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Imaging features of mucopolysaccharidoses in the head and neck
International Journal of Pediatric Otorhinolaryngology 134 (2020) 110022
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Review Article
Imaging features of mucopolysaccharidoses in the head and neck Manal Nicolas-Jilwan
∗
T
Department of Radiology, Division of Neuroradiology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
A R T I C LE I N FO
A B S T R A C T
Keywords: Mucopolysaccharidosis Airway obstruction Dental anomalies Restricted mouth opening Mastoiditis
Ear, Nose and Throat (ENT) involvement by mucopolysaccharidoses is very common, affecting over 90% of patients, and occurs early in the course of the disease. Airway narrowing secondary to glycosaminoglycan deposition results in greatly increased morbidity, mortality and risk of anesthetic complications in these patients. Macroglossia, restricted mouth opening, tracheobronchomalacia, adenotonsillar hypertrophy along with other factors such as a short, rigid and unstable cervical spine, cardiac disease and increased susceptibility to respiratory infections result in a high perioperative mortality and morbidity. Imaging is most beneficial for evaluation of the airway, in particular in patients with obstructive symptoms and prior to intubation. We review the ENT manifestations of mucopolysaccharidoses including airway involvement, otological, oral and dental complications. 3-D reconstructions of the trachea, which is routinely captured on CT imaging of the spine, can be of great value for planning intubation in this patient population.
1. Introduction The mucopolysaccharidoses (MPS) are a heterogeneous group of inherited lysosomal storage disorders, caused by accumulation of undegraded glycosaminoglycans (GAG) leading to tissue damage [1]. They include 7 individual disorders (IS “Scheie syndrome”, IH “Hurler syndrome”, II, III, IV, VI, VII and IX) due to 11 specific enzymatic deficiencies with a combined incidence of 1 in 25000 (Table 1) [2]. They have an autosomal recessive transmission with the exception of MPS II which is X-linked [3]. Ear, Nose and Throat (ENT) involvement by MPS is very common, affecting over 90% of patients, and occurs early in the course of the disease [4,5]. Sleep apnea, otitis media, chronic rhinorrhea, tonsillar and adenoid hypertrophy often predate a diagnosis of mucopolysaccharidosis, in particular in patients with the attenuated phenotype [6]. Knowledge of the spectrum of otorhinolaryngological anomalies and identification of the corresponding imaging features can be of great value for early diagnosis and treatment.
secondary to GAG accumulation which can affect any level of the respiratory tract from lips to lungs [4]. This can result in macroglossia (Fig. 1), adenotonsillar hypertrophy (Fig. 2), infiltration of the walls of the pharynx, larynx and trachea (Fig. 3), as well as chronic rhinosinusitis. The abnormal bony anatomy also contributes to upper airway obstruction and sleep disordered breathing. This includes a relatively high position of the epiglottis (Fig. 1), limited mouth opening secondary to temporomandibular joint dysplasia and micrognathia (Fig. 4), and distortion of the trachea and upper airway secondary to a short neck and deformed spine (Fig. 5) [8]. In particular, patients with MPS IV (Morquio syndrome), who typically suffer a severe spinal dysplasia, can develop acute airway obstruction upon neck flexion which is relieved by extension of the neck when awake and a prone position during sleep [9]. Progressive severe upper airway obstruction may require a tracheostomy, which invariably results in complications in the MPS population, most commonly in the form of infrastomal or stomal narrowing [4].
2. Upper airway obstruction
2.1. Adenotonsillar hypertrophy
Respiratory involvement by MPS is progressive and constitutes a significant cause of mortality and morbidity. Upper airway obstruction typically occurs early in the disease course whereas tracheobronchial involvement usually manifests later [4]. Upper airway obstruction is common in all types of MPS disorders, but is minor in MPS III. It is most prevalent in MPS I, II and VI [7]. It is
Adenotonsillar hypertrophy (Fig. 2) is almost universal in MPS patients and is secondary to GAG deposition [10,11]. Nasopharyngeal narrowing is further aggravated by exaggerated depth of the skull base (Figs. 2 and 4) [4]. Tonsillectomy and/or adenoidectomy can be an effective treatment for obstructive sleep apnea, although the recurrence rate in MPS patients is high [8]. It is estimated at 56% in MPS patients
∗
Department of Radiology (MBC-28), King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia, 11211. E-mail addresses: [email protected], [email protected].
https://doi.org/10.1016/j.ijporl.2020.110022 Received 17 January 2020; Accepted 24 March 2020 Available online 26 March 2020 0165-5876/ © 2020 Elsevier B.V. All rights reserved.
