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A case-based webinar with Prof. Rolando Cimaz (head of the Rheumatology Unit, Meyer Children's Hospital, and Professor of Paediatrics, University of Florence) on the clinical manifestations of inherited metabolic and genetic disorders that mimic juvenile idiopathic arthritis (JIA). For paediatric rheumatologists and general paediatricians working up the child with joint complaints.
Juvenile idiopathic arthritis is a diagnosis of exclusion, and many inherited disorders can mimic it — so a careful diagnostic workup is fundamental. Prof. Cimaz builds the talk around real cases. A tall boy with early myopia, retinal detachments, and joint pain and stiffness but hypermobile elbows turns out to have Stickler syndrome, a type II collagen disorder with prominent ophthalmological and ENT features. A boy with progressive, painful, stiff and contracted joints who became wheelchair-bound is diagnosed — from the bone abnormalities on X-ray — with progressive pseudorheumatoid dysplasia (PPRD), a WISP3 gene disorder. He also shows CACP syndrome (camptodactyly, arthropathy, coxa vara and pericarditis), caused by a lubricin mutation. The unifying theme is that these genetic and metabolic disorders typically have normal inflammatory markers and no true joint swelling, and that a spine or skeletal X-ray read by an expert paediatric bone radiologist is often the key to diagnosis. The second half focuses on the mucopolysaccharidoses as great mimics of JIA. A child with school-age hand stiffness in the MCP and PIP joints, progressive contractures without swelling or tenderness, negative laboratory tests, no response to NSAIDs and bilateral carpal tunnel syndrome illustrates the pattern. Prof. Cimaz explains that it is chiefly the attenuated MPS I (Scheie) and MPS VI (Maroteaux-Lamy) that mimic arthritis, sometimes diagnosed only in the fifth decade despite childhood-onset stiffness, whereas Hunter, Sanfilippo, Morquio and Sly usually declare themselves earlier through systemic involvement. His central message: joint contractures without inflammation — especially with carpal tunnel syndrome, which is rare in children — should prompt consideration of an inherited disorder, screened first with urinary GAGs and confirmed with enzyme and gene testing, because early diagnosis of MPS now allows enzyme replacement therapy and better outcomes.
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This transcript was produced by automatic speech recognition and edited for readability; it has not been fully verified word-for-word. It may contain errors — particularly with names, technical terms, and where English is a speaker's second language. It is provided as a convenience only. For anything clinical, please refer to the video recording to hear exactly what the expert said.
Prof. Rolando Cimaz: Hello to everyone, good morning or good evening depending on where you are, apparently this is a webinar which includes several hundred people. My name is Rolando Cimaz and I am head of the Rheumatology Unit at the Meyer Children's Hospital in Florence as well as Professor of Pediatrics in the University of Florence. This webinar is entitled Avoiding Misdiagnosis, Clinical Manifestation of Inherited Metabolic Disorders for Rheumatologists and General Pediatricians.
A few housekeeping notes before starting, please do not take any screenshots, the webinar record will be available online as soon as it is over. Please do not reproduce slides, content or images and this presentation will last about 20 minutes, it will be followed by a question and answer. You should submit your questions anytime during the presentation via the panel chat questions and the question can be submitted only via text, not verbally.
At the end of the presentation I will try to answer all the questions or at least as many as possible. So the topic of the presentation is Differential Diagnosis of Juvenile Idiopathic Arthritis, in particular the differential diagnosis with inherited diseases and especially metabolic diseases. For those who are not in the pediatric rheumatology field, JIA as we call it is an exclusion diagnosis, so there are many diseases that can mimic JIA, especially at the beginning and a diagnostic workup is fundamental.
The mucopolysaccharidosis are one of the great mimics of JIA and this will be also part of this presentation. There are some instances where the diagnosis is straightforward. I have put in this slide a few photos of typical presentations or typical complications especially of juvenile idiopathic arthritis. From the left top clockwise you see some deformity, this is Valgus deformity in oligoarticular JIA and then you see x- rays with very bad hip involvement, x- rays with cervical spine involvement and fusion, lower right you see synechiae from uveitis, growth disturbances and bilateral hip replacement.
So of all of these there is no doubt that the diagnosis is juvenile idiopathic arthritis and actually if you do a slit lamp examination during the diagnostic workup and you see synechia or you just see inflammatory eye disease in the anterior chamber that is already the diagnosis. I will start the presentation with a clinical case of a patient with nothing particular in the past medical history who presented with myopia diagnosed when he was four and then the following clinical history was complicated by bilateral retinal detachment at 12 and 15 years of age in the right and left eye respectively.
He was quite tall and interestingly enough he had pain and stiffness of the joints and the knees but hypermobility in the elbows. This is not what we see in Juvenile Neuropathic Arthritis. The patient came to rheumatology and it was clear from the beginning that the diagnosis had to be something else. In this case, there is a little quiz, but the answer of this quiz is easy for us, which is not Blau syndrome, which is early- onset sarcoidosis.
