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A 60-minute educational webinar with Dr Cláudia Falcão Reis (medical geneticist, Oporto University Medical Center) and Prof. Mehmet Umut Akyol (paediatric ENT, Hacettepe University, Ankara) on recognising alpha-mannosidosis behind the everyday presentations of recurrent ENT infections, hearing loss and developmental concerns — the red flags that should prompt testing, and when to escalate to metabolic referral. For paediatricians, ENT specialists and metabolic teams.
Alpha-mannosidosis is an ultra-rare, autosomal recessive lysosomal storage disease caused by biallelic MAN2B1 variants and deficiency of acid alpha-mannosidase, which leads to accumulation of mannose-rich oligosaccharides and multisystem disease — including immune deficiency with low IgG and recurrent infections. Dr Cláudia Falcão Reis frames it through “the child who keeps coming back”: recurrent otitis media with effusion, glue ear, hearing loss and speech delay that are managed in isolation across specialties, so the diagnosis is missed for years. Her central message is not to wait for the classic phenotype — the spectrum is wide, from mild to severe, and because treatment exists, hearing loss that keeps recurring deserves a broader work-up that also considers immune status. On diagnosis, the core test is the acid alpha-mannosidase enzyme assay, supported by urinary oligosaccharides and MAN2B1 genetic testing. ENT hearing-loss gene panels often start with GJB2 (Connexin 26) and should be broadened, ideally to include MAN2B1. A negative or “normal” metabolic screen does not exclude the diagnosis — clinicians should confirm with the laboratory whether alpha-mannosidosis was actually checked and whether the enzyme was measured. Because the condition is familial, with a 25% sibling risk, and is not covered by newborn screening, genetic counselling and testing of at-risk siblings are important; where enzyme testing or etiological investigation is not available locally, the child should be referred to a metabolic centre. Prof. Mehmet Umut Akyol explains why ENT is often first to see these children: almost all have early head-and-neck signs — recurrent upper-respiratory-tract and ear infections, otitis media with effusion, adenotonsillar hypertrophy and airway obstruction. The take-home red flag is the combination of unusually frequent respiratory infections with a hernia (or a history of ENT surgery) — that togetherness should prompt referral to a paediatrician, geneticist or metabolic team. He stresses that hearing assessment, distinguishing conductive from sensorineural loss, is essential, and that surgery in these children is high-risk: anaesthesia and cervical-spine involvement make it dangerous in advanced disease, so operate early, before irreversible anatomical changes, in specialised centres. The panel discusses enzyme replacement therapy with velmanase alfa — which improves quality of life, pain and function although it does not cross the blood–brain barrier — the value of a multidisciplinary and international approach with family groups, and voice as a possible future non-invasive biomarker.
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. This session has two presenters, so the speaker attributions are our best reading of the audio and should be confirmed. It is provided as a convenience only. For anything clinical, please refer to the video recording to hear exactly what the expert said.
Dr Cláudia Falcão Reis: Welcome to this new webinar, "The Child Who Keeps Coming Back: Recognizing Alpha-Mannosidosis Behind Recurrent ENT Infections, Hearing Loss, and Developmental Concerns." I'm Cláudia Falcão Reis. I come from the Azores Islands and I work at Oporto University Medical Center, at the Clinic of Medical Genetics Jacinto Magalhães in Portugal. We'll start with some housekeeping, and then begin.
From the perspective of a medical geneticist who works closely with inherited conditions — especially rare disorders that have treatable options — it is paramount to recognise when there is a problem in our approach. Alpha-mannosidosis is a metabolic condition that is not common but is important to diagnose because it is manageable. As an example, a child presents with recurrent otitis and effusion; then at around three years of age comes back again with effusion, recurrent otitis and speech delay. Each time, we think it is just another glue-ear episode, and parents often focus on the hearing as the reason for the speech delay. It can take several specialists and several years before someone assesses the child and realises it is something more. So it is paramount to think about alpha-mannosidosis as a multisystem disorder that can present early with hearing loss.
Alpha-mannosidosis is a genetic condition caused by biallelic pathogenic variants in MAN2B1, which cause deficiency of the lysosomal enzyme acid alpha-mannosidase. That deficiency leads to accumulation of the substrate — mannose-rich oligosaccharides. Importantly, it also impairs the immune system: you can have immunodeficiency with low IgG levels, which may itself be one of the presenting features. The spectrum is quite wide, with mild, moderate and severe forms. It is autosomal recessive, so a family history of consanguinity is relevant, and there is variable expression. It affects both sexes, and most of the time there is no family history of hearing loss or of the condition itself.
