Transcription:
[00:00:00] Dr. Nathalie Guffon: Hello, everyone, and welcome to the last webinar in Series 2 of Spot the Early Signs of alpha-mannosidosis. Today's topic is Differential Diagnosis of alpha-mannosidosis, hearing impairment as an Early Sign in Children. So just before starting, I will give you some messages. Please do not take any screenshots or reproduce any of the slides, content, or images without the express written permission of the speaker. We will have a question and answer session at the end of the webinar. You can submit your question at any time via the questions panel. Your questions can be submitted via text only and not verbally. We will answer as many questions as possible. The webinar will be recorded and available on demand. Next, please. So I would like to introduce my colleague, Dr. Sonia Ayari, who is an ENT at the Femmes Mères Enfants Hospital in Hospice-Civil of Lyon, France. My name is Nathalie Guffon. I am responsible for the reference center for inherited metabolic diseases at the same hospital as Dr. Ayari. Next, please. The main learning objectives of this webinar are listed on the slide. We will review the cause and heterogeneous symptoms of alpha-mannosidosis.
[00:01:54] Dr. Nathalie Guffon: We will describe ENT manifestations and hearing impairment in alpha-mannosidosis. We will also examine hearing impairment as a key red flag for early diagnosis of alpha-mannosidosis, and we will discuss the diagnosis process and differential diagnosis of other lysosomal storage disease. Next, please. just to remind you that alpha-mannosidosis is an ultra-rare lysosomal storage disease with an estimated incidence of 0.1 per 100,000 live births. But the alpha-mannosidosis is underdiagnosed, and current evidence suggests an higher incidence more than 1 per 500,000. alpha-mannosidosis is caused by lysosomal enzyme alpha-mannosidase deficiency, which leads to defective degradation of glycoproteins and accumulation of mannose-rich oligosaccharides in all tissues, resulting in impaired cellular function and apoptosis. Alpha-mannosidosis is a genetic disease with a pathogenic variant in the MAN2B1 gene that leads to enzyme deficiency. Next, please. The inheritance is autosomal recessive, which means that both parents are a carrier of a genetic variant in MAN2B1 gene, and around 25% of the children could be affected with alpha-mannosidosis. To date, 183 variants of MAN2B1 gene have been identified, so it is very difficult to find genotype-phenotype correlation. Next, please. Alpha-mannosidosis is a progressive, multisystemic disease with heterogeneous symptoms. Speech delay and early onset childhood hearing loss are very common. Patients with alpha-mannosidosis present immunodeficiency and recurrent infections, especially upper airway infection, otitis media, and pulmonary infection. Immunoglobulin G deficiency is present in more than 30% of patients. Various degrees of intellectual disability occur in all patients, but early psychomotor development may appear normal or near normal. Unlike other lysosomal storage diseases, these patients can show continuous cognitive development during childhood and early teenage years. About 25% of patients develop acute psychiatric manifestation, generally after 10 years of age. Psychiatric symptoms include acute psychotic crisis with hallucination, confusion, anxiety and depression. Patients with a severe form of the disease may present hydrocephalus. Skeletal abnormalities are also very common and include asymptomatic multiplex dysostosis, kyphoscoliosis, osteoporosis, osteonecrosis and progressive destructive polyarthropathy in adults. Genu valgum is frequent and contributes to gait disturbance. Children present motor function impairment with muscular weakness, mild hypotonia, balance and coordination disorders. Progressive worsening ataxia is common in adults. Patients show some degree of dysmorphia with macrocephaly and coarse facial features like mucopolysaccharidosis, but it may be very subtle and overlooked in alpha-mannosidosis. Craniosynostosis with microcephaly has also been reported. Ocular manifestations include hypermetropia and strabismus. Mild corneal clouding are possible and adult patients may develop retinopathy. Patients may develop respiratory complication with sleep apnea and restrictive pulmonary insufficiency and cardiac complication with mild to moderate valvulopathy and myocardiopathy. Next please. alpha-mannosidosis has been historically described as three subtypes, but at least 50% of patients with non-severe form are neither type 1 or type 2. So prediction of the clinical course of an individual patient is very challenging. So as other lysosomal storage disorders, there is a continuum of clinical severity ranging from severe to mild phenotype. It is important to distinguish a severe form of alpha-mannosidosis which progress rapidly leading to prenatal loss or early death often from central nervous system involvement or severe infection. From the attenuated forms, most patients present with a non-severe phenotype previously classified as mild type 1 or moderate type 2. In this attenuated phenotype, patients present various degrees of the signs and symptoms I previously presented to you. The disease progresses slowly and most patients survive into adulthood. Next please. So after this short introduction, I would like to hand over to Dr. Sonia Ayari who will talk about ENT-manifestation and hearing loss in alpha-mannosidosis.
