The Cleft Palate–Craniofacial Journal 52(3) pp. 352–358 May 2015 Ó Copyright 2015 American Cleft Palate–Craniofacial Association

ORIGINAL ARTICLE A Clinical Multicenter Study of Orofacial Features in 26 Brazilian Patients With Different Types of Mucopolysaccharidosis Erlane Marques Ribeiro, M.D., M.S., Ph.D.c., Cristiane S.R. Fonteles, D.D.S., M.S., Ph.D., Adriana Bezerra Freitas, ˆ D.D.S., Karla Shangela da Silva Alves, D.D.S., M.S., Andre´ Jalles Monteiro, M.S., Ph.D., Carlos Antonio Bruno da Silva, M.D., Ph.D. Purpose: This study aimed to describe the orofacial features of 26 unrelated Brazilian patients with mucopolysaccharidosis and to verify any possible associations between these findings and specific types of mucopolysaccharidosis. Methods: Patients were diagnosed with mucopolysaccharidosis and clinically evaluated. Following consent, a clinical assessment form was completed. Facial and intraoral examination was performed by evaluating facial pattern, malocclusions, dental caries, and tooth identification. Results: Midface deficiency, increased lower facial third, anterior open bite, convex profile, macroglossia, gingival enlargement, and spaced arches were the most frequently observed features. These findings did not allow a differential diagnosis among the different types of mucopolysaccharidosis, except for pitting enamel, which significantly associated with mucopolysaccharidosis IVA (P , .001). Open bite was associated with mucopolysaccharidosis types I, II, III, and VI; however, only one patient with mucopolysaccharidosis IVA expressed this feature (P ¼ .043). Conclusions: Our results suggest that pitted enamel in patients with mucopolysaccharidosis is most likely a feature of mucopolysaccharidosis type IVA; whereas, open bite is rarely observed in these patients. Orofacial features in mucopolysaccharidosis may help pediatric dentists recognize this disorder and minimize the delay between the initial signs/symptoms and diagnosis of the disease. Future studies should focus on the longitudinal manifestations, expression, and severity of mucopolysaccharidosis-associated orofacial anomalies. KEY WORDS:

glycosaminoglycans, malocclusions, metabolic disorders, mucopolysaccharidosis, orofacial abnormalities

The mucopolysaccharidoses (MPS) are a rare, clinically heterogeneous group of metabolic disorders caused by a deficiency or malfunction of the lysosomal enzymes involved in the stepwise degradation of glycosaminoglycans

(GAG), formerly called mucopolysaccharides. The resultant accumulation of undegraded or partly degraded GAG within lysosomes causes permanent, progressive tissue and organ dysfunction. An overall incidence of 1 per 25,000 live births has been estimated, and seven distinct clinical types and numerous subtypes of MPS have been identified. These MPS types share many clinical features with varying degrees of severity, which progress as storage of GAG affects bone, skeletal structure, connective tissues, and organs. All MPS are inherited in an autosomal recessive manner except for MPS II (Hunter syndrome), which is transmitted as an X-linked recessive disorder (Neufeld and Muenzer, 2001). Typical features of MPS I, II, and VI include coarse facies, growth impairment, deafness, cardiovascular complications, airway obstruction, hepatosplenomegaly, progressive joint stiffness, and skeletal deformities (Valayannopoulos et al., 2010). Only severe forms of MPS I and MPS II manifest cognitive impairment; whereas, MPS III usually does not show somatic manifestations but is marked by severe neurological symptoms (Wegrzyn et al., 2010). Mucopolysaccharidosis IVA is

Dr. Ribeiro is Medical Geneticist, Postgraduate Program–Health Sciences, Federal University of Rio Grande do Norte, Natal, Brazil. Dr. Fonteles is Associate Professor, Pediatric Dental Unit, Special Care Clinic, Postgraduate Program–Dentistry; Dr. Freitas is Orthodontist, Pediatric Dental Unit, Special Care Clinic; and Dr. da Silva Alves is Ph.D. student, Postgraduate Program–Dentistry, Department of Clinical Dentistry, Federal University of Ceara´, Fortaleza, Brazil. Dr. Monteiro is Associate Professor, Department of Statistics and Applied Mathematics, Federal University of Ceara´, Fortaleza, Brazil. Dr. da Silva is Visiting Professor, Postgraduate Program–Health Sciences, Department of Endocrinology and ´ Metabolism, Federal University of Rio Grande do Norte, Caico, Brazil. Submitted August 2013; Revised February 2014, March 2014; Accepted March 2014. Address correspondence to: Cristiane Sa´ Roriz Fonteles. Unidade ´ de Pesquisas Cl ´ınicas/Universidade Federal do Ceara´. Laboratorio de ´ Farmacologia Metabolica e Fisiologia Celular, Avenida Jose´ Bastos, 3390, Sala 106, CP 3229, CEP 60.436-160, Fortaleza-Ce, Brazil. E-mail [email protected]. DOI: 10.1597/13-204 352