Sometimes the approach considers only the hearing and the ear; it is important to broaden the scope of evaluation to assess immune status as well. Because it is a multisystem, metabolic condition, different physicians see the child, and there have been reports of children who appear to have non-syndromic hearing loss. The most important thing is to connect the findings, which is best done in a multidisciplinary team setting — though sometimes the child presents first to a single specialty. The main message is that you should not wait for the classic phenotype. The spectrum is large, and since treatment options are available, you want to investigate recurrent hearing loss rather than dismiss it. Macrocephaly is characteristic and can make you think of a storage condition; skeletal problems and organomegaly may occur but are not mandatory, especially early on.
The diagnostic delay can last decades, and the numbers for how long it takes to reach a diagnosis of alpha-mannosidosis are very concerning. There is a large catalogue of conditions in the differential diagnosis, but alpha-mannosidosis is one you can specifically investigate — including as a cause of hearing loss.
If you don't have the ability in your own setting to assess enzyme function or to do etiological investigations, refer the child to a specialty that has those tools. A very important point: a negative work-up is not an exclusion in medical genetics. Sometimes the report says "metabolic screen normal," but you should talk to the laboratory and ask exactly which tests were in scope — and specifically whether alpha-mannosidosis was checked.
For hearing loss, ENTs often order GJB2 (Connexin 26) first and, when it is negative, progress to a broader panel; it is important that acid alpha-mannosidase is actually measured, because the enzyme assay is the core test. Following the ACMG guidelines you can classify a variant as pathogenic or likely pathogenic; if you find only one variant, further work is needed. Laboratories that work with alpha-mannosidosis and other metabolic conditions are excellent — they will call you and tell you what further testing or sample collection is needed. Just remember that alpha-mannosidosis is not part of newborn screening.
There is a 25% risk that siblings also have alpha-mannosidosis, especially younger siblings, who may show a different expression of the condition. Call your medical genetics department about tests ordered from ENT. In everyday clinic, persistent hearing loss leads to molecular diagnosis through gene panels, because alpha-mannosidosis is not at the forefront of your thinking — but if a child keeps coming back with recurrent infections, that should prompt genetic testing. On treatment, the enzyme does not cross the blood–brain barrier, but the reports describe important benefits for quality of life and for pain. My message is coordinated care around recurrent hearing loss: I work with ENTs, who are the greatest of colleagues. Now I'll pass the torch to Professor Mehmet Umut Akyol.
Prof. Mehmet Umut Akyol: Thank you, Cláudia, for the kind introduction. I am Umut Akyol, an otolaryngologist — an ENT — working at Hacettepe University in Ankara, the capital of Turkey, as a paediatric otolaryngologist. I'd love to share my experience. Why is ENT special in these metabolic and rare diseases? First, they are rare, so we don't see them often, we don't know them well, and we don't recognise them. They progress over time, and unfortunately some irreversible morphological and anatomical changes happen during that progression — so even when you diagnose the child, the damage may already be done.
The accumulation — of glycosaminoglycans in the mucopolysaccharidoses, and of oligosaccharides in alpha-mannosidosis — affects every system, and the picture is very heterogeneous: even two brothers can have quite different presentations. We cannot cure these diseases; we treat the complications and try to increase the quality and duration of life for the patient, the family and society. So after diagnosis we should create an effective multidisciplinary approach focused on patient safety and quality of life, and remember that surgical treatment can be tricky and dangerous, which is why early surgery is such an important point.
We have to take care not only of the ears and hearing, but also of voice problems, speech disorders, chewing and swallowing disorders, balance disorders and sleep disorders. In otolaryngology, as elsewhere in the body, whatever is accumulating builds up around the ear and the Eustachian tube, so these children need repeated procedures. We operate on them — for example adenotonsillectomy around the airway — which is dangerous because the accumulation causes airway obstruction; in advanced cases this is really tough.
Because the organ where we first see the signs matters, we are, in a sense, lucky: almost all of these children have some head-and-neck signs early. Unfortunately, most morphological changes happen at this age, and you cannot help much once skeletal, muscular or other anatomical changes are established. The most frequent problems are upper-respiratory-tract infections and ear infections — otitis media, otitis media with effusion, fluid in the ear — and the fluid blocks hearing. Hearing loss matters enormously in little children, because of the huge plasticity of the developing brain. They also have frequent tonsillitis and adenoid enlargement, obstructing the airway. These are the children who, unlike their same-age peers, come to you with many infections and many upper-respiratory-tract problems, often around the time they start daycare.
