# Exploring Real World Case Studies to Help You Spot the Early Signs of Mucopolysaccharidosis (MPS)

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[00:00:12] Dr. Carolina Fischinger: Hello, everyone. I'm Carolina Fischinger Moura de Souza, and I am a medical geneticist in Porto Alegre, in south of Brazil. And I work in a big university hospital dedicated to evaluation patients with rare disorders, especially with lysosomal and MPS disorders. I worked with MPS more than 20 years, and now in this session, I will share with you some cases based on the clinical diagnostic of MPS cases. And the title of this part of presentation is Avoiding the Misdiagnosis and Delay in Diagnosis of MPS in Children. We are doing the Series 5 from webinar 4. Exploring real world cases to help you Spot the Early signs of MPS. Thank you for the invitation and we can go ahead. So some notes for the attendees please do not take any screenshot. Please do not reproduce any of the slides, content, or image without express written permissions of the speakers. We will have like 30 minutes of this presentation, and then you can use the Q& A via text, and I will answer orally. Submit your question at any point during the webinar. I can see in the end. Questions can only be submitted via text and not verbally. As many questions as possible will be answered at the end, and this webinar is recorded. This is my disclosure in this presentation. I don't have any financial interest or commercial products in diagnosis of MPS. So, I will start now. I think you know from other presentations, other webinars, that it's a challenger of MPS suspicion and diagnosis. MPS is associated with a continuum of disease presentation. Traditionally, we'll be divided into different clinical phenotypes that, of course, depends on the enzyme activity, gene variants in the same type of MPS and different types, and the type of the GAG accumulation. Of course, it's other causes that can be associated with the continuum of the clinical presentation that we still don't know. The symptoms found across the entire of MPS spectrum include corneal clouding, organomegaly, cardiac valve abnormality, joint contractures, and disostosis. So, MPS1, that is the focus from this case that I will present, as other, is also associated with a continuous of disease presentation and are divided in two main types. Horner's syndrome, the most severe form, typically manifested during the first year of life, and children rapidly develop significant cognitive impairment and somatic disease in multiple organ system manifestation. This is the most frequent form of MPS1. The attenuated form can be named by Hurler- Scheie or Scheie, are characterized by later onset of symptoms, longer life expectancy, and mild or no central nervous system involvement. We will see some cases from the different types of MPS. It's important to be clear here that the attenuated forms, they start also in the childhood. We need to recognize this form of presentation of MPS because when we don't give the perspective of correct management, the patient will evaluate it with some clinical complications. The symptoms found across the entire MPS1 are, I told before this. So here we can see some spectrum of the MPS1 patients from the attenuated form is in the link side. It's a patient, she is psychologist. She is a shy patient, have many problems in the skeletal and spinal compression. Also, she expressed a corneal clouding, a severe glaucoma, but she develop cognitively totally normal. In the right side, you can see a severe form that we can recognize very early on, very early on life, because the patient have macrocrania, spinal corse phase, spinal compression also, but hernias that is very typical in this form of the disease. And in the middle, a spectrum of Hurler, Scheie, the patient have some more typical senotypical symptoms. Some type of MPS, but without severe neurological manifestation. The first suspicion start, and after the first suspicion, we go to the best clinical evaluation of the patient and start the process of diagnosis. When to suspect, when you see all cases with MPS, we can ask about recurrent airway infections and most of them, they have this manifestation very early before one year of age, that they start with complication like otitis and pulmonary infections. So we can see also a lower airway obstruction associated with chronic dyspnea, stridor, and reduce of endurance of the patient. Umbilical and inguinal hernia, it's very typical when they manifest together. It's a very high suspicion of MPS in the patient need to be evaluated. Ear, nose and throat infections, macroglossia and anomalous dentition, especially in the type four, type six, but also in type two and three. And cardiomyopathy, valve insufficiency and arrhythmias. Hepatomegaly, central nervous system and cognitive delay. Many manifestations concerning to school, veins, hand joint stiffness that you see in most of the... that goes to reduce vision in the patient. So we restart, I select three different cases and one more short case. And I want to explain a little bit about the diagnostic odyssey related to MPS patient. You can see here the patient with three months, two years, five years and 10 years. At one year, the mother complained that the girl has recurrent upper air infections, many otitis and chronic nasal obstruction. otorhinolaryngologist without any specific diagnosis. At two years of age, started with stiff joint contractures, consultation with the orthopedist without