AUTHOR INFORMATION

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Authored by Nancy Braverman, MD, Assistant Professor, McKusick-Nathans Institute of Genetic Medicine, Department of Pediatrics, Johns Hopkins Medical Center

Coauthored by Julie Hoover-Fong, MD, Assistant Professor, Clinical Director, Greenberg Center for Skeletal Dysplasias, McKusick-Nathans Institute of Genetic Medicine, Department of Pediatrics, Johns Hopkins Medical Center; Michael C Ain, MD, Assistant Professor, Departments of Neurosurgery and General Surgery, Division of Pediatric Orthopedic Surgery, Johns Hopkins University School of Medicine

Nancy Braverman, MD, is a member of the following medical societies: American Society of Human Genetics, and Society for Inherited Metabolic Disorders

Edited by Karl S Roth, MD, Chair, Professor, Department of Pediatrics, Creighton University School of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Margaret McGovern, MD, PhD, Vice Chair, Professor, Department of Human Genetics, Mount Sinai School of Medicine; Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Nancy Braverman, MD
Editor's Email:	Karl S Roth, MD

eMedicine Journal, May 22 2006, VOLUME 7, Number 5

INTRODUCTION

Section 2 of 12

Background: Morquio syndrome 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). Currently, 11 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 usually can 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 to other patients with MPS, those with Morquio syndrome 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.

In 1976, the enzyme deficiency in Morquio syndrome type IVA (galactosamine-6-sulfatase deficiency, ie, N-acetyl-galactosamine-6-sulfate sulfatase deficiency) was identified. Shortly thereafter, the enzyme deficiency in Morquio syndrome type IVB was described (beta-galactosidase deficiency). Historically, type IVA was considered to have more severe manifestations than type IVB. However, with the ability to differentiate between types A and B by enzyme analysis, variability in clinical expression within both groups is apparent. No clear clinical differentiation between Morquio syndrome type IVA and IVB exists.

Pathophysiology: GAGs are oligosaccharide components of proteoglycans (macromolecules that provide structural integrity and function to connective tissues). The underlying defect in the MPSs is inability to degrade GAGs. The chronic progressive course is caused by the accumulation of partially degraded GAG, with resulting thickening of tissue and compromising of cell and organ function over time. Some of the clinical manifestations of GAG accumulation are coarse facial features, corneal clouding, thickened skin, and organomegaly. Some of the manifestations of abnormal cell function are mental retardation, growth failure, and skeletal dysplasia. GAGs accumulate in lysosomes and extracellular tissue and are excreted in the urine.

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 composed mainly 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, the degradation of KS is defective because of deficiency of either N-acetyl-galactosamine-6-sulfate sulfatase (GALNS gene) in MPS IVA or beta-galactosidase (GLB1 gene) in MPS IVB (see Image 8). Defective GALNS also affects the catabolism of chondroitin 6-sulfate.

KS is predominantly found in cartilage and cornea, the major organs affected in Morquio syndrome. Heparan and dermatan sulfate have a more generalized tissue distribution. Their normal metabolism in patients with Morquio syndrome spares these patients from mental retardation and disease manifestations observed in other types of MPS.

The specific mechanism(s) 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. A few histological reports in patients exist.

Two 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. These models accumulate GAGs in multiple tissues, including bone, and will be useful for study.

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 (beta-galactosidase and alpha-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. Beta-galactosidase deficiency also causes GM1 gangliosidosis, a neurodegenerative disorder with minimal resemblance to Morquio syndrome. The mutations that cause Morquio syndrome are proposed to affect the catabolism of KS but have little affect on GM1 gangliosides. Deficiency of cathepsin A also results in a secondary deficiency of GLB1; this disorder is galactosialidosis.

Frequency:

• In the US: 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.

• Internationally: The estimated incidence of MPS type IV covers a wide range: 1 case per 75,000 in Northern Ireland, 1 case per 200,000 in British Columbia, and 1 case per 263,157 in Germany. A recent article also identified the first GALNS mutations in Tunisia in 6 affected individuals from 4 unrelated families.

