed the "Manhattan Project of Science" because it has recruited a very large number of the brightest scientific minds into one massive international effort with extraordinary goals. Once the entire human genome is mapped (and the genomes of animals, viruses, bacteria, and insects as well), scientists will probably spend much of the next century studying the data and translating the information into medical diagnostics, treatments, cures, and health interventions that may prevent diseases from occurring. Cloning One of the most newsworthy events of the last decade was the cloning of a six-year old sheep named Dolly. The scientific implications of this technological breakthrough were hardly analyzed before ethical concerns were raised about the specter of cloning human beings. However, as those scientists have now cloned more sheep, calves, and other animals, they have discovered that cloning may not be a healthy endeavor. The ends of Dolly's chromosomes (the telemeres) are shorter than those of a normal sheep at the same age. Because Dolly's mother was six years old when she was cloned, Dolly's chromosomes appeared to be six years old when she was born. Although Dolly appears to be healthy and has had her own lambs in the past few years, she and her offspring may suffer from premature aging because they inherited old chromosomes. Thus, more research is needed before this technology can move forward. If Dolly's chromosomes were six years old when she was born, and her lambs were born two years later, are their chromosomes eight years old? Only time will tell.	Stem Cell Technology Stem cells are the parent blood cells that give birth to red and white blood cells. They are needed to replace bone marrow cells when a person undergoes bone marrow transplantation. If stem cells could be isolated, they would be able to manufacture a continuing supply of blood cells, and perhaps be grown into specific organs or elements of the human body such as muscle, cartilage, or fat. However, until now stem cells have been very difficult to isolate from the blood. Scientists have obtained stem cells from blood in umbilical cords (cord blood) after a baby is born, and from in-vitro fertilization clinics. More recently, scientists have been working on ways to expand the availability of stem cells in the laboratory. Some progress has been made utilizing a hormone that appears to encourage stem cells to grow. If enough dividing stem cells can be grown in laboratories, bone marrow transplantation may become more accessible to more people for genetic diseases. It has been suggested that inserting a normal gene into perpetually dividing stem cells could potentially cure some genetic diseases. Gene Therapy The first human gene therapy experiment was launched in 1990 on a child with Severe Combined Immune Deficiency, a very rare genetic disease. The experiment only partially corrected the genetic defect, but was the first time in history that such a procedure worked. The experiment was carried out by the newest member of the International IP Research Consortium Jean-Laurent Casanova. Since that experiment, more than 300 gene therapy clinical trials have been launched. None of these experiments has cured any disease primarily because scientists have been unable to transport good genes into specific target cells. Moreover, the immune system has recognized the engineered viruses (called "vectors") that ferry the new gene into cells as enemy invaders, thus destroying them. The problems have been how to insert the corrective gene into the nuclei of (continued on page 7 col. 1) (Research Directions continued) thousands, or even millions, of targeted cells; how to camouflage the vector so the immune system will not try to destroy it; and how to stop the transported gene from turning itself off a few days or weeks after it has entered the new cell. Gene therapy is expected to be a major medical technological advancement of the 21st century for hereditary diseases, but progress has been slow and incremental during this past decade. However, many academic scientists and private companies are working on design of new vectors that will hopefully not provoke attacks from the immune system. Some have abandoned viruses and are developing other gene transport systems. While many new methods look very promising in the laboratory, they must be carefully refined before human clinical trials can begin.	Interpreting Science on the Nightly News When IPIF members read or hear about "astonishing medical breakthroughs,' they should be very careful in interpreting exactly what the news announcement said. For example, if you hear an announcement that a drug has cured tumors, find out if it cured the tumors in mice or humans. Many compounds may work in laboratory animals, but not in people. Who sponsored the announcement? Did a company release it, or was it a report about a scientific article published by academic scientists in a peer-reviewed medical journal? If the news was announced in a medical journal, go to the library or search for it on the Internet and read the complete journal article. If the authors of the article were paid by a company to write the article, or if they own stock in the company, they are supposed to print this information in the journal article (in small print) so you can judge for yourself if the author may have a conflict of interest. News reporters don't always get all the relevant facts when they report medical information, and they do not always report them accurately. Some reports about "amazing medical breakthroughs" are about a single uncorroborated study, which is not strong scientific evidence. Additional studies by other scientists that replicate the same findings are needed before the validity of the first study can be corroborated. What were the ages and sex of the people in the study? If the study was done on elderly males and you are a young female, the study may not apply to you. Was the study done on animals, or on tissue in a test tube? The results may have no application to humans. What was the duration of the study, and how long was the follow-up? Using a large number of people in a study for a common disease is very important because there will be wide variety of responses and a better analysis of side effects. However, studies of rare diseases are usually smaller because there are not many people to study, so fewer side effects may be seen. It is also very important to determine if there was a "control group" in the study. This is a group of patients who are given no active treatment (placebo), so that scientists can study if the treated group responded better than those who received a placebo. When people do not know if they are taking a real drug or a dummy pill, it is important for scientists to know whether a response occurred by chance or because of the drug. It is also important to know if the study was "double-blind." This occurs when neither the doctor nor the patient knows whether they have been given the real drug or a placebo. If the doctor is aware that a person is taking an active drug, the doctor's personal expectations may be reflected in the study. Patients should also be "randomly assigned" to the placebo group or the active treatment group to assure that both groups are identical. Understanding how clinical trials work, and how scientists conduct research, is very important not only because it will help you separate the media "hype" that you hear on the news from the medical facts that you need for your own care, but also because it will help you make an informed decision if you are invited to participate in a clinic trial.
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SUPPORT GROUPS A deeply distressful aspect of having a rare disorder is the feeling of isolation. When a parent has a baby born with IP it is very often likely that the physician has never before seen a case. Family members, whose support after the birth of a baby is emotionally very fulfilling, probably never heard of IP. Friends and colleagues are also totally unfamiliar with IP. There are also the instances when an adult with IP has never met anyone else with this disorder. Suzanne Woollams   Pascal Garcia