International Journal of Pediatric Otorhinolaryngology 134 (2020) 110022
M. Nicolas-Jilwan
Table 1 MPS classification. TYPE
EPONYM
ENZYME DEFICIENCY
STORED GAG
GENETIC INHERITANCE
I–H I–S (previously MPS V)
Hurler (severe) Scheie (intermediate severity) Hurler-Scheie (mild) Hunter, mild form Hunter, severe form Sanfilippo A Sanfilippo B Sanfilippo C
Alpha-L-iduronidase Alpha-L-iduronidase
Dermatan sulfate, heparan sulfate Dermatan sulfate, heparan sulfate
Autosomal recessive Autosomal recessive
Dermatan sulfate, heparan sulfate Dermatan sulfate, heparan sulfate Dermatan sulfate, heparan sulfate Heparan sulfate Heparan sulfate Heparan sulfate
Autosomal recessive X-linked recessive X-linked recessive Autosomal recessive Autosomal recessive Autosomal recessive
VI VII
Sanfilippo D Morquio A Morquio B Maroteaux-Lamy Sly
Alpha-L-iduronidase sulfatase L-sulfoiduronate sulfatase Heparan N- sulfatase a-N-acetylgluco-saminidase Heparan-a-glucosaminide N-acetyltransferase N-acetylglucosamine-6-sulfatase Galactose 6- sulfatase b-Galactosidase N-acetylgalactosamine-4-sulphatase Beta-glucuronidase
Autosomal Autosomal Autosomal Autosomal Autosomal
IX
Natowicz
Hyaluronidase
Heparan sulfate Keratan sulfate, chondroitin sulfate Keratan sulfate Dermatan sulfate, chondroitin sulfate Dermatan sulfate, heparan sulfate, chondroitin sulfate Hyaluronan
I–H/S II-A II-B III
IV
L-sulfoiduronate
recessive recessive recessive recessive recessive
Autosomal recessive
Fig. 1. Macroglossia and high position of the epiglottis in a 5-year old boy with Hurler syndrome. Sagittal midline T1-weighted image of the brain demonstrates a high-positioned epiglottis (white arrow). The tongue is large with a characteristic anterior tongue thrust. Note additional features of mucopolysaccharidosis including a J-shaped sella, odontoid hypoplasia with thickening of the periodontoid soft tissues and enlarged adenoids.
[5] compared to 0.55%–1.5% in the general population [12]. 2.2. Nasal obstruction
Fig. 3. Thickening of the wall of the aerodigestive tract at variable levels due to GAG deposition in MPS. a and b Axial T2-weighted images from a cervical spine MRI in a 19-year-old male with Morquio syndrome. There is prominent thickening of the posterior pharyngeal wall (arrow in b) and thickening of the laryngeal wall at the level of the cricoid cartilage (arrow in a). c Axial T2-weighted image in a 9-year-old female with MPS VI demonstrates mild circumferential thickening of the tracheal wall at the cervicothoracic junction (arrow). d Chest radiograph confirms mild tracheal narrowing at the same level (arrow).
Nasal obstruction is typically secondary to turbinate hypertrophy and/or deviation and irregularity of the nasal septum (Fig. 2). It was observed in 38% of 74 MPS patients evaluated by Gonuldas et al. [5]. 2.3. Laryngeal and tracheal involvement Infiltration of the laryngeal wall with GAG (Fig. 3) renders the mucosa redundant and flaccid. The thickened mucosa of the
Fig. 2. Adenotonsillar hypertrophy and chronic otomastoiditis in a 3-year-old girl with MPS VI. a and b Axial T2-weighted images. c Coronal T2weighted image. The adenoids are enlarged (long horizontal arrow in a) and the nasal turbinates are also prominent in size (short horizontal arrows in a). The nasal septum is mildly deviated (curved arrow in a). Hypertrophy of the adenoids predisposes to bilateral chronic otomastoiditis (arrows in b). The transverse diameter of the nasopharynx is reduced due to increased depth of the middle cranial fossae (double headed arrow in c). The palatine tonsils are also enlarged (horizontal arrows in c).
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International Journal of Pediatric Otorhinolaryngology 134 (2020) 110022
M. Nicolas-Jilwan
Fig. 4. Temporomandibular joint and skull base anomalies in MPS. a and b Coronal CT images in a 15-year-old boy with MPS VI. The mandibular condyles are hypoplastic and dysmorphic (horizontal arrows in a). The middle cranial fossae are deep (curved arrows in a and b), which results in narrowing of the nasopharynx (double-headed arrow in b). c 3-D reconstruction of the face in a 4year-old boy with MPS VI. The mandibular condyles are hypoplastic (white arrow). The mandible is hypoplastic with short rami and resultant open bite.
Fig. 5. Tracheal narrowing and tortuosity in MPS. a Axial image from a CT cervical spine of an 11-year-old girl with MPS IV at the tracheal level demonstrates narrowing of the transverse tracheal diameter (arrow). b 3-D reconstruction of the trachea depicts a long segment of tracheal narrowing, starting at the subglottic level, without tracheal tortuosity (arrow). c, d, and e are CT images of an 18 year-old male patient with MPS VI. c axial CT image shows narrowing of the trachea (arrow) d axial CT at the glottic level demonstrates irregular thickening of the laryngeal wall (arrow). e 3-D reconstruction better depicts the extent of tracheal tortuosity and narrowing (long arrow). The larynx is also mildly narrow and irregular (short arrow). Fig. 6. Compression of the trachea by the brachiocephalic trunk at the thoracic inlet in an 11-year-old boy with Hunter syndrome. a Axial image and b coronal image from chest CT done for evaluation of aspiration pneumonia and bronchiectasis. The arrows in a and b point to compression of the trachea (white arrows) by the brachiocephalic trunk (black arrows). c 3-D reconstruction of the trachea better demonstrates the length and degree of tracheal narrowing (arrow).
Tracheal tortuosity is characteristic of MPS and is presumed to be secondary to a disproportionate length of the trachea relative to the short neck of the patient (Fig. 5) [4]. Tracheal stenosis and tracheobronchomalacia (Fig. 5) are more severe and symptomatic in older
aryepiglottic folds and covering the arytenoid cartilages can prolapse into the laryngeal inlet and cause stridor and obstructive sleep apnea. This is most commonly seen with MPS II and IV and is usually evaluated by endoscopy [13].
