Mystery Diagnosis: The NIH Undiagnosed Diseases Program (UDP)

Mystery Diagnosis: The NIH Undiagnosed Diseases Program (UDP)


[Yaffa Rubinstein]
Good afternoon everybody. Thank you for coming here, and so nice to see so many of you here.
Before Helen introduces the speakers, I would like to make a few announcements. This event
has been sponsored by the Biospecimens Interest Group and is supported by the Office of Rare
Disease Research and the Office of Biospecimens and Biorepositories Research at the NCI. If
you would like to get involved in this group, please contact us or log on to our Web site.
I would like to mention also that our next presentation will be in January, and we are
soliciting names for future speakers. So, if you have any suggestions, please let us
know. Also, I would like to let you know that we
are lucky to be the first one to be using the new state-of-the-art equipment that was
installed in this auditorium. Today we have the privilege and honor to have
three outstanding speakers presenting an extraordinary program on the Undiagnosed Disease Program,
which Helen is going to introduce to you. [Helen Moore]
All right, thanks — I add my thanks to your coming today. And I just want to take a moment
and thank Yaffa for organizing this. I’m only an accessory here today. She has done all
the work to make this happen today. And so we’re not going to read lengthy bios this
afternoon but just tell you that the speakers today are, first, Steve Groft, the director
of the Office of Rare Diseases Research at the NIH, John Gallin, director of the NIH
Clinical Center, and William Gahl, clinical director of the NHGRI and director for the
Undiagnosed Disease Program. So, Dr. Groft will start us off. [Stephen Groft]
Thank you, Helen and Yaffa, for this opportunity to present the program that has started maybe
a little bit over a year ago. But before I begin, I do want to first thank the staff
here at the Clinical Center. I think maybe sometimes you don’t hear the comments that
come in from the people, especially in the rare diseases community, but I really can
say without any question that the first question I get when I go and meet with a patient advocacy
group and their scientific and medical advisors, is how do we get a study started at NIH? How
do we get into the NIH system? So I think you can see the esteem that so many people
in the rare disease community really hold for you and the program that you represent
and the research that you conduct here at the NIH. And it really is a tremendous testimony
to the dedication to all the rare diseases that you have become known for. And we certainly
appreciate the efforts of so many of the individuals who have helped with the program as we’ve
initiated here at the Clinical Center. And so I’ll just really give you a little
bit of the background and then we’ll turn it over to the more experienced clinicians
and activities that we’ve been involved with, but I do want to thank the Biospecimens Interest
Group that invited us and have participated in developing the whole program, so Yaffa
and Helen, thank you again. It’s a real privilege and honor to express this program to the NIH
community because it has been one of a tremendous amount of public interest, and I think Bill
will tell you the level of interest that we’ve faced and that they’ve faced within the program
of screening patients and physicians who have patients who would like to come here. Just some background information, first, as
far as getting the diagnosis or the diagnostic odyssey that we talk about, particularly for
the rare diseases where so many times the symptoms do not manifest themselves at one
time, they’re going to carry over a number of years and maybe several decades ’till we
really get the full picture of a disease. But back in 1989, when there was a national
commission on orphan disease, and then this study was replicated in 2002 by the National
Organization for Rare Disorders. We did some patient surveys and you can see there the
numbers that we — tying to diagnosis. And it’s that greater than five years that had
us really concerned as far as taking that long to actually obtain a diagnosis. And I
think all of us can understand the frustrations and the anxieties that go with not having
a diagnosis, not knowing what we have, what are the outcomes that we can even think about.
So, when you start applying this to a pretty large population, you see that there a good
number of people who spend many, many years trying to obtain the diagnosis. We have a — what we call the Genetic and
Rare Disease Information Center that we co-sponsor, our office, the Office of Rare Diseases Research,
with the National Human Genome Research Institute. And after about 10,000 inquiries, we went
back over a three-year period, looking at the inquiries that we received at the information
center, and approximately six percent of the request for information related to undiagnosed
diseases. So you can see that it is a very, very large problem that we’re looking at.
It’s just we don’t hear about it very often. And in 2000, the NIH and our office published
a report of a special emphasis panel on the coordination of rare diseases research. And
in that, we talked about forming specialized centers of research and diagnosis. Unfortunately,
when we were looking at this when we implemented our Rare Diseases Clinical Research Network,
we didn’t focus on the diagnosis. We were focused on research, natural history studies,
training of the next generation of physicians and then the active role of patient advocacy
groups as well as doing clinical trials of the rare diseases. So, we never really got
into developing these specialized centers, and we thought what we’d like to do is everybody
get a little bit of experience here at the NIH. And so what we’re really working towards is
a better characterization and establishing diagnostic criteria for the rare diseases.
