natural history

INTRODUCTION

The following summary of the medical expectations in Morquio Syndrome is neither exhaustivenor cited. It is based upon the available literature as well as personal experience in the MidwestRegional Bone Dysplasia Clinics (MRBDC). It is meant to provide a guideline for the kinds ofproblems that may arise in individuals with this disorder, and particularly to help clinicianscaring for a recently diagnosed child. For specific questions or more detailed discussions, feelfree to contact MRBDC at the University of Wisconsin – Madison [phone – 608 262 6228; fax –608 263 3496; email – modaff@waisman.wisc.edu].

Morquio Syndrome is one of the mucopolysaccharide storage disorders. It affects around 1 inevery 200,000 individuals, is pan ethnic, but varies in incidence quite markedly among differentpopulations. Originally there were two subtypes distinguished as being caused by two differentenzyme deficiencies. However, what had been termed “type B” is no longer considered to be Morquio Syndrome. Therefore Morquio Syndrome, Morquio Syndrome A, Morquio SyndromeType A and mucopolysaccharidosis type IVA all refer to the same process.

As for most mucopolysaccharidoses, signs and symptoms are not present neonatally. Problemsare usually first suspected by around 1-3 years of age and diagnostic confirmation is usuallyfurther delayed, most often occurring between 3 y and 10y of age (mean ~5 y).

Typically firstrecognized features are gait abnormalities, abnormal leg position, chest deformity and/or slowingof growth. Physical features that result in a recognizable phenotype include: disproportionate small staturewith markedly foreshortened trunk; short neck; pectus carinatum; slender arms and legs; hipflexion contractures; knock knee deformity; facial coarsening (late in the course of the disorderand milder than in many mucopolysaccharidoses).

About 25% of affected individuals have what has been termed an “attenuated phenotype”. Whilethey have defined and demonstrable mutations in the same gene, they have far milder phenotypicfeatures than those with more typical Morquio Syndrome.

There is an International Registry from which additional natural history information shouldbecome available.

MEDICAL ISSUES AND PARENTAL CONCERNS TO BE ANTICIPATED

PROBLEM:

LIFE EXPECTANCYEXPECTATIONS:Historically most individuals suffered early death (in adolescence or earlyadulthood). Risks are clearly correlated with the severity of and effective management ofcervical myelopathy, restrictive pulmonary disease and cardiac disease (see below). Even withoptimal treatment, many affected individuals will die in early or mid-adulthood, althoughsurvival to the 6th or 7th decade is not rare.

MONITORING: -.

INTERVENTION: Sensitive counseling of the family and the affected individual is needed toaddress this issue.

PROBLEM:

GROWTH EXPECTATIONS:Birth size is usually normal and growth remains normal for the first 1-2 years oflife. Growth slowing then begins. Linear growth usually stops very early, most often between 7and 12 years of age. (This fact has some relevance in the timing of various surgical interventions,since recurrence of deformity secondary to additional growth should not be expected after about10 years of age.) Ultimate adult height ranges from about 80 cm to 140 cm (32” to 55”) withmean heights of around 122 cm (48”) in males and 113 cm (45”) in females.

MONITORING: There are diagnostic growth grids (height, weight and BMI) available. Theseshould be used to monitor growth.

INTERVENTION: There is no known treatment. Short stature means that there will be considerableadaptive needs in school and workplace etc.

PROBLEM:

DEVELOPMENTEXPECTATIONS: Unlike most other mucopolysaccharidoses, intelligence is normal unlesscomplications intervene. Variations in developmental patterns and, particularly, gross motordelays are to be expected because of the marked short stature and joint abnormalities.

MONITORING: Routine.

INTERVENTION: None.

PROBLEM:

OPHTHALMOLOGICEXPECTATIONS: Corneal clouding is a constant finding. It usually is not severe and usuallycauses little problem. Photophobia may be present. Experience suggests that surgicalintervention is not appropriate even in the most severe cases, since recurrence is inevitable.Rarely, other eye complications may develop – glaucoma (usually in adults); pigmentarydegeneration of the retina (usually in adults and usually mild and clinically silent); cataracts(usually in adulthood but may be clinically significant).

MONITORING: Careful ophthalmologic evaluation every 1-2 years. In those older than around 10y, assessment should include tonometry.

INTERVENTION: None is needed for corneal clouding or pigmentary retinopathy. Glaucoma and cataracts are treated as they would be in an otherwise average individual.

PROBLEM:

EARS AND HEARINGEXPECTATIONS: Hearing loss often begins in mid-childhood. It is usually a mixed loss (bothconductive and sensorineural components) and is frequently progressive. However, it rarelybecomes worse than a moderate loss. Middle ear dysfunction is common.