Ribeiro et al., OROFACIAL FEATURES IN MUCOPOLYSACCHARIDOSIS

TABLE 1

353

Clinical and Biochemical Characteristics of the Mucopolysaccharidoses

Type

OMIM*

Clinical Dysmorphism

Disostose Multiplex

Corneal Opacity

Mental Retardation

Urinary GAG

IH (Hurler) IHS (Hurler-Scheie) IS (Scheie) IIA (Hunter – attenuated) IIB (Hunter – severe) IIIA (Sanfillipo A) IIIB (Sanfillipo B) IIIC (Sanfillipo C)

#607014 #607015 #607016 #309900 #309900 #252900 #252920 #252930

þþþþ þþþ þþ þþþ þþþ þþ þþ þþ

þþþþ þþþ þþ þþþ þþþ þ þ þ

Y Y Y N N N N N

Y N N N Y Y Y Y

DS/HS DS/HS DS/HS DS/HS DS/HS HS HS HS

IIID (Sanfillipo D) IVB (Morquio B) VI (Marateaux-Lamy) VII (Sly)

#252940 #253010 #253200 #253220

þþ þþþþ þþþþ þþþþ

þ þþþþ þþþþ þþþþ

N Y Y N

N N N Late

KS KS DS DS/HS

Deficient Enzyme L-iduronidase L-iduronidase L-iduronidase Iduronate-2-sulfatase Iduronate-2-sulfatase Heparin sulfamidase N-Acetylglucosaminidase Heparan acetyl-CoA:alpha-glucosaminide N-acetyltransferase Galactosamine-6-sulfate sulfatase Beta-galactosidase N-acetylgalactosamine-4-sulfatase Beta-glucuronidase

* OMIM ¼ Online Mendelian Inheritance in Man; GAG ¼ glycosaminoglycans; þ ¼ minimal; þþ ¼ mild; þþþ ¼ moderate; þþþþ ¼ severe; Y ¼ yes; DS ¼ dermatan sulfate; HS ¼ heparan sulfate; N ¼ no; KS ¼ keratan sulfate.

clinically different from other forms of MPS and is characterized by severe spondyloepiphyseal dysplasia (Montano et al., 2007). Clinical and biochemical characteristics of the MPS types are summarized in Table 1. Although orofacial findings in MPS have received limited attention in previous reports, they comprise very specific characteristics that may assist in the early identification and follow-up of these disorders. These orofacial features commonly include gingival enlargement; macroglossia; high-arched palate; anterior open bite; spaced, hypoplastic, and malpositioned teeth (Keith et al., 1990; Downs et al., 1995; Alpoz et al., 2006) with delayed and ectopic dental eruption (Nakamura et al., 1992; Smith et al., 1995); localized dentigerous, cystlike radiolucencies (Roberts et al., 1984; Freitas et al., 2006); dilacerations of the distal roots and deformed dental follicle (Cleary and Wraith, 1995); alterations in the protein structure of enamel and dentin (Guven et al., 2008); enamel pitting (Levin et al., 1975; Kinirons and Nelson, 1990; Rolling et al., 1999); and short and broad mandibular rami with narrow and flat condyles (MacLoed and Macintyre, 1993; Defraia et al., 2005; Kaneyama et al., 2008). Bone marrow transplantation and enzyme replacement therapy may stabilize or reverse many aspects of MPS I, II, and VI, changing the natural course of the disease (Wadenya et al., 2010). However, the impact of enzyme replacement therapy on these MPS-associated orofacial manifestations has not been demonstrated. This study aimed to identify the most prevalent orofacial features in 26 unrelated Brazilian patients with MPS and to verify any existing association between these findings and each of the identified types of this disease in order to assist in clinical diagnosis. METHODS This observational, multicenter, cross-sectional study was approved by the Local Institutional Review Board and by the National Research Ethics Committee of Brazil. The

