In general, MPS 1 is a multisystem disorder that follows a progressive course. Although coarse facial features, short stature, skeletal dysplasia reminiscent of dysostosis multiplex, cardiac and respiratory disease as well as corneal clouding are universal, there are considerable differences regarding the clinical presentation of MPS-IS and MPS-IH patients. These especially refer to the involvement of the central nervous system and corresponding deficits. Thus, these entities shall be presented separately.

Clinical presentation is particularly heterogeneous in MPS-IS patients. Median age at symptom onset is 5 years, but due to rather mild symptoms and insufficient awareness of the disease, most patients are not diagnosed with MPS-IS until late adolescence [3]. Joint contractures, cardiac valve abnormalities and corneal clouding are most frequently reported and about half of MPS-IS patients present the complete symptom triad [7]. Further common findings are coarse facial features, carpal tunnel syndrome, umbilical and inguinal hernia, and hepatomegaly. Bone deformities like kyphosis or gibbus, scoliosis, genu valgum, pes cavus have been described and may cause gait disturbances. Sleep disturbances due to respiratory insufficiency may be experienced and patients may claim a hearing loss. Some patients present with macroglossia. Patients may develop myelopathy, but this condition does generally not manifest before puberty. MPS-IS patients are of normal intelligence; the absence of cognitive developmental delays at the age of two years has been proposed as a clinical feature to distinguish MPS-IS from MPS-IH.

Children suffering from MPS-IH develop first symptoms during their first year of life, and the disease is usually confirmed within months afterwards [3]. Affected individuals may present with any of those symptoms listed for MPS-IS. However, disease progression occurs rapidly and additional symptoms manifest early in life. The major difference between MPS-IH and less severe forms of the disease is profound intellectual disability due to neuronal loss, premature closure of cranial sutures, and possibly hydrocephalus and increased intracranial pressure. Developmental delays, hearing loss and macroglossia contribute to severely reduced language acquisition. Coarse facial features are more pronounced than in MPS-IS patients and may be accompanied by facial and body hypertrichosis. Besides corneal clouding, glaucoma and retinopathy may develop and may eventually cause complete vision loss. Of note, visual impairment may also result from central nervous system involvement. Skeletal dysplasia is striking and although neonates may appear healthy, radiographic studies may reveal signs of dysostosis multiplex at birth. Atlantoaxial subluxation and stenosis of the spinal canal are observed in about a third of MPS-IH patients and results in spinal cord compression and early cervical myelopathy [8]. Vertebral hypoplasia may be observed along the spinal column.

• Splenomegaly

  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]

  Common features were hepatomegaly (80, 88.89%), coarse facies (70, 77.78%), splenomegaly (67, 74.44%), and bone disease (48, 53.33%). CONCLUSION: Most common variety of mucopolysaccharidosis was Hurler/Hurler Scheie followed by Morquio syndrome. [ncbi.nlm.nih.gov]

  […] 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]

• Short Stature

  Patients present with short stature, flat nasal bridge, and joint findings. Urine GAGs are normal in MPS IX. [neurology.testcatalog.org]

  Symptoms of MPS IX are periodically painful soft tissue masses around the joints, acquired short stature and erosion of the hip joint, although joint movement and intelligence are normal (Natowicz et al. 1996, Triggs-Raine et al. 1999). [reactome.org]

  MPS II is found almost exclusively in young males and is clinically characterized by short stature, hepatosplenomegaly, joint contractures, and coarse facies. [centogene.com]

  […] forehead, joint stiffness, and short stature; upper airway obstruction, recurrent ear infections, noisy breathing, and persistent nasal discharge; hirsutism, hearing loss, hydrocephalus, and mental retardation MPS I-H/S - Milder features; normal intelligence [emedicine.medscape.com]

• Developmental Delay

  Analyzes chromosomes in newborns and infants for changes that can explain certain birth defects or developmental delays. Multiple testing options providing information on the genetic health of your baby during the first and second trimesters. [integratedgenetics.com]