[00:08:36] Dr. Sonia Ayari: So, due to their frequency in alpha-mannosidosis, it is important to speak about the ENT manifestations. And one of the most common ENT presentation is recurrent infection. The exact pathogenesis is unclear, but an old study from 2000 reported that immunologic tests can be normal, with normal number of circulating leukocytes, normal level of immunoglobulin main classes, and IgG subclasses. However, post-immunization serum levels of specific antibodies against poliovirus, diphtheria and tetanus-toxoid were significantly reduced. And patient polymorphonuclear neutrophils demonstrated insufficient intracellular bacterial killing in serum. So, this probably reflects a qualitatively less good immune response in such patients. And moreover, some recent studies demonstrated reduced level of IgG in some patients with alpha-mannosidosis, about 30% of them. So, clearly, there is a problem of immunity. Next slide. So, it is described in the literature that children with alpha-mannosidosis present recurrent respiratory tract infection with recurrent rhinopharyngitis or chronic form with snoring, nasal congestion, and persistent nasal discharge. We almost always find hypertrophy of the adenoid tissue, which indicates adenoidectomy.
But in case of alpha-mannosidosis, the symptoms resist even after surgery. And even it's difficult to suspect the disease by the ENT manifestations, but there are some clues that might increase the suspicion of a general disease. The first one is the early appearance of symptoms, usually before one year old and sometimes then six months years. The second is the persistence of symptoms in the surgery or the relapse of the problems. And the third is the association with the other manifestations that my colleague Nathalie already talked about. Next slide, please. Other infectious manifestation in children with alpha-mannosidosis are recurrent acute otitis media with possibility of purulent discharge throughout the outer ear canal. But these manifestations are not specific of the disease and can be seen in the normal child. Next slide. We can also observe in such situations problem of otitis media with effusion, like we can see here in this photo, which will be responsible of conductive hearing loss. Conductive hearing loss is usually mild and rather moderate. Here it's moderate. The pathogenesis appears to be the same as for the normal child with problem of the recurrent infection in the ear and the problem of the dysfunction of the Eustachian tube.
And this situation will lead to the development of otitis media with effusion. And we can see in this study published in 2023, this study investigated by CT scan temporal bone in eight patients with alpha-mannosidosis and showed no closure of the bony part of the Eustachian tube. So the pathogenesis seems to be the same that for the normal child. Next slide. Of this otitis media with effusion, the majority of patients with alpha-mannosidosis have a history of insertion of ventilation tube and adenoidectomy. Some of them can develop chronic otitis media with, like we can see, problem of adhesion of the tympanic membrane to the ossicles or even a problem of cholesteatoma. And this situation is this application for two patients with alpha-mannosidosis. Next slide. And how I said before, these ENT manifestations are frequently reported in the publication about the disease. We can see in this study, the same one last for the last slide, that all patients except one, the youngest one who are two years old, all have a history of ear infection, adenoidectomy, ventilation tube. Next slide. We found also the same features in the other publication of seven cases with alpha-mannosidosis. We can read that the first patient, patient number one, we have recurrent otitis in the infancy. The second, we can read chronic noisy breathing, recurrent colds. The third, we can read grommet for chronic otitis media and so on. Next slide. Next, please. Yes. We can also frequently, we also observe frequently hearing loss and language delay in this syndrome. Hearing loss can be explained by the otitis media with the fusion that we just talked about. But this conductive form of deafness is improved by insertion of ventilation tube. And that's why it is important to repeat hearing testing after ventilation tube to detect sensorineural impairment associated. In case of other form of chronic otitis... No, please. In case of the the last one, please. The past, the precedent one, please. Yes, okay. In case of other form of chronic otitis media like ossicular problems, mixed hearing loss can be observed in older child or adult. In the other hand, sensorineural form of hearing loss is the most common form of hearing loss in this patients. In this study, we can see that six patients out of eight have problem of hearing loss. Only two have normal hearing, number seven and number eight, and there are the youngest patients of this population. Four of them had sensorineural bilateral hearing loss, you can see here. One mixed form of hearing loss, and it's not specified for one patient. In this study, we can see also that the age of the diagnosis of hearing loss vary between six months and ten years.
