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[00:00:07] Prof. Ana Maria Martins: Hello, everybody. Let's continue the series of cases. And today, it will be short stature and other endocrine presenting symptoms of mucopolysaccharidosis. It's a case instead. But first of all, there are some housekeeping. And please do not take any screenshots. Submit your questions at any point via the question panel. Questions can only be submitted via test and not verbally. Here is my disclosures. And the case is part of this paper, short stature as presenting symptoms of attenuated muc- polysaccharidosis type 1 case report and clinical insights. We are going to talk about it. I have a little short introduction. MPS1 is an autosomal recessive rare disease caused by deficiency of alpha- L- iduronidase and a lysosomal enzyme that metabolizes the glycosaminoglycans, GAGs, dermatins, and epinephrine sulfate. MPS1 has an estimated incidence of 1 in 100, 000 live births with a spectrum of phenotypes that range from severe, the Hurler syndrome, to attenuated, Hurler- Scheie, that is intermediate phenotype, and Scheie syndromes. This is depending on neurocognitive involvement and the rate of disease progression. In the area of inborn areas of metabolism, that is my field of work, mainly lysosomal histology disorders, the earlier the disease manifests, the more severe is the enzyme deficiency. In the Hurler phenotype, the signs and symptoms will appear in the first months of life, very early. And the attenuated can be late, like five years old. It's a little bit far. The amount of enzyme residual activity will determine attenuated phenotypes, the Hurler- Scheie, which is intermediate between the most severe and the most attenuated form in the Scheie phenotype. Here we can see the variability of MPS1 expression between severe and attenuated phenotypes. The severe with a face infiltrated by accumulation of gags, thick and dry hair, bifrontal narrowing, thick lips, and macroglossia. In the intermediate phenotypes, Hurler- Scheie, the facial fines are milder when you compare with the severe one, but still have the appearance of MPS. And in the more attenuated phenotype, Scheie can be very discreet and close to normal. Treatment options include enzyme replacement therapy with larunidase, recombinant human edua, and aldrozyme for patients with attenuated MPS1, and hematopoietic exchange cell transplantation with or without larunidase for patients with severe. The severe cases of MPS1, while the patient waiting for the HSCT should receive ERT in the majority of consensus, everybody agree with this, should receive ERT for the patient to be in better condition for transplantation. Treatment outcomes depend on the phenotype and the age of treatment initiation. Early treatment prior to irreversible damage can delay, stabilize, or prevent organic dysfunction and is associated with substantially improved patient outcomes. Unfortunately, there is an important delay in the diagnosis of MPS1, as you are going to see in this case, especially for patients with attenuated disease. In a nice study of natural history of 18 MPS1 patients, 13 of whom had attenuated disease whose symptoms were noted at 18 months, the mean age at biochemical diagnosis was 75 months. So really a big delay. Male patients with history, now we are going to start the case presentation. It's a male patient with history of upper airway infections. It started at three months with otitis media with a frequency of five episodes per year. Underwent ventilation tubes insertion at five years and eight months. Adenoidectomy with four years of age and during childhood was hospitalized multiple times between five and seven years of age for wheezing. He began experiencing hip pain at five years of age and was diagnosed with bilateral leg perts by an orthopedic surgeon. Patient was first evaluated by a pediatric endocrinologist clinic at seven years of age due to his short stature and was treated with luprolide acetate 3. 75 milligrams per month between ages of 13 and 16 years. He combined human growth hormone, the GH. The patient was not labeled as growth hormone deficiency between 14 and 18 years of age. Then the patient presented sleep apnea through his teenagers and at seven years and nine months of age was referred to a metabolic disease center, that is my center, by a pulmonologist who evaluated the patient and suspect of MPS. This pulmonologist takes care of all our patients with polysaccharidosis, that is around 45 patients, and he takes care of these patients. When they saw the patients, he thinks about MPS. Upon examination in my center, the patient was found to have moderate joint contractures, mild facial coarsening features, scoliosis, umbilical hernia, and apoplexyplenomegaly, and heart murmur. His height was 154 centimeters, z- score of minus 2. 94, weight was 43. 7 kilos, and head circumference was 56. 5. Alpha drug- based activity on dried blood spots was 0. 62 micromole per liter and per hour. Reference range between 2. 5 to 16. 7. Urinary gags, 5. 6 milligram gag mole creatinine, and the reference range was 15 to 20 years, less than 4. 9, and the patient has 5. 