And one of the ways that we do it within our office, and we try to extend to this to all
of the institutes, and many of the intramural research program and investigators here in
the Clinical Center have taken advantage of the program to put together scientific conferences
on specific rare diseases or a group of rare disorders, so if you have an interest and
you haven’t heard about our scientific conference program, please contact the office. Just send
a quick note, and we’ll start talking to you about a conference and everything that you
can do and how it all works, so we’re happy to help with this. We’ve seen in recent years this expansion
in newborn screening programs here in the United States, and we think that this is going
to continue to grow. I believe there are about 29 disorders now that are screened in the
States here, here in the United States, and we think that number’s going to grow. We also
have — our programs also focus on the development of genetic diagnostic tests that should be
accompanied by appropriate counseling and information to go back to the patient and
families as well as to the practitioner. But we have a pilot project that actually we started
here in the Clinical Center with Bill Gahl and other investigators, that we’ve tried
to figure out a way to develop genetic tests and to move them out of the research laboratory
into a CLIA-certified laboratory, so we’ve had a nice program, and again, we do make
resources available, so if you’re in the gene discovery mode and you’d like to — and you
think that there is some significance, clinical significance of what we’re looking at as far
as a diagnosis and other information that might be and should be made available to the
patients and the families, we’ll help put together a genetic test and develop the information
that will accompany that test. So, again, please just contact the office and we’ll work
together on that. But what we’re dealing with really is with
a program such as this, there’s a tremendous amount of interest in this program. I think
we’re developing truly a global approach to rare diseases as more and more nations are
coming on board with a focus on rare diseases. For so many years, it seems like the United
States was the only country working in the rare disease area. Then in 1999, the European
Union passed their legislation, and so, we’ve had a tremendous amount of effort. There should
be a good number of collaborations with the European Union investigators and individual
countries, so it’s growing. The program itself, we would like to see it
grow into more — and maybe Bill will talk about this, or John, about expanding into
more of the Intramural Research Program. Most of the patients are being seen by a small
number of investigators, but I think we’d like to see how this could be extended into
other protocols and new protocols and the clinics here at the Clinical Center. At some
point, if additional resources were ever made available, and that’s really money, we’d like
to expand this into the Extramural Research Program and use the Clinical Center here as
a hub of activities that we could, perhaps, extend this out to a lot of the extramural
research community. We have a very large clinical and translational science awards program,
the old general clinical research centers, that are very, very fertile ground for introducing
a program like this. And our Rare Disease Clinical Research Network is also another
area that we think we could extend this and expand the initiative, so it’s something we’d
like to look at. Again, as I mentioned, there’s a tremendous
interest in the program throughout the world, and again, with — when I do go and speak
with partners through the world, this is probably the number one area of interest. How is the
Undiagnosed Diseases Program? How is it working? Is it really functioning? Are you seeing patients,
and what are the results? And so, the partnerships are available. I think it’s just a matter
of us figuring out some way how we can really link up with them. There’s been some proposed
legislation that would develop a national undiagnosed diseases registry, and that has
some complications where, you know, that’s still in the hopper, but we’re not sure where
it’s going. But it is certainly an area of interest as we continue to watch it to see
exactly what they’re going to ask us to produce. And throughout all of this, we have seen the
increase, as many of you probably have observed, the continued involvement of patient advocacy
groups as research partners. And two new groups have started up. One is INOD, In Need of Diagnosis.
And the other is SWAN, the Symptoms Without a Name. And again, as I mentioned, these are
people who have lived for many years without a diagnosis, and the name to their disease,
they know it’s not — most of them are not really good diseases. They’re not doing well,
but they’ve devoted their energy to try to bring an emphasis to obtaining diagnosis for
a lot more patients. So with that I will end, and I’m going to
turn it over to Dr. John Gallin, who is a director of the Clinical Center. I’ll see
if I can get the slides. We may need some help…finding John’s slides. Okay. Are you
getting it from back there? Here we go…Okay, got it. Thank you very much, and John, we’ll turn
it over to you and then to Bill. [John I. Gallin]
Okay, thank you very much. It’s a pleasure to be here, and I want to thank first the
Office of Rare Diseases for sponsoring the whole program of the Undiagnosed Disease Program,
and specifically I want to thank the special interest group for hosting this session today.
I’m just going to spend a few minutes reminding you what kind of facility we have here and
why this makes a special home, and then we’ll turn it over to Dr. Gahl who’s going to really
provide the excitement for today. So what is the vision of the Clinical Center?
In case you don’t know, it’s very simple. As America’s research hospital, we will lead
the global effort in training today’s investigators in discovering tomorrow’s cures. Now, we spent
a lot of time writing this sentence, believe it or not, and things like “America’s” is
a key word. And our hope is that as time evolves, the facility will transform from not only
a national hospital for patients, but also an institution that serves investigators both
here at the Clinical Center and across the nation more so than it has even in the past.
And that particularly relates to the comments Dr. Groft just made. So we opened, you know, in 1953. And since
then we’ve seen more than 350,000 patients, and about half of them have been patients
with rare diseases. Our new hospital opened in 2005. Currently we have 234 beds open.