any specific suspicion. She couldn't run because she get pain. When she ran, she stayed when she was a child, sitting in the school, seeing the colleagues running and playing saucer in the school. And she couldn't do this because a lot of pain and joint contractures. So at age three, she started with inguinal hernia and make consultation with pediatrician surgery. At five, she was submitted to a foot surgery and again, consultation with a pediatric orthopedist. At age six, joint pain, physical limitation, difficulties running and climbing trees. That was very, the patient was very limited in her life because this pain. She started then to consultation with rheumatologist, infantile rheumatologist. So, after this long time, looking for a solution for the problem, she was submitted from 10 to 17 years of age to a treatment for rheumatoid arthritis and was investigated for short stature with endocrinologists, rheumatologists and endocrinologists. You can see how many specialists the patient went. So at age 18, the umbilical hernia having undergone surgery and again, consultation with surgery. At age 17, she was diagnosed with glaucoma, severe glaucoma, and then she came to a big city to this investigation and she went in an ophthalmic consultation and after a new assessment for glaucoma, at age 19, she also, the ophthalmologist noted the corneal opacity. That was started the first suspicion of mucopolysaccharidosis. She was referred to the first reference genetic evaluation, so she was lucky because at age 20, she was concluded the diagnosis of mucopolysaccharidosis and started the clinical trial at that time and she participated in the first clinical trial in Brazil for MPS1. She had this variant, it's very common in Brazil and she participated in the first enzyme replacement therapy clinical trial and as you can see, at age 27, was diagnosed with bilateral carpal tunnel surgery and submitted to a surgery and at age 33, she was submitted to a corneal transplant. Now, she is under ERT, current president of a patient advocacy helping other rare patients to shorten this odyssey that takes 19 years to reach the diagnosis of MPS1, despite she was a typical case of MPS1 when she was a child. Then I start making some questions, what is the wrong disease in the differential diagnosis of MPS1? You can see here, infantile rheumatoid arthritis, gaucher, bone dysplasia, mucolipidosis, leg patters disease. You can choose here what you think that is not a differential diagnosis related to mucopolysaccharidosis. Gaucher is not related to mucopolysaccharidosis because you can see this clinical manifestation but the other disease, infantile rheumatoid arthritis, bone dysplasia, mucolipidosis and leg patterns can be symptoms and can make some confusion related to the differential diagnosis of MPS patients. The second case, she is a female, third child from a consanguineous couple. At age nine months, she was admitted in our hospital because recurrent bronchitis and severe pneumonia. The first suspicion of this case because she gets so many respiratory infections was cystic fibrosis. Then, two months later when she was evaluated in our hospital for cystic fibrosis, she was referred to genetic evaluation and after the genetic evaluation was noted, hepatomegaly, failure to thrive, development delay, and gibbous and coarse face. You can see here in the figure, the gibbous in the right image, the gibbous of the patient, the coarse face, macrocrania, and the development delay when she was 10 months of age. The investigation for NPS started and was concluded that the deficiency was of alpha- hedronidase, very low. She has the typical mutation for Herler form and the GAGS quantification was 601 milligram per milligram creatinine, very, very high. The treatment for this case was she started with ERT at month 16 of age, and she was submitted to stem cell bone marrow transplantation when she was two years and four months of age, 11 months after starting ERT. So here we can see some image after the bone marrow transplantation. She transplanted a little bit late, considering the indication, before two years, but we decided to do this because the patient was very, very severe case. She was evaluated before from the pneumologist group, and we decided together to perform this transplantation. So she was very severe in development delay. She still has some delay, but she started to walk better. She started to improve the development, but you can see still some features, phenotype associated with MPS, despite she is now more than 10 years of age. The fourth case is very recently case that is very nice to share with you. This baby with seven years of age, we didn't see anything different than the normal. The mother decided to refer to the pediatrician that the growth was a lump in thoracic spine. Orthopedics reported a bulge in the thoracic region, having been referred to orthopedics and x- ray and blood count were requested because these symptoms. The background of this growth was normal pre and perinatal. Mother was 19 years of age without any intercourse in pregnancy. There was a cesarean delivery, APGAR score were normal. The weight was two kilos and 200 grams, a little bit lower, but was 34 weeks of gestational time. Length was normal for this time, and the head circumference was also a little bit smaller than expected. So from the time when she was born until nine months when she was referred to our hospital, to the pediatrician group in our hospital, she got bronchitis with five