Mortality/Morbidity:

• In Morquio syndrome, 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 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 predispose them to dental caries.

Race: No racial predilection exists.

Sex: The male-to-female ratio is 1:1.

Age: Patients with Morquio syndrome appear healthy at birth. 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, 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

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History: The patient with Morquio syndrome 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 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 KS continues, mild coarsening of facial features, corneal clouding, and hepatomegaly become apparent.



• Other less frequent findings in Morquio syndrome include hearing difficulties, hernias, and thin tooth enamel with a predisposition to caries.



• A characteristic of all patients with Morquio syndrome 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).



• Additional physical features are hearing difficulties, carious teeth, hepatomegaly, and aortic and/or mitral regurgitation.

  Clinical and Biochemical Features Distinguishing the MPSs and Morquio Syndrome

  MPS Type	Eponym	Deficient Enzyme	Neuro Degeneration	Somatic Features*	Corneal Clouding	Bone/Joint Abnormality	MPS Stored†
  I H	Hurler	a-iduronidase	+++	+++	++	++	DS, HS
  I H/S	Hurler-Scheie	a-iduronidase	—	++	++	++	DS, HS
  I S	Scheie	a-iduronidase	—	+	+	+	DS, HS
  II	Hunter	Iduronidase sulfatase	++	++	—	++	DS, HS
  III‡	Sanfilippo A	Heparan sulfatase	+++	+	—	+	HS
  	Sanfilippo B	N-acetylglucosaminidase	+++	+	—	+	HS
  	Sanfilippo C	Acetyl CoA glucosamine acetyltransferase	+++	+	—	+	HS
  	Sanfilippo D	N-acetylglucosamine-6-sulfatase	+++	+	—	+	HS
  IV	Morquio A	Galactosamine-6-sulfatase	—	+	+/ —	+/ ++ / +++	KS, CS
  	Morquio B	b-galactosidase	—	+	+/ —	+/ ++ / +++	KS
  V	Nonexistent
  VI	Maroteaux-Lamy	N-acetylhexosamine-4-sulfatase	—	+	+	++	DS
  VII	Sly§	b-glucuronidase	—	++	++	++	DS, HS, CS
  IX	Hyaluronidase Deficiency||	Hyaluronidase	—	—	—	+	Hyaluron

  * Somatic features - Organomegaly, facial coarsening
  ^† MPS stored: HS = heparan sulfate, DS = dermatan sulfate, KS = keratan sulfate, CS = chondroitin sulfate
  ^‡ Eye findings may include cherry red spots.
  ^§ Extreme variability in severity; no neurologic degeneration but mental retardation possible
  ^|| Only one patient has been described whose major features were periarticular soft tissue masses.

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

DIFFERENTIALS

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Mucopolysaccharidosis Type I H/S
Mucopolysaccharidosis Type IH
Mucopolysaccharidosis Type II
Mucopolysaccharidosis Type III
Mucopolysaccharidosis Type IS
Mucopolysaccharidosis Type VI
Mucopolysaccharidosis Type VII

Other Problems to be Considered:

Spondyloepiphyseal dysplasia
Multiple epiphyseal dysplasia

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

WORKUP

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Lab Studies:

• Urine spot tests are readily available to screen for mucopolysaccharides (GAG).


• • These tests are associated with false-positive and false-negative results; testing more than one urine sample is recommended.
  
  
  
  • In Morquio syndrome, mildly affected patients do not always excrete KS fragments.
  
  
  
• Semiquantification of urinary GAG can be obtained by spectrophotometric assays with dimethylmethylene blue. Heparan, keratan, and dermatan sulfate can be distinguished by electrophoretic techniques to narrow the differential among the mucopolysaccharidoses (MPSs).

• A new enzyme-linked immunoassay (ELISA) technique has recently been shown to accurately quantify keratan sulfate in urine and blood in patients with MPS 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 are galactosamine-6-sulfatase (ie, N-acetyl-galactosamine-6-sulfate sulfatase) and beta-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.
  
