Dr. Andrea Borgo: 00:00:00 Hello everybody. Welcome to this webinar. My name is Andrea Borgo. I come from University Hospital of Padova. Padova is in Italy, in the northeast part of Italy. I'm an orthopedic manifestation surgeon. of mucopolysaccharidosis and alpha- So before Before starting the webinar, I have to remind you that you are not allowed to take any screenshot. You cannot reproduce any of the slides and you can submit the question with the proper panel in At the end, we are going to to try to answer to as many questions as possible. So What are we going to talk about today too?
Dr. Andrea Borgo: 00:00:48 we are going to talk about the orthopedic manifestation aspect of mucopolysaccharidosis and alpha- of mucopolysaccharidosis and alpha-mannosidosis and In order to recognize some precursor aspect musculoskeletal signs that are able to orientate to a diagnosis and to understand the surgical option and the timing of the surgical option from an orthopedic manifestation of mucopolysaccharidosis point and alpha- of view. So what are we talking about? By definition, a mucopolysaccharidosis and an alpha-mannosidosis are a inherited lysosomal storage disorders that are caused by the lack of function of an enzyme.
Dr. Andrea Borgo: 00:01:26 In MPS, the enzyme is required for the degradation of the glycosaminoglycans that are better known as the mucopolysaccharides, As glycosaminoglycans and in alpha-mannosidosis the required enzyme which is lacking is the one for the degradation of the oligocolysaccharides. And you are probably familiar with this biochemical classification. I put the name of the disease, the eponymous, with the name of the doctor who very first described the pathology, the enzyme that is lacking and the glycosaminoglycans, so the oligoclysaccharides that are stored.
Dr. Andrea Borgo: 00:02:07 I have to say that there is a wide range for alpha-mannosidosis. If you go to the literature, you can find alpha-mannosidosis 1, 2 and 3, though in other classification 1 and 2. But we can say that there is a broad spectrum of disease that is characterized basically with a very attenuated form that is the one... one that lead to early death because of the involvement of the central nervous system and the recurring infection. Obviously, this very severe form is not going to develop any musculoskeletal alteration because of the sudden death.
Dr. Andrea Borgo: 00:02:56 And from an orthopedic manifestation point of mucopolysaccharidosis and alpha- of view, we can have short stature, more current weakness, joint stiffness, ossification delay, and in the hand, trigger finger, carpal tunnel syndrome. In the spine, instability of the upper cervical spine, the very typical thoracolumbar kyphosis. In the hip, we have hip emigration, hip arthritis. In the knee, genuvilus deformity, knee arthritis in young adults. In the ankle, we have ankle valgus deformity and the later on ankle arthritis.
Dr. Andrea Borgo: 00:03:31 And I try to resume all the orthopedic manifestation aspects of mucopolysaccharidosis and alpha- in this, let's say, ortho-biochemical classification. But we are going deeply and deeply side by side to see each one of these aspects. So I have to say that the interest from the orthopedic manifestation community of mucopolysaccharidosis and alpha- about, I think, all the metabolic diseases, especially mucopolysaccharidosis, and lastly also alpha-mannosidosis, is getting common and common.
Dr. Andrea Borgo: 00:04:00 I remember that no more than 10 years ago, we were very afraid to manage with this kind of disease, but now I can show you there are a lot of very orthopedic manifestation journals of mucopolysaccharidosis and alpha- talking about metabolic disease. And I have to say, first of all, that from the lack of the enzyme to the final phenotype, the mechanism is not clearly understood. There are a lot of things that we still don't understand. We can start from three major observations. We have in mucopolysaccharidosis at least, an alteration on the enchondral ossification system.
Dr. Andrea Borgo: 00:04:40 We have an inflammatory reaction and we have a storage of the GAGs inside the soft tissue. We have also, coming especially from the very... the alteration of the autophagy, the enchondral ossification mechanism.
Dr. Andrea Borgo: 00:04:54 And so I'd like to
Dr. Andrea Borgo: 00:04:54 start from these two.
Dr. Andrea Borgo: 00:05:08 electron microscopy, in the right side we have an MPS chondrocyte, in the left side we have a normal chondrocyte, and the difference is very easy to see. What do we see in the pathologic chondrocyte? We see that there is a, the chondrocyte is enlarged, the cytoplankton is short-field with baffles, and the organelles are reducing number and in the stent, and they are displaced toward the plasma lemma. What happened later on? That some vacuoles open into the extracellular matrix, and at the end we find some rosette-like deposits.
