eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Mucopolysaccharidosis Type IV

Nancy E Braverman, MS, MD, Associate Professor, Department of Human Genetics, McGill University
Shunji Tomatsu, MD, PhD, Professor, Department of Pediatrics, Saint Louis University School of Medicine

Updated: Apr 21, 2009

Introduction

Background

Morquio syndrome (mucopolysaccharidosis type IV) is a member of a group of inherited metabolic disorders collectively termed mucopolysaccharidoses (MPSs). The MPSs are caused by a deficiency of lysosomal enzymes required for the degradation of mucopolysaccharides or glycosaminoglycans (GAGs). Eleven distinct single lysosomal enzyme deficiencies are known to cause 7 recognized phenotypes of MPS. All the MPSs are inherited in an autosomal recessive fashion except Hunter syndrome (MPS type II), which is X-linked.

In the early 1900s, Hunter and Hurler first described patients with MPS, whose diseases now bear their names; subsequent MPSs have been assigned numbers and eponyms loosely associated with the chronology and origin of their report.

In 1929, Morquio, a pediatrician in Uruguay, and Brailsford, a radiologist in England, simultaneously described cases of what is now believed to be Morquio syndrome. In the early 1930s, Husler coined the term dysostosis multiplex to describe the constellation of skeletal findings specific to patients with MPS and other lysosomal storage disorders. These included a large skull with a J-shaped sella, anterior hypoplasia of the thoracic and lumbar vertebral bodies, hypoplasia of the pelvis with small femoral heads and coxa valga, oar-shaped ribs (narrow at the vertebrae and widening anteriorly), diaphyseal and metaphyseal expansion of long bones with cortical thinning, and tapering of the proximal phalanges. However, this family of diseases was not described as the MPSs until 1952, when Brante isolated the stored mucopolysaccharides in these patients.

In 1957, Dorfman and Lorincz developed clinical assays to detect urinary mucopolysaccharides. The work of Neufeld et al from the late 1960s demonstrated that mucopolysaccharide accumulation in fibroblasts from patients with Hurler and Hunter syndromes could be corrected by co-culturing them with fibroblasts or tissue extracts from patients with a different MPS. This led to the purification and subsequent identification of each defective enzyme.

The MPSs share a chronic progressive course with multisystem involvement, several physical features, laboratory findings, and radiographic abnormalities; these include facial coarsening, hepatomegaly, excretion of urinary GAG fragments, and leukocyte inclusion bodies. Patients with Morquio syndrome (mucopolysaccharidosis type IV) can usually be clinically distinguished from patients with other MPSs because they do not have coarse facial features or mental retardation and they have additional skeletal manifestations derived from a unique spondyloepiphyseal dysplasia and ligamentous laxity. These skeletal manifestations include odontoid hypoplasia, a striking short trunk dwarfism, and genu valgus.

Compared with other patients who have MPS, those with Morquio syndrome (mucopolysaccharidosis type IV) tend to have greater spine involvement with scoliosis, kyphosis, and severe gibbus, as well as platyspondyly, rib flaring, pectus carinatum, and ligamentous laxity. Odontoid hypoplasia is the most critical skeletal feature to recognize in any patient with Morquio syndrome (mucopolysaccharidosis type IV).

The individual on the front of the scooter is 19 years old and has Morquio syndrome. Her friend on the back is an average-stature 10 year old without Morquio syndrome. On the driver, note the enlargement at the knees and the wrist deformity. Also, note the successful adaptation of the scooter to ambulate.

Note the short trunk and protuberant rib structure in this child with Morquio syndrome. More importantly, notice that Morquio syndrome is not preventing this child from being active and fishing.

Pathophysiology

Dermatan sulfate, heparan sulfate, keratan sulfate (KS), and chondroitin sulfate are the main GAGs in tissues. They are composed of sulfated sugar and uronic acid residues (except for KS, which is mainly composed of galactose 6-sulfate alternating with sulfated N -acetylglucosamine residues) and are degraded in a stepwise fashion from the nonreducing end by a series of lysosomal enzymes. Depending on the specific enzyme deficiency, the catabolism of one or more GAGs may be blocked. Clinical features vary depending on the tissue distribution of the affected substrate and the degree of enzyme deficiency.

In Morquio syndrome (mucopolysaccharidosis type IV), the degradation of KS is defective because of deficiency of either N -acetyl-galactosamine-6-sulfate sulfatase (GALNS gene) in Morquio syndrome type IVA or β -galactosidase (GLB1 gene) in Morquio syndrome type IVB (see Media file 8). Defective GALNS also affects the catabolism of chondroitin 6-sulfate.

Defects in keratan sulfate (KS) degradation resulting in Morquio syndrome.

The specific mechanism or mechanisms by which excess storage of KS results in the skeletal dysplasia unique to Morquio syndrome remains unknown. The biology of KS is currently under investigation. Numerous KS-containing proteins have been identified, and the elucidation of their functional roles will provide a better understanding of the pathophysiology of Morquio syndrome (mucopolysaccharidosis type IV). A few histological reports in patients are noted.

