How To Avoid Misdiagnosis Of Mucopolysaccharidoses (MPS)

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Introduction

Dr. Dafne Horovitz: Series 5, Webinar 1 on Avoiding the Misdiagnosis and Delays of Diagnosis of Mucopolysaccharidosis in Children. I'm supposed to present here how to avoid misdiagnosis of MPSs. I'm supposed to present here how to avoid misdiagnosis of MPSs. I have echo here, okay. And so I'm going to present several practical cases, case studies, and to help you spot the early signs.

Just some practical information. Please do not take any screenshots. The images have been authorized for this teaching class now. Please do not reproduce any of the slides, contents, or images. I'm going to be talking for pretty much half an hour. And there will be a question and answer session following. You can submit any of the questions at any point during the webinar, but all will be answered by the end via text.

So here we go. I'm going to present, I guess I have five or six cases. So patient number one, she presented at eight months with pneumonia. She had repeated airway infections, upper and lower infections, and even a requisition for a sweat test before she came to me. As additional information, her head circumference was always on the upper limits.

Case one: a girl with claw hands and coarse features

And for four months on, she started having diarrhea and a very severe diaper rash that didn't respond to anything. At six months, hepatosplenomegaly was noted. At nine months, umbilical hernia was noted. And I evaluated her when she was one year, two months of age. And she was sent by a pediatrician who did think there was something wrong and something genetic going on.

So we can see that this girl, she has claw hands, coarse facial features. Her hair is coarse as well, it's thick, it's coarse. And I ordered radiological exams. When we go to the radiological exams, we can see that there are some vertebral abnormalities. So we see this anteroinferior projection on the vertebrae. We see here a J- shaped sella, and this is very peculiar in the storage diseases.

So we see what the French would describe as rendezvous des epiphytes. That means an encounter of the epiphysis. They draw like, they have like a confluenting point, a confluence point, like a triangle here. If all the epiphysis of the metacarpals draw towards a single direction here. Well, she was, she had a confirmed diagnosis of MPS type I, type Hurler, the severe type.

Her echocardiogram showed mitral thickening and insufficiency. She had elevated urinary GAG excretion, and her enzyme activity studies showed that plasma Alpha-iduronidase was zero. Her genotyping came several years later, and it's very important to point out. I mean, if you see a case that has the basic clinical features and you have the abnormal enzyme activity, this is the diagnosis.

This is gold standard. And sometimes it takes a while for genotyping. Sometimes we have intronic variants, which are more difficult to catch. But she was a compound heterozygous with two variants, one deletion variant and the other was intronic, next to the splice site. So what are the mucopolysaccharidoses? They are classified in the group of inborn errors of metabolism.

What MPS is, and why diagnosis matters

It's a lysosomal storage disease, and they are multisystem disorders. The stored materials, the stored material is the mucopolysaccharides or glycosaminoglycans. So that's why the short name is MPS and GAGs. And it's all secondary to the enzyme deficiency. So we see here a normal cell and the GAG chains, they are supposed to be broken into little pieces in the lysosomes.

And the GAGs are important components of the connective tissue. In the MPS cell, what happens is that we have an enzyme deficiency and the chains are not broken down. So there's a substrate storage due to an enzyme deficiency. And what makes the patient have the symptoms and the clinical features, it's all storage in all organs and systems.

If we identify the specific enzyme defect, we will be able to classify what kind of MPS it is. So we basically have seven different types of MPS, but it's 11 deficient enzymes. MPS type III, for instance, which is Sanfilippo, we have four different types. Morquio, we have A and B. But those like Hurler and Scheie, it's all MPS I. It's actually, it's very hard to break down.

So it's a continuum. So we see more severe cases, more attenuated cases. The Scheie phenotype is, they have no intellectual disability. And we see the same in Hunter, in MPS II. We see patients who are more attenuated, but that means neurological. So we have the neuropathic type and the non- neuropathic type. The neuropathic type is about two thirds of the patients.