Dr. Andrea Borgo: 00:05:49 And this is the very beginning of the problem in MPS. I don't know if you are familiar with the histology of the growing plate, coming, beginning from the reserve zone to the proliferative one and so on, but without going deeper and I like to show you that there is a very well organized in column histology that is completely lost in MPS like you can see in the right side of the monitor.
Dr. Andrea Borgo: 00:06:15 Also in alpha monoidal doses we have storage of, inside the... bone tissue, I like to show this lymphocyte that is strongly reminded what we say before for the contour sign in MPS. And when does the problem begin? Very early, because I like to show these two samples of human embryo, and this is thoracic vertebra between, in the very transition from the mesenchymal tissue to the cartilaginous tissue, and it happened between the fifth and the seventh week in the prenatal life.
Dr. Andrea Borgo: 00:07:05 So if you remember that the beginning of the problem is the alteration of the chondrification system, you can easily understand that the problem is really... a therapy that is really able to prevent all the manifestation, we should start before birth. So are the therapies nowadays available for MPS able to prevent completely the orthopedic manifestation manifestation? of mucopolysaccharidosis and alpha- No. The answer is no, and we have some clinical observation.
Dr. Andrea Borgo: 00:07:47 The ERT leads to a faster growth, reduce the stiffness, reduce the weakness, augment the bony mass, but have a poor effect on skeletal deformity. At the bone marrow transplant, we know if it is done very early, the skeletal deformity is seen, but they are still present. There are also some experimental studies with new experimental therapy that are not until now performing in humans, but the results are often the same, are still the same. I mean, poor effect on the musculoskeletal system.
Dr. Andrea Borgo: 00:08:22 So we observe in mucopolysaccharidosis dwarfism, I mean short stature, mucular weakness, joint stiffness, ossification delay in the spine, platyspondyly, thoracolumbar kyphosis, hypoplasia, odontoid process, cervical myelopathy, lumbar radiculopathy, and later degenerative arthritis later on. In the upper limbs, we observe trigger finger, carpal tunnel syndrome, and radial deviation of the distal radius of the wrist.
Dr. Andrea Borgo: 00:08:52 In the lower limbs, we observe hip dysplasia and varicose deformity of the knee and ankle and flat foot with later degenerative arthritis later on. Often we say that alpha- mannosidosis is very similar to mucopolysaccharidosis, but if we go deeply and deeply into the literature, we find no report about dwarfism, they almost have normal stature. We found no report about ossification delay.
Dr. Andrea Borgo: 00:09:20 We find the muscular weakness, yes, and we find the stiffness and the contracture, but we found some report about scoliosis that is said to be typical of the alpha- mannosidosis and can be also present in mucopolysaccharidosis, but this is not typical, scoliosis can be present in mucopolysaccharidosis, but this is not typical. We find no report about hand alteration in mannosidosis. We find no report mannosidosis and we find no report about flat foot. some equinus foot deformity, but I have to say that alpha- mannosidosis is also an ultra- rare disease and there are only a few reports.
Dr. Andrea Borgo: 00:10:03 And I like to underline that only moderate cases survive into adulthood. And so what we can find in literature is poor about alpha-mannosidosis and so sometimes we can state that if there is no report about some aspect maybe it's only because the moderate cases are going to survive into adulthood. And so going deeply and deeply, about the short stature we can see that it's very common in MPS especially MPS 1, 4 and 6 while MPS 3 have a normal stature and as I said before there is no report of short stature in alpha-mannosidosis.
Dr. Andrea Borgo: 00:10:44 I underline only from the moderate cases. MPS 2 has an exception because before age 8 we can also observe a stature higher than average leading anyway after 8 years of age to a short stature and the stature is short and disproportional like I wanted to show you in this slide where the shortening of the trunk is prevalent while wearing only a mild shortening of the length. So short and disproportional. What about the stiffness?
Dr. Andrea Borgo: 00:11:23 The stiffness is very typical of this lysosomal storage disorder and this is usually pain less, symmetric without any sign of inflammation. In young patients this is the stiffness most due to the storage of the glucose aminoglycans in the soft tissue. I mean if we take an X-ray of this younger patient for example the joint line and the shape of the bone are almost normal. In adulthood in addition to the problem of the soft tissue we have the dysplasia of the bone so if we take an X-ray of an adult we have also alteration on the joint line.