Three murine models for GALNS deficiency were recently generated and consist of a traditional null model and a more complex model engineered to achieve tolerance when challenged by the human enzyme in therapeutic applications. The latter expresses both the human and mouse GALNS proteins, containing an inactivating missense mutation in the highly conserved cysteine residue within the catalytic domain. The third expresses only the murine missense GALNS. These models accumulate GAGs in multiple tissues, including bone, and will be useful for study. Additional data on these mouse models, presented by Tomatsu et al, reveal that their skeletal phenotype is limited by expression of only KS type I, in contrast to humans who express KS types 1 and 2.²

The GALNS gene is located on chromosome arm 16q24.3 and encodes a 522–amino acid protein that is stabilized in a complex with 2 other lysosomal enzymes (β -galactosidase and α -neuraminidase) and the protective protein cathepsin A. The assembly of these 4 components is necessary for correct posttranslation processing and stability of the component enzymes and for the efficient catabolism of KS. More than 148 unique mutations have been reported in the GALNS gene. A few of these mutations represent founder alleles in certain population groups. Missense alleles represent the most prevalent type of mutations. Milder phenotypes may be explained, in part, by the residual activity of the mutant proteins.

The GLB1 gene is located on chromosome arm 3p21.33 and encodes a 677 catalytically active protein. A minor alternative transcript encodes S-GAL, an elastin-binding protein required for the orderly assembly of elastin and other cell-matrix interactions. β -galactosidase deficiency also causes GM1 gangliosidosis, a neurodegenerative disorder with minimal resemblance to Morquio syndrome (mucopolysaccharidosis type IV). The mutations that cause Morquio syndrome (mucopolysaccharidosis type IV) are proposed to affect the catabolism of KS but have little effect on GM1 gangliosides. Deficiency of cathepsin A also results in a secondary deficiency of GLB1; this disorder is galactosialidosis.

Frequency

United States

Incidence is unknown at present, but estimates may be available soon following the institution of newborn screening for lysosomal storage disorders. Development of newborn screening strategies is underway.

International

The estimated incidence of Morquio syndrome (mucopolysaccharidosis type IV) covers a wide range, including 1 case per 75,000 births in Northern Ireland, 1 case per 200,000 births in British Columbia, and 1 case per 263,157 births in Germany. One study also identified the first GALNS mutations in Tunisia in 6 affected individuals from 4 unrelated families.

Mortality/Morbidity

In Morquio syndrome (mucopolysaccharidosis type IV), mortality and morbidity rates are primarily related to the atlantoaxial instability and subsequent cervical myelopathy. A minor fall or extension of the neck can result in cord transection and subsequent quadriparesis or death. The cervical myelopathy can cause bowel and bladder dysfunction and apnea. Obstructive sleep apnea can cause prolonged periods of hypoxia, pulmonary hypertension, and even death. Airway obstruction also occurs secondary to thickening of tissue in the upper airway from mucopolysaccharide deposition.

Patients with Morquio syndrome (mucopolysaccharidosis type IV) have a predisposition to pulmonary infection because of progressive truncal deformity and immobility. Early onset coronary heart disease and valve thickening (aortic and mitral) with resultant cardiac dysfunction are described in these patients, and endocarditis prophylaxis is recommended. Corneal clouding can cause visual disturbance and photophobia. Enamel abnormalities in patients with Morquio syndrome (mucopolysaccharidosis type IV) predispose them to dental caries.

Based on a natural history study, patients with more severe short stature and those who underwent surgical procedures were reported to have more difficulties ambulating. The current clinical criteria establish that reduced growth and final height are associated with more severe clinical phenotypes. Increased relative weight in this population was also associated with increased morbidity.³

Race

No racial predilection is noted.

Sex

The male-to-female ratio is 1:1, and this is supported by the demographics of the cohort in a natural history study.¹

Age

Patients with Morquio syndrome (mucopolysaccharidosis type IV) appear healthy at birth. The mean age of onset of the disease is 2.1 years, and 76% of children are diagnosed by age 6 years. Children are often evaluated for the first time for spinal deformity, growth retardation, and genu valgus in the second or third year of life. Morquio-specific radiographic changes occurring before phenotypic changes are obvious have been reported. Patients with mild manifestations of Morquio syndrome (mucopolysaccharidosis type IV), regardless of type, have been reported to survive into the seventh decade of life. Patients with severe manifestations, primarily related to cervical instability, do not survive this long.

Clinical

History

The patient with Morquio syndrome (mucopolysaccharidosis type IV) is usually evaluated during the second or third year of life for unusual skeletal features. These include short trunk dwarfism, pectus carinatum, kyphosis, gibbus, scoliosis, genu valgus, flaring of the lower ribs, and joint abnormalities (joints range from hypermobile to contracted).