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International Journal of Pediatric Otorhinolaryngology 134 (2020) 110022
M. Nicolas-Jilwan
trunk and trachea in relation to a narrow thoracic inlet [14]. The abnormal airway anatomy results in a high rate of difficult or failed intubation. 3D-reconstruction of the airway (Figs. 5 and 6) from available CT images, most commonly spine CT studies, is a valuable tool for preoperative airway evaluation and planning in MPS children. It directs selection of tracheal tube size and type and alters decision regarding postoperative monitoring and extubation [15]. Treatment of tracheal stenosis is controversial. Tracheal stent insertion was reported [16–18]. It carries a risk of various complications including granuloma formation, mucus impaction and migration and should be restricted to the most severe cases refractory to other treatments [18]. Granulation tissue formation is the most common cause of stent failure [16]. 3. Oral anomalies Hypoplasia of the mandibular condyles and mandible results in an anterior open-bite and limited mouth opening (Fig. 4) [19]. The mandible is typically hypoplastic, with the mandibular rami short and angled. Restriction of mouth opening is most severe in MPS VI and least severe in MPS III [5]. Gingival hyperplasia and maxillary alveolar ridge hypertrophy are common oral manifestations of Maroteaux-Lamy syndrome (MPS VI). High-arched palate and macroglossia (Fig. 1) are also characteristic of MPS [19]. Dental anomalies are more often seen with Maroteaux-Lamy syndrome than with other mucopolysaccharidoses (Fig. 7) [20]. The teeth can be variably dysmorphic: short, hypoplastic, long roots, poorly calcified, missing teeth and supernumerary teeth [19]. A common manifestation of MPS are unerupted and impacted permanent teeth, associated with hyperplastic tooth follicles [21]. Large dental follicles and dentigerous cysts most frequently affect the first permanent molars which are typically malpositioned [19]. Hyaluronic acid is the major glycosaminoglycan of dentigerous cyst fluid, which is also present in the epithelial lining of the cyst, similar to what is seen in the absence of MPS [22]. A characteristic pattern seen in MPS is designated rosetting of the molar teeth and refers to bilateral multiple impacted molar teeth which conglomerate into a single follicle, with their crowns facing each other and their roots radiating outwards, forming a characteristic rosette of teeth (Fig. 7). This pattern is seen in patients older than 14 years of age [23].
Fig. 7. Characteristic anomalies of the teeth in MPS. a Curved reformation of the jaws from a CT facial bones in a 7-year-old boy with MPS VI. There are multiple unerupted teeth (black arrow). The surrounding dental follicles are enlarged, with several dentigerous cysts noted (white arrow). The dental follicles are largest around the molar teeth (curved arrow). b Coronal CT reconstruction in a 15-year-old female with MPS VI. Rosetting of the molar teeth (arrows) is characterized by bilateral impacted molar teeth which conglomerate into a single follicle, with their crowns facing each other and their roots radiating outwards. Note the dysmorphic shape of the rosette-forming teeth.
4. Otological disorders and hearing loss Hearing loss is often mixed-type and progressive. It is frequently only conductive early in the disease course with a gradual superimposed sensorineural hearing loss as the disease progresses [24]. The sensorineural component is believed to be caused by GAG accumulation in the cochlea, cochlear nerve and brainstem [25]. Kariya et al. [26] also noted a significantly decreased number of cochlear hair cells in Hurler patients compared to healthy controls, which might be an important contributor to the sensorineural hearing loss. The conductive component of hearing loss in MPS patients is secondary to chronic otomastoidits (Fig. 2) and is due to deposition of GAG in the middle ear cavity, mastoid air cells and Eustachian tubes [10,25,27,28]. Eustachian tube dysfunction is also aggravated by adenoid hypertrophy, chronic adenoiditis, thick secretions, and unfavorable skull base anatomy [5]. These abnormalities manifest clinically and radiologically with a high prevalence of chronic otitis media with effusion and recurrent acute otitis media [4,10]. The mastoid air cells are frequently underpneumatized and sclerotic (Fig. 2) [27]. Thickening of the tympanic membrane and soft tissue thickening along the walls of the external auditory canals are common [27]. The efficacy of hearing aids and transtympanic ventilation tubes at improving speech development and communication skills is highly dependant on the patient's cognitive abilities. Correction of hearing impairment is most efficient in mild forms of MPS. The effectiveness is
Fig. 8. Calcification of the stylohyoid ligaments in an 8 year-old female with Hurler syndrome on a lateral radiograph of the cervical spine. The arrows indicate prominent calcification of the stylohyoid ligaments. Note the J-shaped sella and bullet-shaped vertebrae, characteristic of MPS.
patients and in MPS II and IV. They are secondary to infiltration of the tracheobronchial cartilage with GAG [8,14]. Compression of the trachea by the brachiocephalic trunk is a common cause of tracheal narrowing in MPS IVA patients and worsens with age (Fig. 6). It is believed to be secondary to disproportionate growth of the brachiocephalic 4
International Journal of Pediatric Otorhinolaryngology 134 (2020) 110022
M. Nicolas-Jilwan
uncertain with the intermediate and severe phenotypes [27].