6. Sometimes in this age, the gags can be normal, and the genotype analysis revealed two pathogenic variants, R383H and P533R, confirming the diagnosis of MPS1. Here is the timeline of assessment, diagnosis, and treatment, like a summary, what we saw. Between five and seven years, hip pain, recurring respiratory infections. We need to remember that respiratory infections with types of mygia started with three months of age, very, very, very early. Orthopedic assessment and the diagnosis of bilateral leg calvipertors, with the five years by the orthopedist. And between seven and 18 years, short stature in pediatric endocrinologist assessment. And here, we started to treat the short stature before with luprolide acetate, 3. 75, the same dose, and the growth hormone, 0. 1 Y per kilogram per day, between 14 and 18 years old. With 18 years old, short stature, moderate joint contractures, mild facial dysmorphic features, coarsening of features, scoliosis, and an umbilical hernia. Referred to metabolic disease center by treating pulmonologist. Enzyme activity screening for MPS1 positive, and genetic analysis confirming the diagnosis of MPS1. In the restart, enzyme replacement therapy with larval days, with the dose weekly, 0. 58 milligrams per kilo per infusion was Initiated. The prognosis in patients is better, in patients with attenuated phenotype, because they have a bigger residual enzyme activity. Then this guy started to treatment with 18 years old, and he noticed an improvement of the joint's range of motion. Noticed a decrease in abdominal volume, confirmed with the ultrasound. He mentioned that a greater disposition for daily activities. There was no progression to obstructive sleep apnea, and there was no progression of cardiac valve dysfunction. Now he's a physiotherapist, and he's the patient. We can see here some images of the patient at the time of the diagnosis presence of kyphosis and winged escapode, limitation of the elbow and limitation of the joints, the knees. Here is the growth, sorry. Here is the longitudinal growth for patients with attenuated MPS1 from case study. Height of case study patient by age is shown by blue markers. Yes, these blue markers, okay. And by shown by the blue markers with timing and duration of leuprolide acetate and the growth hormone in the laryngeal days, the aldolazine. And as we can see, the patient maintain his growth curve below the third standard deviation. And after starting ERT, he still grew five centimeters and at 159 centimeters at 20 years of age between the third and the second standard deviation. Growth velocity of this patient, growth velocity by age is shown by the blue markers, as you can see here. The patient had a peak after the initiation of the growth hormone of GH, and they have another smaller one when they started laryngitis. Okay, here we have a table with the common presenting early symptoms in patients with attenuated MPS1. Growth delay is one so important, not only for MPS1, for all MPSs, normal birth weight but growth failure or short stature. joint contractures, primarily in hands, claw, hand deformity, joint pain and stiffness, restrictive mobility, carpal tunnel syndrome, recurrent hernias, umbilical and or inguinal, corneal clouding, hepatosplenomegaly, skeletal abnormalities, dysostosis multiplex, kyphosis, scoliosis, hip dysplasia, flattened vertebrae bodies, OR- shaped ribs, short thickened clavicles, bullet- shaped phalanges, dysplastic femoral heads, flattened acetabulum, kosha valga and genovalgum deformities, ear, nose, throat symptoms, recurrent ear infections, remember the otitis media, noisy breathing, sleep apnea, enlarged tongue, macroglossia, and the hearing loss, heart murmur by the valve abnormalities, and surgical history of multiple hernia repairs, PE, tubes, tonsillectomy, and adenodectomy. It's important to alert about all symptoms may not be present in the same patient but are usually progressive in figure 2. One more data about early signs is the auditory screening failure at birth that is referred in a paper about early signs and symptoms of Herlier syndrome. This failed of the auditory test is important too as information and usually we have one or more. Then you can have otitis media that start with two or three months of age, hepatosplenomegaly, and the corneal clouding. It's enough to think, to remember the diagnosis of mucopolysaccharidosis, okay? It's one or two or three, together we can have the suspicion of MPS1. This algorithm is interesting because it's practical for the daily activities. Patients present with short stature or growth delay. Then you are going to a symptom checklist, joint pain and oral contractures, particularly hands, carpal tunnel syndrome, corneal clouding, hepatosplenomegaly, skeletal abnormalities, ENT symptoms, heart murmur, valve abnormalities, and surgical history, multiple vernal repairs, PE tubes, tonsillectomy, and endodectomy. Consider MPS disorder. You can go to the urine gag test, accumulation of gags in lysosomal results in elevated gag in urine, gags, maybe qualitative or quantitative, or you can go direct to the enzyme function test. The enzyme function test is the diagnosis of mucopolysaccharidosis. Measure enzyme activity required for definitive diagnosis. In 