  
  
  • 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, 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
  
  
  
  • AP and lateral views of the odontoid
  
  
  
  • AP and lateral views of the chest
  
  
  
  • Standing AP and lateral views of entire spine
  
  
  
  • Standing pelvis view with visualization of the femoral heads articulating with the acetabulum
  
  
  
  • Preferably standing AP views of the lower extremities, including the entire femur, articulation with tibia (knees for genu valgus), and ankles
  
  
  
  • AP views of at least one foot, one hand, forearm, elbow in extension, humerus, and shoulder
  
  
  
• 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.

TREATMENT

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Medical Care:

• Only palliative measures are currently available for treatment of patients with Morquio syndrome.



• Potential strategies for treatment of patients with the other mucopolysaccharidoses (MPSs), which are currently at different levels of development, include enzyme replacement, gene therapy, and allogenic bone marrow transplantation in which engrafted cells provide the normal enzyme.

• Currently, enzyme replacement therapy is available commercially for MPS type I (Hurler disease), MPS type VI (Maroteaux-Lamy disease), Gaucher disease, and Fabry disease. Early treatment trials are underway for MPS type II (Hunter disease) and Pompe disease.



• The historic observation that 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.
  
  
  

Surgical Care:

• Because all patients with Morquio syndrome have odontoid hypoplasia that can lead to atlantoaxial subluxation, many physicians recommend cervical spine fusion for all of their affected patients. Some physicians recommend fusion of C1 and C2, while others recommend fusion of C1 and C2 and occipital fusion. 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, some elect not to have this surgery.

• A recent article stressed the importance of monitoring craniovertebral posture and mandibular growth after cervical fusion in a patient with Morquio syndrome. 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 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 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, recent published reports describe the use of spinal anesthesia in patients with MPS IV who are undergoing extensive orthopedic procedures.
  
  
  

Consultations: The multisystem involvement of MPS necessitates a comprehensive care plan.

• Patients with Morquio syndrome 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 exists in each pregnancy.

Diet: No specific dietary restrictions exist for patients with Morquio syndrome. 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 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

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Currently, no medications are available to prevent, treat, or cure Morquio syndrome, 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

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Further Inpatient Care:

• Admission for surgical interventions 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 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 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 should receive routine childhood vaccinations as well as influenza and pneumococcal vaccines because their chest and spine deformities predispose them to pulmonary infections.



• Audiology testing is recommended as needed.



• 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.

In/Out Patient Meds:

• Medications for supportive care, such as 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. 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, 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, 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 and their healthcare providers. The authors have compiled information from families that have first-hand experience with Morquio syndrome in their everyday lives. This 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.

    • 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 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 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 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, many families suggest meeting with the classmates of their affected children. These efforts reportedly increase the students’ understanding of Morquio syndrome and the overall acceptance of their child.

    • One mother and her affected daughter have been on a local talk show to discuss Morquio syndrome. They believe this project and their involvement in a local television show about Morquio syndrome 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 yearly or bi-yearly 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 reported that they have had cervical spine fusion; some had the surgery after neurologic symptoms were present while others underwent the procedure before any neurologic complications. Hip surgery was another common procedure reported by these patients. Several people with Morquio syndrome 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 also. One individual reported that, as she ages, she now has increasing stiffness in her elbows that she treats with warm water.

    • Surgical: The universal recommendation from individuals with Morquio syndrome and their families is to request an anesthesiologist experienced in skeletal dysplasias and pediatrics.
  
  
  
  • Patients with MS 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 MS and their families:
    • To the family of a newly diagnosed individual

      “Each person is different. [The person with MS] 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 MS

      “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

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Medical/Legal Pitfalls:

• Patients with Morquio syndrome 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 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.
  
  
  

TEST QUESTIONS

Section 10 of 12

CME Question 1: Patients with mucopolysaccharidosis (MPS) type I (Hurler syndrome) and type III (Sanfilippo syndrome) exhibit neurologic degeneration, and MPS type IV (Morquio syndrome) is characterized by progressive skeletal deterioration. What causes the progressive multisystem deterioration observed in all MPS types?