months, no allergies and no hospitalization or surgeries, but bronchitis were very common and a complaint. Examination with nine months, normal facial appearance, no cyanotics, anicteric, no fever, respiratory, cardiological without any abnormalities, and was described in the records that she have a umbilical hernia and a protrusion at thoracic lumbar level T8L1. This kind was noted the Mongolian spots on the back and on the left knee. The impression of the pediatrician was good development, protrusion in the thoracic lumbar level to be clarified. The mother was orientated to return for a new evaluation after four months and was requested a radiological investigation. Here you can see with six months of age, but the mother took this photo, this picture when she was four months of age and you can see here the gibbous, classical gibbous of MPS patients that is very typical and can be seen after three to four months of age. So she returned with one year and one month, that was the second pediatrician evaluation. The mother reports increase of the bulge in thoracic lumbar spine, inguinal hernia with surgical intervention plan was not so small hernia. The development was as expected for his age, but still cannot walk without support with 13 months. Presence of umbilical hernia and protrusion of thoracic lumbar as the first evaluation and still the presence of Mongolian spots in the back. The X- ray result was lumbar hyperlordosis increases intervertebral space T12 and L1 without anatomical abnormalities. I will show you later this image that it's very important not to accept the report from this evaluation, but to see the image. Here you can see the patient. So the third pediatrician evaluation at our hospital was without any interference, still having the umbilical hernia, still normal development, starting with some dysmorphologic aspect that was described, irritability. Then only when she was one year and seven months, the genetic evaluation were requested. With two years and nine months, more than one year later, because that was the Covid time, that was very difficult to have the patient to see in the outside clinic. She came very late and when she came in that moment, she started with delay of motor and cognitive development. Now the physician could see the umbilical hernia, inguinal hernia, core space, chronic respiratory infections, irritability, paracolumbar gibba, Mongolian spots, macrocrania, and without epitomegaly. So she was the first suspicion. You can see totally different growth one year later with severe core space, severe umbilical hernia. You can see here the gibbous that was noted by the mother when she was four months of age and she complained these symptoms to the pediatrician again, and the Mongolian spots that didn't disappear in this case. It's a totally different patient, but it is the same case that I showed you before. And the image, it's obviously clearly that we have here the morphological alteration in vertebra, mainly lumbar, and alteration in alignment of the thoracolumbar transition that is very suggestive of MPS1. Abdominal ultrasound, slight liver enlargement, eduactivity very low, and glycosaminoglycans quantification very high, considering and concluding the clinical and biochemical diagnostic, because we saw also the presence of dermatin and epirusulfate. Another manifestation that is very typical from MPS is, I explained, in the other presentation. So the complementary evaluation is the electrocardiogram showing ventricular overloaded, CT spine showing the morphological alteration in the vertebra, the CT of the head, very typical, the enlargement of perivascular spaces and the J- shaped encelotorsica, that is very typical also from patient with MPS. And this other manifestation, macrocrania, megacisterna magna, J- shaped encelotorsica and enlargement of perivascular spaces that is very common in MPS cases. with this manifestation that was seen in CT was also seen in brain MRI with this manifestation in peritrigonal regions and cerebral hemispheres and corpucallosum suggestive of areas of enlargement of perivascular space. The echocardio was showing the thickening of little left of aortic and mitral valves and mild regurgitation in both valves. The pressure of pulmonary artery was a little bit high and this patient develop a very severe cardiological manifestation and was submitted to a valve replacement before four years of age. The polysonography showed obstructive respiratory disorders during sleep, the mild, great mild, 4. 8 events hour of sleep, that is considered mild for child. So, she started the enzyme replacement therapy when she was three years of age, two months after the diagnosis. And you can see again, a totally different image from the patient after 10 months of ERT. She was happy again and is starting to improve the clinical manifestation...and also the respiratory complication associated with the MPS. Some other important informants clues that very early signs related to MPS, they are Mongolian spots. You can see here in other case, bone dysplasia, macrocrania and recurrent infections. We can't forget this clinical manifestation that is common for almost 100% of the patients. Here, an image from a spinal, different kinds of bone dysplasia and multiple dysostasis related to MPS. Hip dysplasia, we can also see vertebra changes and high risk for cord compression and column malformation, as you can see here in this cervical region that associated with severe cord compression. Some enlarged ribs growing, it's