Dr. Andrea Borgo: 00:12:01 But this is typically not present in children and probably this is why the enzyme replacement therapy is able to do a stiffening release with the enzyme replacement therapy in younger patients. The ossification delay is typical of a mucopolysaccharidosis. I underline not a reporter for alpha-mannosidosis but I have also to say not sufficiently studied and this is more evident in carpal and tarsal bone. What about the spine?
Dr. Andrea Borgo: 00:12:36 We can have some mild situation like in this case of mucopolysaccharidosis 3, Sanfilippo syndrome or in this case of alpha-mannosidosis and we observe only But we can have also some severe cases like in this Maroteaux–Lamy case where we observed the early onset of the thoracolumbar kyphosis. So what are we going to do for this thoracolumbar kyphosis? Are we going to use the anti-gravitary bracing for all the life? Are we going to operate on them?
Dr. Andrea Borgo: 00:13:22 I have to say that this is not well defined in literature but there was a consensus conference for MPS1 and we can get our inspiration for this consensus conference where it was stated that the anti-gravitary bracing is useful to postpone the surgical treatment and is useful to manage the postoperative period while the indication for the surgical stabilisation is the pain plus the sign of myelopathy.
Dr. Andrea Borgo: 00:13:51 Once upon a time years ago I mean we were more, we look at the deformity progression but from this consensus conference it seems to be not so important while the pain and the documented myelopathy are more important and the proper age to perform the stabilisation of the column of the thoracolumbar kyphosis is between age 5 and 13 and that's why and this is because before age 5 these are high risk of implant failure while after age 13 the deformity is stiff, very stiff and almost impossible to correct.
Dr. Andrea Borgo: 00:14:35 In the spine we observe commonly some joint instability that can be in the upper cervical spine or in the lower part of the cervical spine, a compression due to the glycosaminoglycan storage in the particular tissue or a combination of both.
Dr. Andrea Borgo: 00:14:50 Like in this case for example we can see a compression in the upper cervical spine or in this case for example a more acute patient we can observe an instability that is well documented in extension inflation X- ray or in this magnetic resonance and this is by the way the treatment we did with alda- occipital- cervical fusion.
Dr. Andrea Borgo: 00:15:13 Or we can have some other case of instability of the lower part of the cervical spine, sometimes very difficult to manage also from an orthopedic manifestation of mucopolysaccharidosis point and alpha- of view. The stiffness, we already talked about the stiffness but I like to underline that the stiffness is severe. If you look deeply into this picture you can see that the real abduction of this young girl is no more than 45 degrees and there is she is aged only three and a half and there is a wide compensation between the scapula and the thorax.
Dr. Andrea Borgo: 00:15:48 So the appearance is that she opened the arm 90 degrees but in reality the real movement of the shoulder is no more than 45 degrees. And there is a stiff elbow, a stiff hand and sometimes this stiff elbow and the lack of pronal supination can be one of the very early signs of metabolic disorder.
Dr. Andrea Borgo: 00:16:09 So in case if you see a young child with a stiffness without sign of inflammation or with a symmetric painless and so on, think about metabolic disease and a mucopolysaccharidosis because it is very easy that you are with the proper diagnosis and the same for the carpal tunnel syndrome that I'd like to present this famous study that is in the presence, it considered 163 children with carpal tunnel syndrome and we can say that almost half of them have a mucopolysaccharidosis.
Dr. Andrea Borgo: 00:16:56 So in presence of a carpal tunnel syndrome, please think about the mucopolysaccharidosis because the carpal tunnel syndrome in a child is really uncommon. So if you already know that the patient has a mucopolysaccharidosis, please check for the presence of a carpal tunnel syndrome because I can say like it is assumed in this table here that almost 50% of the patients develop a carpal tunnel syndrome with the exception of MPS4 and there is, I have to say and to underline, no report about carpal tunnel syndrome in alpha-mannosidosis.
Dr. Andrea Borgo: 00:17:34 What about the carpal tunnel syndrome? If you decide to operate them, there is no room for the mini-open procedure that we are used to do in young adults, in young healthy adults I mean, but we have to do wide opening because we have to remove all the glucosaminoglycans that are in the perineum, in the soft tissue. You have to remember that there is also an MPS associated neuropathy, so the compression in the carpal tunnel syndrome is one of the problem but there is also an MPS associated neuropathy.