study sample consisted of all patients diagnosed with MPS (who consented to participate in the study) during the years from 2007 through 2011 attending referral centers for MPS at either the Pediatric Albert Sabin Hospital or the Cesar Cals General Hospital in Fortaleza, Brazil (Fig. 1). Patients who had received bone marrow transplantation, were taking anticonvulsant medications, or were severely affected by the disease and thus unable to comply with dental clinic visits were excluded from the study. Informed consents were obtained from all participants prior to study initiation. The diagnosis of MPS was established whenever enzymatic activity was confirmed to be deficient in leukocytes and/or plasma. These assays were performed at the Laboratory of Inborn Errors of Metabolism, part of the Medical Genetic Service at the Hospital of Clinics (Porto Alegre, Brazil). All patients enrolled in this study were evaluated by a single clinical geneticist, as follows: (1) a clinical assessment form was completed by the child’s legal guardian, (2) medical records were reviewed, (3) patients and/or family members were interviewed based on the information obtained, and (4) physical examination was performed. Once medical evaluation was concluded, patients were referred for dental examination. Intraoral and extraoral examinations were performed by a single pediatric dentist. Occlusion and other related measurements were evaluated by an orthodontist. Facial examination was performed aiming to evaluate facial pattern, proportionality and symmetry of the facial thirds, and facial convexity; whereas, dental examination included the following features: occlusal pattern, eruptive disturbances, dental development, presence/absence of dental caries, and identification of each individual tooth. Dental examiners were blind as to what type of MPS these patients presented. Patients who had been previously submitted to bone marrow transplantation and those who were using medications that could potentially induce gingival overgrowth were excluded from the study. A summary of every child’s medical history was provided following data collection, to be used for dental treatment planning of

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FIGURE 1 Patient recruitment flow chart.

these patients. In order to verify association among orofacial features, gender, and different MPS types and subtypes, the Pearson chi-square test was used. Statistical significance was established when P , .05.

However, all patients who expressed MPS type II (n ¼ 8) were of the male gender.

RESULTS

Four patients enrolled in this clinical study were affected by MPS type I, including one 11-year-old girl with Hurler syndrome and three patients with HurlerScheie syndrome (one 10-year-old boy, one 4-year-old girl, and one 5-year-old girl). These patients commonly presented developmental delay (n ¼ 2), short stature (n ¼ 4), macrocephaly (n ¼ 4), corneal opacity (n ¼ 2), coarse face (n ¼ 2), obstructive sleep apnea (n ¼ 4), adenotonsillar hypertrophy (n ¼ 4), short neck (n ¼ 4),

Of 50 individuals diagnosed as having MPS, 39 patients fulfilled inclusion criteria (Fig. 1). A total of 26 patients (nine girls and 17 boys) consented to participate in this study. In this final sample, distribution of MPS types were as follows: MPS I (n ¼ 4), MPS II (n ¼ 8), MPS III (n ¼ 3), MPS IVA (n¼5), MPS VI (n¼6). No statistical association was observed between MPS types and gender (P ¼ .098).

Mucopolysaccharidosis Type I

Ribeiro et al., OROFACIAL FEATURES IN MUCOPOLYSACCHARIDOSIS

TABLE 2

355

Distribution of Orofacial Features of 26 Patients With Different Types of Mucopolysaccharidosis (MPS)

MPS Type

I†

I

I

I

II† II II II

II

II

II II III† III III IVA† IVA IVA IVA IVA VI† VI VI VI VI VI

Age (y)

4

5

11 10

6

6

7

4

11 15

4

4

5

12

15

35

17

13

33

10

12

5

1

11

2

8

Extraoral features* Enlarged lips Lip competence Mouth breather Midface deficiency Increased lower third Convex profile

þ þ þ þ þ þ

 þ þ þ þ þ

þ  þ þ þ þ

  þ þ  þ

þ þ þ þ þ þ

þ  þ þ þ þ

þ  þ þ þ þ

 þ  þ  þ

þ þ þ þ þ þ

þ  þ þ þ þ

þ  þ þ  þ

 þ    þ

 þ þ þ  þ

þ  þ þ þ þ

þ þ  þ þ þ

 þ  þ þ þ

þ þ  þ þ þ

þ þ þ þ þ þ

 þ  þ þ þ

þ  þ þ þ þ

þ  þ þ þ þ

 þ þ þ  þ

 þ  þ  þ

þ  þ þ þ þ

þ þ    þ

þ  þ þ þ þ

Intraoral feature* Deciduous dentition Mixed dentition Permanent dentition Gingival enlargement Biprotrusion Macroglossia Crossbite Anterior open bite Conoid incisors Crowding Pitted enamel Spaced arches Dental caries

