Skeletal Radiol (2015) 44:579–586 DOI 10.1007/s00256-014-1982-7
CASE REPORT
Hurler syndrome: orofacial, dental, and skeletal findings of a case Arpita Rai Thakur & Venkatesh G. Naikmasur & Atul Sattur
Received: 11 February 2014 / Revised: 30 July 2014 / Accepted: 3 August 2014 / Published online: 20 August 2014 # ISS 2014
Abstract Hurler syndrome is a disorder of mucopolysaccharide metabolism caused due to inherited deficiencies of lysosomal α-l-iduronidase activity. We present a case of a 15-yearold male patient presenting with clinical and laboratory characteristics of the syndrome. A rare combination of skeletal, ophthalmologic, and dental findings was observed in this patient. Mucopolysaccharides excretion spot test of urine was positive and an assay of alpha-l-iduronidase enzyme was deficient, confirming the clinical diagnosis of Hurler syndrome. Keywords Hurler syndrome . Mucopolysaccharidosis . MPS-I . Dental . Oral . Skeletal
Introduction Hurler syndrome, also known as mucopolysaccharidosis-I (MPS-I), is an autosomal, recessively inherited, lysosomal storage disease [1], with the reported frequency of occurrence of 0.99–1.99/100,000 live births [2]. It is characterized by deficiency of α–L iduronidase enzyme, which causes progressive accumulation of two mucopolysaccharides (dermatan and A. R. Thakur (*) Department of Oral Medicine and Radiology, Faculty of Dentistry Jamia Millia Islamia, New Delhi Delhi 110025, India e-mail: [email protected] V. G. Naikmasur : A. Sattur Department of Oral Medicine and Radiology, S.D.M. College of Dental Sciences & Hospital, Dharwad, Karnataka 580 009, India V. G. Naikmasur e-mail: [email protected] A. Sattur e-mail: [email protected]
heparan sulfate) in various tissues presenting as a wide range of clinical manifestations like mental retardation, skeletal deformities, corneal clouding, coarse features, and respiratory and cardiovascular abnormalities [3]. MPS-I has historically been classified clinically into three syndromes based on age of onset, rapidity of progression, and presence and degree of cognitive involvement. The severe form of MPS I is known as Hurler syndrome (MPS I-H) and is characterized by an early onset of symptoms and central nervous system (CNS) effects. Milder forms of MPS I are called Hurler–Scheie and Scheie syndrome and have a late onset with no discernable effects on the CNS [4]. The syndrome is characterized by severe musculoskeletal ramifications, which are together known as “dysostosis multiplex”. Joint stiffness and progressive lumbar Gibbus or kyphosis are common features seen in these patients [5]. The oral and dental findings of Hurler syndrome previously reported in literature include short mandibular rami with abnormal condyles, macroglossia, hyperplastic gingiva, higharched palate, spaced hypoplastic peg-shaped teeth with retarded eruption; and localized dentigerous cyst-like radiolucencies [6–9]. We present the skeletal, orofacial, and dental findings of a case of Hurler syndrome in 15-year-old male patient. The patient reported with the classical features of this syndrome. This report highlights in detail the radiographic features of skeletal and dental manifestations of this syndrome and discusses its treatment. It is noteworthy that such cases present as true diagnostic challenge especially amongst the broad family of mucopolysacchroidoses as many syndromes included in this category have overlapping features. Initial diagnosis is primarily based on a physician’s recognition of signs and symptoms. The biochemical investigations confirm the clinical and radiographic diagnosis.
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Fig. 1 a Clinical photograph of the patient from front showing crouching stance of the patient due to severely stunted growth and skeletal dysplasia. b Clinical photograph of the patient in profile view showing pectus carinatum of chest and Gibbus deformity of back
Case report A 15-year-old male patient reported to the Department of Oral Medicine and Radiology with complaint of dental pain for the duration of 12 days. Detailed history revealed that the patient was suffering from progressive skeletal deformity since birth. He was the firstborn child of a consanguineous couple without a family history of such defects. Developmental milestones were delayed and marked mental retardation was apparent. The patient’s IQ was between 35 and 49. The child was apparently normal at birth but developed the characteristic appearance over the first few years of life. Due to a lack of resources, the parents had never consulted any practitioner for the patient’s deteriorating condition. At the time of presentation, a rare combination of skeletal, ophthalmologic, and Fig. 2 a Clinical photograph of the patient’s upper extremities showing muscle wasting, deformed arms, and claw-shaped hands. b Clinical photograph of the patient lower extremities overall thin lower limbs with prominent knee joints suggestive of severe muscle wasting. Flat foot is evident
dental findings was noted. Hepatosplenomegaly was also observed, 5 cm below the costal margins, firm in consistency, and non-tender. The patient’s parents gave their informed consent to the publication of the included material. Skeletal findings Severely stunted growth with skeletal dysplasia involving all the bones was observed. The patient had retarded growth with a short stature for his chronologic age. Motion in most joints was limited; the patient could not stand or walk and had a crouching stance (Fig. 1a). Overall, the patient had pale, dry, and coarse skin. Pectus carinatum, deformity of the chest characterized by a protrusion of the sternum and ribs, was seen. Marked lumbodorsal kyphosis or Gibbus deformity and
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Fig. 3 a Chest X-ray (PA view) showing crowding of ribs, widening of space between sternum and bodies of ribs; valgus deformity of humerus; submetaphyseal over-tabulation of humerus and expansion of distal shaft. b Lateral radiograph of dorsal lumbar spine confirming pectus carinatum
and kyphosis. Dysplastic vertebral bodies of lower thoracic and upper lumbar bodies are seen. Transverse diameter of vertebral bodies exceeded the height of the same
