Joint And Bone Manifestations Of Mucopolysaccharidoses (MPS)

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Introduction

Dr. Andrea Borgo: Good morning everybody, my name is Andrea Borgo, I am an orthopedic surgeon, I work in Italy, in the northeast part of Italy in Padova Hospital. So today we are going to talk about the joint and bone manifestations of mucopolysaccharidoses. First of all I have to remember that you are not allowed to take any screenshot and yes you can read, please do not reproduce any slides and I have to remember that you can send your question by the panel at the end, I am going to answer.

So by definition at the very beginning what is a mucopolysaccharidoses, I know that you are maybe more familiar than me as an orthopedic surgeon with this kind of disease, it's a lysosomal storage disorder that is caused by the deficiency or the lack of function of an enzyme that is required for the degradation of the glycosaminoglycans and you are probably familiar more than me with this kind of biochemical classification, here we have the name of the mucopolysaccharidoses, the eponymous, so the enzyme that is lacking and the glycosaminoglycans that are stored.

I'd like to move very quickly to an orthopedic point of view, when we are facing with a patient with mucopolysaccharidosis we focus on the short stature or the muscular weakness, the joint stiffness, ossification delay, so in the hand and the trigger finger, carpal tunnel syndrome, we have some problem in the spine, I mean the instability, the thoracolumbar kyphosis, we have some hip migration, hip arthritis, valgus deformity of knee and ankle and so on.

An orthopaedic classification of MPS

So I modified this biochemical classification adding some orthopedic aspects that I divided in some general manifestations, some districtal manifestations, so we are going deeply one by one, so never mind if you are not able to learn it by heart. So I have to say that the interest from the orthopedic community is increased in the last years, no more than 10 years ago we used to talk about MPS like a don't touch my lesion, but as you can see in this slide I just show you that in the last literature, I mean the orthopedic literature, the interest in MPS is rising more and more.

So what is the I have to say that starting from the lack of enzyme to the final phenotype, the mechanism is not clear and not completely understood, we have some three major observations and some other minor observations, I mean data from the literature are a lot but the mechanism is not completely understood. So we know that there is an alteration of the endochondral ossification process and we are going deeply in that We know that there is an activation inflammatory response and in the future there can be also, we can say that in the future maybe some anti- inflammatory drugs will be routinely used in MPS but not for now.

And so we have the glycosaminoglycan soft storage in the soft tissue, but going more deeply in the alteration of the endochondral mechanism of ossification, I like to start from this very old but very clear from my point of view image. We have a chondrocyte, it's a human chondrocyte and we can see, it's an Hurler's - Syndrome chondrocyte, we can see that the cytoplasm is full with vacuoles and all the organelles are reduced in number and reduced in the strength and they are displayed through the plasmalemma.

Later on we can see that some of these vacuoles open into the extracellular matrix and at the end we have some organelles, some rosette- like deposits in the matrix and this is the very very beginning of the problem in MPS, of the bone problem in MPS and this is the very very beginning of the alteration on the endochondral ossification.

Why bone and cartilage are affected

I don't know if you are familiar with the histology of a growth plate, but in a normal child we have the reserve zone, so the proliferative zone, hypertrophic and so on to the metaphysis and there is usually well organized in column organization of the growth plate. You can see on your right side the growth plate in a Hurler's syndrome where we can see disarray all this disorganized aspect of the histology.

So this is the very beginning. So are the therapies nowadays available? Are they able to do something for the bone? We can have from the literature some clinical observation. We know that the ERT, the enzyme replacement therapy, leads to a faster growth, is able to reduce stiffness, to reduce weakness. We observe an augmentation in the bone mass but there is a poor effect in the skeletal deformity.

Also for the bone marrow transplant, where it is indicated, we know if it is early, if it is done very early, it leads to an alternation, but the deformity are still present. From the literature we have some experimental studies in animals and I have to say that they lead more or less to the same result. So attenuation but not complete prevention.