It is not Cogan syndrome, which is a vasculitis with deafness. It is not mucolipidosis type III, but it is Stickler syndrome. Stickler syndrome is an inherited genetic disorder characterized by defects in the collagen type II, in the precursor of the alpha chain of the collagen type II. And it has genetic heterogeneity, transmitted mostly autosomal dominant. with no gender predilection and an interfamilial biodiversity.
Stickler syndrome is a genetic disease that can mimic inflammatory diseases because of the pain and because of the stiffness in the joints, but it has extra- articular manifestations, especially those related to the ear, nose and throat, with depression nasal bridge, antiversion of the nostrils, cleft palate. And it has very prominent ophthalmologic findings, such as myopia, early- onset cataract, vitreo retinal degeneration, chronic uveitis, and last but not least, hearing loss, which can be neurosensorial or transmissive.
So, with arthropathy, this is one of the diseases to suspect, especially when there are ocular and hearing abnormalities and when there is joint laxity on top of the stiffness, such as in the patient that I just presented. Characteristically, the metabolic and the genetic disorders do not have laboratory abnormalities, such as we see frequently in inflammatory arthropathies. Another case is an Italian boy that we have followed over time, born full- term by vaginal delivery with normal pregnancy and negative family history, normal psychomotor development.
This boy, at seven months of age, had a hip ultrasound, which was called abnormal, put on a double diaper, and started to walk very late, two and a half years. At that time, he was complaining of pain in the left hip area. The story went on and on without a diagnosis until, when he was 11, the pain was so severe that he had walking difficulties, articular functional limitation, which was worsening, was admitted and had severe limitation of the joints, not only in the lower limbs but also in the elbows and the flexum contracture of the hips, which are stiff and painful, also on the knees.
This is a photo of the lower limbs of this child when he came to our attention. This is the maximum flexion that he could reach and the maximum extension that he could reach, both at the hips and at the knees. So he was wheelchair- bound. In this case, the quiz that I made was quite easy for us.
This is not a story of juvenile idiopathic arthritis, so A, B, and C are not recommended, but X-Rays were performed and showed several abnormalities without going into details. On the bone abnormalities, a good radiologist was enough to make the diagnosis of progressive pseudo- rheumatoid dysplasia, which is also called PPRD. This is, again, bone dysplasia, a genetic disorder caused by mutation in the WISP3 gene.
For those who are interested, there are reviews. This one is the largest on a cohort of more than 60 affected individuals. A few other examples of bone dysplasia or bone and joint disorders that can mimic JIA and that are on a genetic basis, this is called Camptodactyly Arthropathy Coxa vala Pericarditis Syndrome, abbreviated as CACP, and when pericarditis is present, diagnosis is quite easy if you have pericarditis and campytodactyly, often not all the features are present and in this case diagnosis can be challenging and you can see in the photo the Coxa vala, the Camptodactyly and the Arthropathy.
This disease is caused by a mutation in a protein which is called Lubricin, which is expressed in chondrocytes and synovial sites and important for lubrification. So with this and other bone dysplasia that I don't have time to present, family history is very important but you have seen in our cases as is present in many other occasions that it can be negative.
Exams are not so important in terms of blood investigation. X- rays are very important, so I would do a spine x- ray, which very often is a clue to the diagnosis but needs to be read by experienced radiologists with an interest in pediatrics and in bone and joints. Sometimes you need some more specific instrumental investigation of radiological such as CT scan and MRI but this is just when you have a specific doubt of any inflammatory arthropathies and synovial biopsies now are very rarely done, only in very doubtful cases.
They used to be done more frequently in the past when we did not have the genetic tests that are now available. So as I said, the most important is a regular field by an expert pediatric bone radiologist and these are just examples of bone dysplasia, some that I just showed you and you see how different they are from juvenile idiopathic arthritis, which has to be joint swelling by definition, which is frequently absent, more often absent in the bone dysplasia, functional limitation, joint stiffness and inflammatory symptoms such as a limp in the morning and very little of other bone abnormalities at x- ray, especially at the beginning.
Frequently there are abnormalities in the laboratory tests. This is another child that we have followed in the past who started having difficulty writing and diminished hand function when he went to school. So around six years of age he presented to his physician with stiffness in the MCP and PAP joints, then symptoms worsened, the inflection contracture of the hands, progressive involvement of all joints which are functionally limited, but not swollen, not tender.
Laboratory was negative. At that time we called juvenile chronic arthritis, which was a working diagnosis because we did not have any better explanation however that was no response at all to non- steroidal anti-inflammatory drugs and a particular feature appeared, which was bilateral carpal tunnel syndrome. In this case the attention was raised to a differential diagnosis, which was mucopolysaccharidoses.