scoliosis were evident (Fig. 1b). The neck was abnormally short, giving a clinical appearance of head resting directly over the shoulders, exaggerated cervical curvature, and restricted movements. Flexion contracture limited elbow movements and the patient could not raise his arms above the head. His hands were short and broad, presenting with “clawshaped” deformity (Fig. 2a). Typically, complete extension of legs was not possible and in contrast to the overall thin lower limbs, knee joints appeared thickened suggestive of severe muscle wasting (Fig. 2b). Radiographic survey of the patient was performed. The chest radiograph (Fig. 3a) revealed oar-shaped ribs, characterized by widening of ribs in lateral and ventral portions as well as over constriction of ribs at paravertebral ends. There was splaying of ribs anteriorly. Sterna protrusion at an angle of 45° from its clavicular junction was evident. There was valgus deformity of humerus with submetaphyseal over tubulation of humerus and expansion of distal shaft. Lateral radiograph of dorsal lumbar spine (Fig. 3b) showed kyphosis and dysplastic vertebral bodies of lower thoracic and upper lumbar bodies. Transverse diameter of vertebral bodies exceeded the height of the same. A pelvic radiograph (Fig. 4) revealed hypoplasia of basilar portion of ilia, flaring of iliac wings, thick ischial and pubic bones with coxa valga deformity. Partial subluxation of the femoral heads and long femoral neck was seen. Dysplastic vertebral bodies with convex end plates were also seen on pelvic radiographs. Tibia-fibula and radius-ulna showed marked diaphyseal widening and distortion, with small and deformed epiphysis (Figs. 5a and b). These bones were short of normal length and displayed metaphyseal splaying. A hand and wrist radiograph (Fig. 6a) showed undertubulation of shafts of short tubular bones with bullet-shaped phalanges and proximal pointing of the second to fifth metacarpals. Carpal bones were short of normal length and there was a lack of ossification, suggesting a bone age much less than the
chronological age. Overriding of radius over ulna was noted in both hands and overall reduced density of bones was seen. A radiograph of the feet (Fig. 6b) showed short metatarsals and tarsal bones had not fully ossified, and there was reduced overall density of all bones.
Orofacial and dental findings In addition to bilateral corneal opacity, coarsening of facial features was observed (Fig. 7). The head was large, with a
Fig. 4 Pelvic radiograph showing underdeveloped basal ilia. The acetabulum is partially dislocated with flaring of iliac wings. Dysplastic vertebral bodies with convex end plates was also seen on pelvic radiographs
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Fig. 5 Radiograph of long bones of upper extremities (Fig. 5a) and lower extremities (Fig. 5b) showing marked diaphyseal widening and distortion with small and deformed epiphysis, and splaying of metaphysis of long bones. Short height of long bones
prominent forehead and marked supraorbital ridges. The patient also had a flattened nasal bridge, flared nose, upturned nasal tip, and hypertelorism. Nasal congestion with stertorous breathing through the mouth was noticed. Puffy eyelids and coarse, bushy eyebrows, long eyelashes, and thickened earlobes were seen. The patient had a large mouth with broad, patulous lips. Philtrum of the upper lip was long. No movements were perceptible at bilateral TMJ. Reduced lower facial height was observed. Macroglossia with tongue protruding between the teeth and anterior open bite was evident. An increase in the transverse diameter of the dental arches and flattening of the maxillary alveolar processes anteriorly was attributed to compression between the enlarged tongue and thickened lips. The existing permanent teeth were widely spaced and the gingival tissues were slightly thick. The enamel of the teeth was slightly hypoplastic with a clinical appearance of pitted enamel. Exaggerated conical crown form was exhibited by cuspids and bicuspids. (Fig. 8a and b) Panoramic radiograph (Fig. 9) revealed hypoplastic appearance of the mandibular condyles, which confirmed the clinical finding of limited opening of the mandible. The
condyles were replaced by a flat inclined surface on the right side and a cup-shaped excavation of condyle was evident on the left side. The mandible appeared to be generally small, with reduced height of the ascending ramus while coronoid process was apparently larger than normal. The chronologic development of the teeth was found to be normal for most teeth. However, slightly delayed root formation was found in relation to permanent second mandibular molars and premolars. Open contacts between all teeth were observed. Skull radiographs (A-P and lateral) revealed an enlarged deformed skull with thickened cranium. There was evidence of premature closure of sutures. The orbits were shallow and falx calcification was noted (Fig. 10a and b). Provisional diagnosis of mucopolysacchroidoses was made in this case and Hurler syndrome, Hunter syndrome, and Morquio syndrome were considered for differential diagnosis. Routine laboratory investigations (hemoglobin –12.7 gm%, total leucocyte count 11,900 cell/cm3, and differential leucocyte count) were normal. The erythrocyte sedimentation rate was raised to 101 mm/first hour. Urine analysis showed positive paper spot test for mucopolysaccharides. Hurler
Fig. 6 a Hand and wrist radiograph showing under-constricted shafts of short tubular bones with bullet-shaped phalanges and proximal pointing of the second to fifth metacarpals. Carpal bones were small and all had not appeared, suggesting a bone age much less than the chronological age.
Overriding of radius over ulna is seen in both hands and overall reduced density of bones is evident. b Radiograph of the feet showing short metatarsals. Tarsal bones had not fully developed, and there was reduced overall density of all bones
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Fig. 7 Clinical photograph of the patient showing bilateral corneal opacity
syndrome was diagnosed following observed deficiency of alpha-l-iduronidase enzyme.