[6] P. Arn, I.A. Bruce, J.E. Wraith, et al., Airway-related symptoms and surgeries in patients with mucopolysaccharidosis I, Ann. Otol. Rhinol. Laryngol. 124 (3) (2015) 198–205. [7] F. Santamaria, M.V. Andreucci, G. Parenti, et al., Upper airway obstructive disease in mucopolysaccharidoses: polysomnography, computed tomography and nasal endoscopy findings, J. Inherit. Metab. Dis. 30 (5) (2007) 743–749. [8] D.M. Rapoport, J.J. Mitchell, Pathophysiology, evaluation, and management of sleep disorders in the mucopolysaccharidoses, Mol. Genet. Metabol. 122S (2017) 49–54. [9] K.I. Berger, S.C. Fagondes, R. Giugliani, et al., Respiratory and sleep disorders in mucopolysaccharidosis, J. Inherit. Metab. Dis. 36 (2013) 201–210. [10] M.A. Simmons, I.A. Bruce, S. Penney, et al., Otorhinolaryngological manifestations of the mucopolysaccharidoses, Int. J. Pediatr. Otorhinolaryngol. 69 (5) (2005) 589–595. [11] A. Keilmann, A.K. Läßig, A. Pollak-Hainz, et al., Adenoids of patients with mucopolysaccharidoses demonstrate typical alterations, Int. J. Pediatr. Otorhinolaryngol. 79 (2) (2015) 115–118. [12] A. Monroy, P. Behar, L. Brodsky, Revision adenoidectomy – a retrospective study, Int. J. Pediatr. Otorhinolaryngol. 72 (5) (2008) 565–570. [13] N. Morimoto, M. Kitamura, M. Kosuga, et al., CT and endoscopic evaluation of larynx and trachea in mucopolysaccharidoses, Mol. Genet. Metabol. 112 (2) (2014) 154–159. [14] S. Tomatsu, L.W. Averill, K. Sawamoto, et al., Obstructive airway in Morquio A syndrome, the past, the present and the future, Mol. Genet. Metabol. 117 (2016) 150–156. [15] P.M. Ingelmo, R. Parini, M. Grimaldi, et al., Multidetector computed tomography (MDCT) for preoperative airway assessment in children with mucopolysaccharidoses, Minerva Anestesiol. 77 (8) (2011) 774–780. [16] S.M. Davitt, A. Hatrick, T. Sabharwal, et al., Tracheobronchial stent insertions in the management of major airway obstruction in a patient with Hunter syndrome (typeII mucopolysaccharidosis), Eur. Radiol. 12 (2) (2002) 458–462. [17] C. Kampmann, C.M. Wiethoff, R.G. Huth, et al., Management of life-threatening tracheal stenosis and tracheomalacia in patients with mucopolysaccharidoses, JIMD Rep 33 (2017) 33–39. [18] R. Karl, S. Carola, E. Regina, et al., Tracheobronchial stents in mucopolysaccharidosis, Int. J. Pediatr. Otorhinolaryngol. 83 (2016) 187–192. [19] P.N. Kantaputra, H. Kayserili, Y. Güven, et al., Oral manifestations of 17 patients affected with mucopolysaccharidosis type VI, J. Inherit. Metab. Dis. 37 (2) (2014) 263–268. [20] A.R. Alpöz, M. Coker, E. Celen, et al., The oral manifestations of Maroteaux-Lamy syndrome (mucopolysaccharidosis VI): a case report, Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 101 (5) (2006) 632–637. [21] K.S. Smith, K.B. Hallett, R.K. Hall, et al., Mucopolysaccharidosis: MPS VI and associated delayed tooth eruption, Int. J. Oral Maxillofac. Surg. 24 (2) (1995) 176–180. [22] M.W. Roberts, N.W. Barton, G. Constantopoulos, et al., Occurrence of multiple dentigerous cysts in a patient with the Maroteaux-Lamy syndrome (mucopolysaccharidosis, type VI), Oral Surg. Oral Med. Oral Pathol. 8 (2) (1984) 169–175. [23] T. Nakamura, K. Miwa, S. Kanda, et al., Rosette formation of impacted molar teeth in mucopolysaccharidoses and related disorders, Dentomaxillofacial Radiol. 21 (1) (1992) 45–49. [24] A. Keilmann, T. Nakarat, I.A. Bruce, D. Molter, G. Malm, H.O.S. Investigators, Hearing loss in patients with mucopolysaccharidosis II: data from HOS - the Hunter Outcome Survey, J. Inherit. Metab. Dis. 35 (2) (2012) 343–353. [25] I. Friedmann, E. Spellacy, J. Crow, et al., Histopathological studies of the temporal bones in Hurler's disease [mucopolysaccharidosis (MPS) IH], J. Laryngol. Otol. 99 (1) (1985) 29–41. [26] S. Kariya, P.A. Schachern, K. Nishizaki, et al., Inner ear changes in mucopolysaccharidosis type I/Hurler syndrome, Otol. Neurotol. 33 (8) (2012) 1323–1327. [27] Y.S. Cho, J.H. Kim, T.W. Kim, et al., Otologic manifestations of Hunter syndrome and their relationship with speech development, Audiol. Neuro. Otol. 13 (3) (2008) 206–212. [28] Ç. Gökdoğan, Ş. Altinyay, O. Gökdoğan, et al., Audiologic evaluations of children with mucopolysaccharidosis, Braz J Otorhinolaryngol 82 (3) (2016) 281–284. [29] A.E. Oestreich, The stylohyoid ligament in Hurler syndrome and related conditions: comparison with normal children, Radiology 154 (3) (1985) 665–666. [30] A.R. Pal, E.J. Langereis, M.A. Saif, et al., Sleep disordered breathing in mucopolysaccharidosis I: a multivariate analysis of patient, therapeutic and metabolic correlators modifying long term clinical outcome, Orphanet J. Rare Dis. 10 (2015) 42.
