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[00:00:00] Dr. Christina Lampe: Six of the Spot the Early Signs of MPS online sessions today. And we have Professor Barbara Burton here. She's Professor of Pediatrics of the Northwestern University Feinberg School of Medicine. Hello, Barbara. Hello, Christina. And myself, my name is Christina Lampe. I'm working at the University Hospital of Gießen in the Res- Disease Center in Germany. And we would like to present some cases today and discuss them, but before just some housekeeping notes. So please do not take any screenshots or do not reproduce any of the slides. The format will be around 50 minutes and we will have a question and answer session at the end which will be via text. So please submit your questions at any point via the question panel and we will answer later. And actually we will have an online possibility to see the slides of the webinar again on the mps. spot- early- signs. org later on. So actually for a short introduction to the mucopolysaccharidosis, obviously you are already experts in that after so many webinars, but just as a reminder, we are talking about very rare multisystemic genetic progressive diseases that are life- threatening and extremely heterogeneous. And this is what we would like to show today. So MPSs are a group of seven phenotypical disorders caused by 11 enzyme deficiencies. And the problem are the storage of undergraded glycosaminoglycans. And here you see some pictures of MPS patients. We have patients that have more stiff joints. We have the MPS4A patients that have more hypermobile joints and the MPS3 group with mainly cognitive decline. Here the classification again, and you see the 11 enzyme deficiencies leading to the phenotypical disorders and the heparansulfate that you see here in red is the cause of the CNS involvement. And what you can also see is that MPS4A and six never have cognitive involvement to the fact that they're not storing heparansulfate. And I think Barbara, you will have some cases about that. We are talking about a multisystemic disease with a variability in signs and symptoms, a wide spectrum of disease severity, and not all organs are really affected in all patients. 70%, as I said already, have a cognitive involvement due to the storage of heparansulfate, but not all MPSs have. So the diagnosis is actually challenging. We have an average diagnostic delay of three years across all the MPS types. The signs and symptoms may be subtle or absent, which can lead to potential misdiagnosis. We have early signs and symptoms that are frequent respiratory and or ear infections, hernias, and developmental delay in some patients. And MPS often presents with musculoskeletal manifestations that may resemble other musculoskeletal disorders or conditions. And we see here, for example, in MPS4A, we have a diagnostic delay and a median delay of six and a half years. We have different tests in the diagnostic pathway from screening tests looking for urinary gag excretion. We have the enzyme activity analysis and the dry blood spot test, which is a very easy test, but has to be confirmed afterwards. We have direct tests like the enzyme activity measurement in lycosides or fibroblasts and the molecular testing as a confirmation. Actually, the early and accurate diagnosis of MPS is extremely important to optimize outcomes for patients, in particular in patients where we have a treatment available. So the complex differentiation between the MPSs, the lack of disease awareness, symptom variability, and the clinical resemblance of other disorders makes it a challenge. And with this, I would like to start with the first case, which is a girl that was born after an uneventful pregnancy, normal height and weight at birth, but she showed some desaturations after birth and it was a ventricular septum defect detected. So she was surgically treated at two weeks of age. In the next months, up to six months of age, she had recurrent airway and ear infections with many hospitalizations. She showed a deepness, a mild hepatomegaly, macrocephaly, no head control, no turning up to six months of age, and an inguinal and umbilical hernia. But although she showed so many signs and symptoms, nobody was really connecting them to a disease. So at seven months of age, she had a genetic counseling for a congenital heart defect and hearing loss. and the diagnosis of an MPS1 severe form Hurler syndorme was made at the age of nine months. And at 16 months, she received hematopoietic stem cell transplantation. This is the patient from birth up to 10 months, and you see in red, in the red frame, this was the age when she was diagnosed. And I think, Barbara, we can discuss if there's any early sign from the cross phase or changes that would lead to an earlier diagnosis in that patient. So is it a typical case, yes or no? And if we see for MPS1 Hurler syndrome, we see that recurrent rhinitis, upper airway obstruction, coarse facial features, toracolubar kyphosis, actually, this was not seen in this patient, hernias and hepatosplegia medalli are very common signs and symptoms. And neurological signs like increased head circumference, which was also seen in that patient, speech language delay to enlarged tongue and hearing problems is typical, mildly delayed motor milestones or hydrocephalus could be possible. And if we see in this patient, she showed quite a lot of signs and symptoms here highlighted in red, beside the gibbous or the kyphosis that is very typical for MPS1 Hurler syndrome. So actually I would say, but Barbara, we can discuss later, this is a very typical case and should have been diagnosed much earlier. The second case is a boy that was born in 2016, which actually normal development, but he was never crawling due to some stiffness of the shoulders. He is an MPS2 actually diagnosed at the age of two and a half years, but he showed quite