þ     þ þ þ    þ 

þ      þ þ    þ þ

 þ  þ þ þ  þ þ   þ 

 þ  þ  þ  þ  þ  þ 

 þ  þ þ þ þ     þ þ

 þ    þ þ þ    þ þ

 þ  þ þ þ  þ    þ þ

þ   þ  þ  þ    þ 

 þ  þ   þ þ þ    þ

  þ þ þ þ  þ þ þ  þ 

þ     þ  þ    þ 

þ      þ þ    þ 

þ     þ  þ    þ þ

 þ  þ þ  þ þ þ þ   þ

 þ  þ         

  þ þ  þ þ    þ þ þ

  þ   þ     þ  

  þ þ   þ    þ  

  þ       þ þ þ 

  þ  þ þ  þ  þ þ  

 þ  þ  þ þ þ    þ þ

þ   þ  þ  þ  þ  þ þ

þ   þ    þ    þ 

 þ  þ þ þ  þ     þ

þ           þ 

 þ  þ  þ þ þ    þ þ

* Where ‘‘þ’’ means presence and ‘‘’’ means absence. † MPS I, n ¼ 4; MPS II, n ¼ 8; MPS III, n ¼ 3; MPS IVA, n ¼ 5; MPS VI, n ¼ 6.

cardiopathy (n ¼ 4), umbilical hernia (n ¼ 4), hepatosplenomegaly (n ¼ 4), gibbus deformity (n ¼ 4), clawed hands (n ¼ 4), and joint contractures (n ¼ 4). Only one patient received 12 weekly infusions of enzyme replacement therapy (laronidase) at the time of the study. All patients were mouth breathers and presented midface deficiency, a convex profile, macroglossia, anterior open bite, and spaced arches (Table 2). Mucopolysaccharidosis Type II All patients with MPS II were boys. Two patients presented a mild form of the disease (aged 11 and 15 years); whereas, six patients expressed severe MPS II (aged 4 to 9 years). These patients presented short stature (n ¼ 4), macrocephaly (n ¼ 6), respiratory abnormalities (n ¼ 7), cardiopathy (n ¼ 8), hernia (n ¼ 8), hepatosplenomegaly (n ¼ 7), joint stiffness (n ¼ 8), and skeletal abnormalities (n ¼ 8). Enzyme replacement therapy with idursulfase, at a dose of 0.5 mg/kg weekly, was implemented in four of eight patients before the beginning of this study. The patients who received treatment included two 4-year-old twin boys (four infusions each) and two unrelated 6-year-old boys (3 and 121 infusions, respectively). All patients expressed midfacial third deficiency and a convex profile. Other extraoral features included an increased lower facial third (n ¼ 5) and enlarged lips (n ¼ 5). Intraoral evaluation showed the presence of an anterior open bite on all patients, spaced arches (n ¼ 7), macroglossia (n ¼ 6), and gingival enlargement (n ¼ 6) (Table 2). Most patients (n ¼ 7) were mouth breathers.

Mucopolysaccharidosis Type III We identified three patients with MPS III: one 12year-old girl with MPS IIIA, one 5-year-old boy with MPS IIIB, and one 15-year-old boy with MPS IIIC. All patients presented macrocephaly, coarse face, developmental delay, mental retardation and behavioral disturbances, midfacial third deficiency and a convex profile, and respiratory abnormalities. The most commonly observed intraoral features were gingival enlargement (n ¼ 2) and anterior open bite (n ¼ 2) (Table 2). Mucopolysaccharidosis Type IVA We evaluated five patients with MPS IVA: one 10year-old boy (the only affected person in his family), two females (ages of 17 and 35 years), and two males (ages of 13 and 33 years) from the same family. Two patients presented cardiopathy. Short stature, skeletal abnormalities, a deficient midfacial third, an increased lower facial third, and a convex profile were observed in all cases. Intraoral evaluation demonstrated the presence of pitted enamel on all patients, as well as the frequent expression of anterior open bite, macroglossia, and spaced arches (Table 2). Mucopolysaccharidosis Type VI Six patients with MPS VI were enrolled in this study (3 girls and 3 boys), with ages ranging from 1.9 to 10 years. Short stature (n ¼ 5), macrocephaly (n ¼ 5), respiratory abnormalities (n ¼ 5), cardiopathy (n ¼ 5),