Fig. 9 Panoramic radiograph showing spacing between teeth and conical teeth. Root completion of teeth is delayed for chronological age. Short mandible that is broad, bigonial distance wide, rami are short and narrow. Condyles are underdeveloped and replaced by a flat inclined surface. Coronoid appears hyperplastic. Irregular mandibular arch is seen
Discussion
Dysostosis multiplex is a general term used for the large spectrum of skeletal abnormalities in Hurler syndrome. The general phenomenon is failure of ossification and aberrant bone remodeling of which the exact pathophysiological mechanism remains to be elucidated [13]. Recently it was shown that a reduced cathepsin K activity, due to the accumulation of GAGs, leads to impaired osteoclast activity and decreased subepiphyseal cartilage resorption [14]. As a result, dysostosis multiplex manifests as shortened and thickened bones that are abnormally shaped and may present with articular erosions [14]. MPS I, in particular, results in facial dysmorphia, kyphoscoliosis, stiff joints, and hip dysplasia with subluxation that causes a waddling gait [15]. The anteroinferior beaking of the vertebral bodies has been ascribed to herniation of the nucleus pulposus into the superior aspect of the vertebra below [16]. The extra skeletal radiographic findings which may be seen include hepatosplenomegaly and prominent perivascular spaces [17]. The present case showed almost all these classical manifestations of Hurler syndrome. The diagnosis of the present case was based on characteristic clinical features like corneal clouding, coarse facial features, joint stiffness, hepatosplenomegaly, and mental retardation. Radiographic survey of the patient confirmed the clinical findings presenting with dysostosis multiplex. The dental findings of the syndrome include spaced, hypoplastic, peg-shaped teeth with retarded eruption, flattened
Mucopolysaccharidoses (MPS) are a group of inborn errors of metabolism caused by a deficiency of specific lysosomal enzymes that affect glycosaminoglycan (GAG) catabolism. To date, 11 enzyme defects that cause seven different types of MPS have been identified [5]. Table 1 shows the summary of general and musculoskeletal features of MPS. Hurler syndrome was initially referred in 1900 by Thompson but the complete clinical spectrum was subsequently described by Hurler in 1919 [10]. It is a chronic, progressive disease, affecting bones, joints, facial appearance, eyes, heart, respiratory system, viscera, and sometimes the central nervous system. The symptoms arise after birth and progress rapidly. Most of the untreated patients die due to complications related to brain damage or cardiorespiratory problems [11]. Gorlin et al. described the facial phenotype [12]. A slight coarsening of the facial features at 3–6 months of age is usually the first abnormality detected. The head is large with bulging frontal bones. The skull is often scaphocephalic secondary to premature closure of the metopic and sagittal sutures. The nasal bridge is depressed with broad nasal tip and anteverted nostrils. The cheeks are full. The lips are enlarged and the mouth is usually held open, particularly after age 3 years. Chronic nasal discharge is present and corneal clouding is observed. Fig. 8 a, b Intraoral photographs of the patient showing spacing between permanent teeth, pitting of enamel, and exaggerated conical crown form of cuspids and bicuspids
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Fig. 10 Skull radiographs PA (a) and lateral view (b) revealing an enlarged deformed skull with thickened cranium. There was evidence of premature closure of sutures. The orbits were shallow and falx calcification was noted
Table 1 Summary of general and musculoskeletal features of the MPS syndromes MPS type
Enzyme deficiency
General features
MPS I (Hurler/Scheie)
Alpha-L-iduronidase
MPS II (Hunter)
L-sulfoiduronate sulfatase
MPS III (Sanfilippo)
Heparan sulfate sulfamidase, Nacetyl-alpha-D-glucosaminidase, acetyl-coenzyme A (CoA): alpha-glucosamide N–acetyltransferase, acetyl-coenzyme A (CoA): alpha-glucosamide N–acetyltransferase N-acetylgalactosamine 6-sulfatase (gal-6-sulfatase), beta-galactosidase
Coarse facies, gum Dysostosis multiplex, disproportionate short stature, joint hypertrophy, contractures, Carpal tunnel syndrome (CTS), odontoid macroglossia, hypoplasia, atlanto-axial instability, acetabular dysplasia, initial intellectual coxa valga, genu valgum, trigger digits development normal, then deteriorates, cardiomyopathy, aortic and mitral valve disease, hydrocephalus, hepatosplenomegaly Coarse facies, Dysostosis multiplex, disproportionate short stature, joint X-linked inheritance, contractures, CTS, odontoid hypoplasia, atlanto-axial instaclassic nodular rash bility, acetabular dysplasia, coxa valga, genu valgum, trigger (rare), digits normal intellect initially, progressive neurodegeneration, cervical myelopathy, Most common MPS Mild somatic manifestations only, mild short stature and disorder, contractures in a small proportion (mainly elbow joint) mild dysmorphism, severe behavioral disturbance
MPS IV (Morquio)
MPS VI N-acetylgalactosamine (Maroteaux–Lamy) 4-sulfatase
MPS VII (Sly)
Beta-glucuronidase
MPS type IX
Hyaluronidase deficiency
Normal intellect, severe bony dysplasia
Musculoskeletal features
Severe skeletal dysplasia, dysostosis multiplex, disproportionate short stature, joint hypermobility, odontoid hypoplasia, atlanto-axial instability, acetabular dysplasia, hip dislocations, coxa valga, genu valgum, pes planus, pectus carinatum Carpal tunnel syndrome, Dysostosis multiplex, disproportionate short stature, joint cardiomyopathy, contractures, CTS, odontoid hypoplasia, atlanto-axial instaendocardial bility, acetabular dysplasia, coxa valga, genu valgum, trigger fibroelastosis, digits, pectus carinatum cervical myelopathy, macroglossia Very rare, mild Hurler Dysostosis multiplex, disproportionate short stature, joint type phenotype contractures, odontoid hypoplasia, atlanto-axial instability, acetabular dysplasia, pectus carinatum Very few cases reported Short stature, periarticular soft tissue masses, nodular synovial masses, joint effusions, acetabular erosions