  Those suffering from the most severe form of the disease, which may be referred to as Hurler syndrome, also show developmental delays and intellectual disability. [symptoma.com]

  In general, symptoms may include coarse facies, short stature, enlarged liver and spleen, hoarse voice, stiff joints, cardiac disease, and profound neurologic involvement leading to developmental delays and regression. [neurology.testcatalog.org]

• Coarse Facial Features

  Further common findings are coarse facial features, carpal tunnel syndrome, umbilical and inguinal hernia, and hepatomegaly. [symptoma.com]

  facial features Communicating hydrocephalus (fluid on the brain) Abnormally shaped teeth Life expectancy Life expectancy varies significantly for people with MPS I. [mps1disease.com]

  […] 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 behavior MPS II (mild form) – Similar features [emedicine.medscape.com]

  Symptoms may include DWARFISM; hepatosplenomegaly; thick, coarse facial features with low nasal bridge; corneal clouding; cardiac complications; and noisy breathing. [finto.fi]

• Inguinal Hernia

  hernia, umbilical hernia, multiple dysostosis, hepatosplenomegaly and difficulty in breathing; surgical history: right inguinal herniorrhaphy, umbilical herniorrhaphy, changes compatible with mucopolysaccharidosis (MPS) type VI. [revistamedicina.net]

  Inguinal hernia Hearing loss Recurrent ear infections Corneal clouding Carpal tunnel syndrome Narrowing of the spinal canal (spinal stenosis) Heart valve abnormalities, which can lead to heart failure Short stature Joint deformities (contractures) Dysostosis [rarediseases.info.nih.gov]

• Recurrent Respiratory Infection

  respiratory infections Frequent respiratory infections Multiple respiratory infections respiratory infections, recurrent Susceptibility to respiratory infections [ more ] 0002205 Retinopathy Noninflammatory retina disease 0000488 Sensorineural hearing [rarediseases.info.nih.gov]

• Respiratory Insufficiency

  Sleep disturbances due to respiratory insufficiency may be experienced and patients may claim a hearing loss. Some patients present with macroglossia. Patients may develop myelopathy, but this condition does generally not manifest before puberty. [symptoma.com]

  Clinical features and severity of symptoms of MPS IVA are widely variable, but may include skeletal dysplasia, short stature, dental anomalies, corneal clouding, respiratory insufficiency, and cardiac disease. Intelligence is usually normal. [neurology.testcatalog.org]

• Hoarseness

  In general, symptoms may include coarse facies, short stature, enlarged liver and spleen, hoarse voice, stiff joints, cardiac disease, and profound neurologic involvement leading to developmental delays and regression. [neurology.testcatalog.org]

  Vocal cords can also enlarge, resulting in a deep, hoarse voice. 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). [ghr.nlm.nih.gov]

• Rhinorrhea

  Half patients showed a rhinorrhea complaint, mostly in an intermittent (77.8%) and yellowed (55%) way. The main type of UA infection was acute otitis media. Hearing loss was a symptom in only 9 cases (45%). [arquivosdeorl.org.br]

  Rhinorrhea is common. Sleep apnea as a result of obstructive airway disease and possibly CNS involvement occurs in attenuated MPS I. Gastrointestinal system. [ncbi.nlm.nih.gov]

• Hepatosplenomegaly

  Symptoms may include dwarfism, hepatosplenomegaly, gargoyle-like facies, corneal clouding, cardiac complications, and noisy breathing. [icd10data.com]

  Symptoms may include DWARFISM, hepatosplenomegaly, gargoyle-like facies, corneal clouding, cardiac complications, and noisy breathing. [hon.ch]

• Hepatomegaly

  Sistemik muayenede korneal bulutlanma (11 olgu) işitme kaybı (5 olgu), hepatomegali (4 olgu), adenoid hipertrofi (opere edilmiş 4 olgu), kardiyak tutulum (9 olgu), tüm hastalarda kemik incelemede disostozis multipleks bulguları saptandı. [egetipdergisi.com.tr]