a lot of signs and symptoms that could lead to a diagnosis between one to two years, like a macrocephaly, recurrent airway and ear infections, a hearing loss, language delay and delay in teething. Surgeries were at the age of six months, inguinal hernia on both sides with 18 and sorry, here's a mistake months instead of years adenoidectomy and T-tubes and with two years ventricular peritoneal shunt was needed. So when he was diagnosed at the age of two and a half years, he showed macrocephaly, the recurrent airway and ear infections, hearing loss, he needed hearing aids, a language delay, coarse facial features, an enlarged abdomen, a thoracolumbar kyphosis, joint contractures as you can see on the pictures and then hyperactivity. From the cognitive point of view, you saw that the development at the beginning of his life was quite normal. And the initial symptoms I told you already and I will show you a little bit more about his cognitive involvement in the next slide. But here you see due to his contractures of joint and the quite stiff spine, there were performed a few x-rays and actually the dysostosis multiplex is the description of the radiological science of MPS. And you can see here in the spine that he has some ovoid vertebras, that he has a hip dysplasia, he has widened middle hand bones and a thickened skull. And these are very typical signs for MPS. So dysostosis multiplex should lead to a diagnosis in any case. And here are the neurobehavioral symptoms of this child. So at the age of two and a half years, when he was diagnosed, the language delay and the hearing loss. At age of three years, he lost his fine motor skill and showed a poor attention span and was very impulsive. At the age of four and a half years, he showed mood changes, intellectual disabilities, declined and also his mobility. At five years of age, he showed a loss of interest in people and objects. His attention span declined even more. At the age of five and a half years, he was incontinent. He showed aggressive behavior, sleep problems, and loss of cognitive skills. At the age of three years and three months, he had a developmental testing, so 75 months of age. And you can see that walking, fine motor skills, communication, social and daily life activities are much, much below the normal range. And his cognition was in the age equivalent, like five months of age. To see that the child showed a kind of dementia in early life, this has a big impact on the family, but also on the patient. So for patients, the physical problems, the loss of abilities and being unable to express emotions are leading to frustration, anger, uncertainty, and fear. Fortunately, that child was diagnosed at the age of two and a half years, so at least it could be told to parents what will happen to this child. Is this a typical case? And this we will discuss, Barbara, but I would say, yes, it is a typical case. If we see in severely affected or neuropathic MPS2 patients, the earliest signs and symptoms, hernias, coarse face, hepatomegaly, are in the first two and a half years of life very common. The cognition impairment starts with 3.2 years, mainly having a kind of plateau before they decline more. And this was even shown in that case as well. Behavioral problems are usually starting at the age of four years. Important to say is that patients usually appear healthy at birth and they start with symptoms in the first year of life. The phenotype spectrum ranges from neuropathic, so meaning severe forms with cognitive involvement, to non-neuropathic patients or more attenuated patients with no cognitive involvement. And the earliest signs and symptoms are also described in the literature. And this is otitis, hernia, nasal obstruction, facial features, and enlarged liver and spleen. And I think this was all seen in our patient. And with this, I think, Barbara, we can discuss these cases. And do you agree with me that these are very typical cases?
[00:13:04] Prof. Barbara K. Burton : I do, Christina. I think those are great cases that you've presented. I think both of them are really quite typical, although I would say that the patient with MPS2 with the neuropathic form did seem to be unusually severe, certainly at the very severe end, because with his cognitive testing, I noted even at a very early age, I think he was three, he was already very low. And although I think they would all be abnormal at that age, he seemed to be unusually severe. And of course, we know there's a range of severity, even in the neuropathic patients from, in terms of how early they show the decline, how rapidly they decline, as you pointed out, they can have long plateaus in their development. So just like so many of our other disorders, there is a lot of heterogeneity, but I think your cases are great examples of the delay in diagnosis, because the patients did have quite a few symptoms for some time before. And I think that part of the problem, and you can comment on this if you agree, is that some of the early signs and symptoms are things that are pretty common in the general pediatric population. For example, the ear infections. So if a doctor sees a child with ear infections, they don't necessarily think too much of it. Hernias, hernia is also pretty common. And sometimes the kids will have chronic diarrhea, for example, with MPS2, also very common. Poor facial features, of course, no, but that takes time to develop. So I think one of the keys is, even though some of the signs and symptoms are very common, if you have a collection of them, maybe to think about whether there's any unifying thread that would tie it all together. But yeah, I think they were great examples of what really happens.
[00:15:06] Dr. Christina Lampe: Barbara, do you agree that around four to six airway infections are common in childhood, but if they are more prolonged or more severe, we would think to MPS?
