There is a considerable overlap of clinical features of distinct types of MPS, and they may be impossible to distinguish based on clinical findings alone. Furthermore, patients suffering from a certain type of MPS may present with subtle changes or severe alterations, so the spectrum of disease presentation is broad - even among those carrying defects of the same gene.

Most commonly, MPS induces mental disability, malformations of the skeletal system, and corneal clouding. Mental retardation may be accompanied by developmental delays and may become apparent in infancy; it may or may not progress throughout life. However, MPS patients may also be of normal intelligence. Malformations of the locomotor system may comprise, but are not limited to, short stature, short neck, lumbar kyphosis, scoliosis, pectus carinatum, genu valgum, and pes cavus [1]. In late stages of the disease, life-threatening spinal cord compression may occur, especially in those suffering from severe skeletal dysplasia [2] [3]. Many patients also have joint contractures. While they may present coarse facial features, the latter rarely prompt a diagnostic workup. Corneal clouding was mentioned as another symptom characteristic of MPS and may be associated with glaucoma, retinal degeneration, and optic nerve swelling with subsequent atrophy. These complications may result in visual impairment and even blindness [4].

Beyond neurological, orthopedic, and ophthalmological findings, macroglossia, tonsillar hypertrophy, otitis media and conductive hearing loss, upper airway obstruction, valvular heart disease, hepatosplenomegaly, and bowel dysfunction are frequently reported [4] [5].

• Splenomegaly

  Maroteaux Lamy syndrome is characterized by short stature, coarse facies, corneal clouding, joint stiffness and contractures and splenomegaly. [ggc.org]

  Additional signs and symptoms that may develop include: Enlarged head Chronic nasal discharge Retinal degeneration Splenomegaly Enlarged abdominal organs Skeletal dysplasia Joint stiffness The cause of MPS I is inherited genetic mutations on chromosome [medicinenet.com]

  […] over body 0002230 Inguinal hernia 0000023 Joint stiffness Stiff joint Stiff joints [ more ] 0001387 Mucopolysacchariduria 0008155 Scoliosis 0002650 Short stature Decreased body height Small stature [ more ] 0004322 Sinusitis Sinus inflammation 0000246 Splenomegaly [rarediseases.info.nih.gov]

  […] lips, and enlarged mouth and tongue), short stature with disproportionately short trunk (dwarfism), dysplasia (abnormal bone size and/or shape) and other skeletal irregularities, thickened skin, enlarged organs such as liver (hepatomegaly) or spleen (splenomegaly [en.wikipedia.org]

• Short Stature

  Maroteaux Lamy syndrome is characterized by short stature, coarse facies, corneal clouding, joint stiffness and contractures and splenomegaly. [ggc.org]

  Clinical features and disease severity are variable, but usually include short stature, hepatosplenomegaly, dysostosis multiplex, stiff joints, corneal clouding, cardiac abnormalities and facial dysmorphism. [news-medical.net]

  His skeletal deformity and short stature remained unchanged. The results showed that early ERT initiated at newborn is safe and effective in preventing or slowing down disease progression of MPS VI including bone deformities. [ncbi.nlm.nih.gov]

  The intermediate type has the phenotype similar to that in mucolipidosis iii with coarse hurler-like facies, stiff joints with decreased mobility, and short stature. [icd9data.com]

• Dysostosis

  Most patients presenting beyond the neonatal period have increased urinary glycosaminoglycans and dysostosis multiplex. [news-medical.net]

  Skeletal X-rays revealed characteristic signs of dysostosis multiplex in the older brother at the initiation of treatment that were unchanged two years later, whereas the younger brother showed only slight findings of dysostosis multiplex throughout the [ncbi.nlm.nih.gov]

  Plain radiographs may reveal variable features of “dysostosis multiplex congenita”. [eurorad.org]

  The clinical features include short stature, corneal clouding, hepatosplenomegaly, cardiac abnormalities, and skeletal findings such as dysostosis multiplex and joint contractures. [ggc.org]

• Developmental Delay

  He had mild dysmorphic features with prominent speech developmental delays and, to a lesser extent, motor developmental delays. [ncbi.nlm.nih.gov]

• Pain

  In contrast, pain interference, which characterizes the impact of pain on function, and pain behavior which describes ways that patients cope with and respond to pain are both observable pain behaviors and can be reported by a proxy and the patient. [ojrd.biomedcentral.com]

  Patient 4 was diagnosed at 17 months of age when presented lower limb pain at night, respiratory allergy and repeated upper airways infections. [ncbi.nlm.nih.gov]

  Symptoms included nodular soft-tissue masses located around joints, with episodes of painful swelling of the masses and pain that ended spontaneously within 3 days. Pelvic radiography showed multiple soft-tissue masses and some bone erosion. [en.wikipedia.org]

• Recurrent Infection

  Despite genetic and phenotypic heterogeneity within and between different types of MPS, the disease symptoms and clinical signs often manifest during the first 6 months of life with increasing head size, recurrent infections, umbilical hernia, growth [bjo.bmj.com]

  The MPS diseases share many clinical features that include organomegaly, dysostosis multiplex, decreased growth, and recurrent infections. [genome.jp]

  Heavy-duty grommets are preferred due to recurrent infections and buildup of cerumen. [medicalhomeportal.org]