Here is the very important red flag and take-home message. Keep in mind a child with unusually frequent attacks of upper-respiratory-tract infections who has also undergone — or has a history of — ear, nose and throat surgery, and especially a child with frequent respiratory infections plus a hernia or a history of hernia. That combination can indicate a metabolic disease. Refer to the paediatrician, the geneticist or the metabolic colleagues. Simply by being aware of the togetherness of these two symptoms, you can catch several more patients in your daily practice.
ENT is important not only for diagnosis but because treating these children is tricky: they are very vulnerable, and they are dangerous to operate on — not only for ENT surgery but for any surgery — because anaesthesia is very difficult, especially in advanced disease, and mortality and morbidity rates are high. Yet we have to operate, because they need to hear better in order to learn and develop. My advice: if there is an indication for surgery, do it earlier rather than later. When the disease is really advanced it becomes impossible even to see the neck, because the cervical spine is involved — so we should operate before it becomes more dangerous. These children should be cared for in specialised centres.
Almost all children can have otitis media with effusion causing a conductive hearing loss. But in a little child with frequent respiratory infections and otitis media, if you find a sensorineural component to the hearing loss, that is important. So hearing assessment is essential — send them for audiological examination, and act on a report that shows sensorineural loss. Cláudia, I've talked a lot, and fast — I hope I've conveyed the message. I'm ready for any questions.
Dr Cláudia Falcão Reis: It's a pleasure to listen to you.
Prof. Mehmet Umut Akyol: Thank you. Beyond routine ENT work, in our clinic we are trying to find other ways of diagnosing these children. We have been thinking about voice, since the basic pathophysiology is accumulation in the very delicate soft tissue beneath the vocal cords. There are measurable differences between the voices of MPS patients and those of control patients, so I hope that in the near future we will have easier, non-invasive and inexpensive techniques based on voice.
Dr Cláudia Falcão Reis: Thank you, Professor Umut — a wonderful review of the ENT aspects of alpha-mannosidosis and MPS. ENTs can be the first clinicians to identify the cause of hearing loss that keeps coming back despite two sets of grommets, which puzzles them. My question: as part of your pre-operative routine you check coagulation — should you also check immunological function?
Prof. Mehmet Umut Akyol: The basic answer is no. We are surgeons; we like cutting and stitching, and we don't always know the scientific side. We do have associations and international guidance, but in a normal child without a diagnosis it doesn't really apply — which is why we need practical pointers, and the togetherness of hernia and respiratory infections is a very important one.
Dr Cláudia Falcão Reis: That's a wonderful answer, because you bring the patient back into focus. When you work on rare disorders you get excited about the pitfalls, but in everyday practice it has to be simple. We now live in a time where genetic testing is increasingly accessible and medical geneticists can support the team. If treatment is not succeeding, there may be something more complex underlying the recurrent effusions and infections — and it's fine not to have the tools yourself; refer. As a medical geneticist working with ENTs, I provide the investigations into the cause of hearing loss at an early stage, and we also assess patients as candidates for treatment.
For our listeners: it is a familial condition, so it is paramount to activate genetic counselling for family members — for their own care and for family planning. Can ENT also help assess the hearing of siblings? There is a 25% chance that they also have alpha-mannosidosis.
Prof. Mehmet Umut Akyol: Very important — of course. This is where the multidisciplinary, interdisciplinary approach matters. Whenever we have a suspicion of a metabolic disease, the best thing is to send the child for consultation; it increases the yield. We do the surgery, but we should be aware that genetic consultation is very important for these families — some conditions are mild and may not be diagnosed until 18 years of age, but hearing and ear problems are usually there, so audiological testing over time matters. The team should include experienced members: a neurosurgeon, an orthopaedic surgeon, ENT, an audiologist, a speech pathologist and dentistry.
Dr Cláudia Falcão Reis: Absolutely, spot on. Different colleagues and different countries have different tools. In Porto we have been developing in-house enzyme assays, and you can use a Guthrie card — a simple heel-prick sample — where it is available.