[00:15:20] Prof. Barbara K. Burton : Yes, of
[00:15:23] Dr. Christina Lampe: course. Would this help to divide between?
[00:15:28] Prof. Barbara K. Burton : Maybe. I mean, I don't know that you necessarily have to think about even having four to six airway infections. I mean, that seems like a lot even for a healthy child, but yeah, I think if you have airway infections and ear infections and hernia, just that in itself should suggest at least maybe look at the child more carefully. Do you see anything else? Really make sure you get a good palpation of the abdomen. Sometimes I think in these kids with MPS, it can be a little bit hard to detect the hepatomegaly, because they have kind of thickened skin, as you know, and so they may be a little hard to palpate. And young kids can be hard anyway, because they can be very squirrely. So just look at the child very carefully and see if there are any other signs and symptoms. One thing I might comment on, we're very fortunate in the U.S. in that now we have almost universal newborn screening for MPS 1 in all of our states. It's on the recommended uniform screening panel. And also we have MPS 2 newborn screening in some states. It's now also on the recommended uniform screening panel. And I think that will expand pretty rapidly. One thing that I've noted is that in some of the infants with MPS 1, if we really look at the babies carefully, we can see signs and symptoms even as early as one month, six weeks of age. And I have seen even in some of the MPS 2 infants, symptoms right at birth, hernias, for example, a little bit of coarsening of the facial features, noisy airway, things like that. So I think they might be things that you would not be concerned about or pick up if you didn't have that alert. But I mean, it just tells us that these signs and symptoms are really occurring very early in some kids. If we do x-rays on some of these babies with MPS 1, we see some of the skeletal changes that you've talked about. So it's certainly, we know that the symptoms can occur very early and it takes time for enough of them to mount up that you get a clinical diagnosis. So we're really hopeful that with newborn screening and really early treatment, the outcome is going to be better. But I think in areas where you don't have newborn screening, certainly the clinical recognition is critically important to make sure the kids do get the earliest possible treatment.
[00:18:20] Dr. Christina Lampe: I saw in a newborn MPS 6 or two newborn MPS 6 patients, they had a contracture of shoulders already. Did you see that in the MPS 1?
[00:18:28] Prof. Barbara K. Burton : I have not seen that, but I haven't seen many newborns with MPS 6, honestly, with, you know, haven't had families where I knew, you know, the baby had MPS 6 before clinical diagnosis. So that's an interesting observation and it's something that, you know, you wouldn't necessarily test, right? I mean, you wouldn't really be looking for that in a newborn exam. So that's...
[00:18:58] Dr. Christina Lampe: No, but do you know how they found out? Because they wanted to make x-rays and they do it in hanging the children, so they raised up the arms of the newborn and it was not possible profitably. This is why they said, well, there's something wrong with the child.
[00:19:14] Prof. Barbara K. Burton : So these weren't even kids that had a positive family history. These were just, you know, new cases.
[00:19:24] Prof. Barbara K. Burton : That's fascinating. Yeah, that's interesting. Very interesting.
[00:19:27] Dr. Christina Lampe: But did you see that in MPS1 and MPS2 in the newborns as well?
[00:19:32] Prof. Barbara K. Burton : You know, I don't recall seeing that, but I'm not sure how carefully we looked for that, to tell you the truth. And I do think the shoulders are the most, the earliest affected often. You know, when we look at the older kids, you know, we find problems with shoulder flexion, certainly more significantly than with some of the other joints early on. So that's something I'm going to make a note to myself to make sure that I look at, you know, when we get the next case. Yeah, from newborn screening.
[00:20:03] Dr. Christina Lampe: Yeah, would be interesting. Unfortunately, we have no newborn screening in Germany. I know that in Italy, they start with newborn screening, at least pilot projects. So it is not very common in Europe by now. But I think this is the right way to go for our patients, in particular for treatment, because we know the storage begins prior birth. You saw the newborns with earliest signs and symptoms after birth, if you know. So at the end, we should treat as soon as possible.
[00:20:35] Prof. Barbara K. Burton : Exactly. I agree with you 100 percent.
[00:20:38] Dr. Christina Lampe: What do you think, Barbara? Do we go to your cases, which are not?