  Evidence of an intracellular reservoir in the nasal mucosa of patients with recurrent Staphylococcus aureus rhinosinusitis, J Infect Dis, 2005, vol. 192 (pg. 1023 - 8 ) 25. [academic.oup.com]

• Sleep Apnea

  Furthermore, the airway can become narrow in some individuals, resulting in frequent respiratory infections and sleep apnea. Over time, the cornea becomes opaque, which can cause significant loss of vision. [ivami.com]

  The airway may become narrow in some people with MPS I, causing frequent upper respiratory infections and short pauses in breathing during sleep (sleep apnea). [youtube.com]

  Surgery to remove tonsils and adenoids may improve breathing among affected individuals with obstructive airway disorders and sleep apnea. Sleep studies can assess airway status and the possible need for nighttime oxygen. [en.wikipedia.org]

• Respiratory Insufficiency

  The mucopolysaccharidoses are a group of hereditary disorders pathologically characterized by tissue accumulation of glycosaminoglycans due to deficient lysosomal metabolism which often leads to progressive airway stenosis and respiratory insufficiency [ncbi.nlm.nih.gov]

  Respiratory insufficiency may require treatment with supplemental oxygen. Aggressive management of airway secretions is necessary as well. [rarediseases.org]

  The main clinical manifestations associated with stenosis of the craniocervical junction range from exercise intolerance and lower limb paresis to para- or quadriplegia and respiratory insufficiency of central origin (16,43). [pubs.rsna.org]

• Tonsillar Hypertrophy

  Beyond neurological, orthopedic, and ophthalmological findings, macroglossia, tonsillar hypertrophy, otitis media and conductive hearing loss, upper airway obstruction, valvular heart disease, hepatosplenomegaly, and bowel dysfunction are frequently reported [symptoma.com]

• Hepatomegaly

  The patient was a 2-yr-old girl presenting with skeletal deformity, hepatomegaly, and delayed motor development. [ncbi.nlm.nih.gov]

• Hydrops Fetalis

  Keywords Live Birth Consanguineous Parent Mucopolysaccharidosis Hunter Syndrome Hydrops Fetalis These keywords were added by machine and not by the authors. [doi.org]

  Three cases of non-immune hydrops fetalis born to consanguineous parents were thought to be due to beta-glucuronidase deficiency (MPS VII) on the basis of placental histology and enzyme studies on both parents but no living cases of MPS VII were ascertained [ncbi.nlm.nih.gov]

  The severe neonatal form is the most common type of this syndrome, characterized by hydrops fetalis (abnormal accumulation of fluid in various tissues of the body) and dysmorphic features. [news-medical.net]

  In rare cases, some newborn infants with Sly syndrome may experience abnormal accumulation of fluid in various tissues of the body (hydrops fetalis). MPS VII is currently in clinical trial. [rarediseases.org]

  If the disorder causes hydrops fetalis, stillbirth or death in the neonatal period is likely. Patients may also succumb to cardiac or respiratory failure, or fall into a vegetative state during later stages of life. [symptoma.com]

• Aggressive Behavior

  Affected subjects present developmental delay, attention deficit disorder, uncontrollable hyperactivity, and aggressive behavior, followed by progressive dementia and death in late adolescence. [ncbi.nlm.nih.gov]

  […] intelligence and stature MPS II (severe) – Pebbly ivory skin lesions on the back, arms, and thighs; coarse facial features, skeletal deformities, and joint stiffness; retinal degeneration with clear cornea and hydrocephalus, mental retardation, and aggressive [emedicine.medscape.com]

  In the syndrome's second stage, aggressive behavior, hyperactivity, profound dementia, and irregular sleep may make children difficult to manage, particularly those who retain normal physical strength. [en.wikipedia.org]

• Seizure

  Long term video-EEG monitoring (LT-VEEGM) demonstrated sleep-related hypermotor seizures consistent with NFLE. No case of sleep-related hypermotor seizures has ever been reported to date in MPS. [ncbi.nlm.nih.gov]

  Tonic–clonic seizures are the most common type of seizure in Hunter syndrome, but absent and myoclonic seizures have also been reported. 15 It is possible that absence seizures (petit mal) are under-reported; neurologists should be aware of this and seek [touchneurology.com]

• Communicating Hydrocephalus

  In patients with this disorder, craniocervical compression, carpal tunnel syndrome, and communicating hydrocephalus are common. Traditionally, hydrocephalus occurring in patients with MPS VI has been treated with shunt placements. [ncbi.nlm.nih.gov]

  Although intellectual deficit is generally absent in MPS 6, central nervous system findings may include cervical cord compression caused by cervical spinal instability, meningeal thickening and/or bony stenosis, communicating hydrocephalus, optic nerve [orpha.net]

  Some severe problems, such as hydrocephalus, are more common in neuronopathic disease, whereas others disorders (such as carpal tunnel syndrome and spinal cord compression) are equally likely in both forms of the condition. 15 Chronic communicating hydrocephalus [touchneurology.com]

  Neurological symptoms may include mild to moderate intellectual disability by age 3, communicating hydrocephalus, nerve entrapment, corneal clouding, and some loss of peripheral and night vision. [en.wikipedia.org]

• Papilledema

  Ocular manifestations include corneal clouding, ptosis, acute and chronic angle-closure and open-angle glaucoma, optic nerve atrophy, and papilledema[3]. [eyewiki.aao.org]

