IV ()

In 1929, Morquio and Brailsford independently described b) Decreased mobility in large joints (e.g., cases of what is now believed to be Morquio syndrome. The hips, knees, elbows) exact incidence is unknown but is estimated to be 1 in 75,000 vii. Unusual facial appearance to 1 in 200,000. a) Coarse facies b) Prognathism GENETICS/BASIC DEFECTS c) Broad mouth viii. Eye manifestations 1. Genetic inheritance: autosomal recessive a) Mild corneal clouding 2. Two forms of MPS IV b) Glaucoma a. MPS IVA c) Cataract i. Deficient N-acetyl-galactosamine 6-sulphate sul- ix. Dental features fatase (GALNS) , which is mapped to 16q24.3 a) Abnormally thin enamel ii. Wide spectrum of clinical manifestations b) Spade-shaped incisors b. MPS IVB c) Pointed cusps i. Deficient β-galactosidase (GLB1) gene d) Pitted buccal surfaces ii. Wide spectrum of clinical manifestations e) Frequent caries formation 3. Pathogenesis x. Cardiac manifestations a. Defective degradation of keratan sulfate secondary to a) Aortic valve insufficiency or stenosis deficiency of either N-acetyl-galactosamine-6-sulfate b) Mitral valve thickening and stenosis sulfatase (GALNS gene) in MPS IVA or β-galactosi- c) Cardiac failure dase (GLB1 gene) in MPS IVB xi. Progressive deafness b. Cartilage and cornea: the major organs affected in xii. Hepatomegaly Morquio syndrome since keratan sulfate is predomi- xiii. Upper airway obstruction nantly found in these tissues a) Obstructive sleep apnea b) Nocturnal dyspnea CLINICAL FEATURES xiv. Intelligence usually normal, rarely with progres- 1. MPS IVA sive mental regression a. Classic form b. Mild form i. The most common form i. Almost normal stature ii. Appear normal at birth ii. Mild skeletal abnormalities iii. Skeletal symptoms occurring between 1 and 3 a) Odontoid dysplasia but without atlantoaxial years of age instability iv. Clinical diagnosis usually not made until 3–15 b) Pectus carinatum deformity years of age c) Dysplastic hips v. Skeletal manifestations d) Waddling gait a) Marked dwarfism e) Kyphoscoliosis b) Waddling gait with tendency to fall f) Deformity of femoral heads c) Short neck g) Platyspondyly d) Hypoplasia or absence of the odontoid h) Limitation of joint movement process of the axis with risk of resulting in i) Deformities of metacarpals life-threatening atlantoaxial subluxation iii. Enamel hypoplasia e) Cervical myelopathy iv. Mild corneal clouding f) Gibbus v. Absent keratosulfaturia g) Restrictive chest wall movement 2. MPS IVB h) Pectus carinatum a. Severe form: clinical manifestations as severe as MPS i) Kyphoscoliosis IVA j) Genu valgum b. Mild form k) Semi-crouching stance i. Less severe progression of skeletal dysplasia l) Progressive skeletal deformities frequently ii. Less severe short stature resulting in neurologic compromise 3. Prognosis vi. Joint manifestations a. Atlantoaxial instability and subsequent cervical a) Hypermobile due to ligamentous laxity myelopathy

687 688 MPS IV (MORQUIO SYNDROME)