[00:20:42] Prof. Barbara K. Burton : Yes. Yes. Let's go ahead and go to my cases, which are a little bit different from, you know, what you had presented. I think, you know, we wanted to show the heterogeneity here. I'll go ahead and talk about this case. This is a little bit different than the ones we just heard about from Christina. This is a little girl who was felt to be a perfectly healthy, normal newborn at birth. She had no neonatal issues. She was at the 90th percentile for height, had a good birth weight. And really in the first couple of years of life, she had no unusual problems whatsoever. No recurrent ear infections, nothing unusual about her medical history. No hernias, really nothing that would cause the parents to have any concern about her at all. And her pediatrician was unconcerned. But then between about three and four years of age, she started showing really progressively decreasing growth velocity, started crossing percentiles. And so there was concern about her growth. And at about four and a half years of age, she was referred to a pediatric endocrinologist because of this growth issue. And he did a number of tests, including tests for various hormonal causes of growth deficiency, and really no abnormalities were detected. So she went on along, and by about five years of age, five and a half years of age, she started showing, in addition to this growth issue, problems with an abnormal gauge. She had kind of a waddling gait and was doing some toe walking. By this time, her height had dropped to below the fifth percentile, and she was referred to an orthopedic surgeon because of these issues with gait. He obtained some x- rays, and those were read as being suspicious for a skeletal dysplasia. So she was referred to a geneticist at that time for further evaluation. We can go on to the next slide. So she saw a geneticist who got a complete skeletal survey and agreed that this was suspicious for some type of skeletal disorder and thought that the most likely diagnosis was a condition called spondyloepiphyseal dysplasia, which is a genetically determined skeletal dysplasia involving the epiphyses of the bones and also the spine. At that time in the United States, there was an international skeletal dysplasia registry that you could refer cases to. They would be reviewed both by a genetics team and a skilled radiologist, and they would provide a second opinion, if you will. The patient's x- rays were sent to this registry, and they confirmed the diagnosis. They felt this was spondyloepiphyseal dysplasia congenita as well. So as far as anyone was concerned, the geneticist, the pediatrician, this patient had a diagnosis of SED congenita At the time, genetic testing for skeletal dysplasias was not going on very frequently, so there was no genetic testing done. The diagnosis was made on the base of the radiographic findings. So let's go on. Okay, so over the next few years after that evaluation at six years of age, the patient grew very little. Her growth rate had not only dropped, but now she was essentially not really growing anymore. She developed genu-valgum and she also began to show progressive joint restrictions. Christina was talking about the shoulder restriction in the infants previously. Here she's having them obviously in the hands, but also some restriction of other joints as well. She also developed corneal clouding and also was found to have some hearing loss, possibly related to the fact that she had chronic serosotitis media. So she was given tubes, ear tubes, PE tubes, and her hearing improved somewhat with the tubes, but was still mildly impaired. She was also noted to have some snoring, and because of this she had an ENT evaluation that showed her tonsils and adenoids were enlarged. So she underwent tonsillectomy and adenoidectomy. So at about the age of 10 years, her parents actually became pregnant with another child and they reported to their obstetrician that they had a child with a genetic disorder with spondyloepiphyseal dysplasia. Because of this, the obstetrician wanted them to get some genetic counseling regarding their recurrence risks for this genetic disorder. So he referred them to a geneticist. It happened to be a different geneticist than had seen the child earlier, and in taking a history about the child from the family, the geneticist asked to see photographs of the patient and looked at the photograph you see here and felt like the facial features appeared somewhat coarse. He was also concerned about some of the other findings that the parents reported had emerged in recent years, the corneal clouding and some of the other issues, the need for tonsillectomy and adenoidectomy. So he was suspicious of the possibility of an MPS disorder. So at that time, the patient underwent testing for the possibility of an MPS disorder, and you can see that urine gags were obtained and the total urine gags were elevated. In addition, there was testing of enzymes involved in MPS disorders including arylsulfatase B, which is the enzyme deficient in MPS6, and it was severely deficient in this patient with a level of 1.9 millimoles per hour per microgram as compared to a normal of greater than 15. The patient also had confirmatory genetic testing showing two mutations in the genes for arylsulfatase B, so the diagnosis of MPS6 was confirmed. In the diagnosis, there was some surveillance for other organ system involvement and it was found on echocardiogram that the patient had thickened mitral and aortic valves and mild mitral regurgitation. Her height at this time was again below the 5th percentile at about the 1st percentile, and on careful exam it was noted that she had hepatomegaly with a liver edge 5 centimeters below the right costal margin and she had the generalized joint restrictions. By now, not just her hands, but also her hips, knees, elbows, shoulders also affected, so this is a diagnosis of MPS6 in this