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TABLE 3

Distribution of Parafunctional Habits Among Mucopolysaccharidosis (MPS) Patients

Parafunctional Habits

MPS I (n ¼ 4)

MPS II (n ¼ 8)

MPS III (n ¼ 3)

MPS IVA (n ¼ 5)

MPS VI (n ¼ 6)

Total (n ¼ 26)

2 0 1 1 0 0 4

3 2 3 1 2 1 12

1 1 0 0 1 0 3

2 0 0 0 0 0 2

1 1 0 0 0 0 2

9 4 4 2 3 1 23

Pacifier Finger sucking Bottle-feeding Bruxism Biting objects Nail biting Total

gibbus deformity (n ¼ 5), hepatosplenomegaly (n ¼ 5), joint stiffness (n ¼ 5), and skeletal abnormalities (n ¼ 6) were the most commonly observed clinical features. Except for one 3-year-old boy (104 infusions) and one 7year-old boy (111 infusions), patients were on enzyme replacement therapy with 1 mg/kg of recombinant human N-acetylgalactosamine-4-sulphatase; therapy was initiated prior to participation in this study. Most patients presented midfacial third deficiency (n ¼ 4) and a convex profile (n ¼ 4). Intraorally, the following features were observed: anterior open bite (n ¼ 5), spaced arches (n ¼ 5), macroglossia (n ¼ 4), and gingival enlargement (n ¼ 4). Parafunctional Habits Nonnutritive sucking (pacifiers) was the most commonly observed parafunctional habit among MPS patients (Table 3). Association Between Orofacial Features and Types of MPS Statistical analysis showed no significant association between MPS types and the following orofacial features: enlarged lips (P ¼ .618), lip competence (P ¼ .817), macroglossia (P ¼ .750), midfacial third deficiency (P ¼ .747), increased lower facial third (P ¼ .486), mandibular protrusion (P ¼ .988), crossbites (P ¼ .963), presence of conoid incisors (P ¼ .464), dental crowding (P ¼ .802), spaced arches (P ¼ .242), and gingival enlargement (P ¼ .796) (Table 4). The presence of pitted enamel was significantly associated with MPS IV (P , .001), and the P value remained significant after Bonferroni correction for multiple comparisons. Only patients with this type of MPS manifested this intraoral feature. In addition, the presence of open bite was associated with MPS types I, II, III, and VI (P ¼ .043); whereas, only one patient with MPS IV expressed this feature. There was a trend in the association of maxillary protrusion and MPS (P ¼ .152). Although maxillary protrusion was present in most patients with MPS types II and III, most patients with MPS IV (four of five patients) and VI (five of six patients) did not express maxillary protrusion, and the number of MPS I patients with and without maxillary protrusion were evenly distributed (two of four patients).

DISCUSSION In Brazil, a 4.8-year delay between the time of onset of the signs/symptoms of MPS and the establishment of a diagnosis has been previously described (Vieira et al., 2008). Specific therapies are available for MPS, and early treatment is likely to render favorable changes in the natural history of the disease (Burrow et al., 2007; Nathan and Orkin, 2007; Rohrbach and Clarke, 2007; Beck, 2010). Thus, efforts should be made to minimize this delay. We believe that orofacial characteristics of MPS in children may assist in the early recognition of this disorder. In the present study, most of the studied cases consisted of children of different ages, probably due to the high mortality rate of this disease, with the exception of MPS IVA. The observed predominance of the male sex in the present sample can be explained by the greater number of MPS II cases, which are known to have an X-linked recessive inheritance pattern. As for the different types of MPS, our results agreed with the findings described by Vieira et al. (2008), in which a higher prevalence of MPS II and MPS VI associated with a lower prevalence of MPS III and MPS I were reported. These results differ from the ones reported in other areas of the world (Malm et al., 2008). In addition, MPS IVB and MPS VII have rarely been reported (Lin et al., 2009; Poupelova´ et al., 2010). Dental treatment is usually well tolerated by these patients in an ambulatory setting. However, certain factors must be taken into account when considering management of their care, such as a short, immobile, or unstable neck combined with stiffening of the temporomandibular joint, macroglossia, mental retardation, behavioral disturbances, cardiorespiratory manifestations, and level of risk when receiving general anesthesia (Keith et al, 1990). In the present study, these alterations imposed specific limitations during dental evaluation. If treatment under anesthesia becomes necessary, it should be performed in hospitals with anesthesiologists who are experienced with MPS disorders and their complications (Giugliani et al., 2007; Martin et al., 2008). Pitted enamel was observed in all cases of MPS IVA but was not noted in any of the other MPS types. This defect consists of abnormally thin enamel that is rough due to minute surface pits. The thin enamel results in altered dental shape, in addition to discolored and widely spaced teeth. The enamel appears to be structurally weak, because