And we see that there is a delay between the age of diagnosis of the hearing loss and the age of treating with hearing aid. This can be first with hearing because the implementation with hearing aid can be postponed due to recurrent infection in the ear. And another thing which is interesting in this study is that the patient number five has a newborn hearing screening, which is normal and he developed hearing loss and diagnosis was made at two years old. Next slide, please. Also, this publication found that hearing loss is present in all patients. Seven patients have hearing loss, with five patients with sensorineural hearing loss, and two patients with mixed hearing loss. Another interesting fact in this study is there is a delay between the diagnosis of hearing loss and the diagnosis of the disease with a delay that vary between one year to 19 years. So very important in the case of the patient number five. Next slide. Another publication of in 2024, the same is observed in this study, in this multi-center study they reported 16 patients with alpha-mannosidosis. We found in this study that 93% of the population has hearing loss, sensorineuronal hearing loss, and hearing loss is the first clinical manifestation in 43% of the population studied, followed by speech delay. We can see too that there is a gap between the first clinical manifestation and the diagnosis, the gap is about four to five years. We can see too that during clinical follow up, three patients were already benefit from bone marrow transplantation had sensorineuronal hearing loss which remains stable in two cases, and one patient developed sensorineuronal hearing loss instead of the treatment. And finally, one patient received enzyme replacement therapy, he has normal hearing which remains stable during the observation period, but the observation period is short, it's only of eight months. Next slide. What about our experience in Lyon? So in Lyon we have a cohort of 18 patients, and out of them 17 have sensorineuronal hearing loss and benefit from hearing aids. All patients in our population had a history of speech delay, and we didn't find impairment in vestibular function, but we tested only five patients.
And I don't find in the literature publication about vestibular function and alpha-mannosidosis. Next slide. So to conclude about hearing loss, and especially sensorineuronal hearing loss in alpha-mannosidosis, it is a very frequent complaint in cases of alpha-mannosidosis, and found in 75 to 100% of the population which is published. Hearing loss might lead to suspect diagnosis if this hearing loss is not isolated, but associated with other anomalies like learning disability despite hearing aid, clumsiness, poor coordination or coarse facial appearance. So these children should be addressed to explore lysosomal storage and alpha-mannosidosis. And it is possible to do the diagnosis by the genetic screening. In Lyon, the MAN2B1 gene responsible of the disease is included in the deafness panel chain. But this will make more time and is more expensive. Thank you. And I give again the floor to my colleague, Nathalie.
[00:22:52] Dr. Nathalie Guffon: Thank you, Sonia, for this very comprehensive overview of the ENT manifestation in children with alpha-mannosidosis. But which particular signs may lead an ENT specialist to suspect alpha-mannosidosis in a child with hearing impairment?
[00:23:22] Dr. Sonia Ayari: Sorry, Nathalie, what is your question?
[00:23:27] Dr. Nathalie Guffon: You can't hear me?
[00:23:31] Dr. Sonia Ayari: You asked me a question?
[00:23:32] Dr. Nathalie Guffon: Yes. Which particular signs may lead an ENT specialist to suspect alpha-mannosidosis in a child with hearing impairment?
[00:23:44] Dr. Sonia Ayari: So like I said before, hearing loss may lead to suspect the diagnosis if this hearing loss is associated with other anomalies and especially clumsiness. This clumsiness is frequently reported by the parents. When we have poor coordination and need for the psychometry, even if the vestibular function is normal, because when we receive some children with hearing loss and with sensorineuronal hearing loss, usually we assess the vestibular function. And in situation of alpha-mannosidosis, they have poor coordination. They have clumsiness with a normal vestibular function. And this should suspect the disease. And if there are coarse facial appearance. And moreover, it's not typical for children with sensorineuronal hearing loss to have recurrent infection resistant to different treatment. Or this association is frequently found in alpha-mannosidosis. I hope I answered the question.