• At the time of initial evaluation, families commonly report a history of increased clumsiness and falling.
• Because no mental deficiencies or loss of developmental milestones occurs, this is not a presenting symptom. In fact, this is one important characteristic that distinguishes Morquio syndrome (mucopolysaccharidosis type IV) from many of the other mucopolysaccharidoses (MPSs).
• Because the MPSs are progressive disorders, the patient becomes more severely affected over time. As lysosomal accumulation of keratan sulfate (KS) continues, mild coarsening of facial features, corneal clouding, and hepatomegaly become apparent.
• Other less frequent findings in Morquio syndrome (mucopolysaccharidosis type IV) include hearing difficulties, hernias, and thin tooth enamel with a predisposition to caries.
• A characteristic of all patients with Morquio syndrome (mucopolysaccharidosis type IV) is odontoid hypoplasia. In combination with ligamentous laxity and extradural mucopolysaccharide deposition, this results in atlantoaxial subluxation, with consequential quadriparesis or even death.
• A history of exercise intolerance in patients with Morquio syndrome often predicts the presence of occult cervical myelopathy, which can also cause bowel and bladder dysfunction.

Physical

• The most dramatic finding in patients with Morquio syndrome is their skeletal habitus. This includes short stature with short trunk, pectus carinatum, kyphosis, gibbus, scoliosis, genu valgus, flaring of the lower ribs, and joint abnormalities (joints range from hypermobile to contracted). Patients can alternatively have genu varus.
• Additional physical features are hearing difficulties, carious teeth, hepatomegaly, and aortic and/or mitral regurgitation.[#Table]

Table 1.Clinical and Biochemical Features Distinguishing the Mucopolysaccharidoses and Morquio Syndrome (Mucopolysaccharidosis Type IV)

Causes

Excess deposition of KS underlies the clinical manifestations of this disease (see Pathophysiology).

Differential Diagnoses

Other Problems to Be Considered

The differential diagnosis includes other mucopolysaccharidosis (MPS) disorders (see Table 1) and chondrodysplasias. The chondrodysplasias to consider are the spondyloepiphyseal dysplasias (SED) and the multiple epiphyseal dysplasias (MED).

Workup

Laboratory Studies

The following tests are indicated in patients with Morquio syndrome (mucopolysaccharidosis type IV):

• Urine spot tests are readily available to screen for mucopolysaccharides.
  • These tests are associated with false-positive and false-negative results; testing more than one urine sample is recommended.
  • In Morquio syndrome (mucopolysaccharidosis type IV), mildly affected patients do not always excrete keratan sulfate (KS) fragments.
• Semiquantification of urinary glycosaminoglycans (GAGs) can be obtained by spectrophotometric assays with dimethylmethylene blue. Heparan sulfate (HS), KS, and dermatan sulfate (DS) can be distinguished by electrophoretic techniques to narrow the differential among the mucopolysaccharidoses (MPSs).
• A new enzyme-linked immunoassay (ELISA) technique has been shown to accurately quantify KS in urine and blood in patients with Morquio syndrome type IVA.
• Clinical suspicion should take precedence over screening test results because of their variability.
• The diagnosis is confirmed by direct enzymatic assay in leukocytes or fibroblasts.
  • The enzymes deficient in Morquio syndrome (mucopolysaccharidosis type IV) are galactosamine-6-sulfatase (ie, N -acetyl-galactosamine-6-sulfate sulfatase) and β -galactosidase.
  • University hospitals with expertise in metabolic genetics perform these assays on heparinized blood or fibroblasts cultured from a small (2 mm) skin biopsy.
• For prenatal diagnosis, enzyme activity can be measured in amniocytes or chorionic villi.
• Determination of the carrier state by enzyme analysis is not always possible because the range of enzyme activity in noncarrier and carrier individuals overlaps.
  • Detection of mutations in the GALNS and GLB1 genes can facilitate carrier testing if the family desires.
  • GeneTests lists several institutions that offer enzymatic and mutation analysis for Morquio syndrome (mucopolysaccharidosis type IV).
  • Obtaining specific instructions from the laboratory performing these assays prior to collecting samples from patients is beneficial.

Imaging Studies

• A full skeletal survey should be obtained in a patient thought to have MPS. For Morquio syndrome (mucopolysaccharidosis type IV), the authors recommend the following radiographic studies:
  • Anteroposterior (AP) and lateral views of the skull with visualization of the sella
  • Flexion and extension radiographs of the cervical spine
    
    

    

    Cervical spine, flexion and extension views, in a child aged 5 years and 11 months. These flexion and extension images depict anterior and posterior subluxation, respectively, of the atlas secondary to odontoid hypoplasia.

    
    
  • AP and lateral views of the odontoid
  • AP and lateral views of the chest
    
    

    

    Anteroposterior view of the chest in a child aged 8 years and 4 months with Morquio syndrome. To reference the relatively small size of this chest, this patient's vital capacity was 500 cc, but the expected value based on height and weight was 1400 cc. Widened metaphyses and irregular epiphyses of the humeri and generalized platyspondyly are present. Oar-shaped ribs (widening ribs anteriorly and narrowing at the vertebrae) are easily observed and are another key characteristic of dysostosis multiplex.