So at least at this moment in time, there are a lot of orthopedic aspects in the mucopolysaccharidoses. So coming back to our classification, I divide in some general aspects and I focus later on the spine, upper limb and lower limb. So what about the general aspect? We know that the mucopolysaccharidoses, they are a short stature and this short stature is evident from the early life, except for MPS number II, that let's say, before 8 years of age they can be higher than average, but in the later, later on, and thus adolescent and adulthood, they are shorter and this short stature is a disproportional one.

I mean the shortening of the thumb is prevalent while we have a mild shortening of the limbs, exactly the contrary, for example in achondroplasia where the thumb is, let's say, longer and the limbs are shorter. So the stiffness is another general characteristic stiffness and contracture in children. This stiffness is mostly due to the deposit of the glycosaminoglycans in the articular and soft tissues .

That's why also the enzyme replacement therapy work better in children and the bone dysplasia is more typical of the adult. I mean, if you take an x- ray of that young girl, probably I cannot say that the bones are normal, but they are quite normal. So this, this, this, the same patient when she grew up.

The spine and cervical instability

So, as you probably remember, the beginning of the problem in the mucopolysaccharidosis is the alteration on the chondrification. So the problem, as far as we can see, begins very early, very early during pregnancy. So if you, we theoretically want to act with some drug, we have to start before birth, because at birth we have already, we already have some alteration, some non reversible alteration in the bone structure.

So this is the very beginning and so we can have some mild situation, like, for example, in MPS III, Sanfilippo syndrome. I mean, we know that the bone involvement is not so severe, so we can have some irregular body profiles and platyspondylia, nothing more than like this. But we have some severe situation like in MPS number VI, for example in this young child with that is aged three and a half and she has at three, eight and a half, irregular body profile, hook shape and the early onset of the thoracolumbar kyphosis.

So what can we do for this deformity? Are we going to brace it for life? Are we going to do a surgical instrumented stabilization? So this is not simple but nowadays we have some the result published of a consensus conference for mps1 and we can say that the use of the bracing is useful to postpone the surgical treatment and it is useful to manage the postoperative period.

The indication for surgical instrumentation are mostly based in the sign of myelopathy, not in the deformity progression like we considered years ago. So in the proper age to perform a surgery is between 5 and 13 years, because below 5 there is a nice risk of implant failure, while in the other side, in adolesence, this deformity is stiff and not easy to correct.

So we can, focusing on the upper cervical spine, we can have instability or compression or often a combination of both the problems. So we can see in this magnetic resonance that there is a compression and there is an accumulation in the soft tissue too and suffering of the spinal cord. Or- this is a Morquio patient- we have instability.

So if you look deeply in the tail, the upper cervical spine, we can see that there is flexion and extension movement between the first vertebrae leading to instability. We have some less frequent, lesser in less more real cases, but very difficult to manage. Also instability and compression between the, the junction between the cervical and the thoracic spine.

The upper limb: shoulders, carpal tunnel and trigger finger

Focus about the stiffness in the upper limb, we can. We can see that there is a very severe stiffness and if you look more deeply that there we can see that the real abduction of the humerus, the movement between humeroscapular, is no more than 45 degrees. She's theoretically, the appearance is that she move a 90 degrees, but there is a compesation between the thorax and the scapula.

The real movement of the humerus is no more than 45 degrees. So also focusing on the elbow, on the wrist, we can see that there is no extension, no complete extension, a lack of supination movement. So the stiffness is severe. And going on, on the upper limber and focusing on the carpal tunnel syndrome, I have to say that I'd like to report the result of this study that out of 163 patients- pediatric patients affected by carpal tunnel syndrome, 95, I mean more or less 50%- were affected by mucopolysaccharidoses.

So carpal tunnel syndrome in a child is a very uncommon situation So if you have a child with carpal tunnel syndrome, think about a metabolic disease. We can see that one out of two are affected by the mucopolysaccharidoses. So if you already know that the patient has a mucopolysaccharidoses, check for the presense of a carpal tunnel syndrome Because we can see that statistically more or less half of the patients suffer about this carpal tunnel syndrome and we can, with some surgery we can have a significant amelioration of the situation.