very typical also. It's not so complicated and to analyze it, this and not to accept the report from the radiologist, but to see the image that are doing in the patient because some cases it's better to see this typical malformation related to the vertebra change. Conical metacarpal is also very common in MPS. Some signs appears later like the umbilical hernia, corneal clouding, hands restrictions, one year and five years is totally different that will develop with the time. It's not expect to see this in early sites. Attention to medical history, surgical history, and physical examination. This article show about the history of surgical, hernia, respiratory infections, salivary difficulty, apnea, reflux, laryngomalacia. It's not so common, but some cases we can see. Physical examination, I told you, joint restriction, but it's not so typical in the early signs. Corneal clouding, syphosis, hypotonia, hepatomegaly, sacral dimple, mongolian spots, we see here. It's very common in the patients from Brazil. Some cases are surprising because it seems to be a congenital laryngomalacia and stridor. And this case, for example, was sent to our intensive care because the severe respiratory problems. At age, at month three of age, was the first evaluation. And the first suspicion was Cornelia de Lange syndrome because the hypertrichosis and the karyotype and array was totally normal. After nine months, we can see the typical coarse phase. And he was re- evaluated because hepatomegaly and coarse phase was a typical case of MPS1, severe case. And the first symptoms was laryngomalacia. You can see here, associated with this case, laryngomalacia is not a common symptom, but sometimes we need to put in the order to investigate MPS. Here it is also. The concluding remark, take a home message. MPS is a chronic and progressive disease with high variability among the affected patients and affected more than one organ and systems. And we need to pay attention with some symptoms that is very common in these disorders. And we need to order the investigation to not to put the patient in the odyssey of diagnostic. I thank you so much for the patient family and the physicians and the labs working to improve the life of patients with MPS1. We have a very big group here of MPS patients, but also a group that's dedicated for the treatment and the best clinical management. Thank you. We will have the time for questions. You can put here in the chat your questions that you have. I receive here now one of the questions. Are there any difference in hip progression signs between MPS1 and other types of MPS? The answer is yes. Some MPS like MPS6 and MPS4, more acute, and Maroteaux-Lamy MPS, the patient have more complaint and more progression signs related to the hip compared to MPS1 and MPS2. But I think we need for all the patients to evaluate this because I have very severe MPS2 patients that are related to the accumulation of dermata and eparasulfate that the patient needed to be submitted to a replace of the hip as so severe this case was. But the hip dysplasia is more common in MPS4 and 6. But we can see also in MPS1 and MPS2, but not so common as in the other MPS associated with severe dysplasia. So I receive another question, are siblings always having similar clinical features at the same stage speed as their sibling, given the science? Usually the manifestation of siblings for MPS1, they are very very similar. The molecular results are related to enzyme activity, and as we have lowest enzyme activity as severe as the phenotype, and expected from siblings that they have the same genotype characteristic manifestation, then they have the similar enzyme activity and similar clinical manifestation. From experience that I have from siblings in MPS2, when they are severe form, in the same family, we see only severe forms. In MPS4, when we have severe forms, it's also severe forms, and the stage and speed of manifestation is also can be a little bit different, it depends also on the starting of the treatment. Some cases from siblings start earlier, because the diagnosis of the older brother, then they have opportunity to start earlier, and as we start earlier, they have mild or not severe phenotype, but usually it's the same. Does no cardiac murmur mean no cardiac disease? Should I test anyway? Yes. For example, this third case is a typical case. The murmur, cardiac murmur was normal, but this case, when we did the specific evaluation... manifestation was very severe, and was not represented by a murmur. Then, if you have some suspicion of MPS, like a case that has hernia, umbilical hernia, inguinal hernia, some little development delay, or little joint contractures, my suggestion is to perform echocardiogram, because it is not an invasive test, and can do, it's not expensive, and it's not invasive. When is the latest time for enzyme replacement therapy to be? We can start as early as possible, when the patient is 20, or two months of age. The enzyme replacement therapy needs to be started as early as possible, but for later onset, or the attenuated case, can help a lot. The pain can help also to alleviate the joint contractures, can also protect the cardiological evaluation, cardiological progression of the disease, and can also help the endurance, and the pulmonary test from the patient. It needs to be started as soon as you do the diagnosis, independent of the age. So, thank you, we don't have any other questions. Thank you so much for the audience, and I will end the broadcast.