  Common features were hepatomegaly (80, 88.89%), coarse facies (70, 77.78%), splenomegaly (67, 74.44%), and bone disease (48, 53.33%). CONCLUSION: Most common variety of mucopolysaccharidosis was Hurler/Hurler Scheie followed by Morquio syndrome. [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]

  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]

  In addition, there were improvements in hepatomegaly, sleep apnoea and hypopnoea. [cochrane.org]

• Hydrops Fetalis

  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]

  The most severe form is characterized by hydrops fetalis and premature or very early death. [centogene.com]

  In its rarest form, Sly syndrome causes children to be born with hydrops fetalis, in which extreme amounts of fluid are retained in the body. Survival is usually a few months or less. Most children with Sly syndrome are less severely affected. [en.wikipedia.org]

  Hydrops fetalis Mild to moderate mental retardation by age 3 Communicating hydrocephalus Nerve entrapment Corneal clouding Some loss of peripheral and night vision Short stature Some skeletal irregularities Joint stiffness and restricted movement Umbilical [wikidoc.org]

• Myelopathy

  Patients may develop myelopathy, but this condition does generally not manifest before puberty. [symptoma.com]

  The effect on the skeletal system is the main finding and there is a high risk of cervical myelopathy due to odontoid hypoplasia and severe neurological complication due to atlantoaxial subluxation. [egetipdergisi.com.tr]

  Odontoid hypoplasia is the most serious skeletal finding because, in combination with ligamentous laxity and mucopolysaccharide deposition, it may result in atlantoaxial subluxation, cervical myelopathy or even death. [genedx.com]

  […] multilevel myelopathy affecting both cervical and thoracolumbar spinal regions. [ajnr.org]

• Sleep Disturbance

  Bone deformities like kyphosis or gibbus, scoliosis, genu valgum, pes cavus have been described and may cause gait disturbances. Sleep disturbances due to respiratory insufficiency may be experienced and patients may claim a hearing loss. [symptoma.com]

  We report herein a pediatric case of ADHD who was admitted to pediatric psychiatry several times for sleep disturbances, hyperactivity and speech delay and to pediatric emergency department with corrosive substance ingestion and diagnosed as MPS III B [anadolupsikiyatri.net]

  The MPS I registry reports the following findings in individuals with Hurler syndrome[2]: Coarse facial features (86.4%) Corneal clouding (70.9%) Heaptomegaly (70.0%) Kyphosis/gibbus (70.0%) Hernias (58.9%) Airway-related symptoms, such as sleep disturbances [oncofertility.northwestern.edu]

  The major features of MPS III include the following: Onset of symptoms is usually between 2 and 6 years Presenting symptoms include hyperactive, aggressive and destructive behaviors and sleep disturbances Mental development abnormalities starts slowly [centogene.com]

• Abnormal Gait

  Hypermobile joints and an abnormal gait with a tendency to fall may also be presenting features. Unlike other mucopolysaccharidoses (MPS) intelligence is often preserved. [genedx.com]

  There was marked hepatosplenomegaly with coarse facies and abnormal gait. Intelligence and development was appropriate for age. [sajr.org.za]

• Psychomotor Regression

  Most patients have shown an arrest or slowing down of psychomotor regression. However, dysostosis multiplex has progressed. [adc.bmj.com]

• 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]

  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]

  including runny nose, sinus infections, and sleep apnea Ear infections and hearing loss Numbness and tingling in fingers or feet Heart disease Stiff joints and trouble moving Hernias, which look like a bulge around the belly button or in the groin Diarrhea [webmd.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]

• Macroglossia

  Macroglossia was also verified in almost 100% of cases, pronounced in 40%. MPS II and VI patients showed a more pronounced macroglossia and all type I patients showed only slight macroglossia (Graphic 2). [arquivosdeorl.org.br]