So I have to remember that the compression in the carpal tunnel syndrome is one of the problems because we know that there is also an MPS associated neuropathy. So we have to talk very clearly with the patient, with their family, because if we perform our decompression, obviously this is one of the problem in MPS. So another point is that if we are managing with the MPS patient today we cannot perform such a lengthy procedure like for and healthy adults and so on.

But we have to open, we do a very, very wide opening of the carpal tunnel syndrome in this patient. You can see how thick is the transverse ligament seven here MPS. So another point is that trigger finger. I have to say that the trigger thumb, I mean the thumb, is not a very uncommon situation in children. Usually we can have a trigger thumb in children aged two or three years old, often bilateral disease, not so real.

But the trigger finger, except for the thumb, is a very uncommon situation. So, in the presence of a trigger finger that is not the thumb, always think about a mucopolysaccharidosis, because it is really uncommon in a child to have a trigger finger. So What can we do for this hand deformity, that is, that we have flexion and contracture of the finger and the thumb.

There are some data from literature nowadays that we have some amelioration with some release of the pulley. The tendon are linked to the bone in some points and we can have some release in A1 and A3 position, like I did in this child, with an amelioration of the possibility to open the fingers. So, going down in the lower limb and focusing on the hip, we from this table- that is about general aspect but they like to focus in the hip.

The hip

We can see that the hip dysplasia and the proximal dysplasia of the femur, are very common in the MPS- I don't know if you are familiar with POSNA outcome score that is basically a functional score that is targeting the target is children and adolescents and that is able to give a global functional. But we have a sub score that is the transfer and basic mobility, that in some way is able to quantify the compromise of the mobility of the lower limb.

So in MPS patient we have really a poor score, also in children. So but what happened in the hip of a mucopolysaccharidosis patient? So I'd like to present these series of x- ray. This is the same patient. It's a MPS I patient. I like that if you can see that we have a some, some pattern that are going to change.

So the femoral head is almost around here and is going to lose the sphericity. The acetabula is flat here and remain flat during the years. The neck diaphysal angle- I mean the neck between the angle between the femoral neck and femoral diaphyseal- is going to to sorry, it's going to increase and so the hip is going outside. We can say that the loss of the sphericity of the femoral head we can quantify it with this Mose's technique.

It's very common in mucopolysaccharidoses, especially in MPS I and II, and this kind of patient are going to lose the sphericity between in year 3 and 8. So there's acetabular index. It's a very orthopedic index. It's a quantification of the coverage from the acetabula of the femoral head, and so it's an angular measurement. So in the normal children there is in the first year of age a decrease of the angular.

So the femoral head is going to be covered by the acetabula in the first year. But this is not observed in MPS. The acetabula is not going to cover the femoral head. Some work reported that is take like this. Some other reported this is an augmentation. So it's actually the contrary in those happening in children. But the point is one, and so the acetabula is not going to cover the femoral head in children.

So the cervical diaphyseal angle, I mean the angle between the femoral neck and the femoral diaphysis, that in an adult normally is 135 degrees, can be a little more higher in children but usually go down with the time. In MPS usually we observe an augmentation. So the pelvic tilt. I know that we are familiar with MPS patients and usually you see that there is a forward movement of the acetabula of the pelvis.

And so this, all this alteration in the hip, I mean the the neck diaphyseal angle that is higher than normal acetabula is not going to cover the femoral head, the pelvic tilt lead to a progression of the luxation of the hip, and so we can quantify also this migration with this Reimer index and we know that there is that in MPS I and II, I can say there is an augmentation of the uncovered part of the femoral head.It leads to not normal anatomy between the femural head and the acetabulum.