[00:24:57] Dr. Nathalie Guffon: Thank you, Sonia. So I have another question for you. Serious otitis are very common in young children. And do you think there is other signs that could indicate lysosomal storage disorders?
[00:25:16] Dr. Sonia Ayari: Yes, otitis media with effusion and acute and recurrent acute otitis media and recurrent infection are frequent and can be observed even in the child with alpha-mannosidosis but can be observed too in the normal child. But early appearance of these symptoms before one year and sometimes before six months, persistence of recurrence of this ENT infection despite surgery, surgery which is insertion of ventilation tube, adenoidectomy, and sometimes tonsillectomy with the child who continue with the respiratory tract infection and repeated purulent discharge through the grommet, this should lead to suspect an underlying general disease. It's clear that we are not going to think of alpha-mannosidosis first, but we will do an assessment to look for allergy, gastroesophageal reflux. If this assessment is normal, secondly, we will refer the child to our colleagues to look for an immune deficiency or ciliary dyskinesia. If there is an immune deficiency interesting the IgG, the child should be referred to the metabolic doctor to explore the lysosomal storage.
[00:26:15] Dr. Sonia Ayari: It's clear that we are not going to think of alpha-mannosidosis first, but we will do an assessment to look for allergy, gastroesophageal reflux. If this assessment is normal, secondly, we will refer the child to our colleagues to look for an immune deficiency or ciliary dyskinesia. If there is an immune deficiency interesting the IgG, the child should be referred to the metabolic doctor to explore the lysosomal storage. And during this follow-up, if the diagnosis of sensorineuronal or mixed hearing impairment is made associated with this recurrent infection not explained by the common causes, we should think too about the lysosomal storage disease and refer the child to the metabolic doctor.
[00:27:12] Dr. Nathalie Guffon: Thank you so much for your answer, Sonia. So, we will continue. Next slide, please. So, hearing impairment can be a red flag for early diagnosis of alpha-mannosidosis in children. Next, please. As I said, alpha-mannosidosis is a multisystemic but heterogeneous disease. When faced with a sensory neural hearing impairment in a child, it is important to look for associated signs that can orientate the diagnosis. It may be recurrent infection, especially if they are associated with an IgG deficiency. Very often, the children are described as clumsy. They have mild hypotonia, poor coordination, and fine motor difficulties, then some learning difficulties. Hearing impairment associated with skeletal abnormalities can also be a red flag. But generally, at an early stage, dysostosis multiplex is asymptomatic. If a child has a genu valgum or a kyphoscoliosis or a hip dysplasia associated with hearing impairment, it is important to check for mucopolysaccharidosis and alpha-mannosidosis. Hearing impairment may also be associated with macrocephaly and some degrees of corpus callosum fatigue. This is another red flag. Next, please.
So, now, I think there is one before, no? So, when the diagnosis is suspected, how perform the diagnosis of alpha-mannosidosis? Some hematologists can find you because they find a vacuolated lymphocyte on a sample for count cells. This is not specific for alpha-mannosidosis, but for lysosomal storage disorders. Urinary oligosaccharides is a simple test in countries where it is available. In alpha-mannosidosis, these tests show elevated mannose-rich oligosaccharides. In some labs, this test is done on the same urinary sample as glycosaminoglycans and can increase the diagnosis. Enzymatic determination is easily available, and alpha-mannosidase activity can be measured on leukocytes or in dried blood spots. Low alpha-mannosidase activity is a crucial point to confirm the diagnosis. Genetic test is now easily available in most countries and can be used for prenatal diagnosis or genetic counselling. It can target MAN2B1 gene or be part of hearing loss gene panel, as Sonia said previously. In some cases, exome sequencing has made possible alpha-mannosidase diagnosis, but this always needs to be confirmed by demonstrating alpha- mannosidase activity deficiency. Next please. So the main differential diagnosis of alpha-mannosidosis is mucopolysaccharidosis or mucolipidosis because there are many features in common. There are both progressive multisystemic disease. In both cases, the red flag signs and symptoms are recurrent upper airway infection, chronic renal wear, recurrent otitis media, hearing loss, cross-facial features, hepatomegaly, hernia, and dysostosis multiplex.