  Reversed papilledema in an MPS VI patient with galsulfase (Naglazyme) therapy. Int Ophthalmol. 2009;29(4):267-9. 8. Gomes B, Souza Gda S, Viana G. [nnj.mums.ac.ir]

  Angina; valvular dysfunction; hypertension; congestive heart failure Pulmonary disease – Airway obstruction, potentially leading to sleep apnea, severe respiratory compromise, or cor pulmonale Ophthalmologic disease – Corneal clouding; glaucoma; chronic papilledema [emedicine.medscape.com]

  The symptoms usually include hearing impairment, carpal tunnel syndrome, joint stiffness, discrete corneal opacities, and papilledema. [icd9data.com]

• Stroke

  Patients had lower left ventricular dimensions (z: -1.02±0.1), lower stroke volumes (z: -2.3±0.17), lower left ventricular mass (z: -1.5±0.21), but higher wall thickness (z: +0.8±0.16), and higher work index (z: +2.5±0.2) compared to healthy control subjects [ncbi.nlm.nih.gov]

  Neurological Alliance Collective voice for 80 organisations, including stroke and brain injury. Organisations are listed at https://www.neural.org.uk/our-members/, a good place to start if looking for information on those conditions. [ucl.ac.uk]

  The National Institute of Neurological Disorders and Stroke (NINDS), along with other Institutes at the National Institutes of Health, supports the Lysosomal Disease network, a network of centers that address some of the major challenges in the diagnosis [ninds.nih.gov]

  Diabetes, Digestive & Kidney Diseases Office of Communications & Public Liaison Bldg 31, Rm 9A06 Bethesda, MD 20892-2560 Phone: (301) 496-3583 Email: [email protected] Website: http://www2.niddk.nih.gov/ NIH/National Institute of Neurological Disorders and Stroke [rarediseases.org]

• Unable to Walk

  She was unable to walk for the last 8 months. There were no sensory complaints. There was difficulty in breathing and speaking full sentences due to the shortness of breath. [jcvjs.com]

  In the syndrome's last stage, children become increasingly unsteady on their feet and most are unable to walk by age 10. Thickened skin and mild changes in facial features, bone, and skeletal structures become noticeable with age. [en.wikipedia.org]

• Diarrhea

  The most frequently reported adverse reactions included: chills, vomiting, nausea, arthralgia, diarrhea, tachycardia, abdominal pain, blood pressure increased, and oxygen saturation decreased. [biomarin.com]

  Initial manifestations include: frequent respiratory tract infections (in particular otitis media); umbilical and inguinal hernia; intractable diarrhea; hepatosplenomegaly; and skin lesions resembling an orange peel (on the shoulder, back and thighs). [orpha.net]

  There was no history of constipation, diarrhea, vomiting, bleeding, jaundice, seizure, weight loss or loss of appetite or of consciousness. His bladder habit was normal. The scholastic performance was poor. [omicsonline.org]

  Mps iia usually occurs between 2 and 4 years of age with progressive deterioration, chronic diarrhea, recurrent ear infections, hearing impairment, communicating hydrocephalus with increased intracranial pressure, and death at about 10 and 15 years. [icd9data.com]

  Diet A dietician can help you create a nutrition plan to help your baby control diarrhea and constipation, which may occur in those with severe MPS I. [babysfirsttest.org]

• Chronic Diarrhea

  Mps iia usually occurs between 2 and 4 years of age with progressive deterioration, chronic diarrhea, recurrent ear infections, hearing impairment, communicating hydrocephalus with increased intracranial pressure, and death at about 10 and 15 years. [icd9data.com]

  Chronic diarrhea in mucopolysaccharidosis III B. J Pediatr Gastroenterol Nutr 2009; 49(4):477-480. [DOI via Crossref] [Pubmed] 14. Malinowska M, Wilkinson FL, Bennett W, Langford-Smith KJ, O'Leary HA, JakobkiewiczBanecka J, et al. [anadolupsikiyatri.net]

  Most children with MPS type IIIA have severe neurological impairment by age 6 years Recurrent or chronic diarrhea and seizures occurs in some MPS III patients. [centogene.com]

• Failure to Thrive

  […] to thrive, intellectual disability, and developmental delay.[ 5 12 ] The extensive storage of these glycosaminoglycans is also known to cause meningeal thickening.[ 4 ] Intraoperatively, our patient was noted to have thickened arachnoid membrane, which [surgicalneurologyint.com]

  Affected children may also exhibit failure to thrive and difficulty feeding. Short stature occurs in almost all patients and is described as disproportionate because the trunk may be shorter than the legs. [rarediseases.org]

• Abdominal Pain

  The most frequently reported adverse reactions included: chills, vomiting, nausea, arthralgia, diarrhea, tachycardia, abdominal pain, blood pressure increased, and oxygen saturation decreased. [biomarin.com]

• Heart Murmur

  Slowly progressive valvar heart disease can be present for years without causing symptoms. Eventually, valvar heart disease can cause a heart murmur. [rarediseases.org]

• Widely Spaced Teeth

  The patient had severe infantile global neurodevelopmental delays, macrocephaly with a prominent forehead, coarse facial features with clear corneas, chronic congestion with snoring, wide-spaced teeth, short thick neck, hepatomegaly, an inguinal hernia [ncbi.nlm.nih.gov]

