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Mucopolysaccharidoses: early diagnostic signs in infants and children

Italian Journal of Pediatrics volume 44, Article number: 133 (2018)

Cinzia Galimberti, Annalisa Madeo, Maja Di Rocco & Agata Fiumara

Mucopolysaccharidoses (MPS) comprise a group of lysosomal disorders that are characterized by progressive, systemic clinical manifestations and a coarse phenotype. The different types, having clinical, biochemical, and genetic heterogeneity, share key clinical features in varying combinations, including joint and skeletal dysplasia, coarse facial features, corneal clouding, inguinal or abdominal hernias, recurrent upper respiratory tract infections, heart valve disease, carpal tunnel syndrome, and variable neurological involvement. In the severe forms, these features usually appear in the first months of life, but a correct diagnosis is often reached later when suggestive signs are manifest. All MPS types may have severe or attenuated presentations depending on the residual enzymatic activity of the patient. Based on data from the literature and from personal experience, here we underline the very early signs of the severe forms which should alert the paediatrician on their first appearance. A few early signs are typical of MPS (i.e. gibbus) while many are unspecific (hernias, upper airway infections, organomegaly, etc.), and finding the association of many unspecific signs might prompt the paediatrician to search for a common cause and to carefully look for other more specific signs (gibbus and other skeletal deformities, heart murmur). We stress the need to increase awareness of MPS among paediatricians and other specialists to shorten the still existing diagnostic delay. A timely diagnosis is mandatory for the commencement of treatment as soon as possible, when available, to possibly obtain better results.

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Easy‐to‐use algorithm would provide faster diagnoses for mucopolysaccharidosis type I and enable patients to receive earlier treatment

Anna Tylki‐Szymańska, Linda De Meirleir, Maja Di Rocco, Waseem M. Fathalla, Nathalie Guffon, Christina Lampe, Allan M. Lund, Rossella Parini, Frits A. Wijburg, Jiri Zeman, Maurizio Scarpa

Aim: The aim of this study was to develop an algorithm to prompt early clinical suspicion of mucopolysaccharidosis type I (MPS I). Methods: An international working group was established in 2016 that comprised 11 experts in paediatrics, rare diseases and inherited metabolic diseases. They reviewed real‐world clinical cases, selected key signs or symptoms based on their prevalence and specificity and reached consensus about the algorithm. The algorithm was retrospectively tested. Results: An algorithm was developed. In patients under two years of age, kyphosis or gibbous deformity were the key symptoms that raised clinical suspicion of MPS I and in those, over two years they were kyphosis or gibbous deformity, or joint stiffness or contractures without inflammation. The algorithm was tested on 35 cases, comprising 16 Hurler, 10 Hurler–Scheie, and nine Scheie patients. Of these 35 cases, 32 (91%) – 16 Hurler, nine Hurler–Scheie and seven Scheie patients – would have been referred earlier if the algorithm had been used. Conclusion: The expert panel developed and tested an algorithm that helps raise clinical suspicion of MPS I and would lead to a more prompt final diagnosis and allow earlier treatment.

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Growth patterns in children with mucopolysaccharidosis I and II

World Journal of Pediatrics volume 11pages226231(2015)

Agnieszka Rozdzynska-Swiatkowska, Agnieszka Jurecka, Joachim Cieslik & Anna Tylki-Szymanska

Background: Mucopolysaccharidosis (MPS) diseases lead to a profound disruption in normal mechanisms of growth and development. This study was undertaken to determine the general growth of children with MPS I and II. Methods: The anthropometric data of patients with MPS I and II (n=76) were retrospectively analyzed. The growth patterns of these patients were analyzed and then plotted onto Polish reference charts. Longitudinal analyses were performed to estimate age-related changes. Results: At the time of birth, the body length was greater than reference charts for all MPS groups (Hurler syndrome, P=0.006; attenuated MPS II, P=0.011; severe MPS II, P<0.001). The mean z-score values for every MPS group showed that until the 30th month of life, the growth patterns for all patients were similar. Afterwards, these growth patterns start to differ for individual groups. The body height below the 3rd percentile was achieved around the 30th month for boys with Hurler syndrome, between the 4th and 5th year for patients with severe MPS II and between the 7th and 8th year for patients with attenuated MPS II. Conclusions: The growth pattern differs between patients with MPS I and II. It reflects the clinical severity of MPS and may assist in the evaluation of clinical efficacy of available therapies.

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Orthopaedic challenges for mucopolysaccharidoses

Italian Journal of Pediatrics volume 44, Article number: 123 (2018)

Andrea Borgo, Andrea Cossio, Denise Gallone, Francesca Vittoria & Marco Carbone

Mucopolysaccharidoses (MPS) are a group of diseases characterized by abnormal accumulation of glycosaminoglycans (GAGs). Although there are differences among the various disease types, the osteoarticular system is always involved. The aim of the present study was to establish a framework for MPS-related orthopaedic manifestations and for their treatment. The authors, affiliated to three different Italian Orthopaedic Centres, report data taken from the literature reviewed in light of their accumulated professional experience. Bone alterations make up what is known as dysostosis multiplex, involving the trunk and limbs and with typical radiological findings. Joints are affected by pathological tissue infiltrations. The cervical spinal cord is involved, with stenosis and cervical and occipitocervical instability. In MPS there is a much higher incidence of scoliosis compared with healthy subjects without any particular distinctive feature. Kyphosis of the spine is more frequent and also more severe because of its possible neurological complications, and it is localized at the thoracolumbar level with a malformed vertebra at the top of the deformity.