5. Stylohyoid ligament calcification Prominent calcification of the stylohyoid ligament has been reported in 8 out of 9 children with Hurler syndrome [29] and was defined as a thickness greater than 2 mm on conventional radiographs. This finding is frequently seen on imaging studies of patients with mucopolysaccharidoses (Fig. 8). Its relative prevalence and clinical relevance have not been evaluated. 6. Effect of treatment on ENT complications of MPS The effect of treatment with enzyme replacement therapy (ERT) or bone marrow transplantation on airway involvement by MPS is still unknown. Bone marrow transplantation appears to improve airway obstruction [30]. Enzyme replacement therapy is usually less successful as its efficiency is hindered by inhibitory antibodies to ERT [30]. 7. Conclusion The ENT manifestations of MPS are very common and contribute greatly to the increased morbidity, mortality and risk of anesthetic complications in these patients. Macroglossia, restricted mouth opening, tracheobronchomalacia, adenotonsillar hypertrophy along with other factors such as a short, rigid and unstable cervical spine, cardiac disease and increased susceptibility to respiratory infections result in a high perioperative mortality and morbidity [6]. Imaging is most beneficial for evaluation of the airway, in particular in patients with obstructive symptoms and prior to intubation. 3-D reconstructions of the trachea, which is routinely captured on CT imaging of the spine, can be of great value for planning intubation. Declaration of competing interest The author declares no conflict of interest. Acknowledgements No funding was received for this study. References [1] E.U. Neufeld, J. Muenzer, The mucopolysaccharidoses, in: C.R. Scriver (Ed.), The Metabolic and Molecular Bases of Inherited Disease, McGraw-Hill, New York, 2001, pp. 3421–3452. [2] L. Vedolin, I.V. Schwartz, M. Komlos, et al., Brain MRI in mucopolysaccharidosis: effect of aging and correlation with biochemical findings, Neurology 69 (9) (2007) 917–924. [3] S. Palmucci, G. Attinà, M.L. Lanza, et al., Imaging findings of mucopolysaccharidoses: a pictorial review, Insights Imaging 4 (4) (2013) 443–459. [4] P.M. Bianchi, R. Gaini, S. Vitale, ENT and mucopolysaccharidoses, Ital. J. Pediatr. 44 (Suppl 2) (2018) 127. [5] B. Gönüldaş, T. Yılmaz, H.S. Sivri, et al., Mucopolysaccharidosis: otolaryngologic findings, obstructive sleep apnea and accumulation of glucosaminoglycans in lymphatic tissue of the upper airway, Int. J. Pediatr. Otorhinolaryngol. 78 (6) (2014) 944–949.
5
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Review Article
Imaging features of mucopolysaccharidoses in the head and neck Manal Nicolas-Jilwan
∗
T
Department of Radiology, Division of Neuroradiology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
A R T I C LE I N FO
A B S T R A C T
Keywords: Mucopolysaccharidosis Airway obstruction Dental anomalies Restricted mouth opening Mastoiditis
Ear, Nose and Throat (ENT) involvement by mucopolysaccharidoses is very common, affecting over 90% of patients, and occurs early in the course of the disease. Airway narrowing secondary to glycosaminoglycan deposition results in greatly increased morbidity, mortality and risk of anesthetic complications in these patients. Macroglossia, restricted mouth opening, tracheobronchomalacia, adenotonsillar hypertrophy along with other factors such as a short, rigid and unstable cervical spine, cardiac disease and increased susceptibility to respiratory infections result in a high perioperative mortality and morbidity. Imaging is most beneficial for evaluation of the airway, in particular in patients with obstructive symptoms and prior to intubation. We review the ENT manifestations of mucopolysaccharidoses including airway involvement, otological, oral and dental complications. 3-D reconstructions of the trachea, which is routinely captured on CT imaging of the spine, can be of great value for planning intubation in this patient population.
1. Introduction The mucopolysaccharidoses (MPS) are a heterogeneous group of inherited lysosomal storage disorders, caused by accumulation of undegraded glycosaminoglycans (GAG) leading to tissue damage [1]. They include 7 individual disorders (IS “Scheie syndrome”, IH “Hurler syndrome”, II, III, IV, VI, VII and IX) due to 11 specific enzymatic deficiencies with a combined incidence of 1 in 25000 (Table 1) [2]. They have an autosomal recessive transmission with the exception of MPS II which is X-linked [3]. Ear, Nose and Throat (ENT) involvement by MPS is very common, affecting over 90% of patients, and occurs early in the course of the disease [4,5]. Sleep apnea, otitis media, chronic rhinorrhea, tonsillar and adenoid hypertrophy often predate a diagnosis of mucopolysaccharidosis, in particular in patients with the attenuated phenotype [6]. Knowledge of the spectrum of otorhinolaryngological anomalies and identification of the corresponding imaging features can be of great value for early diagnosis and treatment.
secondary to GAG accumulation which can affect any level of the respiratory tract from lips to lungs [4]. This can result in macroglossia (Fig. 1), adenotonsillar hypertrophy (Fig. 2), infiltration of the walls of the pharynx, larynx and trachea (Fig. 3), as well as chronic rhinosinusitis. The abnormal bony anatomy also contributes to upper airway obstruction and sleep disordered breathing. This includes a relatively high position of the epiglottis (Fig. 1), limited mouth opening secondary to temporomandibular joint dysplasia and micrognathia (Fig. 4), and distortion of the trachea and upper airway secondary to a short neck and deformed spine (Fig. 5) [8]. In particular, patients with MPS IV (Morquio syndrome), who typically suffer a severe spinal dysplasia, can develop acute airway obstruction upon neck flexion which is relieved by extension of the neck when awake and a prone position during sleep [9]. Progressive severe upper airway obstruction may require a tracheostomy, which invariably results in complications in the MPS population, most commonly in the form of infrastomal or stomal narrowing [4].