2018, we have the last MPS International meeting with patients and people that work with these diseases, and we have a testimony of a patient, and she had two exomas and they don't find the variant, the pathogenic variant, and she didn't have measured the enzyme activity. And with more than five years old, she got another physician, and the physician is asked for the enzyme function test. Then the enzyme is easier to make the diagnosis of all mucopolysaccharidosis. In summary, the case presentation highlights the diagnostic journey of a patient with attenuated MPS1 who underwent short- stature follow- up for over 10 years in a pediatric endocrinologist clinic without a correct diagnosis. And it's important to note that assessment of bone aging in children with growth delay is typically done with an X- ray of the left hand and wrist, thus pediatric endocrinologists are in an ideal situation being able to identify early phalangeal abnormalities as bullet- shaped phalanges typical of MPS. Look here. This. This shape. This is very typical of MPS1. The alert for attenuated MPS diagnosis is not only for the endocrinologist, it is also for the pediatrician, rheumatologist, otolaryngologist, orthopedist, cardiologist, and the others. To finish my presentation, I'm going to show you an editorial of this journal, Rheumatology Cambridge from 2011, and they did a supplement of all papers about mucopolysaccharidosis. It's really very good. The Dr. Giovanni Valentino Coppa is a rheumatologist, and he wrote this editorial. And why should a rheumatologist be aware of the mucopolysaccharidosis? And I asked, and the other doctors, like pediatrician, family doctors, orthopedists, endocrinologists, ophthalmologists, neurologists, cardiologists, and ENT doctors. If we don't have the newborn screening for mucopolysaccharidosis everywhere, only in some places, and it's so important the role of these physicians to help these patients and make early diagnosis, because the prognosis of these patients is much better. And here is an example of a girl with delayed diagnosis of Scheie syndrome, MPS1, attenuated form, and the girl at six years of age, health, no significant medical history, stiffness of one finger, since the age of three years, diagnosed with juvenile idiopathic arthritis and treated with steroids. in the picture being that woman at 20 years old, initial corneal opacities, increase the joint stiffness, fingers and shoulders, and diagnosed with rheumatoid arthritis by several rheumatologists and treated with steroids. This is a problem with rare diseases. When you put the stamp of the diagnosis of the patient, if many good physicians saw or a good physician did the diagnosis, nobody changes. But the history of this patient, it's not of rheumatoid arthritis. Initial corneal opacities, increased joint stiffness. It's not from arthritis, and she was treated with steroids, keep the steroids. And the woman here with 31 years old. age, dysplasia of the femoral head and acetabulum, echinovirus foot, dysostosis, multiplex, progressive cardiac dysfunction for valvular disease, treated for rheumatoid arthritis with gold salts and non- inflammatory drugs, and woman here with 53 years old, cardiac surgery, corneal clouding because she did the corneal transplant, had the retinal degeneration, blindness, hearing loss, vertigo, finally diagnosed with MPS1 by a neurologist expert in lysosomal storage diseases. Usually I use this case in classes that's not about mucopolysaccharidosis as an example of rare disease, of the lack of knowledge about MPS for the physicians. It's not the guilt of the physicians. Us, we don't have a discipline, at least in Brazil, of rare diseases in our graduation and no professional health has this kind of approach during the graduation period. Then it's very difficult and we have old classification about the diseases between basic organs and Dr. Saldubrei, which is the father of inborn errors of metabolism, said that this classification, the diseases are in box, like neurology box, cardiology box, and endocrinologist box, and when you have a patient like this with mucopolysaccharidosis, which box is of mucopolysaccharidosis? She has neurological problems, she has ENT problems, she has cardiac problems. Do you understand? We don't have this vision during the graduation period, this whole vision about the patient, not in the box, but look at the patient, look at the patient and hear the history because they are telling you the diagnosis. Thank you. Now I am available for questions and answers. Oh, there is one question. Are upper airway infections, especially otitis media, early and very common only in the most severe form? No. The otitis media is frequent early symptom in all kind of MPSs, like MPS1, MPS2, MPS3, that you don't usually see so much, so much manifestations, but they have otitis early, like two, three months of age, many times, many episodes during the year, then it's important, not only for her patients, for the attenuated patients. It's so important because it's really early, two, three months of age. If you have a patient with otitis media, like every month, they need to insertion the tubes and that didn't work, you need to think about