Mucopolysaccharidoses can have joint and skeletal disease caused by storage of the substrate which is mucopolysaccharide or glycosaminoglycan in synovium, in bone and in particular tissues.
This can give stiffness and joint contractures very frequently, joint pain, over time skeletal deformity and loss of mobility and fractural independence. The clinical manifestation of these skeletal abnormalities are gibbus, spinal deformity, abnormal x- rays on pelvis, thorax, hips and then knock knees, but this is especially the joint stiffness, as you can see in the photo of the hands of this patient that characterizes disorders.
MPS, which is mucopolysaccharidoses , are divided in several types. It is especially the type I and type VI that can mimic the onset of an inflammatory arthropathy. And when we think of MPS I especially, it can be very severe, such as Hurler syndrome, which can be fatal in the first month of life, and you can have more attenuated phenotypes, such as Scheie syndrome, which is MPS IS meaning Scheie.
In this slide, you can see an example of the less severe MPS I, so the Scheie phenotype, of this patient who was diagnosed very late, more than 40 years of age, despite the fact that the first symptoms, which were joint stiffness, appeared in the pediatric age, so in the first decade of life, and then had neurological, pulmonary, gastrointestinal, and cardiac complications, all of which led to the correct diagnosis only after decades.
So there are some cases in which there is dysmorphism in the face, short stature, large abdomen, and many other systemic manifestations. However, in the attenuated forms, skeletal manifestations can be prominent, and outside the bone and joint, there might be just minor hints, such as rhinitis or limited endurance, which may not be enough to suspect the correct diagnosis.
This is an example of a lady who was perfectly normal in the first year of life, and then in adolescence, and as a young adult, began to have complications, and ultimately became blind and wheelchair- bound. We collected a few of these patients, and I want to show you this slide, mainly for two reasons. First, that the family history was negative in most cases, and second, because the hint to the correct diagnosis, which was quite late in some cases, you can see at 54, 53, 33, 41, but what was very helpful was the presence of carpal tunnel syndrome, which in periodic age has a very important role, because you have to suspect a storage disorder of different kinds, and the onset of symptoms in all of these cases was stiffness, mostly in the fingers and the hand, in the first 10 years of life, sometimes even earlier.
There may be other disease manifestations in MPS I, even in the attenuated forms, but sometimes they are minor, such as fatigue, short stature, thick skin, excess hair, and in the less severe types, such as the Scheie, there is no primary CNS involvement, unlike the Hurler disease, which has a severe neurological involvement. The differential diagnosis of patients who ultimately were found to have Scheie syndrome is wide, and these were the misdiagnoses.
In other words, the patients who had Scheie syndrome at the beginning did not have the right diagnosis, but mainly they were called as having inflammatory arthritis, juvenile idiopathic or juvenile arthritis. It is the same if it was in the periodic age, or if they were adults or young adults, rheumatoid arthritis, and then there were other diagnoses that were suspected by the treating tradition.
So the message is mainly that if you have joint contractures without inflammation, clinical and laboratory, so with no joint swelling, that may indicate in the differential diagnosis an inherited disorder such as, for example, the bone dysplasia that I showed you at the beginning or the storage disorder that I just mentioned to you, such as MPS. The differential diagnosis sometimes is very easy.
If you find joint swelling, such as in this knee, with morning stiffness, maybe with uveitis, then there is no additional test to do, but you have a clinical diagnosis of joint swelling of more than six weeks' duration with no other plausible explanation. The MPS are many, as I said, and mainly it's the type Scheie, so MPS 1 S and MPS VI which is Maroteux-Lamy that can mimic juvenile idiopathic arthritis, while in Hunter's, Sanfilippo, Morquio, Sly and so on, diagnosis is sometimes easier because there is a more generalised and systemic involvement, even from the very first months of age.
This is MPS VI, for example, in which also there are bone and joint abnormalities and you can see again that the flexion- contraction of the fingers give a typical claw- hand deformity and are very helpful for the diagnosis. And again, the last point of this slide is probably the most useful because it is rare: carpal tunnel syndrome in pediatrics while the joint stiffness may be present in many other manifestations and, just like MPS I, MPS VI is also under-diagnosed because the presenting symptoms may mimic other diseases and because these are rare disorders.
So you need to think about it and to know the clinical manifestation. So the conclusion of the talk is that joint contracture without inflammation can be a hallmark of an inherited disorder. Bone dysplasia, storage disorder, carpal tunnel is very suspicious. If you suspect storage diseases such as MPS, you can order the test. The screening test is urinary GAG glycosaminoglycans.