2. Upper airway obstruction
2.1. Adenotonsillar hypertrophy
Respiratory involvement by MPS is progressive and constitutes a significant cause of mortality and morbidity. Upper airway obstruction typically occurs early in the disease course whereas tracheobronchial involvement usually manifests later [4]. Upper airway obstruction is common in all types of MPS disorders, but is minor in MPS III. It is most prevalent in MPS I, II and VI [7]. It is
Adenotonsillar hypertrophy (Fig. 2) is almost universal in MPS patients and is secondary to GAG deposition [10,11]. Nasopharyngeal narrowing is further aggravated by exaggerated depth of the skull base (Figs. 2 and 4) [4]. Tonsillectomy and/or adenoidectomy can be an effective treatment for obstructive sleep apnea, although the recurrence rate in MPS patients is high [8]. It is estimated at 56% in MPS patients
∗
Department of Radiology (MBC-28), King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia, 11211. E-mail addresses: [email protected], [email protected].
https://doi.org/10.1016/j.ijporl.2020.110022 Received 17 January 2020; Accepted 24 March 2020 Available online 26 March 2020 0165-5876/ © 2020 Elsevier B.V. All rights reserved.
International Journal of Pediatric Otorhinolaryngology 134 (2020) 110022
M. Nicolas-Jilwan
Table 1 MPS classification. TYPE
EPONYM
ENZYME DEFICIENCY
STORED GAG
GENETIC INHERITANCE
I–H I–S (previously MPS V)
Hurler (severe) Scheie (intermediate severity) Hurler-Scheie (mild) Hunter, mild form Hunter, severe form Sanfilippo A Sanfilippo B Sanfilippo C
Alpha-L-iduronidase Alpha-L-iduronidase
Dermatan sulfate, heparan sulfate Dermatan sulfate, heparan sulfate
Autosomal recessive Autosomal recessive
Dermatan sulfate, heparan sulfate Dermatan sulfate, heparan sulfate Dermatan sulfate, heparan sulfate Heparan sulfate Heparan sulfate Heparan sulfate
Autosomal recessive X-linked recessive X-linked recessive Autosomal recessive Autosomal recessive Autosomal recessive
VI VII
Sanfilippo D Morquio A Morquio B Maroteaux-Lamy Sly
Alpha-L-iduronidase sulfatase L-sulfoiduronate sulfatase Heparan N- sulfatase a-N-acetylgluco-saminidase Heparan-a-glucosaminide N-acetyltransferase N-acetylglucosamine-6-sulfatase Galactose 6- sulfatase b-Galactosidase N-acetylgalactosamine-4-sulphatase Beta-glucuronidase
Autosomal Autosomal Autosomal Autosomal Autosomal
IX
Natowicz
Hyaluronidase
Heparan sulfate Keratan sulfate, chondroitin sulfate Keratan sulfate Dermatan sulfate, chondroitin sulfate Dermatan sulfate, heparan sulfate, chondroitin sulfate Hyaluronan
I–H/S II-A II-B III
IV
L-sulfoiduronate
recessive recessive recessive recessive recessive
Autosomal recessive
Fig. 1. Macroglossia and high position of the epiglottis in a 5-year old boy with Hurler syndrome. Sagittal midline T1-weighted image of the brain demonstrates a high-positioned epiglottis (white arrow). The tongue is large with a characteristic anterior tongue thrust. Note additional features of mucopolysaccharidosis including a J-shaped sella, odontoid hypoplasia with thickening of the periodontoid soft tissues and enlarged adenoids.
[5] compared to 0.55%–1.5% in the general population [12]. 2.2. Nasal obstruction
Fig. 3. Thickening of the wall of the aerodigestive tract at variable levels due to GAG deposition in MPS. a and b Axial T2-weighted images from a cervical spine MRI in a 19-year-old male with Morquio syndrome. There is prominent thickening of the posterior pharyngeal wall (arrow in b) and thickening of the laryngeal wall at the level of the cricoid cartilage (arrow in a). c Axial T2-weighted image in a 9-year-old female with MPS VI demonstrates mild circumferential thickening of the tracheal wall at the cervicothoracic junction (arrow). d Chest radiograph confirms mild tracheal narrowing at the same level (arrow).
Nasal obstruction is typically secondary to turbinate hypertrophy and/or deviation and irregularity of the nasal septum (Fig. 2). It was observed in 38% of 74 MPS patients evaluated by Gonuldas et al. [5]. 2.3. Laryngeal and tracheal involvement Infiltration of the laryngeal wall with GAG (Fig. 3) renders the mucosa redundant and flaccid. The thickened mucosa of the
Fig. 2. Adenotonsillar hypertrophy and chronic otomastoiditis in a 3-year-old girl with MPS VI. a and b Axial T2-weighted images. c Coronal T2weighted image. The adenoids are enlarged (long horizontal arrow in a) and the nasal turbinates are also prominent in size (short horizontal arrows in a). The nasal septum is mildly deviated (curved arrow in a). Hypertrophy of the adenoids predisposes to bilateral chronic otomastoiditis (arrows in b). The transverse diameter of the nasopharynx is reduced due to increased depth of the middle cranial fossae (double headed arrow in c). The palatine tonsils are also enlarged (horizontal arrows in c).
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Fig. 4. Temporomandibular joint and skull base anomalies in MPS. a and b Coronal CT images in a 15-year-old boy with MPS VI. The mandibular condyles are hypoplastic and dysmorphic (horizontal arrows in a). The middle cranial fossae are deep (curved arrows in a and b), which results in narrowing of the nasopharynx (double-headed arrow in b). c 3-D reconstruction of the face in a 4year-old boy with MPS VI. The mandibular condyles are hypoplastic (white arrow). The mandible is hypoplastic with short rami and resultant open bite.