There are about 1,850 people who work for the Clinical Center, and I should add that
there’s about 4,000 people who work for the 17 different institutes that use the Clinical
Center, so in these walls, there’s about 6,000 people working and my hope is that they all
work well together. My sense is that they do. Of those people, there’s about 1,220 credentialed
physicians, which is a rather remarkable number for 234 beds. I don’t think you’ll find that
anywhere in the world. The engine that drives this place are the
clinical protocols, and there are 1,450 active clinical protocols. And the budget for this
year is $362.3 million dollars. So, our nurses say there’s no other hospital
like it. So, what makes this place different? Well, as you all know, every patient is enrolled
on a protocol. Care is free. Our nurses are very highly educated. Every one of them is
a registered nurse. About 15 percent have a master’s degree, and about five percent
have PhDs. The hospital is embedded in an environment with research labs surrounding
it with some of the world’s greatest investigators. Our theme is often first in human and clinical
trials. We can do long-term, high intellectual, and economic risk studies. Because we don’t
write grants, we can respond rapidly to public health emergencies as we have done in the
past, for example, in AIDS and the SARS epidemic. And we have these unique cohorts of patients
with rare diseases. So, we’ve had a long tradition of studying
rare diseases and patients with unknown diagnosis. So what’s new with this Undiagnosed Disease
Program? Well, from my perspective, there are two major things that are new. First of
all, there’s a call for undiagnosed diseases with no phenotype restrictions. So we’re inviting
anybody who has an unexplained problem to make an inquiry. Second, is that, really for
the first time, at least since I’ve been here, a multidisciplinary approach is given to every
patient. And this is shown by this list of consultants which you’re not supposed to read,
but be impressed by the number, so although Dr. Groft said it’s relatively few people
who are involved in this program, I think it’s a very large, robust group representing
almost all the different components of the NIH. But indeed, it could be bigger, and we
hope it gets bigger over time. So, what does the Clinical Center do? Well,
we have an Office of Patient Recruitment and Public Liaison which triages patient calls.
And since May of 2008, there’s been about 1,700 inquiries, and every patient receives
a preliminary screening. All the Clinical Center departments are primed to be helpful,
and I think most of them have been key collaborators, but particularly our general medicine and
pediatrics consult services among others. We have a very large amount of outside inquiries
about this program. You’ve read about it in “Nature;” you’ve read about it in “The New
York Times;” and you’ll be hearing and reading about it more. And the communications staff
from both the Clinical Center and predominantly the Human Genome Institute, as well as the
NIH in general, have been very engaged in trying to help the public understand better
what we do. The Clinical Center obviously provides a certain
amount of space and supplies and special resources, and it’s really the special resources that
I think make this such a marvelous facility. And these resources have evolved the course
of our long tradition of phenotyping patients. So, let me just, in one slide, show you what
I think are some highlights. We have a brand new GMP facility that’s going to open in a
few weeks here on the first floor for making candidate drugs. This is a fabulous resource
that can help once the diagnosis is made and new therapeutic strategies are contemplated
when industry is not capable or interested in helping making a candidate drug. We have a phenomenal amount of imaging equipment
in this facility, working closely with the NMR Center. There are over 27 MRI machines,
for example, in this hospital, some of which serve animals, but the NMR Center’s a facility
to make new machines. A new 7-Tesla machine is about to be unveiled for clinical use,
and we have multi-modality minimally invasive procedural suites, rather unique for the country.
We have a biomechanics lab in the rehab medicine movement for testing and assessing movement,
which Leighton Chan’s group runs. Our blood bank is phenomenal in terms of helping prepare
special kinds of cells for research purposes, both in the lab and the clinic. We are now
priming up to be able to do stem cell therapy when the investigators want to do that. And
the phenotyping capability includes the metabolic sweep for — originally designed to assess
obesity, but is available for testing — wasting syndromes or any syndrome where you want to
characterize the metabolic state of the patient with great precision. We also have some IT tools, and one I want
to mention, and I’m going to end my comments with, is the Biomedical Translational Research
Information System, or BTRIS, which Jim Cimino has been building. And what is BTRIS? Well,
it’s a data and tissue repository, and in view of the interest of this interest group
I wanted to show you in one slide what it does. So, from the Clinical Center, there’s
input into this system from the laboratories, the pharmacy, the imaging facilities, the
CRIS system, the old NIMSS system, and from all the different institutes, they will be
depositing whatever they want to deposit into this system that relates to patients. In the future, the CTSA Network, we hope,
will also contribute to this system. And we will be taking all the biospecimens and tissue
information that’s available at NIH. And I am told there’s over 30 million specimens
out there in freezers and things all over the place. Our goal is to eventually have
all that information linked into this system. And so, what we hope in the future is that
additional institute research data and images will be added every year. The addition of
the stored sample data which comes from these patients with rare diseases will allow investigators
to search samples along with related clinical research data. So you’ll have tissue information.