Dr. Andrea Borgo: 00:18:12 So the transverse ligament is really thickened and so you can see it in this slide, I am sorry for the deformation. And what about the trigger finger? The trigger finger can be present in a child without thinking about metabolic disorder but generally it is the thumb. So the thumb can be, we can observe a trigger thumb in a healthy child, usually between age 2 and 3.
Dr. Andrea Borgo: 00:18:49 But remember if the trigger finger is one of the other finger, I mean a scloded thumb, this is really uncommon because it is really strange in a child to have a trigger finger that is not the thumb. So in case of a trigger finger like in this case, that is one of my patients by the way, that the first sign was a third trigger finger and it was a mucopolysaccharidosis. So think about a metabolic disease especially a mucopolysaccharidosis. Can we do something for this flexion contracture and this thumb contracture in mucopolysaccharidosis?
Dr. Andrea Borgo: 00:19:31 Yes, we can do some release because this is a very orthopedic manifestation and of mucopolysaccharidosis alpha- and very surgical topic but we can cut the A1 and the A3 pulley in order to have some release and at the end these children are able to open widely the hand and they have a better function of the hand.
Dr. Andrea Borgo: 00:19:57 So, what about the lower limb? I like to present this result from a study by White and Armatz and we can see that the presence of dysplasia or proximal femoral epithelial dysplasia is very commonly reported in MPS adults and also in children.
Dr. Andrea Borgo: 00:20:18 I like to present this outcome that is, I don't know if you are familiar with the Posner outcome score that is a functional score that an orthopedic manifestation of mucopolysaccharidosis pediatric and alpha- surgery used to quantify the functional of the musculoskeletal system in children and this score is able to give also a sub-score, the transmic and basic motility score that in some ways is able to quantify the autonomy in walking and so on and in MPS patients this is really reduced. So what happened in mucopolysaccharidosis in the hip joint?
Dr. Andrea Borgo: 00:20:57 This is well described in MPS 1, for example there are several reports in MPS 1. I'd like to show this X- ray that are taken year by year of the same patient and we observe a progression in the loss of sphericity of the femoral head, the flat susceptible that remain flat during the year, the negative fissile angle and finally the migration of the hip. Going more into detail, we can quantify the loss of sphericity of the femoral head with this MOSES technique and we can state that the loss of sphericity in MPS 1 is lost between age 3 and 8.
Dr. Andrea Borgo: 00:21:42 So the cetabular index is an index that orthopedic manifestation surgeons of mucopolysaccharidosis and alpha- use to quantify the coverage from the cetabular of the femoral head with a quantification of the angle and we know that in the normal child this angle is going to decrease with a consequent augmentation of the coverage of the femoral head between the first year of age, more or less between age 2 and 6. In MPS... cetabular
Dr. Andrea Borgo: 00:22:12 is no decreasing at all, it stays more or less like this, one report that there is an augmentation but the... behaviour is different from a normal child where there should be a decrease with a consequent augmentation of the coverage of the femoral head. What about the cervical diaphysial angle?
Dr. Andrea Borgo: 00:22:45 I have to say in a normal person more or less the angle between the diaphysis of the femur and the neck of the femur is more or less 135 degrees and in mucopolysaccharidosis we observe an augmentation of this angle that is going to be almost straight on at the end of the, more or less around 10 years. So no decrease and no hip inside the socket, the cervical diaphysial angle is going straight on like this.
Dr. Andrea Borgo: 00:23:18 And so I know that you are familiar with the mucopolysaccharidosis and so you commonly observe a stiffness of the hip that lead to a movement, a tilting, a forward tilting of the pelvis and this is another point that make the situation on the hip worst. At the end what we observe? the hip that is going outside, outside and outside, I mean no coverage from the setabula, the femoral neck angle is going straight on and the hip is going outside, this is the result. And so we can quantify it with the Raymar index... setabulum and we... age 2 and age 8.
Dr. Andrea Borgo: 00:24:22 So what can we do surgically for the hip joint? We can act in the femoral part, the femoral is straight on and we can do an osteotomy like this and put the femoral head inside the socket like I did in this patient.
Dr. Andrea Borgo: 00:24:41 Usually when we do a procedure like this in a normal child we expect a remodeling of the setabulum and this is not observed in MPS patients, that's why we can act also in the setabulum part, basically with two kinds of procedures, the pelvic osteotomy which aims to restore the correct orientation of the setabulum or the setabuloplasty which aims not to restore the proper orientation of the setabulum but just to add a piece of roof in order to have more contention from the femoral head.