A: Excessive glycosaminoglycan (GAG) degradation
B: Intracellular deposition of partially degraded GAGs
C: Deficiency of 2 peroxisomal enzymes (ie, N-acetylgalactosamine-6-sulfatase and beta-galactosidase)
D: Excess urinary excretion of GAG fragments
E: All of the above

The correct answer is B: Deficiency of a lysosomal enzyme involved in the stepwise degradation of GAGs results in the intracellular accumulation of partially degraded GAGs. GAG accumulation results in coarsening of facial features, corneal clouding, thickened skin, and organomegaly. Secondary cell and organ dysfunction due to GAG deposition is marked by progressive mental and skeletal deterioration.

CME Question 2: Dysostosis multiplex is the term used to describe the characteristic radiologic findings in patients with mucopolysaccharidoses (MPSs) and other lysosomal storage disorders. In Morquio syndrome, what additional skeletal findings are present?

A: Odontoid hypoplasia and spondyloepiphyseal dysplasia
B: Tapering of the proximal phalanges and oar-shaped ribs
C: Anterior hypoplasia of the thoracic and lumbar vertebrae
D: Hypoplasia of the pelvis and diaphyseal expansion of long bones with cortical thinning
E: All of the above

The correct answer is A: The unique skeletal findings in Morquio syndrome are odontoid hypoplasia and spondyloepiphyseal dysplasia. The other findings are typical to dysostosis multiplex.

Pearl Question 1 (T/F): The 2 patterns of inheritance found in the mucopolysaccharidosis (MPS) disorders are autosomal dominant and autosomal recessive.

The correct answer is False: All of the MPS types are inherited in an autosomal recessive fashion except for Hunter disease (MPS type II); this is inherited in an X-linked recessive fashion.

Pearl Question 2 (T/F): The 2 enzymes that are deficient in Morquio syndrome, as well as the enzymes involved in other mucopolysaccharidosis (MPS) types, are found in the Golgi apparatus.

The correct answer is False: All of the MPS disorders are caused by deficiency of a lysosomal enzyme involved in the stepwise degradation of glycosaminoglycans (GAGs).

Pearl Question 3 (T/F): Atlantoaxial instability with secondary cord compression or transection is the major cause of morbidity and mortality in Morquio syndrome.

The correct answer is True: Atlantoaxial instability due to odontoid hypoplasia is the primary cause of morbidity and mortality in patients with Morquio syndrome. These patients are also predisposed to pulmonary infection because of their progressive chest deformity and cardiac valve dysfunction from progressive glycosaminoglycan (GAG) deposition.

Pearl Question 4 (T/F): The physical features commonly associated with Morquio syndrome are short trunk dwarfism, joint laxity, corneal clouding, mental retardation, and possible minimal coarsening of facial features.

The correct answer is False: All are associated with patients with Morquio syndrome except mental retardation. This is one important characteristic that distinguishes Morquio syndrome from many other mucopolysaccharidoses.

PICTURES

Section 11 of 12

Caption: Picture 1. Lateral view of spine in a child aged 8 years 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.
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Caption: Picture 2. Cervical spine, flexion and extension views, in a child aged 5 years 11 months. These flexion and extension images depict anterior and posterior subluxation, respectively, of the atlas secondary to odontoid hypoplasia.
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Caption: Picture 3. Bilateral lower extremity views in a patient aged 22 years 6 months. Metaphyseal irregularities and the characteristic genu valgus deformity are easily observed in this image.
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Caption: Picture 4. Bilateral hand radiographs in a patient aged 22 years 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.
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Caption: Picture 5. Upper extremities in a child aged 6 years 11 months. Note the irregular epiphyses and widened metaphyses. Cortical thinning and mild widening of the diaphysis of the humerus are visible.
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Caption: Picture 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.
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Caption: Picture 7. Anteroposterior view of the chest in a child aged 8 years 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.
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Caption: Picture 8. Defects in keratan sulfate (KS) degradation resulting in Morquio syndrome.
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Caption: Picture 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.
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Caption: Picture 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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