  Some patients present with macroglossia. Patients may develop myelopathy, but this condition does generally not manifest before puberty. [symptoma.com]

  DS, HS α-L-Iduronidase MPS I H/S Hurler-Scheie syndrome Intermediate phenotype, macrocephaly, macroglossia, joint limitations. [hindawi.com]

  […] 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), and a large tongue (macroglossia [ghr.nlm.nih.gov]

• 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]

• Hypertrichosis

  Coarse facial features are more pronounced than in MPS-IS patients and may be accompanied by facial and body hypertrichosis. Besides corneal clouding, glaucoma and retinopathy may develop and may eventually cause complete vision loss. [symptoma.com]

  Excessive hair growth (hypertrichosis) of the face and body can also occur, although scalp hair may be coarse and straight, resembling thatch or straw. [rarediseases.org]

• Corneal Opacity

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

  Tukey's multiple comparison test demonstrated a statistically significant difference in IOP between the mild and severe corneal opacity groups, but not between mild and moderate, or moderate and severe corneal opacity groups. [nature.com]

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

• Visual Impairment

  Ocular manifestations are common in the mucopolysaccharidoses and may result in significant visual impairment. [ncbi.nlm.nih.gov]

  This may perhaps reflect the low incidence of retinopathy in MPS VI, or be attributed to nonocular causes of visual impairment in MPS I patients such as cortical visual impairment. [nature.com]

  Of note, visual impairment may also result from central nervous system involvement. Skeletal dysplasia is striking and although neonates may appear healthy, radiographic studies may reveal signs of dysostosis multiplex at birth. [symptoma.com]

  It is characterized by normal intelligence and stature; however, affected individuals do experience joint involvement, visual impairment, and obstructive airway disease. [neurology.testcatalog.org]

• Hearing Impairment

  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]

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

  The severe form of MPS I is known as Hurler syndrome or MPS I H : Children affected with the severe form may have mental retardation, short stature, stiff joints, speech and hearing impairment, heart disease, and a shortened lifespan. [verywell.com]

  The girl had hearing impairment for which she was provided a hearing aid. The facial features included oblique palpebral fissures, flat nasal bridge, flared nose, and a large mouth with broad lips. [jisppd.com]

  […] of MPS I:[1] Enlarged head, lips, cheeks, tongue, and nose Enlarged vocal cords, resulting in a deep voice Frequent upper respiratory infections Sleep apnea Hydrocephalus Hepatosplenomegaly (enlarged liver and spleen) Umbilical hernia Inguinal hernia Hearing [rarediseases.info.nih.gov]

• Hearing Problem

  Facial features become apparent during the first year, followed by widespread skeletal problems. By the age of three growth usually slows down significantly and intellectual and hearing problems become apparent. [verywell.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

  […] 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]

  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]

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

  These may include joint stiffness, heart problems, corneal clouding and hearing loss. Individuals with Hurler/Scheie syndrome usually have variable clinical symptoms of intermediate severity between the mildest and most severe forms of MPS I. [luriechildrens.org]

  Orthopedic-Bone Changes Short neck, joints stiffness [47], odontoid instability [48], hypo plastic mandible, thoracic cage restriction for kyphoscoliosis [24]. [hindawi.com]

• Macrocephaly

  Symptoms include, macrocephaly, excessive accumulation of fluid in the brain, hepatosplenomegaly, sleep apnea, cornea clouding, spinal cord compression and cognitive impairment. Severe MPS I occurs in approximately 1 in 100,000 newborns. [raredr.com]

  The phenotype varies significantly from mild to severe presentations and may include macrocephaly, short stature, dysostosis multiplex, hepatomegaly, coarse facies, and impairment of cognitive function. [neurology.testcatalog.org]

  Some symptoms (hernia, macrocephaly, respiratory infections, and limited hip abduction) become apparent early in infancy but the complete clinical picture develops during the second year of life.mucopolysaccharidosis (mps) i-s synonyms: scheie syndrome [icd10data.com]