    
    
  • Standing AP and lateral views of entire spine
    
    

    

    Lateral view of spine in a child aged 8 years and 7 months. This radiograph shows advanced platyspondyly, irregularity, and anterior beaking of vertebral bodies characteristic of dysostosis multiplex. Note also the gibbus deformity and lordosis, which are characteristic of Morquio syndrome.

    
    
  • Standing pelvis view with visualization of the femoral heads articulating with the acetabulum
    
    

    

    Multiple abnormalities are present in the pelvis, including dysplastic femoral heads and oblique acetabular roof with coxa valgus deformity. Flared iliac wings usually observed in Morquio syndrome are not well represented in this radiograph.

    
    
  • Preferably standing AP views of the lower extremities, including the entire femur, articulation with tibia (knees for genu valgus), and ankles
    
    

    

    Bilateral lower extremity views in a patient aged 22 years and 6 months. Metaphyseal irregularities and the characteristic genu valgus deformity are easily observed in this image.

    
    
  • AP views of at least one foot, one hand, forearm, elbow in extension, humerus, and shoulder
    
    

    

    Bilateral hand radiographs in a patient aged 22 years and 6 months. Note the tapering of the proximal portion of metacarpals 2 through 5 and small irregular carpal bones. The epiphyseal involvement characteristic of Morquio syndrome is exemplified by the tapered irregular distal radius and ulna. Overall, the bones are osteopenic with cortical thinning.

    
    
    

    

    Upper extremities in a child aged 6 years and 11 months. Note the irregular epiphyses and widened metaphyses. Cortical thinning and mild widening of the diaphysis of the humerus are visible.

    
    
• CT scanning or MRI of the brain stem and cervical spine should be performed to evaluate odontoid hypoplasia and cord compression. The authors recommend additional CSF flow studies in flexion and extension in patients older than 5 years.

Other Tests

• An ophthalmology examination with slit lamp should be performed at the time of initial evaluation to look for corneal clouding. Other rare abnormalities include lens opacities, retinopathy, optic atrophy, and pseudoexophthalmos.

Histologic Findings

• The lysosomes of patients with MPS are engorged with unmetabolized GAG. These appear as vacuoles or inclusion bodies in cells such as lymphocytes, hepatocytes, corneal epithelium, and neurons.

Treatment

Medical Care

• Condition specific height and weight curves are now available to follow patients longitudinally with Morquio syndrome (mucopolysaccharidosis type IV). Final height is attained for most males at age 11 years and for females at age 9 years.
• Only palliative measures are currently available for treatment of patients with Morquio syndrome (mucopolysaccharidosis type IV).
• Potential strategies for treatment of patients with the other mucopolysaccharidoses (MPSs), which are currently at different levels of development, include enzyme replacement therapy (ERT), gene therapy, and allogenic bone marrow transplantation in which engrafted cells provide the normal enzyme.
• Currently, ERT is available commercially for MPS type I (Hurler disease), MPS type VI (Maroteaux-Lamy disease), Gaucher disease, Fabry disease, MPS type II (Hunter disease), and Pompe disease.
  
  Table 2. Enzyme Replacement Therapy for the Mucopolysaccharidoses

• MPS Type	Disease Name	Enzyme Deficiency	ERT	Company	Clinical Use
  I	Hurler	α -iduronidase	Aldurazyme	Genzyme	In use
  IH/S	Hurler-Scheie	α -iduronidase	Aldurazyme	Genzyme	In use
  IS	Scheie	α -iduronidase	Aldurazyme	Genzyme	In use
  II	Hunter	Iduronidase sulfatase	Elaprase	Shire	In use
  III‡	Sanfilippo A	Heparan sulfatase	...	...	...
  	Sanfilippo B	N- acetylglucosaminidase	...	...	...
  	Sanfilippo C	Acetyl CoA glucosamine acetyltransferase	...	...	...
  	Sanfilippo D	N -acetylglucosamine-6-sulfatase	...	...	...
  IV	Morquio A	Galactosamine-6-sulfatase	Unnamed	Vivendy Biomarin	In development
  	Morquio B	b -galactosidase	...	...	...
  VI	Maroteaux-Lamy	N -acetylhexosamine-4-sulfatase	Naglazyme	Biomarin	In use
  VII	Sly§	b -glucuronidase	...	...	...
  IX	Hyaluronidase Deficiency||	Hyaluronidase	...	...	...
  GSDII	Pompe	Acid α -glucosidase	Myozyme	Genzyme	In use

  Note.–This table represents the status of enzyme replacement therapy as of November, 2008. Progress occurs on a daily basis; please investigate further for the most up to date information.
• ERT is currently under development for Morquio syndrome type IVA and will be in trial phase in the near future.
• The historic observation that glycosaminoglycans (GAG) deposition in cultured cells from patients with MPS can be diminished by providing the deficient enzyme in soluble form promoted lysosomal storage disease as a paradigm for treatment with exogenous enzyme.
  • Animal models have facilitated the testing of various therapies, but many technical difficulties remain to be overcome.
  • The refractory response of skeletal abnormalities to enzyme replacement in Hurler and Gaucher disease type 1 is of particular concern in the exploration of therapies for patients with Morquio syndrome (mucopolysaccharidosis type IV).