But there are some differences. First, alpha-mannosidosis is a slower disease and patients survive longer than patients with neuropathic form of mucopolysaccharidosis. Because of immunodeficiency, alpha-mannosidosis patients suffer from infections that are uncommon in mucopolysaccharidosis patients like repeated pneumonia, bone infection, urinary infection, psychiatric manifestation, and ataxia are typical for alpha-mannosidosis. Carpal tunnel syndrome is very frequent in mucopolysaccharidosis and very uncommon in alpha-mannosidosis. And also severe craniocervical stenosis or instability are generally not seen in alpha-mannosidosis but frequent in mucopolysaccharidosis. Next please. So now I will present two cases for illustrating the topic. The first one is a story of a boy who is a child of non- consanguineous parent. He is a third child. He was born after normal pregnancy and delivery with normal weight, height, and head circumference. Neonatal examination was also normal. His medical history begins by recurrent otitis and rhinopharyngitis since the first month of age and finally lead to adenoidectomy and grommet insertion at 21 months of age with no clear improvement. He developed speech delay and was diagnosed with hearing mixed impairment at two years of age. Parents reported also muscular weakness compared to their other child. He was able to walk at 18 months but remained clumsy. Finally a mucopolysaccharidosis was suspected at two years of age because of ENT manifestation associated with progressive macrocephaly, coarse facial features as you can see on the picture, and accelerated growth velocity during the first year of age followed by a decline. Urinary glycosaminoglycans were normal and ruled out the diagnosis of mucopolysaccharidosis. By chance oligosaccharides was performed immediately and showed typical pattern of alpha-mannosidosis with elevated mannose-rich oligosaccharides and the diagnosis was confirmed at two years of age with low enzyme activity. The second child is also a boy from unrelated parents. It is the first child after an uneventful pregnancy. He was born by cesarean section because of fetal distress, but was normal at birth. His story started at 2 months of age because of plagiocephaly, for which he had physiotherapy at 4 months of age. The general practitioner sent the baby at 6 months of age to a pediatrician because of plagiocephaly and acceleration of the growth. The pediatrician sent the baby to the neurosurgeon for suspicion of craniosynostosis at 7 months. At that time, he had normal EEG, normal brain scan and normal ophthalmological exam. So the neurosurgeon prescribed a helmet for 4 hours per day and all the night. Just after the child started with recurrent ENT and respiratory infections with multiple hospitalizations and start with pneumology follow up, was diagnosed for viro-induced asthma. He had initially normal psychomotor development but presented a speech delay at 20 months of age and was unable to walk alone. So at 20 months of age he went to the neuropediatrician who found only mild hypotonia, some improvement in speech and conclude to unspecified mild acquisition delay. Finally, he was able to walk at 23 months of age. Next slide. But he still had multiple infection with asthma crisis. At 27 months, he had a follow- up visit with the neuropediatrician who asked for ENT and speech therapist evaluations because of mildly delayed acquisition with severe speech delay. At 3 years of age the ENT physician noticed hearing loss with otitis media, he prescribed a treatment and finally confirmed neurosensory hearing impairment 4 months later. The boy started with hearing aids, speech therapy, psychometricity and educational support. Few months after he had a little sister who had doubtful neonatal hearing neonatal screening. So she had some evaluation with no more echocardiography, no more abdominal and kidney echography, no ear CT-scan so at 5 years of age he and his sister went to the geneticist because of family hearing loss. The sister has a hearing loss confirmed at 4 months and hearing aids at 7 months of age. The boy continued with multiple infections and asthma crisis and at 5.5 years he had adenoidectomy and the geneticist has performed panel gene for family hearing loss and the panel was negative. The boy developed with abnormal balances, coordination disturbance, abnormal fine motor, but the psychometrician noticed regular progress. He also started with social difficulties in relating at school with other children and suffered from some isolation. He had to repeat the last year of nursery school and was sent to the psychiatric for children. The psychiatrist noticed severe speech delay, severe speech disorder with a child who was understanding better than he expressed, but he didn't find any signs of autism. So at 6 years and a half, he and his sister went to the second genetic visit. The geneticist noticed abnormalities in both child, normal skeletal x-ray in the boy, but ovoid vertebrae in the girl. So he decided to perform exome sequencing. The result came one year later and found two pathogenetic variants in MAN2B1 gene. The diagnosis of alpha-mannosidosis was confirmed in both children with elevated mannose-rich oligosaccharides and a very low leukocyte alpha-mannosidase activity. Next please. So now we have time for a short discussion.