Dr. Andrea Borgo: 00:25:19 And from the literature we know that we can obtain the best result with a combination of the two procedures, I mean in both sides between the femoral part and the acetabular part because if you perform the surgery only the femoral part there is no remodelling in the acetabular... ossified, it never remodelled. So if you look at the result of this kind of surgery, of this kind of let's say surgical reclustration of the hip, we can see that the results are poor.
Dr. Andrea Borgo: 00:25:59 We have by the way only one report of follow- up of MPS1 and that report there is a progression after the surgical restoration, there is a progression of the compromise on the joint line and the patient experienced severe pain.
Dr. Andrea Borgo: 00:26:20 We can discuss a lot because the case areas are not homogeneous because they have a score that is a score that we use mostly to quantify their arthritis, we can discuss if this is the proper score to judge... a surgical reclustration of the hip, the value of the hip score are very low and so when they are young adults they usually come back asking for a total hip replacement because of the pain.
Dr. Andrea Borgo: 00:26:54 And sometimes it can be quite easy to do a total hip replacement like it is in patients, some more patients by the way I do bilateral total hip replacement but we can have some difficulty because there is no roof for the femoral end like I tried to explain before and so we can have some problem in order to find the proper fitting... roof of the acetabulum so we can use sometimes some bony massive transplant or wide cementation or something.
Dr. Andrea Borgo: 00:27:45 And the other problem is that sometimes they are very short and so sometimes we need some custom-made implant because of the size of the patients. What about the valvular deformity or the need that is commonly seen in MPS and also in alpha-mannosidosis?
Dr. Andrea Borgo: 00:28:09 We can act during the growing wage with the MEP epiphysiodesis because if we bridge the growing cartilage only in one side we can block the growing potential medially for example letting it grow laterally obtaining a progression during the age but we have to be very careful because of the short stature these patients are not growing so much so we have to act very early without expecting the later tolerances because otherwise there is no room for progression so we have to plan early intervention because progression delay is commonly observed.
Dr. Andrea Borgo: 00:29:02 This is a clinical picture, a rheological clinical picture of MEP epiphysiodesis for a valvular deformity of the knee in an MPS1 patient and obviously we can correct the deformity also in adults like I did in this case of MPS6 patient but the surgery is not so a little procedure like the MEP epiphysiodesis, you need an open procedure for a metal and so on.
Dr. Andrea Borgo: 00:29:32 This is some surgical... is bigger and bigger sometimes we know that there are some anesthetic problem so we should try to prevent bigger deformity with the MEP epiphysiodesis in children trying to avoid the bigger correction in adults. Also the correction can be done with the classical osteotomy when the deformity is very severe like in this case of Morquio syndrome age 10 because of the severity of the deformity there was no room for MEP epiphysiodesis so I had to perform a distal femoral osteotomy.
Dr. Andrea Borgo: 00:30:19 Later on they can develop a knee arthritis and so on and so they ask for a total knee replacement like I show you for the hip joint.
Dr. Andrea Borgo: 00:30:31 Also, the ankle has a varicose deformity and in the same way we act for the knee we can act for the ankle just bridging the growing cartilage of the ankle in one side obtaining a progressing correction like I did in this patient with a good clinical and radiological result. So in conclusion, I have to say that some orthopedic manifestation of mucopolysaccharidosis and alpha- manifestation of a mucopolysaccharidosis and alpha- mannosidosis, the orthopedic manifestation of mucopolysaccharidosis and alpha- mannosidosis leads to disability and the therapies that nowadays are available lead only to an attenuation of the phenotype without a
Dr. Andrea Borgo: 00:31:17 This early diagnosis is the key for a better prognosis and I like to underline that some orthopedic manifestation of can mucopolysaccharidosis and alpha- manifestation be the first sign of the metabolic disease.
Dr. Andrea Borgo: 00:31:33 So we have to be very, we have to visit this patient, I say me and my colleague as orthopedic surgeon, we have to think about the possibility of metabolic disorder in order to send the patient to the proper specialist and I have to say that an orthopedic surgeon should be part of the multidisciplinary team because when we already know that the patient has a metabolic disorder, we know what he is going to have and we can try to prevent major deformity with a simple procedure especially during the growing age. And so, questions are welcome.