Surgical Care

• Because all patients with Morquio syndrome (mucopolysaccharidosis type IV) have odontoid hypoplasia that can lead to atlantoaxial subluxation, many physicians recommend cervical spine fusion, especially for an atlantodens interval more than 8 mm or space around the cord less than 14 mm.⁴  Some physicians recommend fusion of C1 and C2, whereas others recommend fusion of C1 and C2 and occipital fusion if basilar invagination, inadequate fixation to C1, or occiput-C1 instability is also noted. Patients undergoing cervical fusion wear a halo brace for an extended period after the surgery. Ideally, the surgery should be performed before signs and symptoms of cervical myelopathy occur. However, because of the high risk of this procedure in patients with Morquio syndrome (mucopolysaccharidosis type IV), some elect not to have this surgery.
• Patients with Morquio syndrome (mucopolysaccharidosis type IV) can develop an extradural soft tissue GAG accumulation anterior to the cord at C1, which can cause myelopathy.
• One study stressed the importance of monitoring craniovertebral posture and mandibular growth after cervical fusion in a patient with Morquio syndrome (mucopolysaccharidosis type IV). Excessive mandibular growth occurred after the fusion procedure, thought to be secondary to the new postoperative position of the head, neck, and tongue.
• Other potential operations for patients with Morquio syndrome (mucopolysaccharidosis type IV) include femoral osteotomies and corrective knee surgery for genu valgus deformity. Total joint replacement of hips and/or knees may be necessary. The early use of a back brace may delay or prevent surgical intervention for scoliosis.
• Corneal grafting for progressive corneal haziness has been reported with variable recurrence success.
• The anesthesiologist for any surgery performed on a patient with Morquio syndrome (mucopolysaccharidosis type IV) must be prepared to manage a difficult airway.
  • A preoperative evaluation should be pursued, especially if evidence of cardiac dysfunction, obstructive apnea, or pulmonary insufficiency is present.
  • The authors recommend obtaining preoperative echocardiography, pulmonary function testing, and sleep studies.
  • Elective surgery should be avoided during temporary respiratory compromise (eg, upper respiratory infection [URI], pneumonia).
  • Alternatives to general anesthesia should be considered. For example, the use of spinal anesthesia has been reported in patients with Morquio syndrome (mucopolysaccharidosis type IV) who are undergoing extensive orthopedic procedures.⁵ However, spinal anesthesia can be technically compromised by abnormal vertebrae in these patients, and emergent intubation may still be required.

Consultations

The multisystem involvement of MPS necessitates a comprehensive care plan.

• Patients with Morquio syndrome (mucopolysaccharidosis type IV) should be evaluated regularly by a geneticist, an ophthalmologist, an orthopedist, and a cardiologist.
• Other considerations are consultations with an audiologist and a dentist.
• Genetic counseling should be provided to patients with newly diagnosed MPS and their families. Because this is an autosomal recessive disorder, a 25% risk for the parents to have another child with Morquio syndrome (mucopolysaccharidosis type IV) is noted in each pregnancy.

Diet

• No specific dietary restrictions are indicated for patients with Morquio syndrome (mucopolysaccharidosis type IV).
• On a practical level, these patients should avoid excess body weight to minimize pulmonary compromise caused by the skeletal deformities.

Activity

• A person with Morquio syndrome (mucopolysaccharidosis type IV) can participate in activities as tolerated with a few important restrictions.
• Contact sports could damage the cervical spine and should be avoided.
• Repetitive motions at work or with sports could strain abnormal joints and should also be avoided.

Medication

• Currently, no medications are available to prevent, treat, or cure Morquio syndrome (mucopolysaccharidosis type IV), and supportive measures are used to treat the manifestations of this disorder. These include nonsteroidal anti-inflammatory drugs (NSAIDs) for joint pain, antibiotics for pulmonary infections, and oxygen for pulmonary compromise or obstructive sleep apnea.

Follow-up

Further Inpatient Care

• Admission for surgical interventions in patients with Morquio syndrome (mucopolysaccharidosis type IV) may be required (see Treatment). These procedures include femoral osteotomies, corrective knee surgery for severe genu valgus deformity, and cervical spinal fusion.