Some patients may present to a pediatric rheumatologist with bone dysplasia or with a metabolic disorder, because the presenting symptoms can be osteoarticular and at the onset, as extraskeletal manifestation may be either absent or subtle or overlooked, and a full- blown picture may occur even years later. So this was the last slide of the presentation and now I am happy to answer the questions that have been posed by the panel.
So I repeat the questions because I see them on my computer. The first question is: what is the gold standard for juvenile idiopathic arthritis diagnosis? This is a good question, but unfortunately there is no gold standard, since juvenile idiopathic arthritis is a diagnosis of exclusion, as I said. So the clinical judgment of the treating physician would be the gold standard.
That depends on the experience of the person. You would need, of course, a long-standing duration. By definition it's more than six weeks, but usually, if not treated, it can last even more than nine, ten or twelve or even months. In fact, the old classification, European classification, of juvenile chronic arthritis needed twelve weeks of persistence of arthritis, meaning swelling in a joint seen by a physician and exclusion of other diseases that can mimic, just like the diseases that I mentioned to you, plus a number of other disorders, especially infectious disorder, reactive arthritis, hematologic disorders and so on.
So there is no laboratory test that can give you this diagnosis, but just a clinical observation. Now there is a second question which is related to it: what are the main signs that can differentiate JIA from metabolic disorders? Many- I already mentioned them during my talk- mainly the absence of inflammation. So the metabolic disorder typically have normal inflammatory parameters and absence of joint swelling, that is, presence of palpable synovial fluid.
Sometimes there is, the joint seems swollen but it is periarticular or it is a bony overgrowth. To have a diagnosis of an inflammatory arthropathy you would need joint effusion and also this is usually accompanied by inflammatory signs that I mentioned, which is mainly the joint stiffness or morning limp if it is a lower limbs. The third question: why is it important to make an early diagnosis of mucopolysaccharidosis?
It is important indeed, because now there are effective treatments and that is the enzyme replacement therapy, for not for all of them, but for one, six and others there is a possibility of infusing the enzyme. There is a transplant. They are working on other type of gene therapies but for the time being already that the enzyme replacement therapy is available and it has been shown that if you treat this patient early enough, you can prevent later complications and improve the quality of life.
How is diagnosis confirmed? If I have a suspicion of MPS, you have to do the first test of suspicion, which is a urinary GAG, and then you can do the enzyme and the gene, but these are done in specialized labs only. While the GAG is more diffused and you can probably do it in your own hospital, then the enzyme is done only in metabolic laboratories.
What is the number of specialized center for the treatment of this disorder in Italy? So if the treatment for this disorder means arthritis during idiopathic arthritis, we are many pediatric rheumatologists in the country, mainly the big cities, but every region of Italy practically has at least one center who is dealing with this. If it is meant to be metabolic disorder and mucopolysaccharidoses in particular, there are less.
The exact number I cannot tell, but probably in a country like Italy there are at least three or four in northern Italy, a couple or three in central Italy and two or three in the southern, in the south of the country. So I would imagine a total of 10 to 15 metabolic pediatric metabolic center which deal with metabolic diseases, including MPS.
The genetics is a little bit more diffused because genetic disorders are rare in practically all pediatric units. So this was the last question from the audience, which I thank very much for your attention and I hope that this talk was useful for you. Thank you.
The absence of inflammation. Metabolic and genetic disorders typically have normal inflammatory parameters and no true joint swelling — that is, no palpable synovial effusion. What looks like swelling is often periarticular or a bony overgrowth. Joint contractures and stiffness without inflammatory signs, and without laboratory abnormalities, should point away from JIA and towards an inherited bone dysplasia or storage disorder.
Because carpal tunnel syndrome is genuinely rare in children, so its presence in a child with joint stiffness is highly suspicious for a storage disorder such as MPS. In Prof. Cimaz's collected cases of attenuated MPS I (Scheie), bilateral carpal tunnel syndrome was a recurring and very helpful pointer, and the onset symptom was almost always stiffness of the fingers and hands in the first decade of life — often long before the diagnosis was finally made.
Chiefly the attenuated MPS I (Scheie, MPS I S) and MPS VI (Maroteaux-Lamy). These can present with osteoarticular symptoms — joint stiffness and contractures, a claw-hand deformity — while extra-skeletal signs are absent, subtle or overlooked, so the full picture may only emerge years later; some patients are diagnosed only in their forties or fifties. By contrast Hunter, Sanfilippo, Morquio and Sly are usually easier to recognise earlier because of more generalised, systemic involvement from the first months of life.
Blood inflammatory markers are usually unhelpful; the high-value test is a spine or skeletal X-ray read by a radiologist experienced in paediatric bone and joint disease, which is frequently the clue to a bone dysplasia. If a storage disease such as MPS is suspected, the screening test is urinary glycosaminoglycans (GAGs), widely available, followed by enzyme activity and gene testing in specialised metabolic laboratories to confirm the specific diagnosis.
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