  Other possible features include pulmonary compromise, valvular heart disease, hearing loss, hepatomegaly, fine corneal clouding, and widely spaced teeth with abnormally thin enamel with increased risk of caries formation. [genedx.com]

  spaced teeth Wide-spaced teeth Widely-spaced teeth [ more ] 0000687 5%-29% of people have these symptoms Abnormal aortic valve morphology 0001646 Abnormal tendon morphology Abnormal shape of tendon 0100261 Avascular necrosis Death of bone due to decreased [rarediseases.info.nih.gov]

  Also seen are coarse facies, short nose, broad mouth, and widely spaced teeth with thinned enamel. The patient may have a waddling gait. [sajr.org.za]

  They also tend to look similar: Shorter than average, with stocky build Large head, bulging forehead Thick lips, widely spaced teeth, and large tongue Short, flat nose with wide nostrils Thick, tough skin Short, broad hands with curving fingers Knock-knees [webmd.com]

• Dental Caries

  CONCLUSION: Mothers' SOC of children/adolescents with MPS was associated with dental caries experience in their children. [ncbi.nlm.nih.gov]

  Specialty Collaborations & Other Services Dental Dental caries and abscessed teeth occur because teeth in MPS I tend to be poorly formed and have fragile enamel, which causes susceptibility to infection and decay. [medicalhomeportal.org]

  Mouth and Throat Sore on lips Color/ cracks/ ulceration Oral cavity Mucus membrane color Gum-bleeding/ ulceration/ swelling Missing teeth Dental caries Tongue Odor from mouth Difficulty in swallowing Tonsils ✓ ✓ ✓ ✓ ✓ ✓ ✓ Absent Pink color, no cracks [slideshare.net]

• Gingival Hypertrophy

  Such characteristics include chubby faces, thickened lips due to the overgrowth of the gums (gingival hypertrophy), an unusually prominent forehead (frontal bossing), and a broad, flattened bridge of the nose. [rarediseases.org]

• Hirsutism

  Other manifestations include corneal clouding, organomegaly, heart disease, short stature, hernias, facial dysmorphism and hirsutism. Radiological examination of the skeleton reveals the characteristic pattern of dysostosis multiplex. [orpha.net]

  […] much slower progression; normal intelligence and no hydrocephalus; hearing impairment and loss of hand function MPS III – The most common MPS disorder; severe central nervous system (CNS) involvement and only minimal somatic involvement; coarse hair, hirsutism [emedicine.medscape.com]

  Patients with MPS III are mentally retarded with severe hirsutism and synophrys. All mucopolysaccharidoses are inherited as autosomal recessive except for the Hunter syndrome (MPS II) which is an x linked disease. CASE REPORT Mrs. [bhj.org.in]

• Corneal Opacity

  On the other hand, these deposits may be present in most patients, but given the high prevalence of corneal opacity in MPS VI, these deposits become difficult to see and may go unnoticed. [eyewiki.aao.org]

  Regardless of phenotype, all patients had various degrees of infiltrated facies, short stature, dysostosis multiplex, joint contractures, and corneal opacity typical of the disease. [ncbi.nlm.nih.gov]

  Typical symptoms are stiff joints, corneal opacities, carpal tunnel syndrome and mild skeletal changes. Aortic valve disease can be present. [orpha.net]

  Biomicroscopy is not useful because the opacity of the anterior corneal layers prevents the endothelial microscopy examination. [ijponline.biomedcentral.com]

  opacities, preserved intelligence, among others. [scielo.org.co]

• Visual Impairment

  Although mental development proceeds normally in Maroteaux-Lamy patients, the progression of physical and visual impairments ultimately impedes psychomotor abilities. [themedicalbiochemistrypage.org]

  The main cause of visual impairment in these patients is, as noted above, the deposition of glycosaminoglycans at the cornea and subsequent hypo-transparency[7]. [eyewiki.aao.org]

  These complications may result in visual impairment and even blindness. [symptoma.com]

  impairment Impaired vision Loss of eyesight Poor vision [ more ] 0000505 Percent of people who have these symptoms is not available through HPO Aortic regurgitation 0001659 Autosomal recessive inheritance 0000007 Dysostosis multiplex 0000943 Hirsutism [rarediseases.info.nih.gov]

  Patients may suffer from glaucoma, severe visual impairment with retinal degeneration, optic nerve compression and atrophy, and the loss of peripheral vision. [medicalhomeportal.org]

• Retinal Pigmentation

  CONCLUSION: Our multimodal analysis reported here attempted to contribute to the knowledge of the natural history of GAG deposition in the eye, focusing on the retina and retinal pigment epithelium. [ncbi.nlm.nih.gov]

  Retinal degeneration GAG deposition within retinal pigment epithelial cells and in the photoreceptor matrix leads to progressive photoreceptor loss [13]. Optic nerve atrophy may also occur with advanced retinal degeneration [14]. [ijponline.biomedcentral.com]

• Hearing Impairment

  During 36 months of ERT, symptoms typical of MPS VI including short stature, progressive dysmorphic facial features, hepatosplenomegaly, hearing impairment, corneal clouding, and dysostosis multiplex were largely absent in the younger sibling. [ncbi.nlm.nih.gov]

  impairment – Deafness Musculoskeletal disease – Short stature; joint stiffness; symptoms of peripheral nerve entrapment Findings from examination may include the following: MPS IH – Corneal clouding, hepatosplenomegaly, skeletal deformities (dysostosis [emedicine.medscape.com]