  DS, HS α-L-Iduronidase MPS I H/S Hurler-Scheie syndrome Intermediate phenotype, macrocephaly, macroglossia, joint limitations. [hindawi.com]

• Genu Valgum

  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]

  Bone deformities like kyphosis or gibbus, scoliosis, genu valgum, pes cavus have been described and may cause gait disturbances. Sleep disturbances due to respiratory insufficiency may be experienced and patients may claim a hearing loss. [symptoma.com]

  Clinical features related to bone lesions may include marked short stature, cervical stenosis, pectus carinatum, small lungs, joint rigidity (but laxity for MPS IV), kyphoscoliosis, lumbar gibbus, and genu valgum. [novapublishers.org]

  valgum, hypermobile joints Waddling gait with frequent falls Qualitative urine glycosaminoglycan (GAG) analysis demonstrates keratan sulfate and chondroitin 6-sulfate. [centogene.com]

• Joint Deformity

  Some individuals with MPS I have short stature and joint deformities (contractures) that affect mobility. Most people with the severe form of the disorder also have dysostosis multiplex, which refers to multiple skeletal abnormalities seen on x-ray. [ghr.nlm.nih.gov]

  This treatment can also improve other features such as cardiac, facial appearance, liver and spleen enlargement, joint symptoms, and hearing symptoms. However, significant bone, joint, and heart valve disease may still occur despite HSCT. [newbornscreening.info]

  […] hand Claw hand Claw hand deformities Claw hands Claw-hand deformities Split-hand [ more ] 0001171 30%-79% of people have these symptoms Abnormal nasal morphology Abnormal of nasal shape Abnormal of shape of nose [ more ] 0005105 Abnormality of the hip [rarediseases.info.nih.gov]

• Arthralgia

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

  Less commonly reported infusion reactions included nausea, diarrhea, feeling hot or cold, vomiting, pruritus, arthralgia and urticaria. Additional common adverse reactions included, back pain and musculoskeletal pain. [aldurazyme.com]

  ] 0001171 30%-79% of people have these symptoms Abnormal nasal morphology Abnormal of nasal shape Abnormal of shape of nose [ more ] 0005105 Abnormality of the hip bone Abnormality of the hips 0003272 Abnormality of the tonsils 0100765 Apnea 0002104 Arthralgia [rarediseases.info.nih.gov]

• Short Neck

  Airway evaluation: abnormal neck anatomy, short neck with limited mobility, hyromental and thyromentonian distance less than 6 cm, severely limited jaw protrusion, mouth opening inferior to 6 cm, mallampati IV and snoring. [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]

  On examination, child had dysmorphic features such as frontal bossing, hypertelorism, saddle nose, low-set ears, macroglossia, short stature, short neck, kyphosis of lumbar spine, pigeon chest, widening of wrist, bowing of legs, doubling of malleoli, [jcor.in]

  Features include short-trunk dwarfism, short neck, joint hypermobility, respiratory disease, cardiac disease, impaired vision with corneal clouding, hearing loss, dental abnormalities, hepatomegaly, and elevated urinary keratan sulfate. [invitae.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]

  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]

  […] vermilion border Full lips Increased volume of lip Plump lips Prominent lips Thick lips [ more ] 0012471 Thickened skin Thick skin 0001072 Tracheal stenosis Narrowing of windpipe 0002777 Umbilical hernia 0001537 Showing of 66 | Last updated: 3/1/2020 [rarediseases.info.nih.gov]

• Hypertelorism

  On examination, child had dysmorphic features such as frontal bossing, hypertelorism, saddle nose, low-set ears, macroglossia, short stature, short neck, kyphosis of lumbar spine, pigeon chest, widening of wrist, bowing of legs, doubling of malleoli, [jcor.in]

  In a significant number of cases,2,9 the initial diagnosis might be suspected from the ENT consultation with a special emphasis on anamnesis and examination (prominent torus frontalis, hypertelorism, sunken nasal dorsum, anteverted nostrils, thickened [elsevier.es]