So what can we do? We can perform some surgery that are ,we copy this kind of surgery from the hip dysplasia, obviously, and we can do. We can have basically two kind of surgery. A surgery that is in the proximal femur who is aiming to put the femoral head inside the socket- it's a varus osteotomy , like I did in this MPS I patient.

Usually in the normal child when you perform a varus osteotomy, The acetabula is going to remodel, or we can act also in the pelvis, basically with some pelvic osteotomy which aim is to reorientation of the acetabulum, or some acetabuloplasty with no reorientation but just adding a piece of bone laterally in order to have a reorientation of the bone roof.

So, as we said, when you perform only the femoral osteotomy, there is no, no remodeling in the acetabulum. So the best result in the literature are when there is an association between the femoral osteotomy and also reorientation or some augmentation of the acetabulum, so both sides. But what happened after this kind of surgery in the hips? We have only one study, by the way, and it's a long follow- up and we have to say that the results, once the anatomy is restored the results are very poor, I have to say.

There is a progression of the compromise of the joint line. The patients are painful. We can discuss a lot if the PODCI score that was used here to judge the function is the proper one, because it's a score that basically was taken for, I mean arthritis, not dysplasia. But the point is one: even if you restore the anatomy, there is a progression of the deterioration of the hip and the patient are painful so at the end they come when they are young adults, usually asking for an arthroplasty.

An arthroplasty we remove the femoral head from one side, we remove the acetabulum from the other side and we make a total hip replacement with the two components. This is a case of mine. It's a more acute patient and with a bilateral arthroplasty of the proximal femur, but this was quite a simple case because there are the situation, as you probably remember, there is no roof.

So it's a very high- demanding surgery sometimes and we have some solution, some bone cementation, some bone transposition and so on. But the surgery is not so easy sometimes. And also the problem is the size of the arthroplasty, because they are very short and sometimes the prostheses that are available in the market are too large for that kind of patient and sometimes we have to do some custom- made implants.

The lower limb and early diagnosis

So, lower limb- you know that all MPS patients have a valgus deformity of the knee and we can in children, where there is the open physis, we can act with this kind of bridging. It's a hemiepiphysiodesis technique.

We perform a stopping only in one side of the epiphysis and we let the epiphysis to go only on the other side, obtaining a progression during the growth of the correction. But we have to remember that this kind of patient are not open as normal. So this kind of procedure should be done very early in life. So- and it is an example, for example the proximal. We perform here a proximal hemiepiphysiodesis because, by the way, the proper side is usually the proximal tibia.

This is quite different from a normal fit child, let's say, that usually has a deformity on the distal femur. But it is the preoperative surgery, the hemiepiphysiodesis. Obviously, we can perform a correction of the lower limb axis also in adults with the proximal osteotomy, but it's a it's a heavy surgery full of metal and so on. Or we can perform the correction in the distal femur.

It depends where is the deformity like. In that case it's a Morquio syndrome. But to prevent with a simple hemiepiphysiodesis it's better. Obviously later on this kind of patient develop arthritis of the knee that can require a total knee replacement when they are adults. So another deformity that is commonly observed is the vaglus deformity of the ankle and in the same way we perform in the knee, we can perform a hemiepiphysiodesis in the middle part of the tibia, like I did in this patient, with a good clinical and radiological result.

So later on we can observe some degenerative arthritis in the ankle in adults, but usually the arthritis in the ankle is not so painful. So at least in my experience, they don't ask for a procedure for surgical protocol. They ask for hip pain, knee pain, but not ankle pain. We commonly observe a flat foot, I have to say I'm not to correct flat foot, I am not going to correct flat foot in MPS patients but are usually insole generally or special shoes.

So coming back to our classification, I underline some general aspects, some aspects in the spine, some aspects in the upper limbs, some in the lower limbs and they are here resumed. So drawing some conclusion, I mean that in this presentation I show you that the orthopaedic manifestation in MPS lead to disability and an important point that at least until now all the best therapy that we can do lead to an attenuation of the orthopaedic manifestation but there is no complete solution.