  The symptoms usually include hearing impairment, carpal tunnel syndrome, joint stiffness, discrete corneal opacities, and papilledema. [icd9data.com]

  Hearing impairment. Umbilical hernias and inguinal hernias. Joint stiffness and skeletal deformities. Cardiomyopathy and coronary heart disease. Hepatosplenomegaly. [patient.info]

• Hearing Problem

  For example, children who have heart problems may undergo the imaging test echocardiography, and children who have hearing problems may undergo audiometry. The prognosis depends on the type of mucopolysaccharidosis. A normal life span is possible. [msdmanuals.com]

  The most usual clinical manifestations are short stature, coarse facial features, mental retardation, respiratory and cardiovascular complications, bowel dysfunction, organomegaly, umbilical or inguinal hernias, hearing problems, ocular impairment, and [karger.com]

  Pediatricians, surgeons, specialists who assess and treat heart problems (cardiologists), specialists who assess and treat hearing problems (audiologists), specialists who assess and treat eye problems (ophthalmologists), specialists who assess and treat [rarediseases.org]

• Joint Stiffness

  Maroteaux Lamy syndrome is characterized by short stature, coarse facies, corneal clouding, joint stiffness and contractures and splenomegaly. [ggc.org]

  […] and micrognathia; corneal clouding, joint stiffness, and heart disease MPS IS - Aortic valve disease, corneal clouding, and joint stiffness; normal intelligence and stature MPS II (severe) – Pebbly ivory skin lesions on the back, arms, and thighs; coarse [emedicine.medscape.com]

  A typical clinical presentation includes such symptoms and characteristics as short stature, facial dysmorphism, skeletal deformities, pulmonary dysfunction, joint stiffness and contractures, myocardial hypertrophy, neurological symptoms, and mental retardation [ncbi.nlm.nih.gov]

  Joint stiffness, corneal clouding, umbilical hernia, abnormal facies, hepatomegaly, joint contractures, and cervical myelopathy occur. Death tends to be in their 20s. [patient.info]

• Macrocephaly

  The features of MPS VI include macrocephaly, hydrocephalus and macroglossia. Often these individuals also develop abnormalities of heart valves, hepatosplenomegaly and umbilical hernia or inguinal hernia. [ivami.com]

  The patient had severe infantile global neurodevelopmental delays, macrocephaly with a prominent forehead, coarse facial features with clear corneas, chronic congestion with snoring, wide-spaced teeth, short thick neck, hepatomegaly, an inguinal hernia [ncbi.nlm.nih.gov]

  Individuals with MPS I may have a large head (macrocephaly), a buildup of fluid in the brain (hydrocephalus), heart valve abnormalities, distinctive-looking facial features that are described as "coarse," an enlarged liver and spleen (hepatosplenomegaly [youtube.com]

  Hirsutism, macrocephaly, and limited joint movements. Four types, each with a different enzyme deficiency, are recognized: a, b, c and d. [icd9data.com]

  She had macrocephaly with short stature, bilateral corneal clouding, coarse facial features and large ears. The wrists on both sides were hyperextensible with dysostosis multiplex of limbs. There was no mental retardation. [jcvjs.com]

• Genu Valgum

  The unique skeletal features are distinguished by a disproportional short stature, odontoid hypoplasia, spinal cord compression, tracheal obstruction, pectus carinatum, kyphoscoliosis, platyspondyly, coxa valga, genu valgum, waddling gait, and laxity [ncbi.nlm.nih.gov]

  valgum, short stature, spinal curvature, odontoid hypoplasia, ligamentous laxity, and atlantoaxial instability MPS IV (mild) – Much slower progression of skeletal dysplasia MPS VI – Features very similar to MPS IH MPS VII – Features similar to MPS IH [emedicine.medscape.com]

  Clinical features include short trunk dwarfism, dysostosis multiplex, progressive spinal deformity, short neck, pectus carinatum, genu valgum, pes planus, and odontoid hypoplasia with varying degrees of severity. [icd9data.com]

• Platyspondyly

  The unique skeletal features are distinguished by a disproportional short stature, odontoid hypoplasia, spinal cord compression, tracheal obstruction, pectus carinatum, kyphoscoliosis, platyspondyly, coxa valga, genu valgum, waddling gait, and laxity [ncbi.nlm.nih.gov]

  Characteristic findings included hypoplasia of odontoid peg, universal platyspondyly gibbus, and kyphosis of the dorsal region with widening of disc spaces. [sajr.org.za]

  […] beta-galactosidase deficiency mucopolysaccharidosis (mps) iv b this type is caused by beta-galactosidase (ec 3.2.1.23) deficiency and is marked a milder phenotype consisting of dysostosis multiplex, pectus carinatum, odontoid hypoplasia, kyphosis, genua valga, platyspondyly [icd9data.com]

  The frequent abnormalities that are seen in these children include deficiency of the anterior and middle column of the spine that gives rise to platyspondyly, presence of an anterior peak, coined or beaked vertebrae, and kyphoscoliosis. [jcvjs.com]

• Coxa Valga

  The unique skeletal features are distinguished by a disproportional short stature, odontoid hypoplasia, spinal cord compression, tracheal obstruction, pectus carinatum, kyphoscoliosis, platyspondyly, coxa valga, genu valgum, waddling gait, and laxity [ncbi.nlm.nih.gov]