Further Outpatient Care

• The authors recommend that patients with Morquio syndrome (mucopolysaccharidosis type IV) be evaluated yearly by a geneticist, who can supervise a multidisciplinary care approach.
• Depending on the degree of atlantoaxial stability at the time of diagnosis, routine flexion or extension radiographs to monitor for subluxation are recommended.
• A sleep study is recommended if signs of cervical myelopathy or obstructive apnea are present.
• Ideally, patients with Morquio syndrome (mucopolysaccharidosis type IV) should be referred to an orthopedic surgeon at the time of diagnosis to evaluate for occult cervical instability, scoliosis, or kyphosis. The orthopedist should have experience in managing skeletal dysplasias because multiple orthopedic procedures may be required.
• Ophthalmologic evaluations should be performed regularly.
• Attention to daily oral hygiene and professional dental cleaning and evaluation every 6-12 months is necessary to minimize the effects of thin dental enamel.
• Echocardiography should be performed to evaluate for valvular disease associated with mucopolysaccharide deposition; abnormalities should be monitored by a cardiologist.
• All patients with Morquio syndrome (mucopolysaccharidosis type IV) should receive routine childhood vaccinations, as well as influenza and pneumococcal vaccines, because their chest and spine deformities predispose them to pulmonary infections. Guidelines for immunizations have been established.⁶
• Audiology testing is recommended as needed. Guidelines for hearing assessment in infants and children have been established.⁷
• Counseling may be beneficial in childhood and adolescence to help patients cope with the teasing or depression often associated with physical limitations and dysmorphic features.

Inpatient & Outpatient Medications

• Medications for supportive care, such as nonsteroidal anti-inflammatory drugs (NSAIDs) for joint pain, antibiotics for pulmonary infections, and oxygen for pulmonary compromise and obstructive sleep apnea, can be used to treat the manifestations of this disorder.

Complications

Many potential complications exist for patients with Morquio syndrome (mucopolysaccharidosis type IV). They include the following:

• Atlantoaxial instability
• Skeletal abnormalities (see Physical) leading to subsequent difficulties with ambulation and pain
• Cervical myelopathy
• Pulmonary compromise
• Valvular and coronary heart disease
• Hearing deficits
• Corneal clouding
• Dental caries

Prognosis

• Patients with mild manifestations of Morquio syndrome (mucopolysaccharidosis type IV), regardless of type, have been reported to survive into the seventh decade of life.
• Patients with severe manifestations, primarily related to cervical instability and pulmonary compromise, often do not survive beyond the second or third decade of life.
• Length of survival may improve with the improved comprehensive care available to these patients today.