And we see multisystem involvement everywhere. Brain, the eyes, the heart, the liver, the lungs, the joints, the bones. This is storage in the conjunctiva. And we have to think about this group of disorders in order to achieve diagnosis. It's very hard to get to diagnosis like this just by chance. So if you think MPS and order the urinary GAGs, for instance, then you can have a very strong suspicion.

But the gold standard for diagnosis would be the enzyme activity assays and also the DNA- based investigation. Nowadays, it's even easier through DNA because there's some panels available, like for brain, for bone disorders, for multiple metabolic diseases. Some children are getting screened neonatally. So we get a lot more of DNA- based investigation, but it's always, if you start through DNA, it will be very important to do the enzyme studies as well to confirm.

So it's a progressive disorder and this is the same patient. So the patient is born absolutely normal. Here, we can already see some coarse facial features and it's getting more and more coarse. And the child has some developmental disability. And this is pretty much maybe six months after diagnosis. She did progress a lot. I saw her around this point of time.

But here you can see very, very coarse faces and enlarged abdomen, umbilical hernia, joint restriction. The hair has no shine and we see the progression throughout time. This child wasn't even two years old at the time.

Recognising the pattern across specialties

So what about rare diseases in pediatrics? So 80% of the rare diseases are genetic and usually rare diseases are chronic, progressive, degenerative. Most of them do begin in infancy or childhood. So it's a major importance. It's very, very important that the pediatrician is aware of those diseases because most of them will go through the pediatrician and it's an opportunity to diagnose those terrible diseases.

And the importance of diagnosis would be because sometimes I hear from colleagues, oh, but what's the point? There's nothing to do. There is a lot to do. Sometimes even giving a name to a rare disorder is extremely important for the family and for the child's health. So we have the diagnosis. We know what's going on. We can promote help.

We can prevent complications. We can offer treatment if it's available or rehabilitation. And also very, very important, the family counseling because these are inherited disorders and the chance of the parents having a child with that disorder to have another one, they are very big. So we have to talk about recurrence risks and prevention. Well, now patient number one.

Case two: an early, severe presentation

This is a two- year- old girl. Her parents were first cousins. She had adequate weight and stature at birth, but her growth curve, actually this drew the attention to that there was something going wrong because initially she was big and then she just stopped growing and actually was pretty short. So she stagnated. And these are images. So the girl is here pointed with the arrow.

So she is with another little friend and we can see here she's okay regarding growth. Here she kind of look, she looks bigger and her head also looks bigger than the other little girl. And here she is at two, short for her age. we have some additional information on her. So she had upper airway infection from four months on.

She always had a runny nose and she had a suspected allergy. She was even investigated for immune deficiency for so many infections. At 17 months, she had an inguinal hernia repair. And when joint restriction appeared, then the pediatrician sent her to genetic evaluation. So this is in one of her first evaluations and we can see she has joint restriction.

She had restriction on her elbows, on her shoulders, on her knees. She can't put her arm up all the way. She has claw hands. Her wrists are a bit enlarged. Her ribs are prominent. We can see that in the image. It shows here the rib. She had mild coarse faces and corneal clouding. And of course, I mean, when we get the X- ray, we see exactly that image, that triangular drawing of the epiphysis which is the epiphyseal encounter.

And she also had delayed bone age. On echocardiogram, she had mitral thickening with mild to moderate rate regurgitation. Polysomnography showed a mild obstructive sleep apnea. Her X-rays, I mean, I didn't show all the images, but dysostosis multiplex. It's actually a term. There are so many abnormalities in the bone that the term for that is dysostosis multiplex. But we have abnormalities in the chest, in the lung bones, in the rib, in the hip, everywhere.

And on spine MRI, we can already see a cranial cervical junction stenosis. So we had a confirmed case, a diagnosis of MPS type VI, which is a Maroteaux-Lamy syndrome. Another patient, patient number three. This was the first child of a non-consanguineous couple. She was born at term by C- section, weighing two kilos, 735 grams, 48 centimeters. And unexpectedly, she showed tachypnea and discomfort.