Ribeiro et al., OROFACIAL FEATURES IN MUCOPOLYSACCHARIDOSIS

TABLE 4

357

Association of Orofacial Features and Parafunctional Habits With Different Types of Mucopolysaccharidosis (MPS)

MPS Types

I*

II

III

IV

VI

P Value†

Enlarged lips Lip competence Mouth breathing Macroglossia Deficient midthird Increased lower third Convex profile Maxillary protrusion Mandibular protrusion Crossbite Open bite Conoid incisors Crowding Gingival enlargement Spaced arches Caries Pitted enamel Pacifier Thumb sucking Bottle Bruxism Biting objects Nail biting

2/4 2/4 4/4 3/4 4/4 3/4 4/4 2/4 2/4 2/4 4/4 1/4 1/4 2/4 4/4 1/4 0/4 2/4 0/4 1/4 1/4 0/4 0/4

6/8 4/8 6/8 6/8 7/8 5/7 8/8 5/8 3/8 4/8 7/8 2/8 1/8 5/8 7/8 4/8 0/8 3/8 2/8 3/8 1/8 2/8 1/8

2/3 2/3 2/3 1/3 3/3 2/3 3/3 2/2 1/3 1/3 2/3 1/3 1/3 2/3 1/3 2/3 0/3 1/3 1/3 0/3 0/3 1/3 0/3

3/5 4/5 2/5 3/5 5/5 5/5 5/5 1/5 2/5 2/5 1/5 0/5 2/5 2/4 3/4 1/4 5/5 0/4 0/4 0/4 0/4 0/4 2/4

2/6 3/6 4/6 4/6 5/6 3/6 6/6 1/6 2/6 2/6 5/6 0/6 1/6 5/6 5/6 4/6 0/6 2/6 0/6 2/6 0/6 0/6 0/6

.618 .817 .415 .750 .747 .486 – .152 .988 .963 .043 .464 .802 .796 .242 .564 ..001 .627 .345 .509 .571 .345 .123

* Data expressed as the number of patients with a specific type of MPS affected by a feature or habit in relation to the total number of patients affected by this type of MPS. † Chi-square test. Significance established at P , .05.

it exhibits a tendency to fracture and flake off (Knirons and Nelson, 1990), predisposing these areas to dental caries. The presence of defective deciduous enamel suggests that in these patients the disease process may be active early in intrauterine life and/or immediately after birth. The expression of orofacial features did not differ among MPS types I, II, III, and VI. The most commonly observed alterations in these types of MPS were related to facial pattern, in addition to macroglossia, gingival enlargement, and spaced arches. The factors that may contribute to the emergence of orofacial alterations in MPS patients are as follows: (1) MPS-associated facial alterations; (2) infiltration of GAG within the airways, leading to a mouthbreathing habit, macroglossia, and enlargement of lips and gingiva; (3) dysostosis, which alters facial bone growth and causes flattening of the condylar heads, (4) prenatal interference in dental structure due to the physiopathology of the disease, and (5) parafunctional habits. The severity of clinical alterations was also observed to increase with age, due to the progressive nature of the disease (Valayannopoulos et al., 2010). Patients with MPS IH after hematopoietic stem cell transplantation (HSCT) are likely to present delayed dental development, malocclusion, and dental anomalies, particularly hypodontia and microdontia (Wadenya et al., 2010). Thus, this therapy fails to prevent or reduce the expression of dental alterations in MPS patients. Transplantation is not a commonly used treatment strategy in Latin America (Munoz-Rojas et al., 2011), and none of the presently reported MPS patients received this therapy in our study. However, once diagnosis had been established, some patients received enzyme replacement therapy. There are