You’ll have clinical information. You’ll have phenotyping information, genetic information,
et cetera, all available in one place. And hopefully this will be a valuable resource
to the community. And finally, as we begin to partner with the
extramural community, our dream is that this kind of a system will become a national resource
containing a vast amount of information that will enable hypothesis generation, hypothesis
testing before even going and doing experiments. So, if you’re interested in BTRIS, and it’s
just been unveiled and become activated, you can learn more about it at this site. So, those are my comments, and now I’d like
to introduce Dr. Gahl who’s going to tell you about what’s happening in this clinic. [William A. Gahl]
Well, thanks you very much. I want to thank the special interest group for Biospecimens
for their invitation and John and Steve, especially my institute, but most of all, all of you
who have contributed to this program so much. If there’s one message I want to send out
to all of you, it’s that we have cases up here that have not been fully explored, and
if any of you are interested, I would like you to come up to us and tell us your interest,
your specialty area. And if you want to pursue any of these disorders, please do because
they still remain mysteries, and we can use all the help we can get. So, I guess it’s this one. All right, I’ll
use the bottom one. I’m fine. Yeah, that’s what I was hitting. So this started with the Office of Rare Disease
getting all sort of inquiries that really couldn’t be answered, and Steve mentioned
that already. But in addition, there was a retreat in 2007 at which the directors of
the ICs thought of ways in which to sort of enhance or rejuvenate the Clinical Center,
and one of those ways was to recreate the fascinoma clinics of the 60s and 70s. You’ll
probably recall that most of the leadership of the NIH is now in the members of the second
Half-Century Club, so they remember back to the 60s and 70s when they did this themselves.
And I think they remember that fondly, so they wanted to do that. And so we have the
goals of the program to assist patients, come to a diagnosis, but also discover new diseases
that will reveal something to us about biochemistry, about pathways, about cell biology. And I’d
like to show you today about how we’re moving towards some of those goals. The way this programs works is that we receive
medical records and also a summary letter from the physician. Actually, sometimes we
don’t receive that and we have to ask for it, but we’re supposed to get it. And then
we triage the submitted records and send them out to specialists in the area that the cover
letter and the records indicate. They get back to us and we’ll make a decision about
whether to accept or decline the patient and then tell the patients and the physicians.
And then if the — for the accepted patients, they come back to us for about a week admission,
and we have delay time now for admission, probably about two to three months for both
pediatrics and adults. So this got a lot of press and actually Dr.
Zerhouni was part of the announcement almost a year and half ago now. And you can just
sort of read all the people who are interested in this. This struck a cord with people. I
think it’s because many of them had trouble reaching, let’s say, a team that would look
at everything comprehensively and sort of universally. Instead, they’d have to go to
one specialist and then another specialist, et cetera. So there was a significant amount
of press. Fine. So, this is what happened. Basically we’re
inundated and couldn’t really handle it. And, in fact, another way of looking at it is sort
of Lucy without the candy. So out of desperation we sought more support and actually received
support from the leadership at the NIH and from individual institutes and especially
from individual investigators, many of whom are in the audience. The number of inquiries we’ve had since May
of 2008 is really 2,300. The number of medical records is clearly over 900. I don’t even
actually know. We do have a database, however. Most of the patients we’ve been able to reject,
and many of them eminently rejectable, any of us would reject. Some of them are a little
bit more questionable, and I’m sure that occasionally we make mistakes. But we have accepted about
190 individuals on — many on my service, many on other services throughout the NIH
to existing protocols. We have about 150 charts that are currently active and under evaluation.
And 13 of the patients that we have either seen or were about to see have died before
they got here or shortly after they got here, which really speaks to the severity and criticality
of the patients that apply to this, as well as a number of the patients who don’t have
that criticality. Most of the cases are actually neurological cases, and many of the cases
are pediatric cases that are very complicated. We now have expanded our personnel hired by
the UDP to these numbers here, so we have a reasonable contingent of individuals. And
these are the personnel who are currently with us as paid personnel and we’re acquiring
more sort of as we speak, just working on a couple of other contracts. And the consultants
here — again, a significant list of individuals from all the disciplines of the NIH. We have planning meetings in which we triage
some of these charts and update the database. And often, we have to ask for specific further
information in the form of slides or images. And we get it. People really do not resist
this. After all, they get free medical care here. Of course, there may be some other reasons,
too. And the pediatrics group now is headed by
Dr. Cynthia Tifft who’s in the second row here. She just came on board as the deputy
clinical director in NHGRI, and she’s conducting the pediatric portion of this now. Then we have open meetings once a month, which
is basically to sort of show off many of the interesting cases that we have with images
and slides and a lot of contributing individuals here, many of whom spend a considerable amount
of time preparing for these meetings. And then I sort of conduct the meeting, and we
learn about new cases that are of interest. So I wanted to tell you about some genetic
aspects of this pursuit and then give you some cases. The genetic analysis, in addition
to using targeted diagnostics that are CLIA-certified and molecular and are send-out tests that
we pay for. Besides that, we do some unbiased screening with SNP analysis. And these SNPs
are done by Dr. Tom Markello through the NHGRI Genomics Core, which we have access to. And
there’s some significant software that’s involved that was really developed in part by Tom and
in part was able to be purchased. We’re able to determine two things. One is
the copy number variance. In other words, you’re supposed have two copies. Do you have
only one? Do you have none? In other words, are there deletions? Or do you have a duplication
and have three copies? And runs of homozygosity or heterozygosity — is no longer, no longer
exists in this individual patient. And that can speak towards autosomal recessive disease
or genes in the region of, let’s say inappropriate homozygosity, that would be candidates. So,
the way that this works as a single nucleotide polymorphism is an area within the genome
that has a natural variation in many of us. And it isn’t a one percent to 99 percent ratio;
it’s really a 30/70, 60/40, 50/50 or so, so these are common variants, and they’re defined
by a single nucleotide but surrounded by other bases so that one can determine whether a
person has, for example, the A or the T in the first case, or the C or the G in the second
case. And so, these SNPs are selected by Illumina,
in this case, across the board. And they’re selected approximately every 3,000 bases so
that one can determine to basically use these as signals or as markers for the absence of
a region of sequence. And that absence can be on one allele or on two alleles, or it
can be a duplication. And we can determine that, and I’ll sort of show you how in this.