She was sent to the neonatal ICU and had invasive ventilation, but discharged at 18 days. And nobody found out exactly why this happened. Mother is a nurse and she observed there was something wrong with her child. She thought the daughter looked different and she had edema. And after the intensive care unit discharge, she thought that the baby was always pretty tired, took her to an echocardiogram.

There was some ventricular hypertrophy and they thought it was because of the pulmonary, the respiratory issues, but she also had mitral insufficiency. She had abnormal hearing screening tests and also the evoked potential. And we could already see chest deformity, breathing stridor and airway secretion. Then the mother took her to a geneticist because she was a nurse, because she was very, very alert to the signs.

And the geneticist, sure enough said, well, this looks like a storage disease and sent her to a reference center. So this is the girl right when she arrived. We can see that she had a slightly infiltrated face. She has excessive skin in the neck. There's gum hypertrophy. Her ribs are prominent. So we can see here the ribs and she had an enlarged abdomen with hepatosplenomegaly, huge mongolic spots at the back and lumbar gibbus.

There was no claw hand at that point. She was very young still. She was about two months old. And as additional exams for diagnostic confirmation, we asked for a skeletal X- ray. And of course, she already had dysostosis multiplex. Her urinary GAGs were elevated. Her enzyme activity was very low and her genotype showed homozygous mutation that was compatible with the severe phenotype of MPS I. So she had a clinical diagnosis confirmed that three months, we started ERT right away and we indicated stem cell transplant.

So she underwent transplant after having used ERT. So she was in much better condition to receive the transplant. So, we do see very much a diagnostic odyssey in rare diseases. Because the initial presentation, especially in young children, they have similar signs and symptoms if we compare it to more common diseases. But when there is multisystem involvement, we also see those children, I mean, the child is very young and has already been to two or three different specialists besides the pediatrician.

Red flags and clues to look for

And the specialist hardly ever evaluates the patient as a whole. So we really need the pediatrician to look well into that. And sometimes we see a diagnostic delay of several years in many cases. So basically, it's just too much for just one child. And this has to go back to the pediatrician. We have to think about it.

If the child has a hernia, upper airway infections, and suddenly is not growing, you have to think of something else besides isolated things. So there are some clues to diagnosis for rare diseases. We have to think about family history. So all the MPS types are autosomal recessive besides Hunter syndrome, which is MPS II, which is X- linked.

So we have to pay attention. If the parents are consanguineous, you have to think of a genetic disease. And don't think that they will come and tell you they're first cousins or if they're related. We have to make the question. So you have to ask. And if the answer is yes, think it might be genetic or even family history.

Anybody else in the family with similar symptoms, and sometimes we will hear. I have a family of MPS II patients, which is the X- linked type, that the mother came to me pregnant, and she said, all the boys in my family stop walking and die before they turn 10. That was many years ago. I thought it could be maybe a Duchenne muscular dystrophy, and then she brought me more information and just a little, a small headshot of one of her brothers that died, and for sure it was MPS.

Other things we have to think about, what happens really early? So this is an example. This is a very interesting paper. It was published in 2017, and from the Program of Neurodevelopment in Rare Disorders. So they saw 55 Hurler patients evaluated before transplant, and the median age of their diagnosis was 9.3 months, which you may think is early, but earlier, even better.

So what do they have as medical history? So most of them had otitis, noisy breathing or snoring. Many of them had hernia, joint restrictions, corneal clouding, respiratory infections, and many even had adenoidectomy and tympanostomy tubes. Many had been shunted already, and this is a very interesting slide as well. We can see that more than 80% had at least one manifestation already at age one month, and over 98% had at least one manifestation already at age six months.

So this is very early presentation. If we are attentive to the signs, we can diagnose. So this is another case, patient number four. So this was a big baby. Boy was born weighing almost five kilos, 55. 5 centimeters, head circumference was proportional to his height, and was very healthy at birth. At 23 days, he presented cyanosis and had a cardiopulmonary arrest.