Prof. Mehmet Umut Akyol: That brings another important point, Cláudia: it should be not only an interdisciplinary approach but an international one, because these are very rare cases and we need all the data. And family groups are very important.
Dr Cláudia Falcão Reis: Very important, absolutely.
Dr Cláudia Falcão Reis: We have a question from the chat: is there a point in the disease progression where ENT surgery does more harm than good? That's for Professor Umut.
Prof. Mehmet Umut Akyol: Yes, but it depends on the patient, because every patient is different. For alpha-mannosidosis, when we're talking mostly about hearing and the ear, it is more or less clear, and children will use hearing aids because of the mixed and sensorineural components of the loss. In some other diseases such as MPS, where the airway is also obstructed by the disease, there may be nothing left in our hands except tracheotomy — and sometimes it is not even possible to open one. That is where you have to decide. Unfortunately, in these progressive diseases, such decisions do arise.
Dr Cláudia Falcão Reis: Another interesting question: you mentioned voice as a potential future biomarker — is that something a general paediatrician could realistically notice, or does it need formal assessment to be meaningful?
Prof. Mehmet Umut Akyol: Perfect question. Let me tell you how I began this voice work. Years ago a colleague, an anaesthesiologist at my university, brought her three-year-old — a lovely child, still a lovely young woman now. She had a harsh voice, and a couple of months later some ear problems; I noticed she was not quite typical. I suggested sending her for metabolic assessment, and it turned out to be an MPS case. Some of these children have a rather rock-star-like, harsh voice; others sound quite normal — because that delicate submucosal tissue of the vocal cords is vulnerable to any change that alters the voice. So voice can be a useful prompt to send a child for metabolic consultation.
Dr Cláudia Falcão Reis: Thank you to everyone in the audience for being with us to talk about alpha-mannosidosis, and the child who keeps coming back with these conditions. Professor Umut, we loved your drawings — they were beautiful. Thank you so much, and we hope to see you at a future webinar.
Prof. Mehmet Umut Akyol: Thank you very much, Cláudia. Bye bye.
Dr Cláudia Falcão Reis: Thank you.
Because alpha-mannosidosis is a multisystem lysosomal storage disease that often presents early with exactly these everyday problems — recurrent otitis media with effusion, glue ear, hearing loss and speech delay — which are usually managed in isolation across ENT, audiology and developmental services. When a child “keeps coming back” with recurrent ear infections and hearing loss that does not settle despite the usual treatment, the pattern, rather than any single symptom, should raise suspicion of an underlying metabolic condition. Clinicians should not wait for the full classic phenotype, because the spectrum is wide and effective treatment is available.
The combination of unusually frequent upper-respiratory-tract and ear infections with a hernia (or a history of hernia or ENT surgery) is the take-home red flag — it is the togetherness of these features, not one alone, that matters. A child who has needed repeated courses of antibiotics, keeps returning every few weeks, or has already undergone ear, nose or throat surgery, and who also has a hernia or developmental concerns, should prompt referral to a paediatrician, geneticist or metabolic team. Simple awareness of this pattern lets clinicians catch extra patients in everyday practice.
The core diagnostic test is the acid alpha-mannosidase enzyme assay, which can be run from blood or a dried blood spot (Guthrie card); it is supported by urinary oligosaccharides and confirmatory MAN2B1 genetic testing. ENT hearing-loss gene panels frequently start with GJB2 (Connexin 26) and should be broadened when negative, ideally to include MAN2B1. Crucially, a negative or “normal” metabolic screen does not exclude the diagnosis: clinicians should check with the laboratory whether alpha-mannosidosis was actually included and whether the enzyme itself was measured, and refer to a metabolic centre when these tools are not available locally.
Because the disease progresses and many of its morphological changes are irreversible, so recognising and acting early is decisive. ENT surgery in these children is high-risk — anaesthesia is difficult and, in advanced disease, cervical-spine involvement and airway obstruction make procedures dangerous — so needed surgery is best done early, before changes advance, and in a specialised centre. Enzyme replacement therapy with velmanase alfa improves quality of life, pain and function (though it does not cross the blood–brain barrier), and because there is a 25% risk to siblings, at-risk family members should be identified and tested so they too can benefit from earlier care.
This content is intended for healthcare professionals only. The views expressed are those of the presenters and do not necessarily reflect those of Excellence in Pediatrics; their inclusion does not imply endorsement. The content is provided for educational purposes only and does not constitute medical advice or replace independent clinical judgement.