And, so if you have, for example, 10 SNPs in a row that are missing, you know you’ve
got roughly 30 kilobases missing and maybe a portion of a gene that’s missing. Things
of that sort are what we can do. And it turns out by convention that the less
frequent allele is called the B allele, and so everybody of us who is diploid is AA, BB,
or AB. And this is a picture of the distribution of some of these individuals, so that would
be BB, AB, AA, and A and B, and these are essentially intensity plots of the signal
that comes out of a SNP analysis of the Genomics Core. So, here, for example, is a listing of a number
of SNPs with their R ratios. And an R ratio is the ratio of the A to B — or actually,
B to A. And if the ratio is 1 — in other words, you’re heterozygous — you’re log to
the base-2 of R is going to be 0. So, for example, this means that the person is heterozygote
because that reads .0084, which is close enough to zero. So the way that one uses this is
to determine the intensity, and if you have an intensity that’s logs below the 0 to 1,
or -1 to +1 range, namely here — if the intensity is that low, it means it’s deleted. And then
you can line this up with a human genome database to determine what genes are in that region,
what genes could be deleted, therefore, what genes could be candidates to be looked at
for the causative gene. And in this case, when you expand the previous
slide where there were only a couple of SNPs visible. Here you have really all of these
SNPs that are — have very low intensity, indicating a deletion. That deletion is 32
SNPs, 60 kilobases involved, and in fact, it corresponds to the particular deletion
that we see in a disease that I study, which is cystinosis, a very common 57,257 base pair
deletion which accounts for half of the North American and European individuals who have
cystinosis. So this is sort of proof of principle that we can pick these things out. The other issue is that you can measure heterozygosity
versus homozygosity. And this illustrates that, so this now is the B allele frequency
plotted on the ordinate. And over here are the AAs. Their B allele frequency is 0. Here’s
the BBs. Their B allele frequency is 1. And the B allele frequency is .5 for heterozygotes.
So, you can see that these are homozygotes. These are homozygous SNPs, and these are heterozygous
SNPs. And this is a centromere for which there are no SNPs. So, if you were to expand this on the next
slide, you’re only going to see the middle line, only you’re going to see the middle
line for all sorts of different chromosomes. And here, for example, is a loss of heterozygosity,
or an absence of heterozygosity. So, if you thought that this was an autosomal recessive
disorder, you could look in this region, see what genes are there, and they could be candidates.
Now, in general, this type of analysis will give you more candidates than you can possibly
use, so that, really, this is a first step towards pursuing a genetic diagnosis. So here’s another area that you may have seen.
And here’s an individual whom we saw very early in the course of this program who gave
no history of consanguinity, but if you look at all these spots, it does have consanguinity
all over the place and has approximately a three to four percent — a three to four percentage
— percent of all this person’s genome is homozygous, which could correspond to roughly
a second-cousin relationship among the parents. Because remember, people who are first cousins
share one-eighth of their genes; first cousins, once removed, one-sixteenth; and second cousins,
one-thirty-second, which would be about three percent or so. So, one can discover this type
of issue. So, let me tell you now about some of the
cases that we’ve seen here. And remember, what I’m going to show you know is really
a distillate of a huge number of charts that people have gone through and discarded with
cause the majority of them. And so, perhaps every decent case that we’ve seen here represents
50 to 100 cases that have been looked through and culled. We don’t know what’s going on with this next
group of patients. This patient, in fact, we haven’t even seen yet, but she’s fascinating
in a way because this is a before and this is the way she is now. And she feels that
the room is so hot — I’m sorry, I think I can do this like this, yeah — the room feels
so hot but only on her face, not on the rest of her body, so she keeps the temperature
in the room at 58 degrees and has a fan blowing on her face. And her face is painful, and
nobody knows exactly why she has this dysautonomic symptomatology but only in a segmental area.