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Musculoskeletal manifestations of lysosomal storage disorders

M Aldenhoven, R J B Sakkers, J Boelens, T J de Koning, N M Wulffraat

Lysosomal storage disorders (LSDs), a heterogeneous group of inborn metabolic disorders, are far more common than most doctors presume. Although patients with a severe LSD subtype are often readily diagnosed, the more attenuated subtypes are frequently missed or diagnosis is significantly delayed. The presenting manifestations often involve the bones and/or joints and therefore these patients are frequently under specialist care by (paediatric) rheumatologists, receiving inadequate treatment. Since effective disease-specific treatments, including enzyme replacement therapy and stem cell transplantation, have become available for certain LSDs and timely initiation of these treatments is necessary to prevent the development of severe, disabling and irreversible manifestations, early diagnosis has become essential. The challenge is to raise awareness for better recognition of the presenting signs and symptoms of LSDs by all doctors who may encounter these patients, including rheumatologists.

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Characterization of Hip Morphology in Children With Mucopolysaccharidosis Types I and II

Journal of Pediatric Orthopaedics: June 2016 - Volume 36 - Issue 4 - p 370-375 doi: 10.1097/BPO.0000000000000463

Ashby, Elizabeth; Baker, Markus; Eastwood, Deborah M.

Background: The purpose of this study is to describe the natural history of hip morphology in patients with mucopolysaccharidoses (MPS) I and MPS II. Methodology: This is a retrospective radiographic analysis of 88 hips in 44 children with MPS I and II. Radiographs were examined to determine hip migration, femoral head sphericity, and acetabular dysplasia at different ages throughout childhood. In individual hips, change in morphology and rate of change were analyzed. Results: There was a high rate of hip migration and femoral head dysplasia in both MPS I and MPS II. Progressive migration was seen in three-quarters of hips and progressive femoral head deformity in over half of hips. Acetabular dysplasia was variable, ranging from normal to severely dysplastic, but did not change with time. Overall, hips were more dysplastic in MPS I than MPS II. Conclusions: Hip morphology is variable in MPS I and MPS II ranging from almost normal to severely dysplastic. Some hips do not deteriorate with time and thus surgical intervention may not be necessary in all cases. Deterioration is slow allowing time to plan a holistic approach to treatment.


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Why should rheumatologists be aware of the mucopolysaccharidoses?

Rheumatology, Volume 50, Issue suppl_5, 1 December 2011, Pages v1–v3,

Giovanni Valentino Coppa

 Although each individual MPS disorder is somewhat rare, together their frequency is not irrelevant (incidence ∼1 : 25 000). As a group, most of them share, from an early stage of the disease, common clinical features involving bones and joints (joint stiffness, decreased joint mobility, carpal tunnel syndrome, bone abnormalities, etc.). Due to their multiple musculoskeletal manifestations, patients with MPS disorders sooner or later (but fairly often before their underlying illness has been recognized) have to see a rheumatologist. Consequently, it is important that rheumatologists are aware of the clinical manifestations that could be related to MPS diseases, what else to look for and what diagnostic procedures are available.

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ENT and mucopolysaccharidoses

Ital J Pediatr. 2018; 44(Suppl 2): 127.
Published online 2018 Nov 16. doi: 10.1186/s13052-018-0555-0

Pier Marco Bianchi, Renato Gaini, and Silvano Vitale

MPS are rare, progressive, and multisystem diseases with insidious signs and symptoms. Various ENT manifestations appear in the early stage of MPS, including otitis media, macroglossia, adenotonsillar hypertrophy, nasal obstruction, OSAS, progressive respiratory disorders, and hearing loss. As the incidence of hearing loss is high in MPS patients, hearing loss should be determined at an early stage. After the diagnosis, the required treatments should be started promptly with the aim of increasing the quality of life. However, it has to be considered that this is only possible as a result of regular and systematic follow-up.

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Mucopolysaccharidosis Type I

Diagnostics (Basel). 2020 Mar; 10(3): 161.
Published online 2020 Mar 16. doi: 10.3390/diagnostics10030161

Francyne Kubaski, Fabiano de Oliveira Poswar, Kristiane Michelin-Tirelli, Ursula da Silveira Matte, Dafne D. Horovitz, Anneliese Lopes Barth, Guilherme Baldo, Filippo Vairo, and Roberto Giugliani

One century after the report of the first cases of MPS I, many advances in the understanding of this complex disease have been achieved. Several tools have also been developed for its diagnosis, including biochemical and genetic techniques that enable patient diagnosis, carrier identification, and prenatal diagnosis. The first successful therapeutic intervention (bone marrow transplantation) was reported in 1980, and in 2003, intravenous replacement therapy with a recombinant enzyme (laronidase) became available. Although these therapeutic approaches transform the natural history of the disease, several problems remain, with unmet needs related to the CNS manifestations of the disease, the skeletal abnormalities, the heart valve problems, and the corneal clouding, among others. 

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Open issues in Mucopolysaccharidosis type I-Hurler

Orphanet Journal of Rare Diseases volume 12, Article number: 112 (2017)

Rossella Parini, Federica Deodato, Maja Di Rocco, Edoardo Lanino, Franco Locatelli, Chiara Messina, Attilio Rovelli & Maurizio Scarpa

MPS I-H is a complex disorder, mostly due to heterogeneity of IDUA mutational profile, which is largely responsible for phenotypical and clinical heterogeneity. Early diagnosis is instrumental in achieving the most appropriate treatment tailored to the different clinical manifestations of MPS I. Newborn screening is a good option for early diagnosis: nowadays regional screening pilot projects are already in place for MPS I measuring IDUA activity using dried blood spots, although reliable markers for early prediction of the phenotype allowing the decision of an appropriate therapeutic intervention has yet to be fully validated. Moreover, verifiable outcome predictors and markers still need to be identified and to be made comparable amongst different reference centres.

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