Patient Education

• Aside from their professional caregivers, several additional resources for patients with mucopolysaccharidosis exist, including Society for the Study of Inborn Errors of Metabolism, Online Mendelian Inheritance in Man, International Morquio Organization, National MPS Society, The National Organization for Rare Disorders, Inc, National Institute of Neurological Disorders and Stroke, and Little People of America, Inc.
• This section was written for those individuals with a family member affected by Morquio syndrome (mucopolysaccharidosis type IV) and their healthcare providers. The authors have compiled information from families that have first-hand experience with Morquio syndrome (mucopolysaccharidosis type IV) in their everyday lives. The following information is not intended to be a formal study; it is simply information and suggestions from these families in response to several questions.
  • Examples of how the diagnosis was made and at what age include the following:
    • Age 8 months: This child was initially seen by an orthopedist for standing with bent knees. Later, more testing (not specified) was performed at a large institution and the diagnosis was made.
    • Age 14 months: The child was not crawling like her siblings. Her doctor performed a urine test, skin biopsy, and bone marrow aspirate to establish the diagnosis in 1964.
    • Age 1 year: The diagnosis was suspected from radiographs that were performed to evaluate this child's kyphosis and scoliosis. A blood test confirmed the diagnosis.
    • Age 3 years: Decreased growth rate was noted at a routine pediatric appointment. A radiologist noted abnormalities of the ends of the bones on MRI. A skin biopsy by a geneticist confirmed the diagnosis.
    • Age 3 years: After this child reported back pain, his pediatrician found a protrusion in his back. Referral to a geneticist who collected blood, urine, and a skin biopsy confirmed the diagnosis of Morquio syndrome (mucopolysaccharidosis type IV).
    • Age 4 years: This child was first seen by a geneticist to evaluate a skin lesion. The geneticist thought that her skeleton was consistent with Morquio syndrome (mucopolysaccharidosis type IV) and performed radiographic studies (skeletal survey) and a urine test for diagnosis.
    • Age 4 years: This child had little growth through age 2 years and none from age 3-4 years. After referral to an endocrinologist, hand radiographs revealed findings suggestive of mucopolysaccharidosis (MPS). A skin biopsy was performed to confirm the diagnosis.
  • Examples of common physical difficulties these patients have and their methods to overcome them include the following:
    • To avoid carrying heavy books to and from school, use 2 sets of textbooks; one for home and one for school.
    • For difficulty walking the same speed and distance of peers, try an electric scooter or tricycle at school, work, or home.
    • One person reports that his classmates pull him in a wagon to travel long distances at school.
    • A palm pilot or laptop computer can be used to take notes in school if weak wrists are a problem.
    • To participate in field trips, an adult family member of one affected individual always went along.
    • One technique that was nearly universal among all parents was to meet with school personnel at the beginning of each school year to explain Morquio syndrome (mucopolysaccharidosis type IV) and some of the physical limitations their children may have.
    • In college, one individual requested a ground floor dorm room, a lower rod in her closet, and a lower keyhole in her door.
  • The following are examples of social difficulties these patients experience and how they have managed them:
    • In addition to educating school administrators, teachers, and counselors about Morquio syndrome (mucopolysaccharidosis type IV), many families suggest meeting with the classmates of their affected children. These efforts reportedly increase the students' understanding of Morquio syndrome (mucopolysaccharidosis type IV) and the overall acceptance of their child.
    • One mother and her affected daughter have been on a local talk show to discuss Morquio syndrome (mucopolysaccharidosis type IV). They believe this project and their involvement in a local television show about Morquio syndrome (mucopolysaccharidosis type IV) have made acceptance of the affected daughter in their community much easier.
  • Other medical concerns families reported and how they are managed include the following:
    • Dental: Several individuals reported hypoplastic (thin, weak, poorly formed) tooth enamel and cavities. Braces were difficult for some because of the thin tooth enamel, and the teeth required capping. Some have formal dental cleaning every 3 months with annual or biannual fluoride treatments to help prevent cavities.
    • Aural: Only a few individuals required hearing aids for various degrees of hearing loss. Most denied difficulties in this area.
    • Cardiac: No one reported any heart abnormalities that required surgery or medications. In general, those that responded are evaluated by a cardiologist with echocardiography every 1-2 years.
    • Ocular: Nearly everyone reported some degree of corneal clouding, but no one thought that his or her vision was severely impaired by it.
    • Skeletal: Several people with Morquio syndrome (mucopolysaccharidosis type IV) reported that they have had cervical spine fusion; some had surgery after neurologic symptoms were present, whereas others underwent the procedure before any neurologic complications. Hip surgery was another common procedure reported by these patients. Several patients also reported joint laxity and pain, primarily in the knees, ankles, and wrists. They managed these problems with plastic braces and adaptive tools in the kitchen to compensate for their weak grip. Most avoided carrying heavy objects. One individual reported that she now has increasing stiffness in her elbows that she treats with warm water.
    • Surgical: The universal recommendation from individuals with Morquio syndrome (mucopolysaccharidosis type IV) and their families is to request an anesthesiologist experienced in skeletal dysplasias and pediatrics.
  • Patients with Morquio syndrome (mucopolysaccharidosis type IV) had similar routine health schedules, as follows:
    • Consultation with a pediatric neurologist, orthopedist, and primary care physician every 6 months
    • Yearly eye, ear, and cardiology evaluation
    • Yearly visit to neurologist and spine surgeon with annual hearing examination
    • Biannual eye examination and dental appointment
    • Evaluation with an orthopedist every 6 months and a pediatric cardiologist, ophthalmologist, and otolaryngologist once every year
    • Consultation with a pediatrician as needed, orthopedist every 6 months, dentist every 3 months, ophthalmologist every 6-12 months, and cardiologist every 1-2 years
    • Yearly neck, spine, and hip radiographs with yearly eye examinations
  • Below is advice from people with Morquio syndrome (mucopolysaccharidosis type IV) and their families:
    • To the family of a newly diagnosed individual "Each person is different. [The person with Morquio syndrome] did not develop a lot of the problems we were told she would.When we received the diagnosis, we decided that this was part of her life—not her life.Assume your child can live a normal life. Help your child get solid education and be active socially.Each case is different! There are all different levels of severity. Take one day at a time. Get a good medical team.Keep things as "normal" as possible, but take extra measures for small children to be gentle with a Morquio child.I never discourage him from doing anything unless it jeopardizes his health or his body. I expect him to finish school and go to college just like my daughter."
    • To the physicians treating patients with Morquio syndrome (mucopolysaccharidosis type IV)  "Find out what experts say. Read literature, but also talk to other physicians and researchers about Morquio.Please listen to the family. We may not be physicians, but we can tell you about our child.Work as a team. Involve the parents in every step of their child's care. Don't treat parents with an air of superiority. Teach and help them as much as possible."
    • To other newly diagnosed individuals "Find at least one physician that knows Morquio [syndrome] to oversee care at least once a year. Find other families and join Little People of America and The National MPS Society. Read their newsletters, see their web sites, and go to their conferences.Be aware of the potential problems and your own limitations. Do not let the diagnosis dictate who you are or how you live your life."