no previous reports of the effects of such therapy on the oral alterations of MPS patients, and the present case series did not show a reduction in the severity of these oral manifestations in comparison to those who were not receiving enzyme replacement therapy. Because not all patients were presently receiving this type of treatment, we believe this topic should be further investigated in a more controlled setting. Management of MPS patients must include routine dental examinations, radiographic evaluations at 6-month intervals, and regular at-home dental care (Giugliani et al., 2007), as well as preventive anticaries measures to ensure oral health, avoiding further complications. Almost 50% of the currently evaluated patients had compromised oral health, presenting a great challenge during routine dental examination. This preventive approach is of the utmost importance, because these patients may be at risk for bacterial endocarditis as well as aspiration pneumonia due to the neurological involvement, which can greatly complicate the execution of more complex dental procedures. There are no current protocols for the evaluation and dental treatment of MPS patients. Previously, Waldenya (2010) suggested the establishment of preventive measures for oral health maintenance in a patient with MPS I who had received a bone marrow transplant (BMT). The author suggested the implementation of the same preventive measures used in patients without MPS subjected to BMT. However, BMT guidelines are not designed to meet the specific limitations observed in most MPS patients, such as mouth-opening limitations, arm-joint restrictions, and clawhand deformities, which may impose difficulties in the establishment of a dental home. In addition, a nonnutritive

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Cleft Palate–Craniofacial Journal, May 2015, Vol. 52 No. 3

sucking habit was the most prevalent parafunctional habit observed among MPS patients. This prevalence was greater among patients with MPS II and MPS III, probably due to the presence of neurological alterations and behavioral disturbances, imposing a greater challenge for families to manage these alterations (Wegrzyn et al., 2007). In conclusion, orofacial manifestations in MPS patients are frequent and may help dentists recognize this disorder. Pitting enamel is a clinical sign that merits special attention to differentiate MPS IVA from other MPS types and other diseases with skeletal abnormalities. Our results suggest that orofacial features do not differ in MPS types I, II, III, and VI. The most commonly observed alterations in these MPS types are related to facial pattern, macroglossia, gingival enlargement, and spaced arches. Orofacial anomalies in MPS patients are specific features that must be included during their evaluation as a means of providing knowledge on the severity of the different types of mucopolysaccharidosis. Acknowledgments. We are indebted to our patients and their families. We also would like to thank the MPS Brazil Network for biochemical analysis, Lucas Serafa for references, and Nathalia B.M. Escossia for assistance in data collection.

REFERENCES Alpoz AR, Coker ¸ M, Celen ¸ E, Ersin NK, Gokcen ¸ D, van Diggelenc OP, Huijmansc JG. The oral manifestation of Maroteaux-Lamy syndrome (mucopolysaccharidosis VI): a case report. Oral Surg Oral Med Oral Pathol Oral Endod. 2006;101:632–637. Beck M. Therapy for lysosomal storage disorders. Life. 2010;62:33–40. Burrow A, Hopkin RJ, Leslie ND, Tinkle BT, Grabowski GA. Enzyme reconstitution/replacement therapy for lysosomal storage diseases. Curr Opin Pediatr. 2007;19:628–635. Cleary MA, Wraith JE. The presenting features of mucopolysaccharidosis type I (Hurler syndrome). Acta Paediatr. 1995;84:337–339. Defraia E, Marinelli A, Antonini A, Giuntini V. Abnormal mandibular growth after craniovertebral surgery in Morquio syndrome type A. Angle Orthod. 2005;75:461–464. Downs AT, Crisp T, Ferretti G. Hunter’s syndrome and oral manifestations: a review. Am Acad Pediatr Dent. 1995;17:98–100. Freitas DQ, Tempest LM, Sicoli E, Lopes-Neto FC. Bilateral dentigerous cysts: review of the literature and report of an unusual case. Dentomaxillofac Radiol. 2006;35:464–468. Giugliani R, Hamatz P, Wraith JE. Management guidelines for mucopolysaccharidosis VI. Pediatrics. 2007;120:405–418. Guven G, Cehreli ZC, Altun C, Sencimen ¸ M, Ide S, Bayari SH, Karacay ¸ S. Mucopolysaccharidosis type I (Hurler-Scheie): Oral and radiographic findings and ultrastructural/chemical features of enamel and dentin. Oral Pathol Oral Radiol Endod. 2008;105:72–78. Kaneyama K, Segami N, Hatta T. Congenital deformities and developmental abnormalities of the mandibular condyle in the temporomandibular joint. Congenit Anom (Kyoto). 2008;48:118– 125. Keith O, Scully C, Path MRC, Weidmann GM. Orofacial features of Scheie (Hurler-Scheie) syndrome (a-L-iduronidase deficiency). Oral Surg Oral Med Oral Pathol. 1990;70:70–74. Kinirons MJ, Nelson J. Dental findings in mucopolysaccharidosis type IVA (Morquio’s disease type A). Oral Surg Oral Med Oral Pathol. 1990;70:176–179.