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

  Patients present with characteristic coarse facial features, hypertelorism, and a flattened nasal dorsum. [jamanetwork.com]

• Frontal Bossing

  Radiology of skull, face, chest, long bones, and spine showed short stubby small bones, frontal bossing, thick ribs, thickened metaphyses of long bones, spinal thoracolumbar kyphosis highly suggestive of MPS (type IV). [jcor.in]

  X-ray of the skull showed frontal bossing with J-shaped sella (Figs 1B and 1C). [sajr.org.za]

  Scaphocephaly, thickened calvarial bones with increased density, omega-shaped sella, frontal bossing, underpneumatisation of paranasal sinuses. 2. Inferior beaking of the vertebral bodies, focal kyphosis at thoracolumbar junction.3. [ijaweb.org]

• Coarse Face

  Initial diagnosis was made at MediScan system, Fetal Care and Research Foundation, Mylapore, Chennai, in the light of clinical findings like coarse face, low nasal bridge, and the following radiographic findings which included spatulated ribs, gibbus [jisppd.com]

Most patients suffering from MPS 1 have a family history of complaints consistent with this disease. Even if such data are not available, findings of general, ophthalmological and neurological examination, as well as radiographic studies, may prompt a strong suspicion of mucopolysaccharidosis. Clinical features of distinct types of mucopolysaccharidosis may overlap, though, and a target-oriented workup is necessary. The assessment of glycosaminoglycan excretion in urine is helpful to diagnose and distinguish related entities. Qualitative and quantitative analyses should be performed; MPS 1 patients typically excrete excess dermatan and heparan sulfate. However, this approach has limited sensitivity and it is strongly recommended to either determine IDUA activity or to employ molecular biological techniques to demonstrate gene defects consistent with MPS 1. With regards to the former, IDUA activity may be evaluated in leukocytes, dried blood spots or fibroblasts. Recently, a modified IDUA assay has been described that allows for the precise quantification of residual IDUA activity, and such results may enable the physician to predict the course of the disease [5].

• Enlargement of the Spleen

  Stiffened joints Skeletal (bone) Carpal tunnel syndrome Heart (valve) disease Recurrent upper airway infections Lung disease/sleep apnea Corneal clouding Spinal cord compression Enlarged liver and spleen Hernia (inguinal or umbilical) Hearing loss Delayed [mps1disease.com]

  Symptoms of MPS I + MPS II Abnormal bones, including shortened stature and spine problems Intellectual disabilities Heart disease Enlarged liver and spleen Joint stiffness Vision or hearing loss Depression Chronic Pain Shortened lifespan Prevalence / [sangamo.com]

  In general, symptoms may include coarse facies, short stature, enlarged liver and spleen, hoarse voice, stiff joints, cardiac disease, and profound neurologic involvement leading to developmental delays and regression. [neurology.testcatalog.org]

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

• Enlargement of the Liver

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

Enzyme replacement therapy and hematopoietic stem cell transplantation are the mainstays of treatment of attenuated MPS 1 and MPS-IH, respectively. Hematopoietic stem cell transplantation has been shown to improve the neurological outcome and to increase survival times in patients suffering from the most severe form of the disease. Nevertheless, long-term follow-ups revealed disease progression years after the successful realization of this procedure [6]. Stem cell transplantation should be performed as early as possible, ideally in infants aged less than four months. Due to morbidity and mortality associated with this therapeutic measure, it is currently not recommended for MPS-IHS and MPS-IS patients. Enzyme replacement therapy consists of weekly administration of 100 U/kg recombinant IDUA (laronidase; Aldurazyme®) per kg body weight; this compound has obtained approval for MPS 1 treatment in 2003 [9]. Patients should be prepared for intravenous laronidase application with antihistamines and/or antipyretics that are to be administered one hour prior to treatment with recombinant IDUA. Of note, laronidase is also given to patients diagnosed with MPS-IH after stem cell transplantation. Although the compound does not cross the blood-brain barrier and thus cannot prevent glycosaminoglycan accumulation within the central nervous system, it is likely to have a positive effect on the patient's quality of life [10].