patient who was previously thought to have spondyloepiphyseal dysplasia. Could we go on to the next slide? Okay, so the symptoms of MPS that we see in this patient are short stature and the skeletal findings that were initially thought to be suggestive of skeletal dysplasia but would be within what Christina had described as dysostosis multiplex, the findings that we see in patients with MPS disorders, the coarse facial features which developed over time. She certainly did not have them in infancy. If you could see the photograph I showed on the initial slides of her when she was a baby, she looked perfectly normal. The otitis media, hearing loss, the enlarged tonsils and adenoids, the corneal clouding, the joint restrictions, the hepatomegaly. So she had many, many of the typical features of an MPS disorder, but in this case as compared to the other two you saw, they developed somewhat later in this child. Really it was the skeletal features that were the initial tip-off, the more prominent features early on. This just shows us some of the variability we see in the disorders in terms of the timing of the development of various findings. I think some of the other lessons we learn here from this case are that first of all MPS disorders can present as a skeletal dysplasia. The skeletal findings can be the earliest manifestations that you see. When you look at the skeletal findings and the radiographic findings, there is a lot of overlap with what we see in certain skeletal dysplasias that are not related to MPS metabolism. Things like spondyloepiphyseal dysplasia or multiple epiphyseal dysplasia. I had a few other lessons from that that we seem to have lost over, but one of the other things that I wanted to say is that when diagnoses have not been confirmed on genetic grounds particularly, we have to keep an open mind. If over time we have a patient that we think has a specific diagnosis, but we start to see findings that maybe don't fit with that diagnosis and we start to see additional findings, we always need to take a step back and rethink the diagnosis. Is this something we were missing? Because we know that with rare disorders there can be considerable overlap among diagnoses. We don't want to get things engraved in stone unless they're totally documented molecularly and keep an open mind because sometimes the diagnosis may change over time. With that, let's go on and discuss one more case that also illustrates some of the variability and heterogeneity that we see in MPS disorders. This is again a case of a patient who really in early childhood had no obvious problems whatsoever. The family thought he was perfectly healthy and normal. Pediatrician, the same. There had been nothing unusual in his medical history until he was about eight years of age now when he was seen in an emergency room with complaints of bilateral hip pain. His past medical history was reviewed. Again, it was pretty unremarkable. Some x-rays were obtained and the presumptive diagnosis made in the emergency room was of bilateral leg calvae perthes disease. The patient was referred to an orthopedic surgeon. Now I'm sure most of you know that while bilateral leg calvae perthes disease can occur, it is more commonly unilateral, but in this case it was bilateral, a little bit unusual but certainly not unheard of. On the next slide we'll see that the patient went to see an orthopedic surgeon and the orthopedic surgeon examined him, noted he had an abnormal gait and seemed to have right hip pain on inflection and adduction, but otherwise the exam was felt to be pretty unremarkable You can see that he was of normal stature. His height was at the 67th percentile for age. Weight was normal. His head circumference was normal. This particular physician was aware that sometimes bilateral leg calvae perthes might be associated with a protein C deficiency, so he did testing for that. And then we'll go on to the next slide. And so he felt like at this point that the diagnosis was a little unclear. He felt this could be bilateral leg calvae Perthes disease, but he also considered the possibility of multiple epiphyseal dysplasia. So the family decided to get a second opinion from a different orthopedic surgeon. They did so, and he felt like the picture was somewhat confusing. He ordered an MRI of the hips and spine. That was done. He felt like both the imaging and the pain were consistent with either leg calvae Perthes or developmental dysplasia of the hip. But he was a little concerned because he thought there was only minimal pain on internal hip rotation, should be more with those diagnoses. He wondered about the possibility of some neuromuscular disorder being responsible for some of the pain. He wasn't really sure what was going on, so he recommended physiotherapy, a CT of the pelvis, nerve conduction, velocity testing, and EMG. The CT scan revealed bilateral osteochondritis dissecans worse in the right hip with uncovering of the right femoral head and some bony fragments in the hip. Looking at the imaging and the earlier imaging and x-rays that had been obtained, the physician felt like, well, the most likely diagnosis is multiple epiphyseal dysplasia, the nerve conductions, and EMG were normal. Next slide. So the patient continued to have pain over the next few years, and at 14 years of age he was seen by yet a third orthopedic surgeon, who at this point noted that he had developed scoliosis. You can see on the chest x-ray shown here, he had a 30-degree curve. To try to treat the pain, he performed a femoral osteotomy, but there was no significant improvement in the hip pain. He now was starting to develop some bilateral knee pain. This physician felt like, well, the most likely diagnosis to me now with the spine involvement looks to be spondyloepiphyseal dysplasia, and because of this persistent hip pain that the patient had had now for somewhere in the neighborhood of six years, he