Lin HY, Lin SP, Chuang CK, Niu DM, Chen MR, Tsai FJ, Chao MC, Chiu PC, Lin SJ, Tsai LP, et al. Incidence of the mucopolysaccharidoses in Taiwan, 1984–2004. Am J Med Genet A. 2009;149A:960–964. Levin LS, Jorgenson RJ, Salinas SF. Oral findings in the Morquio syndrome (mucopolysaccharidosis IV). Oral Surg. 1975;39:390–395. MacLeod SPR, Macintyre DR. Bilateral hypoplasia of mandibular condyles in Hurler’s syndrome. Oral Surg Oral Med Pathol. 1993;75:659–660. Malm G, Lund AM, Mansson J, Heiberg A. Mucopolysaccharidoses in the Scandinavian countries: incidence and prevalence. Acta Paediatr. 2008;97:1577–1581. Martin R, Beck M, Eng C, Giugliani R, Hamatz P, Muenzer J. Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome). Pediatrics. 2008;121:e377–e386. Montano AM, Tomatsu S, Gottesman GS, Smith M, Orii T. International Morquio A registry: clinical manifestation and natural course of Morquio A disease. J Inherit Metab Dis. 2007;30:165–174. Munoz-Rojas MV, Bay L, Sanchez L, van Kuijck M, Ospina S, Cabello JF, Martins AM. Clinical manifestations and treatment of mucopolysaccharidosis type I patients in Latin America as compared with the rest of the world. J Inherit Metab Dis. 2011;34:1029–1037. Nakamura T, Mika K, Nonaka K, Anan H, Higash S, Beppu K. Rosette formation of impacted molar teeth in mucopolysaccharidoses and related disorders. Dentomaxillofac Radiol. 1992;21:45–49. Nathan DG, Orkin SH. Musing on genome medicine: enzymereplacement therapy of the lysosomal storage diseases. Genome Med. 2009;1:1141–1143. Neufeld E, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Basis of Inherited Disease. New York: McGraw-Hill; 2001:3421– 3452. Poupelova´ H, Ledvinova´ J, Berna´ L, Dvrakova´ L, Kozich V, Ellerder M. The birth prevalence of lysosomal storage disorders in the Czech Republic: comparison with data in different populations. J Inherit Metab Dis. 2010;33:387–396. Roberts MW, Barton NW, Constantopoulous G, Butler DP, Donahue AH. Occurrence of multiple dentigerous cysts in a patient with Maroteaux-Lamy syndrome (mucopolysaccharidosis, type VI). Oral Surg. 1984;50:169–175. Rohrbach M, Clarke JTR. Treatment of lysosomal storage disorders progress with enzyme replacement. Drugs. 2007;67:2697–2716. Rolling I, Clausen N, Nyvad B, Sindet-Pedersen S. Dental findings in three siblings with Morquio’s syndrome. Int J Pediatr Dent. 1999;9:219–224. Smith KS, Hallett KB, Hall RK, Wardrop RW, Firth N. Mucopolysaccharidosis: MPS VI and associated delayed tooth eruption. Int J Oral Maxillofac Surg. 1995;24:176–180. Wadenya RO, Stout AM, Gupta A, Monge J. Hurler syndrome: a case report of a 5-year follow-up of dental findings after bone marrow transplantation. Spec Care Dentist. 2010;30:14–17. Wegrzyn G, Jakobkiewick-Banecka J, Narajczyk M, Wisniewski A, Piotrowska E, Gabig-Ciminska M, Kloska A, Slominska-Wojewodzka M, Korzon-Burakowska A, Wegrzyn A. Why are behaviors of children suffering from various neuronopathic types of mucopolysaccharidoses different? Med Hypotheses. 2010;75:605– 609. Valayannopoulos V, Nicely H, Harmatz P, Turbeville S. Mucopolysaccharidosis VI. Orphanet J Rare Dis. 2010;5:1–20. Vieira T, Schwartz I, Munoz V, Pinto L, Steiner C, Ribeiro M, Boy R, Ferraz V, de Paula A, Kim C, et al. Mucopolysaccharidoses in Brazil: what happens from birth to biochemical diagnosis? Am J Med Genet A. 2008;146A:1741–1747.

A clinical multicenter study of orofacial features in 26 brazilian patients with different types of mucopolysaccharidosis.

This study aimed to describe the orofacial features of 26 unrelated Brazilian patients with mucopolysaccharidosis and to verify any possible associati...
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