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alveolar ridges with hyperplastic gingivae, macroglossia, and a high-arched palate. The mandible is short and broad, with abnormal condyles [6, 7, 9]. All these features were seen in our patient. Other features seen in Hurler’s syndrome, but not observed in this case, were absence of the articular eminence and calcification of the stylohyoid ligament. Dentigerous cystlike lesions are also reported; these are almost always bilateral, appear to start within the dental follicle, and occur chiefly in the mandible [18]. In a recently reported case, decreased pulp space in primary molars, taurodontism, and ectopy of mandibular molars were seen, which were not observed in this case [19]. The radiographic findings of skull show that the skull is enlarged and demonstrates a long antero-posterior dimension (dolichocephaly). The frontal bones are often prominent with heavy supraorbital ridges, and the skull vault may be thicker than normal [9]. In the present case, enlarged deformed skull with thickened cranium was observed in accordance with previous report. Also noticeable was limited motion of the TMJ. Traditionally, treatments for MPS I have aimed at relieving symptoms. More radical treatments have been explored including bone marrow transplantation, which has become the treatment of choice for carefully selected Hurler patients. Enzyme replacement therapy (alpha-Liduronidase, Aldurazyme) is now available to treat the intermediate and milder phenotypes (Hurler–Scheie and Scheie) as well as recently more severely affected patients [20]. The development of enzyme enhancement therapy, substrate reduction strategies, and also of gene therapy for lysosomal storage diseases and other metabolic disorders, and the various combinations of such strategies, are possible future developments. As a result of these improved therapies, patients with Hurler syndrome may increasingly need dental treatment. It is therefore useful for the dental practitioner to be aware of the clinical and radiographic features of Hurler’s syndrome. Because of the progressive nature of mucopolysaccharidosis type I (MPS I), these patients need to be regularly monitored. The focus of these evaluations should be to identify potential problems early at a time when intervention would decrease morbidity and enhance the quality of life. Patients with mucopolysaccharidosis type I (MPS I) may have cardiovascular manifestations together with difficult airway access, which means that these patients have far greater risks for general anesthesia than others [21]. The short, immobile, or unstable necks found in this group of patients combined with stiffening of the TM joint, macroglossia, or mandibular prognathism means that normal anesthetic intubation may be impossible. Furthermore, the developing dental tissues are extremely sensitive to the effects of chemotherapy and all teeth developing at the time of bone marrow transplant may be affected. The input of the dental practitioner is essential in the care of such patients. The practitioner must provide dietary and oral hygiene advice, as well as preventive measures such
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as fissure sealants and appropriate fluoride supplementation to prevent the development of caries. The dental practitioner is well placed to detect dental caries at an early stage and prevent their progression [19].
Conflict of interest None.
References 1. Leroux S, Muller JB, Boutaric E, Busnel A, Lemouel F, AndroGarçon M, et al. Hurler syndrome: early diagnosis and treatment. Arch Pediatr. 2014;21(5):501–62. 2. Lowry RB, Renwick DHG. Relative frequency of the Hurler–Hunter syndrome. N Engl J Med. 1971;284:221–2. 3. McKusick VA, Neufeld EF, Disease TMS. The metabolic basis of inherited disease. 5th ed. New York: McGraw-Hill; 1983. p. 751–77. 4. D’Aco K et al. Diagnosis and treatment trends in mucopolysaccharidosis I: findings from the MPS Registry. Eur J Pediatr. 2012;171:911–9. 5. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic & molecular bases of inherited disease, vol. III. 8th ed. New York: McGraw-Hill; 2001. 6. Keith O, Scully C, Weidmann GM. Orofacial features of Scheie (Hurler–Scheie) syndrome (alpha-L-iduronidase deficiency). Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1990;70:70–4. 7. Thomas S, Tandon S. Hurler syndrome: a case report. J Clin Pediatr Dent. 2000;24:335–8. 8. Worth HM. Hurler’s syndrome. A study of radiologic appearances in the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1966;22:21–35. 9. Gardner DG. The oral manifestations of Hurler’s syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1971;32:46–57. 10. Afifi AK, Sato Y, Waziri MH, Bell WE. Computed tomography and magnetic resonance imaging of the brain in Hurler’s disease. J Child Neurol. 1990;5:235–41. 11. Weisstein JS, Delgado E, Steinbrach L, Hart K, Packman S. Musculoskeletal manifestations of Hurler syndrome: long-term follow-up after bone marrow transplantation. J Pediatr Orthop. 2004;24: 97–101. 12. Gorlin RJ, Cohen Jr MM, et al. Syndromes of the head and neck. 4th ed. New York: Oxford Univ. Press (pub.); 2001. 13. van der Linden MH, Kruyt MC, Sakkers RJ, de Koning TJ, Oner FC, Castelein RM. Orthopaedic management of Hurler’s disease after hematopoietic stem cell transplantation: a systematic review. J Inherit Metab Dis. 2011;34:657–69. 14. Wilson S, Hashamiyan S, Clarke L, Saftig P, Mort J, Dejica VM, et al. Glycosaminoglycan-mediated loss of cathepsin K collagenolytic activity in MPS I contributes to osteoclast and growth plate abnormalities. Am J Pathol. 2009;175:2053–62. 15. Herati RS, Knox VW, O’Donnell P, D’Angelo M, Haskins ME, Ponder KP. Radiographic evaluation of bones and joints in mucopolysaccharidosis I and VII dogs after neonatal gene therapy. Mol Genet Metab. 2008;95(3):142–51. 16. Tandon V, Williamson JB, Cowie RA, Wraith JE. Spinal problems in mucopolysaccharidosis I (Hurler syndrome). J Bone Joint Surg [Br]. 1996;78-B:938–44. 17. Hurler G. Über einen Typ multipler Abartungen, vorwiegend am Skelettsystem. Z Kinderheilkunde. 1920;24(5-6):220–34. doi:10. 1007/BF02222956.