Fig. 5. Tracheal narrowing and tortuosity in MPS. a Axial image from a CT cervical spine of an 11-year-old girl with MPS IV at the tracheal level demonstrates narrowing of the transverse tracheal diameter (arrow). b 3-D reconstruction of the trachea depicts a long segment of tracheal narrowing, starting at the subglottic level, without tracheal tortuosity (arrow). c, d, and e are CT images of an 18 year-old male patient with MPS VI. c axial CT image shows narrowing of the trachea (arrow) d axial CT at the glottic level demonstrates irregular thickening of the laryngeal wall (arrow). e 3-D reconstruction better depicts the extent of tracheal tortuosity and narrowing (long arrow). The larynx is also mildly narrow and irregular (short arrow). Fig. 6. Compression of the trachea by the brachiocephalic trunk at the thoracic inlet in an 11-year-old boy with Hunter syndrome. a Axial image and b coronal image from chest CT done for evaluation of aspiration pneumonia and bronchiectasis. The arrows in a and b point to compression of the trachea (white arrows) by the brachiocephalic trunk (black arrows). c 3-D reconstruction of the trachea better demonstrates the length and degree of tracheal narrowing (arrow).
Tracheal tortuosity is characteristic of MPS and is presumed to be secondary to a disproportionate length of the trachea relative to the short neck of the patient (Fig. 5) [4]. Tracheal stenosis and tracheobronchomalacia (Fig. 5) are more severe and symptomatic in older
aryepiglottic folds and covering the arytenoid cartilages can prolapse into the laryngeal inlet and cause stridor and obstructive sleep apnea. This is most commonly seen with MPS II and IV and is usually evaluated by endoscopy [13].
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trunk and trachea in relation to a narrow thoracic inlet [14]. The abnormal airway anatomy results in a high rate of difficult or failed intubation. 3D-reconstruction of the airway (Figs. 5 and 6) from available CT images, most commonly spine CT studies, is a valuable tool for preoperative airway evaluation and planning in MPS children. It directs selection of tracheal tube size and type and alters decision regarding postoperative monitoring and extubation [15]. Treatment of tracheal stenosis is controversial. Tracheal stent insertion was reported [16–18]. It carries a risk of various complications including granuloma formation, mucus impaction and migration and should be restricted to the most severe cases refractory to other treatments [18]. Granulation tissue formation is the most common cause of stent failure [16]. 3. Oral anomalies Hypoplasia of the mandibular condyles and mandible results in an anterior open-bite and limited mouth opening (Fig. 4) [19]. The mandible is typically hypoplastic, with the mandibular rami short and angled. Restriction of mouth opening is most severe in MPS VI and least severe in MPS III [5]. Gingival hyperplasia and maxillary alveolar ridge hypertrophy are common oral manifestations of Maroteaux-Lamy syndrome (MPS VI). High-arched palate and macroglossia (Fig. 1) are also characteristic of MPS [19]. Dental anomalies are more often seen with Maroteaux-Lamy syndrome than with other mucopolysaccharidoses (Fig. 7) [20]. The teeth can be variably dysmorphic: short, hypoplastic, long roots, poorly calcified, missing teeth and supernumerary teeth [19]. A common manifestation of MPS are unerupted and impacted permanent teeth, associated with hyperplastic tooth follicles [21]. Large dental follicles and dentigerous cysts most frequently affect the first permanent molars which are typically malpositioned [19]. Hyaluronic acid is the major glycosaminoglycan of dentigerous cyst fluid, which is also present in the epithelial lining of the cyst, similar to what is seen in the absence of MPS [22]. A characteristic pattern seen in MPS is designated rosetting of the molar teeth and refers to bilateral multiple impacted molar teeth which conglomerate into a single follicle, with their crowns facing each other and their roots radiating outwards, forming a characteristic rosette of teeth (Fig. 7). This pattern is seen in patients older than 14 years of age [23].
Fig. 7. Characteristic anomalies of the teeth in MPS. a Curved reformation of the jaws from a CT facial bones in a 7-year-old boy with MPS VI. There are multiple unerupted teeth (black arrow). The surrounding dental follicles are enlarged, with several dentigerous cysts noted (white arrow). The dental follicles are largest around the molar teeth (curved arrow). b Coronal CT reconstruction in a 15-year-old female with MPS VI. Rosetting of the molar teeth (arrows) is characterized by bilateral impacted molar teeth which conglomerate into a single follicle, with their crowns facing each other and their roots radiating outwards. Note the dysmorphic shape of the rosette-forming teeth.
4. Otological disorders and hearing loss Hearing loss is often mixed-type and progressive. It is frequently only conductive early in the disease course with a gradual superimposed sensorineural hearing loss as the disease progresses [24]. The sensorineural component is believed to be caused by GAG accumulation in the cochlea, cochlear nerve and brainstem [25]. Kariya et al. [26] also noted a significantly decreased number of cochlear hair cells in Hurler patients compared to healthy controls, which might be an important contributor to the sensorineural hearing loss. The conductive component of hearing loss in MPS patients is secondary to chronic otomastoidits (Fig. 2) and is due to deposition of GAG in the middle ear cavity, mastoid air cells and Eustachian tubes [10,25,27,28]. Eustachian tube dysfunction is also aggravated by adenoid hypertrophy, chronic adenoiditis, thick secretions, and unfavorable skull base anatomy [5]. These abnormalities manifest clinically and radiologically with a high prevalence of chronic otitis media with effusion and recurrent acute otitis media [4,10]. The mastoid air cells are frequently underpneumatized and sclerotic (Fig. 2) [27]. Thickening of the tympanic membrane and soft tissue thickening along the walls of the external auditory canals are common [27]. The efficacy of hearing aids and transtympanic ventilation tubes at improving speech development and communication skills is highly dependant on the patient's cognitive abilities. Correction of hearing impairment is most efficient in mild forms of MPS. The effectiveness is
Fig. 8. Calcification of the stylohyoid ligaments in an 8 year-old female with Hurler syndrome on a lateral radiograph of the cervical spine. The arrows indicate prominent calcification of the stylohyoid ligaments. Note the J-shaped sella and bullet-shaped vertebrae, characteristic of MPS.
patients and in MPS II and IV. They are secondary to infiltration of the tracheobronchial cartilage with GAG [8,14]. Compression of the trachea by the brachiocephalic trunk is a common cause of tracheal narrowing in MPS IVA patients and worsens with age (Fig. 6). It is believed to be secondary to disproportionate growth of the brachiocephalic 4
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uncertain with the intermediate and severe phenotypes [27].