More cases: reading the X-rays

Mother ran him into the hospital, and he was in the ICU for 10 days. During the hospital admission, they saw mitral insufficiency in a newborn. Then he had eight episodes of pneumonia during the first year with three cardiopulmonary arrests. So this is a very severe baby, and he was sent to cardiac surgery at 13 months to have a mitral valve repair and a ring placement.

Nobody in the ICU or in the pediatrics unit thought about the diagnosis, the basis of the diagnosis. They were only seeing the heart. But the cardiac surgeon looked at the valve, and he said it's very abnormal, and there are signs of storage material.

And he said he needed to investigate storage diseases. And surely, I mean, this is just an illustration. This is not the child's valve. But we can see here the difference between a normal and a storage valve. So this is what the surgeon saw. And if you look into congenital mitral insufficiency, we cannot find any literature regarding isolated mitral insufficiency.

So we need to consider an underlying disease. This is very important. And so finally he was evaluated by our group at 19 months. He had already coarse facial features, umbilical hernia, joint restriction, claw hands. He had delayed bone age. He had the typical hand of MPS with dysostosis multiplex, and here we can see the projection. It looks like Santa Claus boots, usually in the lumbar vertebrae.

But very important, look at his x- ray. The x- ray. So a child who's had eight pneumonias, of course he did have chest x- rays. And besides looking at the pulmonary parenchyma, we have to look at the bone. So if we look at the bone, we can see that those ribs are widened and they are petal shaped ribs.

So this is a clue to diagnosis. Look at the bone in the x-ray. So this is our patient. Another patient. This little girl had difficulties in walking and went to be seen by an orthopedist. Orthopedics refer to endocrinology because she had short stature and they thought there was something else that they couldn't actually figure out. She had nasal discharge as well, very frequent. Chest deformity, genu valgum, her wrists were wide.

We can see here, this is very typical of the MPS, lax joints, and hepatosplenomegaly. The bone disease here is much more severe. So we can see here in the hip irregularities. Here we can see abnormalities in the femur. Some of them will have hip luxation. Here we can see in the vertebrae, again, this projection, but very malformed vertebrae, and many abnormalities here in the hands.

The late bone age, just the same, and the epiphyseal encounter, MPS IVA. And this is actually my last patient. So this little girl came to me. She was 11 months old, and she was referred by an ophthalmologist because the ophthalmologist thought there was something peculiar about her. She thought she looked different. Her neck was wide and short, and she had a white forelock here and a hypopigmentation of the eyebrow, which actually isn't very important, but it drew her attention.

And it was good that she sent her to genetics. Then looking at her story, she had an inguinal hernia with an overextrusion at three months and had to go through surgery. And she also had allergy throughout. And at nine months of age, she was admitted with pneumonia and atelectasis. So this is where the pneumologist saw her. And on physical examination, her head was a little big for her age.

She had very, very mild corneal clouding. She has a very slight lumbar gibbus. The neck was actually short and development totally normal. I told the parents, I need those exams very, very quickly. I think it can be MPS, and we need to diagnose and treat right away if this is MPS. And so they went. But these are the exams the father brought me.

And that was very important. I mean, he had an archive with all her exams, and there was one lateral image. And here in the lateral image, we can see the malformed vertebrae, and in her chest x- ray, I know there was atelectasis, pneumonia, but I looked at the bone. And in the bone, we can see the enlarged ribs, the oar shaped ribs.

So we really have to pay attention to those chest x- rays and look for the petal- shaped ribs. Well, additional x- rays, now we have an x- ray trying to look at bone and we can see here the abnormalities and this is where the gibbus was in the hands. We can see the delayed bone age, the epiphyseal encounter, everything we expect in MPS.

Why early treatment matters

We confirmed MPS VI. She started right away with enzyme replacement therapy and since she was very young and enzyme replacement therapy is for the whole life, we did talk a lot about transplant and the parents decided that she would undergo stem cell transplantation and so she did at a very young age. So to conclude, we have to think about why do we need early diagnosis?