  Our study shows that progressive acetabular dysplasia as well as coxa valga and hip displacement are highly prevalent and progressive over time in patients with MPS I-H, despite successful HSCT. [journals.lww.com]

  The epiphyseal centers not well developed, the pelvis is poorly formed with small femoral heads and coxa valga. The clavicles are short, thick and irregular and the ribs are oar shaped. Phalanges are shortened and trapezoidal in shape. [themedicalbiochemistrypage.org]

  Affected individuals usually present with unusual skeletal features including short trunk dwarfism, odontoid hypoplasia, pectus carinatum, kyphosis, gibbus, scoliosis, genu valgus, coxa valga, and flaring of the lower ribs. [genedx.com]

  Frontal view of the femurs revealed enlarged acetabular cavities with rough margins, and poorly formed femoral epiphyses and widened femoral necks with coxa valga (Fig. 4). [sajr.org.za]

• Short Neck

  Initial physical examination revealed the presence of a coarse facies, short neck, kyphosis, restricted joint movements and deformities, and cardiac murmur besides a normal intellect. [ncbi.nlm.nih.gov]

  Figure 1: shows Coarse facial features with depressed nasal bridge, a short neck, long philtrum. Figure 2: showing dorso lumbar scoliosis with anterior breaking at D12, L1,2,3 with ovoid shaped vertebra. [omicsonline.org]

  Examination and testing may reveal short stature (flat vertebrae cause a short trunk), short neck, kyphosis or scoliosis with pectus carinatum (pigeon chest) and, at the cervical spine, odontoid hypoplasia; atlanto-axial instability may be associated [sajr.org.za]

  Patients have coarse facial features, short neck and trunk, skeletal abnormalities (hypoplasia of hip acetabula, flared iliac wings, hypoplasia of L1 to L2 vertebral bodies, and lumbar kyphosis), hernias, and corneal clouding. [accessanesthesiology.mhmedical.com]

  Affected children may also have an abnormally large head (macrocephaly), a short neck and broad chest, delayed tooth eruption, progressive hearing loss, and enlargement of the liver and spleen (hepatosplenomegaly). [rarediseases.org]

• Thick Lips

  The early signs usually are coarsening of facial features with enlarged mouth, thick lips, and eye problems that progressively become worse. [medicinenet.com]

  These symptoms may include kyphosis (curvature of the spine causing a “lump on the back”), joint stiffness, coarse facial features (flattened nose bridge, thick lips and an enlarged tongue), corneal clouding, hearing loss, heart problems, an enlarged [luriechildrens.org]

  Physical symptoms generally include coarse or rough facial features, thick lips, an enlarged mouth and tongue, short stature with a disproportionately short trunk (dwarfism), abnormal bone size or shape (and other skeletal irregularities), thickened skin [ninds.nih.gov]

  They also tend to look similar: Shorter than average, with stocky build Large head, bulging forehead Thick lips, widely spaced teeth, and large tongue Short, flat nose with wide nostrils Thick, tough skin Short, broad hands with curving fingers Knock-knees [webmd.com]

• Hypertelorism

  Clinical manifestations Upper airways Facial coarseness, hypertelorism, sunken nasal dorsum, anteverted nostrils, thickened lips, gingival hyperplasia [19] and dental distortions. [hindawi.com]

Molecular biological analyses are the gold standard of MPS diagnosis and allow for a reliable identification of the type of the disease. However, diagnostic delays of several years are common. While lumbar kyphosis should definitely raise suspicion as to a lysosomal storage disease, most symptoms are non-specific if considered separately. Thus, MPS diagnostics are not usually carried out until the patient or their parents relate a complex medical history comprising several of the events described in the previous paragraph.

MPS diagnostics should include:

• Imaging studies. Skeletal anomalies are a clinical hallmark of MPS and should be evaluated to assess best treatment options and to prevent severe complications like spinal cord compression. Beyond the clinical findings described above, imaging often reveals macrocephaly, atlantoaxial dislocation, wedge-shaped vertebral bodies and platyspondyly, spatulate ribs, bullet-shaped metacarpals, as well as hypoplastic epiphyses and thickened diaphyses leading to hip dysplasia and deformities of other joints [1] [6]. Focal or diffuse white matter lesions, ventriculomegaly, communicating hydrocephalus, and eventually cerebral atrophy may be visualized by magnetic resonance imaging [6].
• Laboratory analyses of urine samples. The measurement of total glycosaminoglycans is usually followed by the separation of subfractions for qualitative analyses. The excretion pattern of urinary glycosaminoglycans allows for a tentative diagnosis of a specific type of MPS. In detail, patients suffering from MPS types 1 or 2 are likely to excrete abnormal amounts of heparan sulfate and dermatan sulfate. MPS type 3 is associated with an increased excretion of heparan sulfate, whereas MPS type 4 manifests in elevated concentrations of chondroitin 6-sulfate and keratan sulfate. While urine samples from MPS type 6 patients contain large amounts of dermatan sulfate, MPS type 7 is characterized by high urinary levels of heparan, dermatan, and chondroitin sulfate. Finally, MPS type 9 patients excrete hyaluronan [7].
• Before molecular biological tools became widely available, the activity of determined lysosomal enzymes was assessed in fibroblasts or leukocytes.
• Genetic studies to determine the underlying mutation [8].