performed bilateral hip replacement surgery. Next slide. He also thought there was diagnostic uncertainty, and given the history of the various diagnoses that had been considered in the past, obtained gene panel testing, which had fairly recently been made available in our country on a no-cost basis. So a skeletal dysplasia gene panel was ordered that had the genes for spondyloepiphyseal dysplasia, also for multiple epiphyseal dysplasia, and many of the other skeletal dysplasias, but also had included the genes for MPS4A, the Galen S gene, and the patient was found to have two mutations in the Galen S gene, one known pathogenic mutation and one likely pathogenic mutation, suggesting the diagnosis of mucopolysaccharidosis type 4A or Morquio A syndrome. To absolutely confirm this, after the genetic testing was obtained, Galen S enzyme activity was measured and was severely deficient, and the patient also had urine glycosaminoglycans or GAGs measured, and you can see that the total GAGs were normal, 2.4, with a normal range up to 6.5. This is a very important point, I think, because many of the MPS4A patients. do have normal total urine gags, certainly the more attenuated patients like this one, so you really cannot use that as your sole diagnostic test for all MPS disorders. It's certainly not going to be helpful for many of the patients with MPS 4. We can actually get false negatives with some of the others as well if you are only measuring total gags, but certainly very commonly with MPS 4a, but in looking at the fractionated gags, which can be analyzed by tandem mess spectrometry, he did have mild elevations of keratin sulfate, and that's another important point I want to make is that the elevations of keratin sulfate may not be that dramatic. I think if we saw mild elevations, let's say of dermatin or heparin sulfate like this, in a patient where we're thinking about MPS 1 or 2, we would dismiss them as probably not significant, but with MPS 4a, again, it's different. You know, they do not have to be dramatically elevated, so really all of the testing in this patient was consistent with MPS 4a and confirmed the diagnosis. We can go on to the next slide, but this is of course a very attenuated case. The picture you're seeing here shows a much more typical patient or a classical patient, if you will, with the more severe rapidly progressive form of MPS 4a, where you see very significant short stature and the obvious bony deformities. You see the bowing of the arms. You can see you get a hint of the ligamentous laxity. The other things that you see here listed show some of the other typical features of MPS 4a. Now historically, many people have referred to this as a skeletal dysplasia, and many people have thought of it as a skeletal dysplasia, like some of the other conditions I mentioned, but in reality, like all of the MPS disorders, it is a multisystemic condition. We see manifestations in all of the other organ systems, even though the skeletal manifestations often are the most prominent and certainly the ones that bring the patient to attention. But we see things like corneal clouding, like the pulmonary involvement, both due to the very small thorax with pectus carinatum, but also to the airway involvement. We see hepatosplenomegaly. We see ear infections, hearing loss, dental abnormalities, cardiac valve involvement, and so on. So it is a multisystemic disease. And here you see a variety of patients with MPS 4a showing the heterogeneity, including the gentleman on the right side who's a perfectly normal stature and doesn't have any obvious skeletal deformities, just like the patient I just described. So there's a very broad spectrum... MPS disorders. We see much more attenuated patients and then the more severe end of the spectrum, like we saw with our first two cases. And I think the MPS 6 case I showed you is more of an intermediate case. She had a lot of manifestations, but somewhat later in life and not as severe as the most severely early onset cases. So next slide. So lessons from this case, again, I mentioned that the MPS disorders do occur across a broad spectrum and like the previous case, they can present like a skeletal dysplasia or as bilateral hip disease. So this needs to be kept in mind, particularly if you don't have genetic confirmation of an alternative diagnosis. And I think really genetic confirmation of the diagnosis is really important. to avoid misdiagnosis considering the overlap. So Christina, what are your thoughts about these patients? Do you – have you seen something similar?
[00:44:06] Dr. Christina Lampe: Actually, yes. This is very common. The spondyloepiphyseal dysplasia is a very common misdiagnosis in attenuated MPS patients. I know that from at least two Moquio patients, non- classical Moquio patients that were diagnosed as spondyloepiphyseal dysplasia from the clinical picture without genetics and misdiagnosed actually. And then it took from six to 11 years in one patient to get the diagnosis of molecular A. And I – actually I was – I was – we know around 436 skeletal dysplasias now. So it's – and they are quite similar. So it is difficult. And you said that you have a genetic panel, a skeletal dysplasia panel. Actually, we don't have that by now in Germany. And I worked on that panel with a group of experts. And I really like it because I think it really helps to differentiate because most skeletal dysplasias have no treatment. But we have a treatment in MPS and it would be – or it is extremely important to diagnose as early as possible and to differentiate between a skeletal dysplasia and an MPS patient. But I think it shows really how variable the disease can be. And also the first case with MPS6, the girl that did not show the so-called typical signs and symptoms at the beginning. But if you see the progression of the disease, it started later but it was not less severe. Do you agree, Barbara?