586 18. Hingston EJ, Hunter ML, Hunter B, Drage N. Hurler’s syndrome: dental findings in a case treated with bone marrow transplantation in infancy. Int J Paediatr Dent. 2006;16:207–12. 19. Guven G, Cehreli ZC, Altun C, Sençimen M, Ide S, Bayari SH, et al. Mucopolysaccharidosis type I (Hurler syndrome): oral and radiographic findings and ultrastructural/chemical features of enamel and dentin. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;105:72–8.
Skeletal Radiol (2015) 44:579–586 20. Wraith JE, Beck M, Lane R, van der Ploeg A, Shapiro E, Xue Y, et al. Enzyme replacement therapy in patients who have mucopolysaccharidosis I and are younger than 5 years: results of a multinational study of recombinant human alphaL-iduronidase (laronidase). Pediatrics. 2007;120:e37–46. 21. Sjogren P, Pedersen T, Steinmetz H. Mucopolysaccharidosis and anaesthetic risks. Acta Anaesthesiol Scand. 1987;31: 214–8.
CASE REPORT
Hurler syndrome: orofacial, dental, and skeletal findings of a case Arpita Rai Thakur & Venkatesh G. Naikmasur & Atul Sattur
Received: 11 February 2014 / Revised: 30 July 2014 / Accepted: 3 August 2014 / Published online: 20 August 2014 # ISS 2014
Abstract Hurler syndrome is a disorder of mucopolysaccharide metabolism caused due to inherited deficiencies of lysosomal α-l-iduronidase activity. We present a case of a 15-yearold male patient presenting with clinical and laboratory characteristics of the syndrome. A rare combination of skeletal, ophthalmologic, and dental findings was observed in this patient. Mucopolysaccharides excretion spot test of urine was positive and an assay of alpha-l-iduronidase enzyme was deficient, confirming the clinical diagnosis of Hurler syndrome. Keywords Hurler syndrome . Mucopolysaccharidosis . MPS-I . Dental . Oral . Skeletal
Introduction Hurler syndrome, also known as mucopolysaccharidosis-I (MPS-I), is an autosomal, recessively inherited, lysosomal storage disease [1], with the reported frequency of occurrence of 0.99–1.99/100,000 live births [2]. It is characterized by deficiency of α–L iduronidase enzyme, which causes progressive accumulation of two mucopolysaccharides (dermatan and A. R. Thakur (*) Department of Oral Medicine and Radiology, Faculty of Dentistry Jamia Millia Islamia, New Delhi Delhi 110025, India e-mail: [email protected] V. G. Naikmasur : A. Sattur Department of Oral Medicine and Radiology, S.D.M. College of Dental Sciences & Hospital, Dharwad, Karnataka 580 009, India V. G. Naikmasur e-mail: [email protected] A. Sattur e-mail: [email protected]
heparan sulfate) in various tissues presenting as a wide range of clinical manifestations like mental retardation, skeletal deformities, corneal clouding, coarse features, and respiratory and cardiovascular abnormalities [3]. MPS-I has historically been classified clinically into three syndromes based on age of onset, rapidity of progression, and presence and degree of cognitive involvement. The severe form of MPS I is known as Hurler syndrome (MPS I-H) and is characterized by an early onset of symptoms and central nervous system (CNS) effects. Milder forms of MPS I are called Hurler–Scheie and Scheie syndrome and have a late onset with no discernable effects on the CNS [4]. The syndrome is characterized by severe musculoskeletal ramifications, which are together known as “dysostosis multiplex”. Joint stiffness and progressive lumbar Gibbus or kyphosis are common features seen in these patients [5]. The oral and dental findings of Hurler syndrome previously reported in literature include short mandibular rami with abnormal condyles, macroglossia, hyperplastic gingiva, higharched palate, spaced hypoplastic peg-shaped teeth with retarded eruption; and localized dentigerous cyst-like radiolucencies [6–9]. We present the skeletal, orofacial, and dental findings of a case of Hurler syndrome in 15-year-old male patient. The patient reported with the classical features of this syndrome. This report highlights in detail the radiographic features of skeletal and dental manifestations of this syndrome and discusses its treatment. It is noteworthy that such cases present as true diagnostic challenge especially amongst the broad family of mucopolysacchroidoses as many syndromes included in this category have overlapping features. Initial diagnosis is primarily based on a physician’s recognition of signs and symptoms. The biochemical investigations confirm the clinical and radiographic diagnosis.