We haven’t seen this patient yet. We have seen these kids, and they have short
stature, dysarthria, bowel and bladder dysfunctions and dysmorphisms and — again, we’ve seen
these individuals, but we don’t know what they have, and so, we’re interested in having
bone experts look into this. Here’s a little girl who has cranioectodermal
dysplasia. And you can see the dysmorphisms in her face. In fact, she has sister, and
her sister is under psychiatric care because her sister doesn’t understand why people make
fun of her sister. Her problem is that she has no roots to her teeth. Her sweat glands
are missing, so she has many signs of ectodermal dysplasia, but this doesn’t really fit any
particular of the 150 different types. In sort of summary here, her main problem is
that she has thickening of the skull, and this bony overgrowth is impinging on the optic
nerve canal so that she has some papilledema as well, and that may need to be released
at some point. Again, we don’t know what’s going on, nor
do we know what’s happening with this girl with microcephaly seizures and developmental
delay. And believe me, there are many, many of these individual cases. Or this five-year-old
girl who has liver disease and pancreatitis and also some neurological delays, but the
interesting thing from a metabolic standpoint is that within her liver she has areas of
beginning fibrosis. She has some inflammatory cells here, and she has copper accumulation.
But the copper accumulation in her liver is not associated with Wilson disease or any
typical pattern of that copper distribution, which is always in zone 1. Instead, she has
it in zone 3, which is the furthest away from the vasculature. And our pathologists have
said they’ve never seen this, and neither have other liver pathologists. So this is
a — particularly a different type of copper accumulation. She also has a biliary canaliculus here, and
you can see the lumen. This is apparently abnormal. In other words, this should be a
virtual space, not a real space that you can see. And this reflects the fact that the columnar
cells are swollen and they’re surrounding that lumen. Again, we don’t know what we’re
doing in this case, nor do we know what we’re doing with these individuals who have all
these different disorders, including one who has a major accomplishment and probably could
increase that number. Now I want to tell you about some interesting
cases that we actually have a lead on and that some people are working on. And here’s
a 21-year-old woman who has lung nodules, which you can see here. You know, these things
do not belong there. And she has ascietes, and her ureter has been kinked, so she had
hydronephrosis. All these things are thought to be related to her main defect, which, again,
we don’t know about but on biopsy of the cheek overgrowth — she has this type of a pattern,
which is both fibrous and inflammatory. And she has some plasma cells there, eosinophils,
and she has some of the hematopoietic-derived stem cell markers within that biopsy of her
cheek and lung. In her liver it shows essentially the same thing, some fibrosis but a lot of
inflammatory material as well. And Dr. Kleiner has made the diagnosis of angiolymphoid hyperplasia
with eosinophilia and fibroinflammatory disease, a descriptive diagnosis, and Dr. Aksentinovich
has discovered that there’s increased IL-8 and IL-1R intercirculation, so these are clues
towards the type of inflammatory reaction that might occurring. And now we have a lot
of other tissue by virtue of really a biopsy that Dr. Carter Van Waes did on her in a four-hour
operation here at the NIH to collect material to try to find out what types of cytokines
are being emitted and what type of therapeutic efforts we may make directed towards those
inflammatory molecules. Here’s a 46-year-old woman who has in her
kidneys a thrombotic microangiopathy, but she also has granulomas on her skin, and interestingly
increased circulating vascular endothelial growth factor. This is her kidney biopsy,
and you can see that there is thickening along the vascular wall and that the mesangium is
increased within her glomerulus. She also has blunted podocytes, and this really is
reminiscent of preeclampsia, in which you know is due to the production by placenta
of an inhibitor of VEGF, so that there no longer is enough trophism by VEGF of the kidney
cells, and therefore the patients get renal disease, hypertension, and the treatment is
essentially removal of that antibody by delivery. In other words, get rid of the placenta, get
rid of the antibodies. So, here’s a woman who shows some findings
of preeclampsia but due to a different cause besides the placenta. In other words, it’s
probably a genetic defect either in the VEGF itself or possibly in a VEGF receptor. So
that’s currently under investigation along with a collaborator at Beth Israel. And this
is the woman who was in “The New York Times” article who has some of the similar findings.
She also has the thrombotic microangiopathy in her kidney. She also has problems with
her venous lakes within her skull, and she lost her right eye because of retinal vascular
problems, and you can see she has really systemic disease. She has actually died by stopping
therapy because her therapy was so significant that she was losing a lot of blood through
her gut and decided not to continue with the transfusions, and three days later she died.