So the MPSs are progressive and incapacitating diseases. We will have treatment available with proven effect in health and quality of life so it's very important especially that we diagnose early those diseases that are treatable and we will modify the natural history of disease. The role of the pediatrician will be the diagnostic suspicion, referral to specialists, and of course to take care of the whole pediatric routine with special attention to specific needs regarding the diagnosis.

So going back to patient number one, so at 22 months of this Hurler child, she had mitral insufficiency, hepatosplenomegaly, sleep apnea, repeat airway infection, she had cranial hypertension, she needed a shunt and she did this right after she started enzyme replacement therapy. She had corneal clouding, dysostosis multiplex, and a delayed development. At six years of age, she was doing much better.

I mean we started enzyme replacement at 22 months. Her cardiac disease progressed but more slowly so she has mitral and aortic insufficiency and needed to be on captopril and furosemide. She got shunted at two years of age. She has no hepatosplenomegaly. Her bone disease was stable. There was no sleep apnea and that finished kind of right away, less airway infections.

The corneal clouding was actually even more subtle and she's been having many gains in development and her IQ was above the expectation for MPS I, the severe type. To conclude, in the diagnosis of rare diseases, we have signs and symptoms that may be very, very similar to common diseases. We have to suspect when multiple problems are combined.

For diagnosis, we have to consider all the time. We have to look very carefully at the whole clinical history and it's like getting a puzzle together.

Questions and answers

Well, I have a question here. Patient 2, are upper airway infections always signs of MPS? Are there more aggressive types of MPS regarding musculoskeletal impairment or does it depend on the patient?

Each patient is different. The upper airway infections, upper and lower, they can look like any other pediatric airway infection. And the whole point is that when we see those infections in a child that for instance has hernia or whose parents are consanguineous or who has short stature, we have to look into it better. And the musculoskeletal impairment, it also depends.

Sometimes it's not so obvious. Sometimes we have cases which are more attenuated so they won't be so short in infancy or they won't have the claw hand. Some patients are misdiagnosed for rheumatic fever, for example, because they have something in the joint and something in the heart. So actually there are many, many phases of MPS and we can get to the diagnosis from different specialties or organs or systems.

Okay, case three regarding hearing screening. At what stage is hearing affected? This is also very variable between patients.

So many patients do pass the hearing screening and they will have hearing affected later in life. The hearing is affected, it's multifactorial. It's not only the storage, but it's the storage plus the multiple infections. So depending on how you treat the infections, you won't affect hearing. But hearing screening, abnormal hearing screening can be a sign, yes. Normal hearing screening and then problems in hearing can be a sign also. Normal hearing screening altogether, it's not MPS. False, it can still be MPS.

Regarding patient four, are the oar shaped ribs a key sign in all cases? I would say if you want like one take home message here today is look at the X- ray beyond the lungs because we are going to see skeletal signs. And if we see those enlarged ribs, you have to think of a storage disorder.

Okay, how would a 12-month delay in diagnosis impact musculoskeletal signs compared to starting treatment earlier?

This is a very interesting question. And we do have a lot of experience in very young children treated. So the earlier you start treating, the better outcome you expect. We do have here in Brazil, some patients who have started treatment in the first, actually first weeks of age. And those children have less bone disease when we compare to children who started even at one or two years of age.

So always the earlier the better. There are some sibling studies also published from Italy, from Australia. So the disease is still there even if we start enzyme replacement very early. But the earlier we start, the less bone disease we're going to see.

Which growth chart should I use for determining growth in MPS patients?

I'm not sure we have growth charts for MPS because even MPS is so widely variable. I would use the normal growth charts because they will point for the alarm sign. So the head circumference is high up and growth is lower except for MPS II. Usually they are big enough. But even if we see the head circumference above the line of the stature, this should be together.

So one, for instance, in a centile 90 or 98 and the other in percentile 25, this is not good. This is a big head proportionally. Well, I guess this is about it. So I thank you very much for being here, for sending the questions and this will end today's presentation but for sure there are going to be other seminars where you're going to have the opportunity to learn more about MPS. Thank you very much for being here.

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