Dr. Andrea Borgo: 00:32:16 So we have a first question, the question is if there are any differences between the hip involvement and the progression of the hip involvement in MPS1, the difference between MPS1 and other form of MPS, yes. So I have to say that most of the literature that are now available is about MPS1 but there are some reports that allow us to make some difference between the hip involvement and the progression in MPS. Usually more or less 70% of the hips in MPS1 are involved, they are going to lose the sphericity.
Dr. Andrea Borgo: 00:33:29 In MPS2, for example, more or less 50%, so a bit less.
Dr. Andrea Borgo: 00:33:34 The severity of the loss of the sphericity is higher in MPS1, is a bit lower in MPS2 and there is a faster loss of sphericity in MPS1, there is a slower loss of sphericity in MPS2 and the emigration at the end is observed in more or less 70% of patients of MPS1 while only in more or less in 50% of MPS2. I also to say that there is usually an involvement in MPS3 of the hip but it is almost 50% of the patients that are aged at least 10 years have a compromise of the hip in MPS3 but the problem is generally when there is a compromise of the hip they are really poor condition and so there is no room for surgery.
Dr. Andrea Borgo: 00:34:44 There are some reports in literature about, there is only one report about total hip arthroplasty in MPS3 and there are some reports about steroid injection because usually they are poor condition and so there is no room for a major surgical intervention. I also to say that there are some reports of MPS6 because the hip joint is always involved in MPS6 but generally they are pain free, the symptoms are not so severe and generally there is a low tendency to migration. I have to say that in MPS3 the role of surgery is not so, it's not clear until now.
Dr. Andrea Borgo: 00:35:37 other question, the following one is, can you resume the precocious musculoskeletal signs suggested for MPS? Yes, so as an orthopedic surgeon and as a general practitioner, there are some musculoskeletal signs that are really uncommon in children and should be, and we should think about a metabolic problem when we see, when we are facing with a child with this kind of symptoms. And these symptoms, and this sign, the joint stiffness, that is generally a symmetric one without any pain, without any sign of inflammation.
Dr. Andrea Borgo: 00:36:25 In case of symmetric painless stiffness, think about a metabolic disorder, think about a mucopolysaccharidosis. In my experience, one of the first signs is the lack of pronation of the elbow. Another sign, another very uncommon situation is the carpal tunnel syndrome. A child with a carpal tunnel syndrome is really an uncommon situation. Think about a mucopolysaccharidosis every time that
Dr. Andrea Borgo: 00:36:57 Another point is the trigger finger, I mean, I repeat, the trigger thumb can be easily seen in a child, but a trigger finger that is not a thumb is really uncommon in a child, so in presence of a trigger finger that is not a thumb, think about a metabolic disorder, think about a mucopolysaccharidosis. And the other point is the spine deformity with special reference to the thoracolumbar kyphosis.
Dr. Andrea Borgo: 00:37:29 That, by the way, is not pantonymonic of mucopolysaccharidosis because it can be also seen in achondroplasia, for example, but this situation, I mean, the thoracolumbar kyphosis in a child is really uncommon. So in presence of a thoracolumbar kyphosis in a child, think about a problem, it can be achondroplasia, it can be a metabolic disorder, but send the patient to the proper specialist. Other questions? Yes. Which is the proper timing for MMP epiphysiodesis in mucopolysaccharidosis or alpha-monodosis?
Dr. Andrea Borgo: 00:38:24 So as I said before, they are short, I mean, mucopolysaccharidosis patients are short and they have a short stature and so there is no growth expectancy. So we should act earlier and especially in MPS4 and MPS6 we should act very early. I have to say in MPS4 we should perform an MMP epiphysiodesis around the knee, around age 4 more or less, in MPS6 around age 6 or not later than 6. In MPS1, especially if they underwent bone marrow transplant and so they are growing a bit more, we can wait until 8, 7, 8.
Dr. Andrea Borgo: 00:39:17 And about alpha-mannosidosis since we are commonly dealing with attenuated cases and there is no short stature, we can wait until 7, 8. So in more acute patients, MPS4, we should act with an MMP epiphysiodesis very early, around 4, around 6 in MPS6 and we can wait until 7, 8 years old children in MPS1 or alpha-mannosidosis. So I see there are no more questions. So it was a pleasure and have a nice time, hope this webinar is useful for you and bye-bye to everybody.