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Fig. 1 a Clinical photograph of the patient from front showing crouching stance of the patient due to severely stunted growth and skeletal dysplasia. b Clinical photograph of the patient in profile view showing pectus carinatum of chest and Gibbus deformity of back
Case report A 15-year-old male patient reported to the Department of Oral Medicine and Radiology with complaint of dental pain for the duration of 12 days. Detailed history revealed that the patient was suffering from progressive skeletal deformity since birth. He was the firstborn child of a consanguineous couple without a family history of such defects. Developmental milestones were delayed and marked mental retardation was apparent. The patient’s IQ was between 35 and 49. The child was apparently normal at birth but developed the characteristic appearance over the first few years of life. Due to a lack of resources, the parents had never consulted any practitioner for the patient’s deteriorating condition. At the time of presentation, a rare combination of skeletal, ophthalmologic, and Fig. 2 a Clinical photograph of the patient’s upper extremities showing muscle wasting, deformed arms, and claw-shaped hands. b Clinical photograph of the patient lower extremities overall thin lower limbs with prominent knee joints suggestive of severe muscle wasting. Flat foot is evident
dental findings was noted. Hepatosplenomegaly was also observed, 5 cm below the costal margins, firm in consistency, and non-tender. The patient’s parents gave their informed consent to the publication of the included material. Skeletal findings Severely stunted growth with skeletal dysplasia involving all the bones was observed. The patient had retarded growth with a short stature for his chronologic age. Motion in most joints was limited; the patient could not stand or walk and had a crouching stance (Fig. 1a). Overall, the patient had pale, dry, and coarse skin. Pectus carinatum, deformity of the chest characterized by a protrusion of the sternum and ribs, was seen. Marked lumbodorsal kyphosis or Gibbus deformity and
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Fig. 3 a Chest X-ray (PA view) showing crowding of ribs, widening of space between sternum and bodies of ribs; valgus deformity of humerus; submetaphyseal over-tabulation of humerus and expansion of distal shaft. b Lateral radiograph of dorsal lumbar spine confirming pectus carinatum
and kyphosis. Dysplastic vertebral bodies of lower thoracic and upper lumbar bodies are seen. Transverse diameter of vertebral bodies exceeded the height of the same
scoliosis were evident (Fig. 1b). The neck was abnormally short, giving a clinical appearance of head resting directly over the shoulders, exaggerated cervical curvature, and restricted movements. Flexion contracture limited elbow movements and the patient could not raise his arms above the head. His hands were short and broad, presenting with “clawshaped” deformity (Fig. 2a). Typically, complete extension of legs was not possible and in contrast to the overall thin lower limbs, knee joints appeared thickened suggestive of severe muscle wasting (Fig. 2b). Radiographic survey of the patient was performed. The chest radiograph (Fig. 3a) revealed oar-shaped ribs, characterized by widening of ribs in lateral and ventral portions as well as over constriction of ribs at paravertebral ends. There was splaying of ribs anteriorly. Sterna protrusion at an angle of 45° from its clavicular junction was evident. There was valgus deformity of humerus with submetaphyseal over tubulation of humerus and expansion of distal shaft. Lateral radiograph of dorsal lumbar spine (Fig. 3b) showed kyphosis and dysplastic vertebral bodies of lower thoracic and upper lumbar bodies. Transverse diameter of vertebral bodies exceeded the height of the same. A pelvic radiograph (Fig. 4) revealed hypoplasia of basilar portion of ilia, flaring of iliac wings, thick ischial and pubic bones with coxa valga deformity. Partial subluxation of the femoral heads and long femoral neck was seen. Dysplastic vertebral bodies with convex end plates were also seen on pelvic radiographs. Tibia-fibula and radius-ulna showed marked diaphyseal widening and distortion, with small and deformed epiphysis (Figs. 5a and b). These bones were short of normal length and displayed metaphyseal splaying. A hand and wrist radiograph (Fig. 6a) showed undertubulation of shafts of short tubular bones with bullet-shaped phalanges and proximal pointing of the second to fifth metacarpals. Carpal bones were short of normal length and there was a lack of ossification, suggesting a bone age much less than the
chronological age. Overriding of radius over ulna was noted in both hands and overall reduced density of bones was seen. A radiograph of the feet (Fig. 6b) showed short metatarsals and tarsal bones had not fully ossified, and there was reduced overall density of all bones.