[00:45:49] Prof. Barbara K. Burton : Oh, absolutely. I agree 100%. Yeah, very true. And she did, I think, you know, I didn't emphasize it. I showed some photos over time. I think even certainly before many of those other symptoms appeared, there was one picture in the middle with her with her backpack as she's heading off to kindergarten. And at that time, the only thing her physicians had been concerned about was her growth. But I think she already was showing some mild coarsening of the facial features that hadn't been present earlier. And that was progressive over time. But definitely, it became quite severe. She had clearly multisystemic involvement. And so you're absolutely right. The fact that you may have somewhat later onset doesn't mean it's really a mild disease. That is for sure. And I couldn't agree with you more about the skeletal dysplasia as being difficult to differentiate purely on a radiographic or clinical basis because, like you said, there's so many and so much variability. But I think you made a great point, which I didn't mention. And I think it was great that you pointed that out that very few of those are treatable whereas MPS disorders are. So it really behooves us to try to weed those out as early as possible if there's any chance that that's what we're dealing with so that the patients can get the benefit of treatment and also of surveillance for some of these other organ system problems that might not be obvious on exam. You might not have a murmur, but the patient still may have significant valve disease, for example. And you would have no reason to get an echocardiogram. But once you know the diagnosis, of course you would. So it's very important in that regard as well, I think. I think over time, you know, we used to think these attenuated cases were just a small fraction, but I think they were the ones most likely to be misdiagnosed. So now as we're getting a little bit better with diagnosis, probably still not good enough, we're seeing that they constitute a larger segment of the patient population than we used to believe for sure.
[00:48:07] Dr. Christina Lampe: Actually, we had a diagnosis of an MPS4A non-classical patient at the age of 27 years of age. And she was not diagnosed in our hospital, but in a genetic department in another university. And she had the first signs and symptoms at the age of nine years with hip pain, with walking problems. She always received physiotherapy, but nobody was thinking to make any genetic testing. With 24, 25 years of age, she received both sides hip replacement, and she went to a rheumatological hospital. And the rheumatological hospital thought to MPS, and they made testing on MPS1. And it was not MPS1, so it was negative. And so they excluded MPS, and she was sent out again without diagnosis.
[00:49:04] Prof. Barbara K. Burton : Wow.
[00:49:04] Dr. Christina Lampe: And this is actually also a problem that you always have to, there's an overlap of symptoms in different MPSs, in particular concerning the skeleton. So you really need to exclude all MPSs. You cannot say, okay, this is not MPS1, and I don't think it is MPS4A, for example. And this lady actually was sent out from the geneticist who did not know that there's a treatment available. And she was another three years without treatment before she Googled and she found the treatment, and she started treatment six months ago.
[00:49:46] Dr. Christina Lampe: Wow.
[00:49:46] Dr. Christina Lampe: So also, this shows actually, I think, how important it is to make awareness for these diseases. And Barbara, I have one question. How do you engage your orthopedics surgeon to make genetic testings? In Germany, they are really difficult. They don't make any testings. They operate or they don't, but they- No,
[00:50:11] Prof. Barbara K. Burton : I mean, I think it is an issue. I think there's been slow progress in that regard, but I'm sure there are many patients still who are not getting genetic testing, who are cared for in orthopedics alone, who don't have access to a geneticist. Of course, I think geneticists are much more quicker to go that route, but I think gradually, there's been a lot of effort put into patients who are seen in specialized skeletal dysplasia clinics. And we have quite a few centers that have clinics like that in the US, both in our academic centers, but also in some of our Shriners Hospitals that specialize in orthopedic problems. So there's been efforts to get them on board with it. And I think because often, genetics plays a role in those clinics along with orthopedics, it works. But I think where orthopedic surgeons may be operating independently, yes, it's much more difficult, I agree with you. And they don't necessarily have the awareness of the importance of it. I mean, they're trying to provide symptomatic treatment. You saw it, even in my case, you saw these guys, you know, they operate, they try to relieve the pain, but we didn't get to genetic testing till we've been through the third one. So yeah, it's still an issue even in our country as well, I would say, yeah.
[00:51:39] Dr. Christina Lampe: But spondyloepiphyseal dysplasia and Perthes disease are the really very common misdiagnosis
[00:51:46] Prof. Barbara K. Burton : in- Absolutely correct. That's been my experience as well. Definitely the case.
[00:51:53] Dr. Christina Lampe: Barbara, one question to your first case. You said she dropped down from the growth percentile, but in a later age. We know in the severely affected patients, they drop down at the age of two and a half to three and a half years, but this was very late. Do you think we could also use this as a earliest sign or early sign in attenuated cases that they have no puberty growth spurs?