In any case, supportive care should be provided to MPS 1 patients. It should be adjusted to the individual needs of the affected person and may comprise physiotherapy, orthopedic measures, provision of hearing aids, analgesia, prophylactic administration of antibiotics, supplementation of oxygen, and psychological support. Surgical interventions may become necessary to remedy joint contractures, skeletal deformities, cardiac valve insufficiency or stenosis, spinal cord compression, and other pathological conditions. A multidisciplinary team is required to support the patient and their family, and this team should be consulted in regular follow-ups. Periodic performance of pulmonary function tests, echocardiography, and neurological evaluation, among others, are of major importance to estimate disease progression and the patient's risk of complications.

As has been indicated above, only confirmation of nonsense mutations on both alleles allows for the prediction of a patient’s phenotype from their genotype. If so, the patient is likely to develop MPS-IH. Otherwise, the heterogeneity of underlying phenotypes has not yet allowed for establishing unequivocal genotype-phenotype correlation [2]. In contrast, residual activity of IDUA directly correlates with the outcome. Quantification of low IDUA activity requires a very sensitive assay, but has been achieved: Dutch researchers have proven MPS-IS patients to show residual IDUA activity of 0.8% of control values, while MPS-IHS and MPS-IH were associated with a residual activity of 0.3% and <0.2%, respectively [5]. Still, more extensive studies on this subject are required to provide general reference ranges.

Patients suffering from MPS-IS may have a near-to-normal life expectancy, but the disease is still associated with considerable morbidity. Individuals affected by MPS-IHS often die in early adulthood. To date, the prognosis of MPS-IH patients is poor. Most patients die within their first decade of life from respiratory or heart failure. Hematopoietic stem cell transplantation is the treatment of choice, and if performed at a very young age when cognitive function is not yet impaired, this therapy may improve survival and neurodevelopment [6].

All forms of MPS 1 are caused by mutations in the IDUA gene. This gene is located on the short arm of chromosome 4 and encompasses approximately 18 kb, which include 14 exons that are assembled to a 653-amino acid precursor protein. To date, more than 200 distinct mutations have been described in MPS 1 patients [1]. The majority of known sequence anomalies corresponds to missense mutations, while nonsense mutations and gene variants leading to alternative splicing, deletions and insertions account for minor shares of MPS 1-related defects [2]. Genotype-phenotype correlations have been established insofar as nonsense mutations generally trigger MPS-IH; affected patients carry such mutations on both alleles and are unable to synthesize functional IDUA. In contrast, residual activity of IDUA may be detected in patients with missense mutations of the respective gene, and it may attenuate the severity of the disease. In this context, only trace amounts of functional IDUA are encountered in MPS-IHS patients, while enzymatic activity is maintained to a greater degree in MPS-IS patients. According to the current knowledge, enzymatic activity as assessed in an individual patient determines the course of the disease. Moreover, modifying factors have not been identified so far; all forms of the disease are inherited as an autosomal recessive trait.

The overall incidence of MPS 1 has been estimated to 1 in 100,000 live births [3]. About 61% of affected neonates develop MPS-IH, while MPS-IHS and MPS-IS account for 23% and 13% of all cases, respectively. In the cited study, the remainder of cases was classified as undetermined. While Caucasians were overrepresented in the MPS 1 Registry, this may be due to most study participants being Europeans or North Americans. A literature review reveals that people of all races and both genders may be affected by the disease.