Miscellaneous

Medicolegal Pitfalls

• Patients with Morquio syndrome (mucopolysaccharidosis type IV) may have physical limitations and may require modification of their learning environment. Per section 504 of the Rehabilitation Act of 1973, students enrolled in programs and activities that receive federal assistance from the US Department of Education who have "substantial limitation of a major life activity" from a disability are entitled to regular education.
• By law, public schools are required to modify the learning methods and environment to meet the needs of the disabled student.
• Patients with Morquio syndrome (mucopolysaccharidosis type IV) and their families should be encouraged to contact their local school about these issues if modifications are not already in place.
• Several potential resources exist to help families, including a designated 504 representative in each school district, a principal, a social worker from a local children's hospital, or a lawyer.
• The Rehabilitation Act applies to all Americans with physical and mental limitations as outlined in this document.

Multimedia

Media file 1: Lateral view of spine in a child aged 8 years and 7 months. This radiograph shows advanced platyspondyly, irregularity, and anterior beaking of vertebral bodies characteristic of dysostosis multiplex. Note also the gibbus deformity and lordosis, which are characteristic of Morquio syndrome.

Media file 2: Cervical spine, flexion and extension views, in a child aged 5 years and 11 months. These flexion and extension images depict anterior and posterior subluxation, respectively, of the atlas secondary to odontoid hypoplasia.

Media file 3: Bilateral lower extremity views in a patient aged 22 years and 6 months. Metaphyseal irregularities and the characteristic genu valgus deformity are easily observed in this image.

Media file 4: Bilateral hand radiographs in a patient aged 22 years and 6 months. Note the tapering of the proximal portion of metacarpals 2 through 5 and small irregular carpal bones. The epiphyseal involvement characteristic of Morquio syndrome is exemplified by the tapered irregular distal radius and ulna. Overall, the bones are osteopenic with cortical thinning.

Media file 5: Upper extremities in a child aged 6 years and 11 months. Note the irregular epiphyses and widened metaphyses. Cortical thinning and mild widening of the diaphysis of the humerus are visible.

Media file 6: Multiple abnormalities are present in the pelvis, including dysplastic femoral heads and oblique acetabular roof with coxa valgus deformity. Flared iliac wings usually observed in Morquio syndrome are not well represented in this radiograph.

Media file 7: Anteroposterior view of the chest in a child aged 8 years and 4 months with Morquio syndrome. To reference the relatively small size of this chest, this patient's vital capacity was 500 cc, but the expected value based on height and weight was 1400 cc. Widened metaphyses and irregular epiphyses of the humeri and generalized platyspondyly are present. Oar-shaped ribs (widening ribs anteriorly and narrowing at the vertebrae) are easily observed and are another key characteristic of dysostosis multiplex.

Media file 8: Defects in keratan sulfate (KS) degradation resulting in Morquio syndrome.

Media file 9: The individual on the front of the scooter is 19 years old and has Morquio syndrome. Her friend on the back is an average-stature 10 year old without Morquio syndrome. On the driver, note the enlargement at the knees and the wrist deformity. Also, note the successful adaptation of the scooter to ambulate.

Media file 10: Note the short trunk and protuberant rib structure in this child with Morquio syndrome. More importantly, notice that Morquio syndrome is not preventing this child from being active and fishing.

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Keywords

mucopolysaccharidosis type IV, Morquio syndrome, MS, mucopolysaccharidosis type IVA, OMIM 253000, mucopolysaccharidosis type IVB, OMIM 253010, lysosomal storage disease, MPS IVA, MPS IVB, dysostosis multiplex, lysosomal storage disorders, facial coarsening, hepatomegaly, platyspondyly, rib flaring, pectus carinatum, mental retardation, growth failure, skeletal dysplasia, obstructive sleep apnea, short trunk dwarfism, pectus carinatum, kyphosis, gibbus, scoliosis, genu valgus, flaring of the lower ribs, exercise intolerance, treatment, diagnosis

Contributor Information and Disclosures

Author

Nancy E Braverman, MS, MD, Associate Professor, Department of Human Genetics, McGill University
Nancy E Braverman, MS, MD is a member of the following medical societies: Alpha Omega Alpha, American Society of Human Genetics, Society for Inherited Metabolic Disorders, and Society for the Study of Inborn Errors of Metabolism
Disclosure: none None None

Coauthor(s)

Shunji Tomatsu, MD, PhD, Professor, Department of Pediatrics, Saint Louis University School of Medicine
Shunji Tomatsu, MD, PhD is a member of the following medical societies: National MPS Society, Japan
Disclosure: Nothing to disclose.

Medical Editor

Karl S Roth, MD, Professor and Chair, Department of Pediatrics, Creighton University School of Medicine
Karl S Roth, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Pediatric Society, American Society for Clinical Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, and Southern Society for Pediatric Research
Disclosure: MDS Pharma Salary Employment

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Margaret M McGovern, MD, PhD, Professor and Chair of Pediatrics, Stony Brook University, New York
Margaret M McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics and American Society of Human Genetics
Disclosure: Genzyme Grant/research funds PI

CME Editor

Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine
Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine
Disclosure: Baxter Honoraria Consulting

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors Julie Hoover-Fong, MD and Michael C Ain, MD,to the original writing and development of this article.

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