IPIF has maintained a list of people who wish to be in touch with others, but many people live far apart from each other and have contact only by e-mail or telephone, not face to face. Also, they frequently do not speak the same language. It is for these reasons that many organizations create support groups. A family member or by someone who has the disorder usually establishes them. These individuals take it upon themselves to create a support group within their country. These groups typically elect a president and frequently a secretary and treasurer. Members are required to pay modest dues, and meetings are organized by the elected officers in a central location anywhere from once a year to several times a year. There are now 6 groups for IP. The first was started in Spain, then in France, followed by Denmark, Australia/New Zealand and the United Kingdom. If someone is reading this who wishes to establish one in his or her country it might be helpful to contact one of the organizers listed below who, I'm certain, would be more than pleased to be of assistance.   Marta and Gerard Vilaseca Saenz de Santamaria with Iris

AUSTRALIA/NEW ZEALAND Suzanne Woollams North Island, New Zealand E-mail: firlawn@xtra.co.nz DENMARK Jeanne Ravnsgaard Valby E-mail: crazie@get2net.dk FRANCE Pascal Garcia Orleans E-mail: PascalGarcia1@aol.com SPAIN Marta and Gerard Vilaseca-Saenz de Santamaria Barcelona E-mail: comesp@gmx.net UNITED KINGDOM Claire Britton Essex E-mail: Clairects@aol.com Nicola Blasdale Devon E-mail: blasdale@compuserve.com

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AMY SUSAN PALLER, M.D. Professor of Pediatrics and Dermatology Northwestern University Medical School, Head, Division of Dermatology Children's Memorial Hospital and member of the IPIF Scientific Advisory Council) By Walter H. Stern Describing the recent identification of the gene that causes IP as a "vast stride forward", Dr. Amy S.Paller is very optimistic that the time is in sight when there will be a solution to the issues concerning IP. A prominent pediatric dermatologist, long concerned with genetic disorders that affect the skin, Dr. Paller can now foresee a future when prenatal testing for IP will be routine for affected families. With impressive credentials, Dr. Paller has fashioned a career that has delved deeply into those genetic defects that cause both generalized and mosaic disorders of the skin and has written extensively on the subject. Dr. Paller has served as chief of pediatric dermatology at the Children's Memorial Hospital of Northwestern University in Chicago for the past 13 years. She is a member of the Board of Directors of both the American Academy of Dermatology and the Society for Investigative Dermatology, is president of the Chicago Dermatological Society, and is secretary-treasurer of the Society of Pediatric Dermatology. Her work as a member of IPIF's Scientific Advisory Council is invaluable. Dr. Paller has been aware of IP since her earliest days in medical studies and offered her collaboration at the very founding of IPIF formerly called NIPF. Her copious writing (more than 200 papers), her laboratory research with grants from the National Institutes of Health and the March of Dimes and her participation as an editor or editorial board member of several prestigious journals have given Dr. Paller a broad perspective on the interaction between heredity, environment and medical practice, especially in identifying and managing many of the dermatological problems that beset patients. Her own "Color Atlas of Dermatology" serves as a visual guide to practitioners of dermatology. She is an editor of the foremost text on Pediatric Dermatology, and the editor of the dermatology section of a leading textbook on Pediatrics.

She serves as a professor of both pediatrics and dermatology at Northwestern University Medical School. A native of Cleveland, Ohio, Dr. Paller is a graduate of Brown University, having obtained both her undergraduate and a master's degree in genetics there. She earned her medical degree at the Stanford University School of Medicine, and performed residencies in both Pediatrics and Dermatology at Northwestern University before training in laboratory research as a NIH-sponsored fellow at the University of North Carolina in Chapel Hill. While it may seem obvious that Dr. Paller's professional life has been far from dull, her private moments are equally invigorating. At home in Wilmette, Illinois, she shares the fun and excitement of three sons with her husband, Etahn Cohen, a lawyer. Before becoming immersed in her medical pursuits, Dr. Paller once entertained thoughts of a musical career as a singer and, to this day, relaxes at the piano singing excerpts from opera and musical comedy. As a family, the Cohen-Paller team enjoys biking and soccer with the boys as well as theater and movies.

NEED FOR CONTRIBUTIONS AND FUNDING IPIF is grateful to its supporters for their ongoing generosity. IPIF needs your contributions now to continue its valuable work, the services it provides, as well as funding the expenses of the International IP Research Consortium. Raising funds for a rare disorder is extremely difficult. Most public foundations wish only to fund the larger, better known health organizations. Usually those which are receiving the most publicity. As ground breaking as the identification of the gene NEMO that causes IP was, there were no newspapers in the U.S. willing to carry the story. Even Government agencies have refused financial support. Therefore, it is up to the families, friends and relatives of those with IP to help. If you have not become a member, or have not renewed your membership please consider doing so. Several individuals have taken the opportunity to make a gift in honor of a deceased friend or loved one, or sent in a contribution to celebrate a special occasion such as a birthday, anniversary, graduation, etc. When such a contribution is made a letter is sent, to the family being so honored, acknowledging the contribution. One may also consider giving a fund-raising event such a tea party, cocktail party, auction, etc. Please keep in mind that whatever the reason your contribution is essential.     The information provided in our newsletter should not be substituted for personal, professional advice. It is our intention to keep you informed and ask you to always check any treatment with your physician.

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