MPS diagnosis. There is another one here. What are the most common findings with MPS1 attenuated forms? We have some publications about MPS1 registry and we have one publication about the Shea phenotype. More than 80% of the patients, the attenuated patients, at the moment at diagnosis has stiffness of the distal phalanges. distal phalanges stiff, they couldn't extend completely the fingers. It's an important one, the otitis media, the hernia that can be early, early like first years of life. When you saw in the severe phenotype is in the first year of life we have a hernia and the otitis, all these features. But these hands, it's so important. Then you look at the hands and after you can look the elbow and the shoulder and probably there is another issue in these joints. Then it's important for the attenuated patients to make early diagnosis because they have a better prognosis, because they have a residual activity of enzyme. The response is much, much better for this patient. Now we have another question. What are the main differences in the evolution of patients with MPS severe and attenuated forms? Well, the patient, the severe patient, they have the complications of the disease really early in the first month of life. You are going to make the diagnosis of cardiac involvement, neurological involvement, EMT, sinus and symptoms during the first between until the sixth month of age, 98%, 98%, 90% of the patients with the Hurler syndrome has at least one or two of these classical symptoms, sinus and symptoms. The attenuated patient, no. They probably are going to start with otitis very frequently, but only they are going to have really alert signs for the physician, like this guy with five years old with leg calvipeders. This is alert and it's important because it's a disease that we don't have one etiology and if you don't know the etiology, it's important to think about any rare diseases because we don't know rare diseases. That it's important when you have a challenge with a patient who has a problem like this, leg calvipeders. We don't know why we need to think about one rare disease that can be any of the mucopolysaccharidosis, can be gaucher disease, can be other rare diseases, not only mucopolysaccharidosis. Then the signs and the symptoms are going to be later. The complications are going to happen later too in the patient with attenuated phenotype. is one question about would you give GH to all MPS patients? No, for no MPS patients. It's not the conduct. We have some papers about and in general we don't have a great success with the GH therapy. We saw a good result in this case but it's not a conduct that you extend for all patients with MPS. If you look you can read some papers and nobody, it's not a consensus to give GH for mucopolysaccharidosis patients. Thank you for the question. Did the girl in the presentation responded to growth hormone? Well, in the case presentation was a boy and the boy responded. He gained some centimeters during this period but as I said it's not a consensus. Does the use of growth hormone increase or worsen kyphosis? I think so. I think it's worse for the kyphosis. Well how do you clinically differentiate MPS1 and mucolipidosis mild type? Well we have some similar characteristics, but the best way to distinguish it is doing the activity, the enzyme activity measure, the enzyme activity of this patient. We have twins with mucolipidosis and they start the investigation as mucopolysaccharidosis and we find out the diagnosis because it's not everything from MPS. MPS is very, very peculiar and they are similar in the facial aspects, the gingive, that we have hypertrophy, but the best way it's really to do the, to measure the enzyme activity. I know Scheie is out of summer assessment, but to you, Scheie more in girls? No. No. It's, I have, well I have more girls too, but we have more girls in every, every disease because we have more, more girls in the world. But it's not nothing, nothing was published about, about this curiosity. I have girls, more girls with MPS1 attenuated phenotype like Scheie. I have one boy, one girl. For MPS1 it's the same, it's 50% boys and girls. Low enzyme levels in two tests with EDUA gene in enterozygosis in molecular, what is the next step? Or you can measure the urinary gags, but if you have a low enzymatic levels below the reference value is mucopolysaccharidosis, or you can have, maybe you can check mucolipidosis too, or multiple deficiency of multiple sulfatases. You can, you can try to, but if the enzymatic level is below the reference range, you are having one patient. And sometimes, like I told about the testimony of the girl in the MPSC international meeting of patients, and she did two exons and they didn't find the two mutations, only one variant, not two. And she has mucopolysaccharidosis. The enzymatic measure, it's the most important exam for mucopolysaccharidosis because sometimes the urinary gag is negative. If it is positive, it's okay, wonderful, can help us. But if it's negative, you couldn't exclude the diagnosis. One more. No, no further question. Thank you so much for all, for the questions, for the attention, and I hope to see you in another occasion. Bye- bye.