• Delayed Bone Age

  Delayed bone age and elongated sella turcica were found. Pituitary MRI scans showed an empty sella in cases 2 and 3. Like other dysmorphic dwarfisms, we were unable to find hormonal deficiencies that could justify the short stature. [aem-sbem.com]

• Enlargement of the Spleen

  Individuals with MPS I may have a large head (macrocephaly), a buildup of fluid in the brain (hydrocephalus), heart valve abnormalities, distinctive-looking facial features that are described as "coarse," an enlarged liver and spleen (hepatosplenomegaly [youtube.com]

  • Lysosome disease is a condition that affects many parts of the body • This disorder lipase deficiency is an inherited • This accumulation of lipids leads to several health problems, including an enlarged liver and spleen 4. [slideshare.net]

  […] liver and spleen, hernias, chronic nasal congestion and ear infections. [luriechildrens.org]

  Individuals with this disorder often have a large head (macrocephaly), a buildup of fluid in the brain (hydrocephalus), an enlarged liver and spleen (hepatosplenomegaly), and a soft out-pouching around the belly-button (umbilical hernia) or lower abdomen [ghr.nlm.nih.gov]

• Enlargement of the Liver

  The accumulation of GAGs interferes with the way certain cells and organs in the body function and can lead to a number of serious symptoms including hearing loss, declined cardiac function, obstructive airway disease, enlargement of the liver and spleen [efpia.eu]

  Additional findings include short stature, heart abnormalities, breathing irregularities, liver and spleen enlargement (hepatosplenomegaly), and/or neurological abnormalities. [rarediseases.org]

MPS is considered potentially treatable with enzyme replacement therapy, hematopoietic stem cell transplantation, substrate reduction therapy, or gene therapy [9]:

• With regard to the former, laronidase, idursulfase, and galsulfase have been approved for the treatment of MPS types 1, 2, and 6, respectively. These enzymes are effective in controlling somatic manifestations of MPS, but skeletal anomalies and valvular heart disease don't usually respond to this kind of therapy. Furthermore, neither of these recombinant human enzymes is able to cross the blood-brain-barrier, so MPS-related central nervous system disorders won't be alleviated either.
• Hematopoietic stem cells of a healthy donor are a life-long source of lysosomal enzymes. Due to morbidity and mortality associated with the procedure, hematopoietic stem cell transplantation is usually reserved for those suffering from severe MPS. It should also be noted that disease progression has been reported years after the successful transplantation of stem cells. In order to improve the outcome, the transplantation should be performed as early as possible, and the donor shouldn't be a carrier of MPS-related mutations [10].
• To date, substrate reduction and gene therapy remain in experimental stages. Substrate reduction therapy aims at limiting the formation of glycosaminoglycans, thereby reducing the necessity of enzymatic degradation. Promising results have been achieved in cell culture and animal models with rhodamine B and genistein. What's more, the latter has been used in small clinical trials and has been demonstrated to improve joint mobility [11]. Gene therapy of MPS has not yet been realized in men. However, vector-mediated gene transfer has been shown to mitigate peripheral and central symptoms and to prolong survival [9].

Beyond that symptomatic and supportive care should be provided according to the individual needs of the patient.

Severe MPS is usually fatal within the first two decades of life. If the disorder causes hydrops fetalis, stillbirth or death in the neonatal period is likely. Patients may also succumb to cardiac or respiratory failure, or fall into a vegetative state during later stages of life [9]. By contrast, mild forms of the disease are associated with near-to-normal life expectancy.

All types of MPS are monogenic disorders. In detail, they are triggered by pathogenic mutations of one of the genes encoding for lysosomal enzymes that are required for the degradation of glycosaminoglycans. Except for MPS type 2, all forms of MPS are inherited in an autosomal recessive manner. The gene related to MPS type 2 is located on the X chromosome, so this disease is classified as an X-linked metabolic disorder [5]. Mutations of the following genes have been associated with single types of MPS:

• MPS type 1 - IDUA, to be found on 4p16.3, encoding for α-L-iduronidase
• MPS type 2 - IDS, to be found on Xq28, encoding for iduronate 2-sulfatase
• MPS type 3 - SGSH, NAGLU, HGSNAT, or GNS, to be found on 17q25.3, 17q21.2, 8p11.21, and 12q14.3, encoding for N-sulfoglucosamine sulfohydrolase, N-acetyl-α-glucosaminidase, heparan-α-glucosaminide N-acetyltransferase, and N-acetylglucosamine-6-sulfatase, respectively
• MPS type 4 - GALNS or GLB1, to be found on 16q24.3 and 3p22.3, encoding for N-acetylgalactosamine-6-sulfatase and galactosidase β1, respectively
• MPS type 6 - ARSB, to be found on 5q14, encoding for arylsulfatase B
• MPS type 7 - GUSB, to be found on 7q11.21, encoding for glucuronidase β
• MPS type 9 - HYAL1, to be found on 3p21.31, encoding for hyaluronidase 1

The overall incidence of MPS has been estimated to be 1 in 25,000 life births [5] [6]. Still, the incidence rates vary greatly between distinct types of MPS. The most common type of MPS is MPS type 2, which may account for more than half of all cases [5]. The least common type of MPS is MPS type 9. This disease has been described by Natowicz et al. in 1996, and only four patients have been reported to date [12] [13] [14].