Orofacial and dental findings In addition to bilateral corneal opacity, coarsening of facial features was observed (Fig. 7). The head was large, with a
Fig. 4 Pelvic radiograph showing underdeveloped basal ilia. The acetabulum is partially dislocated with flaring of iliac wings. Dysplastic vertebral bodies with convex end plates was also seen on pelvic radiographs
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Fig. 5 Radiograph of long bones of upper extremities (Fig. 5a) and lower extremities (Fig. 5b) showing marked diaphyseal widening and distortion with small and deformed epiphysis, and splaying of metaphysis of long bones. Short height of long bones
prominent forehead and marked supraorbital ridges. The patient also had a flattened nasal bridge, flared nose, upturned nasal tip, and hypertelorism. Nasal congestion with stertorous breathing through the mouth was noticed. Puffy eyelids and coarse, bushy eyebrows, long eyelashes, and thickened earlobes were seen. The patient had a large mouth with broad, patulous lips. Philtrum of the upper lip was long. No movements were perceptible at bilateral TMJ. Reduced lower facial height was observed. Macroglossia with tongue protruding between the teeth and anterior open bite was evident. An increase in the transverse diameter of the dental arches and flattening of the maxillary alveolar processes anteriorly was attributed to compression between the enlarged tongue and thickened lips. The existing permanent teeth were widely spaced and the gingival tissues were slightly thick. The enamel of the teeth was slightly hypoplastic with a clinical appearance of pitted enamel. Exaggerated conical crown form was exhibited by cuspids and bicuspids. (Fig. 8a and b) Panoramic radiograph (Fig. 9) revealed hypoplastic appearance of the mandibular condyles, which confirmed the clinical finding of limited opening of the mandible. The
condyles were replaced by a flat inclined surface on the right side and a cup-shaped excavation of condyle was evident on the left side. The mandible appeared to be generally small, with reduced height of the ascending ramus while coronoid process was apparently larger than normal. The chronologic development of the teeth was found to be normal for most teeth. However, slightly delayed root formation was found in relation to permanent second mandibular molars and premolars. Open contacts between all teeth were observed. Skull radiographs (A-P and lateral) revealed an enlarged deformed skull with thickened cranium. There was evidence of premature closure of sutures. The orbits were shallow and falx calcification was noted (Fig. 10a and b). Provisional diagnosis of mucopolysacchroidoses was made in this case and Hurler syndrome, Hunter syndrome, and Morquio syndrome were considered for differential diagnosis. Routine laboratory investigations (hemoglobin –12.7 gm%, total leucocyte count 11,900 cell/cm3, and differential leucocyte count) were normal. The erythrocyte sedimentation rate was raised to 101 mm/first hour. Urine analysis showed positive paper spot test for mucopolysaccharides. Hurler
Fig. 6 a Hand and wrist radiograph showing under-constricted shafts of short tubular bones with bullet-shaped phalanges and proximal pointing of the second to fifth metacarpals. Carpal bones were small and all had not appeared, suggesting a bone age much less than the chronological age.
Overriding of radius over ulna is seen in both hands and overall reduced density of bones is evident. b Radiograph of the feet showing short metatarsals. Tarsal bones had not fully developed, and there was reduced overall density of all bones
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Fig. 7 Clinical photograph of the patient showing bilateral corneal opacity
syndrome was diagnosed following observed deficiency of alpha-l-iduronidase enzyme.
Fig. 9 Panoramic radiograph showing spacing between teeth and conical teeth. Root completion of teeth is delayed for chronological age. Short mandible that is broad, bigonial distance wide, rami are short and narrow. Condyles are underdeveloped and replaced by a flat inclined surface. Coronoid appears hyperplastic. Irregular mandibular arch is seen
Discussion
Dysostosis multiplex is a general term used for the large spectrum of skeletal abnormalities in Hurler syndrome. The general phenomenon is failure of ossification and aberrant bone remodeling of which the exact pathophysiological mechanism remains to be elucidated [13]. Recently it was shown that a reduced cathepsin K activity, due to the accumulation of GAGs, leads to impaired osteoclast activity and decreased subepiphyseal cartilage resorption [14]. As a result, dysostosis multiplex manifests as shortened and thickened bones that are abnormally shaped and may present with articular erosions [14]. MPS I, in particular, results in facial dysmorphia, kyphoscoliosis, stiff joints, and hip dysplasia with subluxation that causes a waddling gait [15]. The anteroinferior beaking of the vertebral bodies has been ascribed to herniation of the nucleus pulposus into the superior aspect of the vertebra below [16]. The extra skeletal radiographic findings which may be seen include hepatosplenomegaly and prominent perivascular spaces [17]. The present case showed almost all these classical manifestations of Hurler syndrome. The diagnosis of the present case was based on characteristic clinical features like corneal clouding, coarse facial features, joint stiffness, hepatosplenomegaly, and mental retardation. Radiographic survey of the patient confirmed the clinical findings presenting with dysostosis multiplex. The dental findings of the syndrome include spaced, hypoplastic, peg-shaped teeth with retarded eruption, flattened
Mucopolysaccharidoses (MPS) are a group of inborn errors of metabolism caused by a deficiency of specific lysosomal enzymes that affect glycosaminoglycan (GAG) catabolism. To date, 11 enzyme defects that cause seven different types of MPS have been identified [5]. Table 1 shows the summary of general and musculoskeletal features of MPS. Hurler syndrome was initially referred in 1900 by Thompson but the complete clinical spectrum was subsequently described by Hurler in 1919 [10]. It is a chronic, progressive disease, affecting bones, joints, facial appearance, eyes, heart, respiratory system, viscera, and sometimes the central nervous system. The symptoms arise after birth and progress rapidly. Most of the untreated patients die due to complications related to brain damage or cardiorespiratory problems [11]. Gorlin et al. described the facial phenotype [12]. A slight coarsening of the facial features at 3–6 months of age is usually the first abnormality detected. The head is large with bulging frontal bones. The skull is often scaphocephalic secondary to premature closure of the metopic and sagittal sutures. The nasal bridge is depressed with broad nasal tip and anteverted nostrils. The cheeks are full. The lips are enlarged and the mouth is usually held open, particularly after age 3 years. Chronic nasal discharge is present and corneal clouding is observed. Fig. 8 a, b Intraoral photographs of the patient showing spacing between permanent teeth, pitting of enamel, and exaggerated conical crown form of cuspids and bicuspids