MONITORING: Maintain a high level of clinical suspicion regarding middle ear disease. Hearingassessment, at least yearly, should be done beginning at diagnosis and continuing throughoutlife.

INTERVENTION: Aggressively treat middle ear dysfunction with use of pressure equalizing tubesas needed. Consider use of pneumococcal vaccine in hopes of reducing frequency of middle earinfections. Hearing aids, FM transmitter system in school, preferential seating etc. should beused in those with more than borderline loss.

PROBLEM:

DENTALEXPECTATIONS: Enamel is uniformly abnormal – thin, rough and hypoplastic. This affects boththe primary and secondary teeth. There is marked increased frequency of tooth fractures, flakingand caries.

MONITORING: All individuals should have early and aggressive dental care.

INTERVENTION: Consider early use of sealants, fluoride treatments. Orthodontia has beensuccessful in those with Morquio Syndrome, but it must be done carefully because of the enamelabnormalities.

PROBLEM:

PULMONOLOGICEXPECTATIONS: Breathing problems may arise either from restrictive or obstructive sequences.Restrictive pulmonologic disease can be secondary to the diminished chest size, anomalous chestshape with or without problems secondary to kyphoscoliosis. Obstructive symptoms are alsomultifactorial – intrinsically small airways, possibly accumulation of storage material in airways,and superimposed adenoidal and tonsillar hypertrophy. Breathing difficulties may also arisebecause of neurologic complications. Respiratory muscle paralysis secondary to cervical cordproblems historically was a common cause of death; this should no longer be the case.

MONITORING: Involvement of a pulmonologist is almost always warranted. Careful clinicalhistory and family observation of breathing in sleep should be followed by polysomnography ifthere is suspicion of obstruction. Pulmonary function testing should begin in late childhood, andshould be repeated every 1-2 years.

INTERVENTION: If obstruction is identified, usual treatments are appropriate, e.g. tonsillectomyand adenoidectomy, use of cpap, etc. All individuals should receive influenza vaccine everyyear.

PROBLEM:

CARDIACEXPECTATIONS: Mild heart disease is exceedingly common. It usually is valvular and usuallyleft sided (aortic and mitral valves). It is remarkably benign in most children but may becomeimportant in adult life. Rarely, patients develop a cardiomyopathy.

MONITORING: Cardiologic and echocardiographic assessment should be completed at the time ofdiagnosis and probably every 2 to 3 years thereafter.

INTERVENTION: If valvular incompetence is present, should have SBE prophylaxis for dentalwork and surgeries.

PROBLEM:

CERVICAL SPINEEXPECTATIONS: This is one of the most critical issues in care of individuals with Morquiosyndrome. High cervical myelopathy and/or sudden respiratory deaths may arise if notappropriately cared for. There appear to be three contributing factors to C-spine problems –odontoid hypoplasia, ligamentous laxity causing instability of C1-C2, and thickening of the softtissues anterior to the upper cervical cord (presumably secondary to chronic movementassociatedirritation). C-spine problems are virtually always present and are often progressive.C-spine compression may cause any of the following: slow, progressive myelopathy; suddenparalysis (particularly with injury); sudden death (probably secondary to ischemia of therespiratory control centers of the medulla); marked increased risks associated with anesthesia(see below). Early signs of myelopathy include: decreased endurance (for walking etc.);hyperreflexia and clonus, particularly in the legs; problems with bowel and/or bladder control.

MONITORING: Lateral flexion, neutral and extension cervical spine x-rays should be obtainedbeginning at around 2 y of age and repeated yearly. Multiposition MRI with flow studies shouldbe done if any instability is evident on C-spine films, or if any clinical suspicion of cervicalmyelopathy arises, and, in any event, beginning at around age 6 y and then repeated every 1-2years.

INTERVENTION: There is a developing consensus that prophylactic fusion surgery is appropriate ifthere is any evidence for instability or compression. Surgical options that are most oftenrecommended include the following: A. Occiput-C1-C2 posterior fusion in asymptomatic orminimally symptomatic individuals. This is often recommended at 6-8 y of age. This is lessrisky surgery than any other alternative and often allows for normalization of the os and theanterior soft tissues. B. Combined anterior and posterior approach with anterior decompressionand combined fusion; this is appropriate in those who are already significantly symptomatic.(Note that posterior decompression is never indicated, is inappropriate, and has resulted incatastrophic outcomes.) Individuals who undergo fusion may develop instability just inferior tothe terminus of the fusion and so need ongoing monitoring (neurologic reassessments, yearly Cspineplain films, multiposition MRI if symptoms recur).