i. Cord transection and subsequent quadriparesis 7. Echocardiography for cardiac involvement or death secondary to a minor fall or extension of a. Aortic valve insufficiency or stenosis the neck b. Mitral valve thickening and stenosis ii. Bowel and bladder dysfunction and apnea sec- c. Ventricular hypertrophy ondary to cervical myelopathy 8. Slit-lamp examination for corneal clouding iii. Prolonged periods of hypoxia, pulmonary hyperten- 9. Mutation analysis sion, and even death from obstructive sleep apnea iv. Airway obstruction secondary to thickening of GENETIC COUNSELING tissue in the upper airway from mucopolysac- 1. Recurrence risk charide deposition a. Patient’s sib: 25% b. Predisposition to pulmonary infection because of pro- b. Patient’s offspring: not increased unless the spouse is gressive truncal deformity and immobility a carrier in which case there will be 50% of offspring c. Early-onset coronary heart disease and valve thick- affected ening (aortic and mitral) with resultant cardiac 2. Prenatal diagnosis dysfunction a. Demonstration of GalNac-6S or Gal-6S sulphatase defi- d. Visual disturbance and photophobia secondary to ciency in cultured amniotic fluid cells or chorionic villi corneal clouding b. Abnormal electrophoretic pat- e. Predisposition to dental caries secondary to enamel tern in amniotic fluid abnormalities c. Mutation analysis in amniocytes or chorionic villi 3. Management DIAGNOSTIC INVESTIGATIONS a. Orthopedic management i. Surgery to stabilize the upper cervical spine, 1. Urine MPS spot tests: associated with false-positive and usually by spinal fusion, can be lifesaving for false-negative results spinal cord compression 2. Excessive urinary excretion of keratin sulfate: determina- ii. Bilateral osteotomies to correct the knock-knee tion by spectrophotometric assays with dimethylmethyl- deformity (severe coxa valgum) ene blue b. Anesthetic difficulties 3. Metachromatic granules in cultured fibroblasts i. Difficult endotracheal intubation due to odontoid 4. Diagnosis confirmed by direct enzymatic assay in leuko- hypoplasia and atlanto-axial instability cytes or fibroblasts ii. Compression of the cord during hyperextension a. N-acetylgalactosamine-6-sulfatase deficiency (classic of the neck form) iii. Reduction in vital capacity, functional residual b. β-galactosidase deficiency (mild form) capacity, and total lung capacity due to chest cage 5. Radiographic features dysfunction (kyphoscoliosis and pectus carinatum) a. Short trunk dwarfism c. Infection control b. Dysostosis multiplex d. Medications for glaucoma c. Spondyloepiphyseal dysplasia (the hallmark of the e. Cornea transplant not very helpful syndrome) f. Hearing aids helpful d. Odontoid hypoplasia g. Hernia repairs e. Sternal protrusion h. Cardiac management f. Platyspondylia i. Aortic regurgitation g. Kyphosis ii. Endocarditis prophylaxis h. Hyperlordosis iii. Cardiac valve replacement historically not con- i. Scoliosis sidered for these patients j. Ovoid deformities of the thoracic vertebrae i. Potential strategies for treatment including k. Hook-shaped lumbar bodies replacement, gene therapy, and allogenic bone mar- l. Long pelvic configuration row transplantation in which engrafted cells provide m. Coxa valga the normal enzyme n. Genu valgum o. Ulnar deviation of the wrist REFERENCES p. Valgus deformity of the elbow q. Inclinations of distal ends of radius and ulna toward Bagshaw RD, Zhang S, Hinek A, et al.: Novel mutations (Asn 484 Lys, Thr 500 Ala, Gly 438 Glu) in Morquio B disease. Biochim Biophys Acta each other 1588:247–253, 2002. r. Metacarpal deformities Baker E, Guo XH, Orsborn AM, et al.: The Morquio A syndrome s. Short phalanges (mucopolysaccharidosis IVA) gene maps to 16q24.3. Am J Hum Genet t. Epiphyseal deformities of the tubular bones 52:96–98, 1993. u. Wide metaphysis Bartz HJ, Wiesner L, Wappler F: Anaesthetic management of patients with mucopolysaccharidosis IV presenting for major orthopaedic surgery. v. Osteoporosis Acta Anaesthesiol Scand 43:679–683, 1999. 6. CT and MRI of the brain and cervical spine for evaluation Beck M, Braun S, Coerdt W, et al.: Fetal presentation of Morquio disease type of odontoid hypoplasia and cord compression A. Prenat Diagn 12:1019–1029, 1992. MPS IV (MORQUIO SYNDROME) 689

Beck M, Glossl J, Grubisic A, et al.: Heterogeneity of Morquio disease. Clin Muenzer J: Mucopolysaccharidoses. Adv Pediatr 33:269–302, 1986. Genet 29:325–331, 1986. Nelson J, Broadhead D, Mossman J: Clinical findings in 12 patients with MPS Beck M, Petersen EM, Spranger J, et al.: Morquio’s disease type B (beta-galac- IV A (Morquio’s disease). Further evidence for heterogeneity. Part I: tosidase deficiency) in three siblings. S Afr Med J 72:704–707, 1987. Clinical and biochemical findings. Clin Genet 33:111– Blaw ME, Langer LO: Spinal cord compression in Morquio-Brailsford’s dis- 120, 1988. ease. J Pediatr 74:593–600, 1969. Nelson J, Kinirons M: Clinical findings in 12 patients with MPS IV A Braverman N, Hoover-Fong J: Mucopolysaccharidosis type IV. Emedicine, (Morquio’s disease). Further evidence for heterogeneity. Part II: Dental 2003. http://www.emedicine.com findings. Clin Genet 33:121–125, 1988. Brailsford JF: Chondro-osteo-dystrophy, roentgenographic and clinical fea- Nelson J, Thomas PS: Clinical findings in 12 patients with MPS IV A tures of a child with dislocation of vertebrae. Am J Surg 7:404–407, 1929. (Morquio’s disease). Further evidence for heterogeneity. Part III: Bunge S, Kleijer WJ, Tylki-Szymanska A, et al.: Identification of 31 novel Odontoid dysplasia. Clin Genet 33:126–130, 1988. mutations in the N-acetylgalactosamine-6-sulfatase gene reveals exces- Neufeld EF, Muenzer J: The Mucopolysaccharidosis. In: Scriver CR, Beardet sive allelic heterogeneity among patients with Morquio A syndrome. al., Sly WS, Valle D (eds): The Metabolic and Molecular Bases of Hum Mutat 10:223–232, 1997. Inherited disease Vol II, 7th ed, New York: McGraw-hill, 1995: Chih-Kuang C, Shuan-Pei L, Shyue-Jye L, et al.: MPS screening methods, the 2465–2494. 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Fig. 2. Lateral view of the spine showing platyspondyly, anterior beaking of vertebral bodies, and lumbar gibbus similar to those seen in .

Fig. 1. A boy with MPS IVB showing coarse facial appearance and short trunk. MPS IV (MORQUIO SYNDROME) 691

Fig. 3. Radiographic studies showing dysostosis multiplex with prox- imal conical metacarpals and angling of the ulna toward the radius with dysplastic ulnar and radial growth plates.