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Fig. 10 Skull radiographs PA (a) and lateral view (b) revealing an enlarged deformed skull with thickened cranium. There was evidence of premature closure of sutures. The orbits were shallow and falx calcification was noted
Table 1 Summary of general and musculoskeletal features of the MPS syndromes MPS type
Enzyme deficiency
General features
MPS I (Hurler/Scheie)
Alpha-L-iduronidase
MPS II (Hunter)
L-sulfoiduronate sulfatase
MPS III (Sanfilippo)
Heparan sulfate sulfamidase, Nacetyl-alpha-D-glucosaminidase, acetyl-coenzyme A (CoA): alpha-glucosamide N–acetyltransferase, acetyl-coenzyme A (CoA): alpha-glucosamide N–acetyltransferase N-acetylgalactosamine 6-sulfatase (gal-6-sulfatase), beta-galactosidase
Coarse facies, gum Dysostosis multiplex, disproportionate short stature, joint hypertrophy, contractures, Carpal tunnel syndrome (CTS), odontoid macroglossia, hypoplasia, atlanto-axial instability, acetabular dysplasia, initial intellectual coxa valga, genu valgum, trigger digits development normal, then deteriorates, cardiomyopathy, aortic and mitral valve disease, hydrocephalus, hepatosplenomegaly Coarse facies, Dysostosis multiplex, disproportionate short stature, joint X-linked inheritance, contractures, CTS, odontoid hypoplasia, atlanto-axial instaclassic nodular rash bility, acetabular dysplasia, coxa valga, genu valgum, trigger (rare), digits normal intellect initially, progressive neurodegeneration, cervical myelopathy, Most common MPS Mild somatic manifestations only, mild short stature and disorder, contractures in a small proportion (mainly elbow joint) mild dysmorphism, severe behavioral disturbance
MPS IV (Morquio)
MPS VI N-acetylgalactosamine (Maroteaux–Lamy) 4-sulfatase
MPS VII (Sly)
Beta-glucuronidase
MPS type IX
Hyaluronidase deficiency
Normal intellect, severe bony dysplasia
Musculoskeletal features
Severe skeletal dysplasia, dysostosis multiplex, disproportionate short stature, joint hypermobility, odontoid hypoplasia, atlanto-axial instability, acetabular dysplasia, hip dislocations, coxa valga, genu valgum, pes planus, pectus carinatum Carpal tunnel syndrome, Dysostosis multiplex, disproportionate short stature, joint cardiomyopathy, contractures, CTS, odontoid hypoplasia, atlanto-axial instaendocardial bility, acetabular dysplasia, coxa valga, genu valgum, trigger fibroelastosis, digits, pectus carinatum cervical myelopathy, macroglossia Very rare, mild Hurler Dysostosis multiplex, disproportionate short stature, joint type phenotype contractures, odontoid hypoplasia, atlanto-axial instability, acetabular dysplasia, pectus carinatum Very few cases reported Short stature, periarticular soft tissue masses, nodular synovial masses, joint effusions, acetabular erosions
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alveolar ridges with hyperplastic gingivae, macroglossia, and a high-arched palate. The mandible is short and broad, with abnormal condyles [6, 7, 9]. All these features were seen in our patient. Other features seen in Hurler’s syndrome, but not observed in this case, were absence of the articular eminence and calcification of the stylohyoid ligament. Dentigerous cystlike lesions are also reported; these are almost always bilateral, appear to start within the dental follicle, and occur chiefly in the mandible [18]. In a recently reported case, decreased pulp space in primary molars, taurodontism, and ectopy of mandibular molars were seen, which were not observed in this case [19]. The radiographic findings of skull show that the skull is enlarged and demonstrates a long antero-posterior dimension (dolichocephaly). The frontal bones are often prominent with heavy supraorbital ridges, and the skull vault may be thicker than normal [9]. In the present case, enlarged deformed skull with thickened cranium was observed in accordance with previous report. Also noticeable was limited motion of the TMJ. Traditionally, treatments for MPS I have aimed at relieving symptoms. More radical treatments have been explored including bone marrow transplantation, which has become the treatment of choice for carefully selected Hurler patients. Enzyme replacement therapy (alpha-Liduronidase, Aldurazyme) is now available to treat the intermediate and milder phenotypes (Hurler–Scheie and Scheie) as well as recently more severely affected patients [20]. The development of enzyme enhancement therapy, substrate reduction strategies, and also of gene therapy for lysosomal storage diseases and other metabolic disorders, and the various combinations of such strategies, are possible future developments. As a result of these improved therapies, patients with Hurler syndrome may increasingly need dental treatment. It is therefore useful for the dental practitioner to be aware of the clinical and radiographic features of Hurler’s syndrome. Because of the progressive nature of mucopolysaccharidosis type I (MPS I), these patients need to be regularly monitored. The focus of these evaluations should be to identify potential problems early at a time when intervention would decrease morbidity and enhance the quality of life. Patients with mucopolysaccharidosis type I (MPS I) may have cardiovascular manifestations together with difficult airway access, which means that these patients have far greater risks for general anesthesia than others [21]. The short, immobile, or unstable necks found in this group of patients combined with stiffening of the TM joint, macroglossia, or mandibular prognathism means that normal anesthetic intubation may be impossible. Furthermore, the developing dental tissues are extremely sensitive to the effects of chemotherapy and all teeth developing at the time of bone marrow transplant may be affected. The input of the dental practitioner is essential in the care of such patients. The practitioner must provide dietary and oral hygiene advice, as well as preventive measures such
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as fissure sealants and appropriate fluoride supplementation to prevent the development of caries. The dental practitioner is well placed to detect dental caries at an early stage and prevent their progression [19].
Conflict of interest None.
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