PROBLEM:

KYPHOSIS AND KYPHOSCOLIOSISEXPECTATIONS: This is common but highly variable in severity. There are no data in theliterature about whether the curve can continue to progress after cessation of growth. However,early cessation of growth does mean that fusion surgery if needed can be done quite earlywithout fear of development of disproportionate anterior growth of vertebrae. Kyphosis issometimes sufficiently severe to cause neurologic abnormality secondary to cord tethering.

MONITORING: Clinical spine assessment should be done yearly. If a curve is evident andprogressive, then radiologic monitoring should be completed. In those with kyphosis, history ofneurologic abnormality – increasing clumsiness, leg weakness, bowel and bladder incontinence,etc. should be sought.

INTERVENTION: The usual approaches to intervention are effective.

PROBLEM:

JOINT HYPERMOBILITYEXPECTATIONS: This particularly affects the small joints and, most severely, the wrists. It maybe progressive. Wrist hypermobility may be sufficiently severe to affect activities of dailyliving, hand writing, etc.

MONITORING: Clinically assess severity of hypermobility and evaluate consequences onactivities of daily living and school activities.

INTERVENTION: If wrist hypermobility is severe, wrist splinting may benefit fine motorfunctioning. Consider early keyboarding in school if hand writing is problematic.

PROBLEM:

COXA VALGAEXPECTATIONS: Hip changes are virtually constant. Coxa valga often progresses to completedisappearance of the femoral heads. Although one might expect that surgery for repositioning ofthe femoral heads would slow arthritic changes, this has not be demonstrated and surgery is notof any proven benefit.

MONITORING: -

INTERVENTION: -

PROBLEM:

GENU VALGUMEXPECTATIONS: Knock-knee deformity is virtually constant, usually severe and oftendebilitating.

MONITORING: Clinically assess severity of valgus deformity. Early referral to a pediatricorthopedist is appropriate.

INTERVENTION: Varus osteotomy surgery is clearly indicated. Timing of that surgery is often anissue. If done very early then there is a high probability of recurrence. However, since growth iscompleted in children with this disorder by around 10 y of age, this is a reasonable age tocomplete the surgery (if intervention is not essential before that time). There is generalconsensus that leg surgery should be done after cervical fusion is accomplished.

PROBLEM:

FOOT POSITION ABNORMALITIESEXPECTATIONS: Clubbed/splayed/skewed feet are common (but only occasionally requiringsurgery). Pes planus is virtually constant.

MONITORING: Clinical.

INTERVENTION: If pes planus is associated with pain with walking then in-the-shoe orthotics canbe used.

PROBLEM:

ARTHRITISEXPECTATIONS: Development of degenerative arthritic changes of weight bearing joints iscommon in adults.

MONITORING: Query adolescents and adults regarding chronic pain.

INTERVENTION: This commends limitation of repetitive weightbearing (often self imposed forother reasons by affected individuals). Both total hip and total knee replacement surgery havebeen accomplished in adults who develop intractable pain and disability secondary todegenerative arthritis. However, it is very challenging surgery that should be undertaken only byorthopedists with extensive experience with special circumstances.

PROBLEM:

OBESITYEXPECTATIONS: Low activity level predisposes to excess weight gain. Obesity can exacerbatethe respiratory and orthopedic problems.

MONITORING: Diagnosis-specific charts for weight and for BMI are available.

INTERVENTION: Weight management should include low impact or non-weight bearing aerobicexercise program; aquatic therapy is particularly helpful (and is also beneficial for orthopediccomplications).

PROBLEM:

ANESTHESIA RISKEXPECTATIONS: Risks are increased secondary to pulmonologic, cardiologic and neurologicsequelae.

MONITORING: Careful assessment of cervical spine status, pulmonologic status and cardiologicinvolvement should be completed prior to any anesthetic episode.

INTERVENTION: Fiberoptic intubation is usually needed and compulsive postoperativepulmonologic care is essential.

GENETICS AND MOLECULAR BIOLOGY

Morquio Syndrome is an autosomal recessive process. That means that a couple who has had one child affected by this disorder will have a 25% risk that any subsequent child will also beaffected. In contrast, the affected individual has very little risk to have an affected child. This isof some relevance since fertility in affected individuals is normal. Females have carriedpregnancies to term, although respiratory compromise late in pregnancy is likely, and Cesareansection inevitable.Morquio Syndrome arises secondary to deficiency of an enzyme called N-acetylgalactosamine-6-sulfatase. This results from loss of function mutations in both copies of the gene, GALNS.Many different mutations have been detected in GALNS and there is some genotypic-phenotypiccorrelation – that is, the mutations present to some extent predict the severity of clinicalmanifestations.

Richard M. Pauli, M.D., Ph.D.,
Midwest Regional Bone Dysplasia Clinics
revised 8/2009