The early diagnosis and the early therapy is the key for a better prognosis. I have to underline that some orthopaedic signs could be the first signs of an NPS and so also the orthopedic surgeon should be ready to, not to do the diagnosis of MPS obviously because we have to send to the specialist, the metabolic specialist but to understand that some signs are not normal and need some consultation with a metabolist.

And I have to say that in the follow- up of that patient an orthopedic surgeon has to be part of the team because they are really in need of some surgical procedure in children and also in adults.

Questions and answers

So if you have any questions, they are welcome. So there is a first question. The timing of the hemiepiphysiodesis in MPS patients. So probably understood the meaning of the hemiepiphysiodesis is to lock the cartilage in one side. So obviously we have to have, we should have an open physis in order to make this kind of procedure to work.

So I have to say that usually for MPS I and II, we can perform the surgery around 7 to 10 years. But we have to point out very, but there are some patients, especially more acute patients in MPS IV or MPS VI that they are not growing at all. So we have to perform this kind of surgery very early in the life, I mean around 4 or 5 years in order to have some correction.

Otherwise we have only, let's say they are not going worst but they are not too correct. We cannot expect any correction. So basically the answer is 7 to 10 years in MPS I and II. 4 and 5 years in MPS IV and VI. So we have another question. Okay so which are the most common musculoskeletal signs that suggestive of MPS.

So, I have to say first the stiffness. A stiff child is not normal obviously. But a stiff symmetric child with no pain, with no sign of logosis, no labotoristic sign, normal exams and so on with a symmetric stiffness It's really very suggestive of metabolic disease, especially MPS. So the stiffness at the beginning. Second is the thoracolumbar kyphosis.

Thoracolumbar kyphosis in a child is very uncommon. This is not pathognomonic of MPS. Could be also called dysplasia or other skeletal deformity, but this is very uncommon. So the other point, another point is the carpal tunnel syndrome. As I said before, carpal tunnel syndrome in a child is really uncommon, really really uncommon.

Trigger finger, not the thumb, as I say, the thumb could be- um, it's a common observation in children, but a finger that is not a thumb is really uncommon. So these basically are the orthopedic sign that. So anesthesia and airways management linked to um orthopedic patient- okay, see as um. As you probably know, um, the- I mean the anesthetic management of this kind of patient, with the special referring to the management of the airways- is, uh, really a changing, so challenging sometimes.

But I like to underline that except for the spine surgery, all the orthopedic procedure can be basically done in a local, regional anesthesia. I mean, for example, we can perform carpal tunnel syndrome and trigger femur surgery in a local anesthesia. Only with anesthesia of the upper limb we can prefer, we can perform epiphysiodesis or even total knee arthroplasty in peripheric anesthesia.

We can even perform some um total hip arthroplasty in peripheral anesthesia. So, whenever it is possible, think about a local, regional anesthesia because this is really safer for the patient. Um, and try also to do some surgery in order to prevent the deformity that are going to appear later on, for example. Uh, it is, we can perform a simple epiphysiodesis instead of waiting a lot and do when they are, when they are already grown up, uh, not the osteotomy, because it's a simple procedure.

So so i'm checking for other questions. Another question is better to have kyphosis or lordosis, for those in terms of MPS. Yes, when, we have a spine deformity, um, in order to have a early diagnosis of MPS, we have to focus on the thoracolumbar kyphosis. Okay, and, as I said before, this is not only, it can be also some spinal dysplasia, chondroplasia and so on.

Generally, in chondroplasia, for example, this thoracolumbar kyphosis is going to get a little better without surgery during the years, but in mucopolysaccharidosis we have no amelioration at all. So if in presence of a thoracolumbar kyphosis, we have to rule out some pathologies that can be by, there can be metabolic disease can be also some skeletal dysplasia, but it is not normal to have a thoracolumbar kyphosis.

Okay, so there are no more questions. So I thank you a lot for your attention and have a nice, have a nice afternoon here- or a night, it depends wherever you are- and bye- bye.

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