But she sent us her body, and we have performed an autopsy on it and have that tissue to study
now. This is a 39-year-old man who had slowly progressive
neurological problems, and you can see that there is some diffuse leucoencephalopathy,
which progressed, at this time, relatively slowly, but since then — I’ll just show you
a couple of areas where there’s some abnormalities here. But since then you can see the extent
of brain volume loss that this person has had over the last three years or so. And we
brought him in on two occasions, and we’ll probably bring him in again under Dr. Toro’s
service and essentially excluded the diagnosis of leucoencephalopathy and made the diagnosis
of primary progressive multiple sclerosis based upon a number of oligoclonal bands,
increased protein, increased IgG within the CSF. But Camilo also measured the EBV antibody
titers and found them to be elevated, and also the PCR was increased, so this wasn’t
just the presence of antibodies. It was also the presence of the virus itself, and now
Drs. Bielekova of NINDS and Jacobsen of NINDS and Dr. Cohen, Jeffrey Cohen, and Camilo Toro
are investigating this EBV infection as a possible cause primary progressive multiple
sclerosis, which is essentially hypothesized within the literature, and this may be an
index or sentinel case that might be able to demonstrate that. I just want to tell you about two success
stories and then I’ll sort of be finished. One is a 52-year-old woman who, without taking
steroids and without essentially working out — well, she might have worked out a little
bit, but she didn’t work out like this. And it did not have any of the standard endocrinological
abnormalities that might cause this. It had the development of increased musculature to
an incredible extent. And this was becoming painful for her. She had strains in her muscles.
Of course, she didn’t like her appearance either, but in addition she had real pain,
and it was becoming problematic. You can see on the CT scan here how big her paraspinal
muscles are. Now, some of us in the audience, perhaps half of us might not mind this real
much, but this is not a good thing to have. And these are her rib muscles, and then so
she has incredible increase in the size of her muscles. And when we did CTs of her head,
even the muscles that are essentially not used very often, or that we can’t hypertrophy,
were hypertrophied. For example, the rectus muscles of her eye were huge, like three,
four times as big as our neuroradiologist had ever seen. So, she has this for some reason.
The EMG was myopathic, but a muscle biopsy was read as normal. We brought the patient
in because this was fascinating. The referring physician from Duke said, “In my 38 years,
I’ve never seen…” blah, blah, blah, okay. So it turns out that we did a second biopsy
even though the last biopsy was done only a year ago. And Dr. Quan had it sent to AFIP
and our pathologists here and together made the diagnosis of amyloid myopathy. In other
words, the amyloid was seen in the thickened walls of the vessels, and stain on Congo red
and protein aggregates were there on EM. This led us to consider – I’m sorry — the possibility
of amyloidosis, and in fact, one of the most common causes of that would be multiple myeloma.
So we looked for plasma cells in a bone marrow that we did here as well and found 10 percent
plasma cells, which is sufficient to make the diagnosis. And it hadn’t been seen before. And the follow up that — Dr. Minoli referred
her to the Mayo Clinic. Now, she was become short of breath and fatigued. She had involvement
— a little bit of controversy, but it was considered — she had involvement of her atria,
and if she would get involvement of her ventricles, that’s considered to be very bad and could
easily lead to death within months. But at the Mayo Clinic, she underwent a stem cell
transplant, had some post-transplant complications, but then recovered, is feeling very well now
and is no longer having all the muscle pain and, I’m told, feels better day by day. We
do expect a full recovery. And in the very, very rare cases in the literature, the muscle
mass is said to go down to normal, so we feel very good that we’ve caught this. And I just would draw one sort of lesson from
this, and that is that this is a woman who on two occasions requested to be seen at the
Mayo Clinic and was turned down by the specialty clinics there and frankly, probably would
have been turned down by a specialty clinic here as well. So her access to medical care
for this particular disorder was because a broad net was cast for people like her. And
the irony of it is that when she finally was diagnosed, she was welcomed with open arms
by Mayo Clinic. Oops, yes. So, then the last case is this sibship that
we saw with calcification of the large vessels and also the joints. So, can anybody tell
if there’s an abnormality here? So this is, of course, the bone and the kneecap, but you
know, this vessel here is without contrast. So this is a plain film showing the outline
of her vessels, and here it is on a pelvic film. You can see all that. This hurts the
patients because there’s poor circulation, and they can’t — if they walk for a block,
they have to stop, and it hurts them a lot. And here you see it as well, also all the
way down to the foot. And then in the hands there’s calcification in the joints here,
right here, here, here. It’s all over — I didn’t want to put arrows all over the place.
So, this is the pedigree. Turns out there are five children. They’re adults. They’re
in their 50s, and they have this, all. And Dr. Boehm’s lab with Cynthia St. Hilaire
worked on this and got fibroblasts from a biopsy we did. And this shows the control,
and this shows the affected woman, and this is the acquisition of calcium over the course
of three weeks, and in the control there is none after three weeks. This is all the stain
for calcium microcrystals by an assay they performed. And this is critically important
to point out to us that the problem is not with circulating calcium or phosphate abnormalities,
but really it was intrinsic to the cells. So that was the first step. At the same time,
Dr. Markello was doing a SNP analysis and found a region of homozygosity here that was
shared by all five affected individuals but not by the parents. So, this spoke to a recessive
disorder and spoke to this region here which could be affected. That region involved 22
megabases in which there are almost 8,000 SNPs, so this is a large region. And again,
that’s the issue here; that is a large region, 92 genes. None sort of were pointed out — none
struck themselves to us as, you know, real helpful. But on the other hand, we had Dr.