IDUA is a lysosomal enzyme catalyzing the hydrolytic cleavage of dermatan sulfate and heparan sulfate. In MPS 1 patients, IDUA activity is severely reduced and thus, glycosaminoglycans accumulate in lysosomes. This condition initially disturbs lysosomal function, but the progressive enlargement of these cell organelles eventually has detrimental consequences for the whole cell and the tissue it forms part of. Furthermore, glycosaminoglycans may alter gene expression and thus affect the composition of the extracellular matrix. Recent studies have shown such pathophysiological events to be involved in MPS 1-associated cartilage and bone damage [4], but it is tempting to speculate that these mechanisms also contribute to lesions of other organs. In fact, inappropriate accumulation of dermatan sulfate and heparan sulfate is mainly observed in connective tissue and the wide distribution of connective tissue in the human body explains why affected individuals develop multisystem sequelae.

Affected families may benefit from genetic counseling. Furthermore, chorionic villus sampling and amniocentesis allow obtaining specimens suitable for enzyme activity assessment and genetic screens. Thus, prenatal diagnosis of MPS 1 is feasible. In the case of positive results, parents-to-be may be offered the possibility of a premature termination of pregnancy. Neonates born to families with a history of MPS 1 should be tested as early as possible. This way, treatment may be initialized before irreversible organ damage occurs. This is of particular importance for individuals suffering from MPS-IH since this disease requires hematopoietic stem cell transplantation within the first months of life. With regards to milder forms of the disease, pediatricians are encouraged to realize regular examinations, to monitor development and growth, and to refer their patients to specialists if doubts arise.

Mucopolysaccharidosis 1, also referred to as MPS 1, is a lysosomal storage disease. MPS 1 is inherited as an autosomal recessive trait and is triggered by distinct mutations of the gene encoding for the enzyme α-L-iduronidase (IDUA). This enzyme is expressed in lysosomes and catalyzes the breakdown of determined glycosaminoglycans, namely of dermatan sulfate and heparan sulfate. In MPS 1 patients, a functional deficiency of α-L-iduronidase results in the progressive accumulation of glycosaminoglycans in lysosomes, and this condition eventually interferes with cellular, tissue and organ functions. Because this entity affects virtually all organ systems, affected individuals may present complex and heterogeneous symptoms. Depending on the severity of the disease, the following forms of MPS 1 may be distinguished:

• Scheie syndrome (MPS-IS) follows a chronic but relatively mild course and patients primarily present with skeletal, cardiac and ocular symptoms.
• Hurler Scheie syndrome (MPS-IHS) describes an intermediate form of MPS 1.
• Hurler syndrome (MPS-IH) is the most severe form of MPS 1 and patients additionally experience symptoms of central nervous system compromise.

Of note, MPS-IS and MPS-IHS correspond to attenuated MPS 1.

Mucopolysaccharidosis 1 (MPS 1) is a rare genetic disorder. It is provoked by mutations of the gene encoding for the enzyme α-L-iduronidase (IDUA), and this enzyme is required for the breakdown of determined glycosaminoglycans, namely of dermatan sulfate and heparan sulfate. These may be encountered in virtually any tissue and because MPS 1 patients are unable to synthesize functional IDUA, these molecules accumulate within cell organelles called lysosomes. In fact, MPS 1 is commonly classified as a lysosomal storage disease. Eventually, build up of glycosaminoglycans interferes with cellular, tissue and organ function. This leads to complex and heterogeneous symptoms, and MPS 1 patients may present with coarse facial features, short stature, skeletal dysplasia, cardiac and respiratory disease as well as corneal clouding. Those suffering from the most severe form of the disease, which may be referred to as Hurler syndrome, also show developmental delays and intellectual disability.

Hematopoietic stem cell transplantation in early infancy is recommended to patients diagnosed with Hurler syndrome, and these individuals may subsequently receive recombinant IDUA. The latter replaces the defective enzyme and thus allows for partial degradation of glycosaminoglycans. Thereby, the patient's quality of life is improved. Unfortunately, there is no cure for MPS 1 and while mild forms of the disease are associated with a near-to-normal life span, they are also related to significant morbidity. Patients diagnosed with Hurler syndrome may live to their twenties if hematopoietic stem cell transplantation is performed early and successfully.

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