While both males and females may be affected by MPS, MPS type 2 is generally diagnosed in males. This is because the causal mutation is located on the X-chromosome. Nevertheless, heterozygous females have been described to present symptoms characteristic of this type of MPS [5].

Glycosaminoglycans are to found on the cell surface and in the extracellular matrix. They are involved in a myriad of physiological processes, e.g., in ligand-receptor interaction and cell proliferation. In the central nervous system, they are required as promoters of neurogenesis and enhancers of synaptic plasticity. Eventually, they are taken up by endocytosis or autophagy, and the respective vesicles fuse with lysosomes. Glycosaminoglycans may be recycled or degraded in lysosomes, namely be those enzymes that are deficient in MPS patients. Thus, undegraded or partially degraded substrates accumulate in the lysosomes, which initially causes the dysfunction of that organelle but eventually interferes with the function of the whole cell [9].

Via the bloodstream, poorly degraded glycosaminoglycans may reach virtually all tissues and organs. Therefore, all types of MPS are multisystem diseases, even though the activity of the affected enzyme is physiologically limited to determined types of cells [5]. Furthermore, glycosaminoglycans have been speculated to induce the secretion of cytokines, which may mediate degenerative joint disorders [9].

Genetic counseling should be offered to affected families, and they should be informed that both a child's genotype and phenotype can be determined prenatally. However, prenatal screens for MPS are not carried out on a routine basis and in the absence of a positive family history, parents may not be aware they carry a pathogenic mutation. Indeed, more than one-fifth of IDS mutations, which account for MPS type 2, are de novo mutations [8]. In this context, and because an early diagnosis is crucial for an optimum outcome, newborn screenings for MPS and other lysosomal storage diseases have been proposed in distinct countries, but no consensus has yet been reached on how to achieve high sensitivity, high specificity, and cost-effectiveness. While some authors prefer the assessment of enzyme activities [15], others favor the measurement of glycosaminoglycan concentrations in blood samples [16]. At the same time, costly follow-ups of false-positive cases have to be avoided [17].

MPS refers to a group of heterogeneous metabolic disorders. Affected individuals carry mutations of one of eleven genes that encode for lysosomal enzymes involved in the breakdown of glycosaminoglycans. Glycosaminoglycans are - usually highly sulfated - polysaccharides comprising disaccharide repeats, and they may also be referred to as mucopolysaccharides. The type of disaccharide to be found in glycosaminoglycans varies and is the basis of their classification as heparin sulfate/heparan sulfate, chondroitin sulfate/dermatan sulfate, keratan sulfate or non-sulfated hyaluronan. Glycosaminoglycans are part of the synovial fluid, the articular cartilage and bones, of heart valves, cornea and vitreous humor as well as mast cell granules, among others. In MPS patients, they progressively accumulate in the respective tissues but eventually reach the bloodstream and are excreted in urine. Therefore, additional tissues and distant organs are generally involved in the disease, and urine analyses are very useful in MPS diagnostics.

A total of seven types of MPS are distinguished to date, namely MPS types 1 to 9, except for types 5 and 8, which are no longer considered distinct entities. It should be noted that subtypes are differentiated in case of MPS type 1 (Scheie syndrome, Hurler Scheie syndrome, Hurler syndrome), MPS type 3 (Sanfilippo syndromes A to D), and MPS type 4 (types 4A and 4B, which are also referred to as Morquio A and Morquio B). MPS types 6 and 7 are also known as Maroteaux-Lamy syndrome and Sly syndrome, respectively. MPS type 9 is a rare entity that may also be referred to as Natowicz syndrome. All types of MPS have been associated with determined genetic defects, so molecular biological studies have become the gold standard for their diagnosis.

Mucopolysaccharidosis (MPS) is a general term referring to a group of hereditary disorders. The cells of MPS patients are unable to properly degrade glycosaminoglycans, compounds to be found in joints and bones, heart valves, ocular tissues and others. This is due pathogenic mutations of those genes that encode for the enzymes required for the breakdown of glycosaminoglycans. Consequently, glycosaminoglycans - which may also be referred to as mucopolysaccharides - accumulate within cells, reach the bloodstream, are distributed throughout the body, and interfere with the function of multiple tissues and organs.

The spectrum of disease presentation is broad. The clinical hallmarks of MPS are mental retardation, short stature and further anomalies of the skeleton, and visual impairment, but between individual patients, there are considerable differences regarding the symptoms and their severity. Thus, the diagnosis cannot be made based on clinical findings alone. Because glycosaminoglycans are excreted in urine, the analysis of urine samples is very useful in the workup of a suspected case. The tentative diagnosis can be confirmed once the activity of the deficient lysosomal enzyme is measured or the underlying mutation is determined.

Treatment options depend on the type of MPS. There are at least seven variants of the disease, and enzyme replacement therapy is available for only three of them. Patients suffering from severe MPS may undergo hematopoietic stem cell transplantation, but the procedure is associated with significant morbidity and mortality. New therapeutic approaches are substrate reduction therapy and gene therapy, but to date, they remain in the experimental stage. In sum, the prognosis of an individual patient largely depends on the severity of their disease: While those affected by mild MPS may have a near-to-normal life expectancy, severe MPS is often fatal before adulthood.

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