[00:40:39] Dr. Sonia Ayari: So I have a question for you Nathalie. So to try to improve the diagnosis of this disease, should I refer to the metabolic doctor all the children with sensorineuronal deafness knowing that there is one deaf child per 100 births and almost 1 in 500 will develop deafness secondarily which correspond to 700 children per year in our country with deafness. Should we refer to the metabolic doctor all these children with deafness?
[00:41:22] Dr. Nathalie Guffon: No, clearly not because we were not able to see all the patients and probably it will not, it remains a very rare disease so maybe it will not be very useful. I think we have to increase the awareness of the disease and to continue to communicate with the doctors, pediatricians, ENT, neuropediatricians, geneticists about this disease and about the associated mild symptoms to increase a daily diagnosis. One important thing is hearing deafness plus macrocephaly or hearing deafness plus some unusual learning difficulty, some clumsiness, patients with alpha-mannosidosis, even young patients, have very, very poor coordination. It's very difficult for them to play with other, with a ball or something like that. There are very difficulties in fine motor function so this can be checked at school by the, by the, by the institutor. So this mild sign plus hearing loss maybe we have to check. We have also to communicate about, of course, association between hearing loss and coarse facial fracture, but very mild coarse facial fracture and something very subtle. So even if it's very mild, it will be important to check and also these children more often are at the beginning higher than the other and after it's declined, but not so much as mucopolysaccharidosis patients, for example, and also if we have hearing loss plus genu valgum or plus some joint or skeletal problems, it will be also important to check. For us in metabolic disease, we say that neurosurgery hearing loss plus recurrent ENT infection is a good thing to check for alpha-mannosidosis, but I clearly understand that it's very, it's too much frequent. So maybe we have to consider sensorineural hearing loss plus IgG deficiency or hearing impairment plus recurrent infection, but not only ENT infection. For example, repeated pneumonia or arthritis or septicemia or something like that.
[00:44:51] Dr. Sonia Ayari: Okay, thank you. So the diagnosis is very challenging to do this diagnosis, but we should check for the other anomalies and like you said, recurrent infection, hearing loss, sensorineural hearing loss should lead us to check other anomalies which lead us to do this diagnosis. Thank you, Nathalie.
[00:45:22] Dr. Nathalie Guffon: Thank you. So now I have to start with the Q&A session. I invite all the attendees to ask a lot of questions that we can hopefully answer. So at the moment there is one question for Sonia and it is which ENT surgery procedure has the best improvement in health living standards?
[00:45:57] Dr. Sonia Ayari: The surgery is the same that for the normal child. So if we have acute otitis media or if we have chronic otitis media with the fusion, we will put a grommet like we do for the other child. So there is not a specific surgery for these children.
[00:46:31] Dr. Nathalie Guffon: Another question for you, Sonia. You mentioned relapse of the problems after surgery. How common is this?
[00:46:42] Dr. Sonia Ayari: It's frequent. It's frequent to do adenoidectomy and then some months later he begins again to have snoring, to have nasal discharge. It's about 80% I think. I don't have exact number, but I think it's a high number of relapse.
[00:47:07] Dr. Nathalie Guffon: Okay. If respiratory, physical or speech therapy is used for alpha-mannosidosis patients, yes, of course. They have all symptomatic treatment with hearing impairment. Speech therapy is very important for them and they can progress and they can learn to speak if it's not too late. And physical therapy is also important. It's not like for mucopolysaccharidosis. We don't want that the physiotherapist works on joint or something like that, but we want more work and balance and coordination and endurance and muscle efficiency, but it's very important for the patient. It may be physical therapy only or psychomotricity. For respiratory, yes, some patients require salbutamol or corticoid or some treatment for pseudo- asthma and some also respiratory re- education to improve the flow.
[00:49:02] Dr. Sonia Ayari: Okay, thank you.
[00:49:07] Dr. Nathalie Guffon: It seems there is no further questions, so I will close this webinar and thank you all of you for your attendance and Sonia for your participation.
[00:49:20] Dr. Sonia Ayari: Thank you, Nathalie.
[00:49:21] Speaker 3: Thank you.
[00:49:23] Dr. Sonia Ayari: Goodbye.
[00:49:25] Dr. Nathalie Guffon: Goodbye.