[00:52:21] Prof. Barbara K. Burton : Well, yes. And you know, the other thing I think about that, and I've asked pediatric endocrinologists about this specific case. You know, if you saw a patient like that, would you be content just to get the hormonal testing or would you wanna get some skeletal x-rays to see and, you know, I've gotten mixed response. Some say, well, if they don't see anything else on the patient, they might not get any skeletal x-rays, but I think it's a good clue that maybe that would be something important to think about doing because you might get tipped off. I mean, it could be MPS, but it could also be some other skeletal dysplasia, some other, you know, skeletal disorder if you don't have any growth hormone or thyroid insufficiency and so forth. So I think if you see a patient where really you don't have a good explanation for why they're having, you know, such growth failure and it's not consistent with the family, you know, stature and so forth that, you know, looking for radiographic features would be an important clue. Yes, I do. I think in this girl, if that endocrinologist who saw her had gotten skeletal x-rays, he surely would have seen some findings. There would have been findings and that would have led to more detailed evaluation at that point, although they might've come to the same conclusion that they did a couple of years later, which was erroneous and inaccurate, but yeah, at least it would have happened a little bit earlier. So, I know we had, you know, we're coming near the end of the time and we had wanted to allow a little time for questions, but as I scan down, I don't see any questions that have come into the chat. So, oh, well, wait, now I do have one that just came in. So, let me say, I'll let you address this one, Christina. How would an 18-month or more delay in referral impact the progression and treatment of MPS?
[00:54:36] Dr. Christina Lampe: I mean, we know the earlier we start treatment, the better it is. I mean, this is for sure clear. I mean, 18 months, it's actually a quite early diagnosis if you don't have newborn screening.
[00:54:50] Prof. Barbara K. Burton : This is an 18-month delay. So, in other words, what I think that means is if you have symptoms and then you don't make the diagnosis till 18 months later.
[00:55:00] Dr. Christina Lampe: Okay. I mean, this is, it's for sure a pity. I mean, this is 18 months loss of treatment in that case. And I think, yeah, this can happen because we have this unspecific signs and symptoms in most MPS patients at the beginning. And it is really difficult to combine them and see a holistic view of the patient or to have a holistic view and then to make a diagnosis. So I think it is not uncommon if we see the median delay is three years. But nevertheless, I mean, this is why we are doing this case reports to show that it is so important to make an early diagnosis. Barbara, what do you think?
[00:55:41] Prof. Barbara K. Burton : Oh, absolutely. And not just for treatment. The other thing is, you know, some of the complications of MPS require surgical interventions. So we see these patients having tonsillectomies, ear tube placement, hernia repairs. And if you don't, if you're not aware that it's a patient with an MPS disorder, you may not be taking the same precautions that you otherwise would because we know that airway is often very compromised in patients with MPS disorders. So they really need to be cared for in a facility that's equipped to deal with a difficult airway.
[00:56:15] Prof. Barbara K. Burton : So whereas some kids, certainly in the U.S., they would get a tonsillectomy in an outpatient surgical center and so forth that may really not have that experience. We can avoid that if we know what the underlying diagnosis is. We can also make sure the patient doesn't have cardiac disease or pulmonary disease that we need to be aware of and take precautions, you know, when they need surgical procedures. So I think there's just all kinds of reasons why, you know, the outcome's going to be better if we make the diagnosis in a timely fashion.
[00:56:51] Dr. Christina Lampe: Yeah, and we have a lot of surgical interventions prior diagnosis. So this is why it is, as you are right, it's extremely important.
[00:57:01] Prof. Barbara K. Burton : Absolutely. So I think we have skipped over our conclusion slide very quickly, but certainly I think we can conclude by saying that, you know, we've looked at a number of cases today that illustrate the broad spectrum of MPS disorders in terms of the signs and symptoms that we see, the presentation of the patient, the severity of the initial symptoms, the organ system involvement. We've talked about some of the reasons for diagnostic delay and some of the things that we can keep in mind that would allow us to recognize the diagnosis earlier and the importance of definitive diagnostic testing and genetic testing to confirm the diagnosis so that the patient really can have an optimal outcome. I know I've certainly enjoyed talking with you today, Christina, about these cases. It's been a pleasure doing this with you and appreciate having been involved to do so. I hope our audience found it helpful. So thank you for allowing me to participate.
[00:58:15] Dr. Christina Lampe: Thank you very much, Barbara. It was really a pleasure to discuss and to show really the variability of this group of diseases and, yeah, I think I always learn from these cases. So thank you, Barbara. It was really helpful also for me again to widen my eyes for the diseases. Last word is yours, Barbara. I started.
[00:58:41] Prof. Barbara K. Burton : Okay. Well, let me just say to everyone, have a good morning, afternoon, evening, wherever you are, and thank you for joining us for this presentation today.