St. Hilaire and Dr. Boehm involved, so they suggested one, and they have now identified
a gene in concert with us. And this is going to be, I think important for learning things
about the mechanism of calcification of vessels in general. And all this required a collection
of specimens, all sorts of different specimens, which we continue to do. It really is an important
issue for us in our handling and distribution of specimens. So, the good parts of this are that virtually
every patient is pleased with the attention and the hope that we provide to them, and
occasionally we solve a case. And can see some of the cases could be new diseases. I
think I’ve noticed that around the bedside, around the tables of discussion, this has
brought specialists closer together over cases. It reminds me of when I was a resident as
opposed to a bench researcher. It bolsters our protocols, we think, and there may be
new protocols that come from this. Not so good is the fact that our triage of necessity
is a difficult process for us, and the patients who are rejected are not really happy, and
in fact some of the patients who are rejected send me notes. I get a lot of notes. One of
the notes says, “You are a jerk.” And I think that that’s something — maybe a topic of
future discussion, maybe a whole conference could be held on that. [laughter] But I would say that nobody has ever stood
up and said, “You lie.” [laughter] So this is your chance, everyone who’d like
to stand up. Anybody? [laughter] Okay, so we’ll let that go. One of the other
problems is that we’ve gotten congressional inquiries, and most of the congressional inquiries
are from patients — from representatives or senators whose constituents have not applied
to the program. So, they decided that they were going to go to their senator or representative
first before actually applying. Of course this makes the response very easy, but it’s
really not the appropriate thing to do. Okay, so we’re a little bit late sometimes
with getting back to patients, and part of that is because we’re overwhelmed, and part
of it is because our consultants don’t get back to us in a timely fashion. And, as I
said, the patients we see are at a distillate, and, again, many of the patients don’t really
have the objective findings that correspond to their complaints. In the future, we need
to expand our basic research investigations into some of these distilled cases, because
they’re really good cases and we worked hard on phenotyping them. We’d like to use this
program as a model for how we use genetics in the future for investigating rare diseases,
and we’d like to post the cases to this community here and ask you for your input. So, if any
of you have expertise in the disorders that may be related to the ones we have up here,
please let us know, because we’re reasonably anxious to offload some of these cases. And
we’d like to consult international experts via the Web and create UDP clinics throughout
the United States if possible, that is to say, if there’s support on the behalf of the
extramural people or the leadership here. So, we found that in order to fulfill the
mission of the UDP, we have to admit patients to our service and then consult other services,
and that’s one of the wonderful things about NIH, is that people are generous about their
consultatory services. Again, many of the patients would not come here if they had to
come to a particular specialty, and this is a program that really doesn’t fit into the
natural paradigm of professional advancement. In other words, a young investigator, I would
not recommend get involved as the major part of his or her pursuit in this program, because
it’s so high risk, but the benefits can be enormous as well if you strike gold. Triage
is difficult, failure is common, and patients are desperate. And I’ll just give you the
final example of how desperate patients are. Here’s a 46-year-old man who began to have
neurological disease, both cerebellar and cerebral, and this is what he writes.
And this is the letter that his daughter sent
to us over this, and I’m not going to read this; I’m going to let you read this. I guess it’s obvious that a program like ours
can’t be influenced by anything of this sort, but we will be seeing this patient in a week
or so. So, I think Hemingway said it best about the patients that we see and the difficulties
in life. “The world breaks everyone, and afterwards some are stronger in the broken places.” And
I think Thoreau also said “The mass of men lead lives of quiet desperation.” And this
is a program that lets us see really the juxtaposition of science and sadness in the world, and lets
us as investigators see the human condition in the person of all the patients who apply
and whom we see for a week here at the Clinical Center. Thank you for your attention. [applause] So I suppose — I think people should leave,
but if anyone wants to — if anyone wants to ask any questions, I will stay here and
answer them for the stragglers. [end of transcript]

7 thoughts on “Mystery Diagnosis: The NIH Undiagnosed Diseases Program (UDP)

  • lol I was diagnosed with eosinophilic granuloma in my skull bone, yet the biopsy report said it was clean, nevertheless I still keep the tissues in my fridge.

  • This is EXCELLENT. So many of us are desperate for programs like this so that we don't completely lose faith in the medical community. Living without a diagnosis is endlessly devastating. The destruction and agony of living without a diagnosis is unfathomably inhumane. Is it still necessary for a doctor to submit an application for this program on behalf of the patient? Or can the patient simply apply independently? Some of us do not have doctors because we are too sick to work and afford doctor visits.

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