[6] P. Arn, I.A. Bruce, J.E. Wraith, et al., Airway-related symptoms and surgeries in patients with mucopolysaccharidosis I, Ann. Otol. Rhinol. Laryngol. 124 (3) (2015) 198–205. [7] F. Santamaria, M.V. Andreucci, G. Parenti, et al., Upper airway obstructive disease in mucopolysaccharidoses: polysomnography, computed tomography and nasal endoscopy findings, J. Inherit. Metab. Dis. 30 (5) (2007) 743–749. [8] D.M. Rapoport, J.J. Mitchell, Pathophysiology, evaluation, and management of sleep disorders in the mucopolysaccharidoses, Mol. Genet. Metabol. 122S (2017) 49–54. [9] K.I. Berger, S.C. Fagondes, R. Giugliani, et al., Respiratory and sleep disorders in mucopolysaccharidosis, J. Inherit. Metab. Dis. 36 (2013) 201–210. [10] M.A. Simmons, I.A. Bruce, S. Penney, et al., Otorhinolaryngological manifestations of the mucopolysaccharidoses, Int. J. Pediatr. Otorhinolaryngol. 69 (5) (2005) 589–595. [11] A. Keilmann, A.K. Läßig, A. Pollak-Hainz, et al., Adenoids of patients with mucopolysaccharidoses demonstrate typical alterations, Int. J. Pediatr. Otorhinolaryngol. 79 (2) (2015) 115–118. [12] A. Monroy, P. Behar, L. Brodsky, Revision adenoidectomy – a retrospective study, Int. J. Pediatr. Otorhinolaryngol. 72 (5) (2008) 565–570. [13] N. Morimoto, M. Kitamura, M. Kosuga, et al., CT and endoscopic evaluation of larynx and trachea in mucopolysaccharidoses, Mol. Genet. Metabol. 112 (2) (2014) 154–159. [14] S. Tomatsu, L.W. Averill, K. Sawamoto, et al., Obstructive airway in Morquio A syndrome, the past, the present and the future, Mol. Genet. Metabol. 117 (2016) 150–156. [15] P.M. Ingelmo, R. Parini, M. Grimaldi, et al., Multidetector computed tomography (MDCT) for preoperative airway assessment in children with mucopolysaccharidoses, Minerva Anestesiol. 77 (8) (2011) 774–780. [16] S.M. Davitt, A. Hatrick, T. Sabharwal, et al., Tracheobronchial stent insertions in the management of major airway obstruction in a patient with Hunter syndrome (typeII mucopolysaccharidosis), Eur. Radiol. 12 (2) (2002) 458–462. [17] C. Kampmann, C.M. Wiethoff, R.G. Huth, et al., Management of life-threatening tracheal stenosis and tracheomalacia in patients with mucopolysaccharidoses, JIMD Rep 33 (2017) 33–39. [18] R. Karl, S. Carola, E. Regina, et al., Tracheobronchial stents in mucopolysaccharidosis, Int. J. Pediatr. Otorhinolaryngol. 83 (2016) 187–192. [19] P.N. Kantaputra, H. Kayserili, Y. Güven, et al., Oral manifestations of 17 patients affected with mucopolysaccharidosis type VI, J. Inherit. Metab. Dis. 37 (2) (2014) 263–268. [20] A.R. Alpöz, M. Coker, E. Celen, et al., The oral manifestations of Maroteaux-Lamy syndrome (mucopolysaccharidosis VI): a case report, Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 101 (5) (2006) 632–637. [21] K.S. Smith, K.B. Hallett, R.K. Hall, et al., Mucopolysaccharidosis: MPS VI and associated delayed tooth eruption, Int. J. Oral Maxillofac. Surg. 24 (2) (1995) 176–180. [22] M.W. Roberts, N.W. Barton, G. Constantopoulos, et al., Occurrence of multiple dentigerous cysts in a patient with the Maroteaux-Lamy syndrome (mucopolysaccharidosis, type VI), Oral Surg. Oral Med. Oral Pathol. 8 (2) (1984) 169–175. [23] T. Nakamura, K. Miwa, S. Kanda, et al., Rosette formation of impacted molar teeth in mucopolysaccharidoses and related disorders, Dentomaxillofacial Radiol. 21 (1) (1992) 45–49. [24] A. Keilmann, T. Nakarat, I.A. Bruce, D. Molter, G. Malm, H.O.S. Investigators, Hearing loss in patients with mucopolysaccharidosis II: data from HOS - the Hunter Outcome Survey, J. Inherit. Metab. Dis. 35 (2) (2012) 343–353. [25] I. Friedmann, E. Spellacy, J. Crow, et al., Histopathological studies of the temporal bones in Hurler's disease [mucopolysaccharidosis (MPS) IH], J. Laryngol. Otol. 99 (1) (1985) 29–41. [26] S. Kariya, P.A. Schachern, K. Nishizaki, et al., Inner ear changes in mucopolysaccharidosis type I/Hurler syndrome, Otol. Neurotol. 33 (8) (2012) 1323–1327. [27] Y.S. Cho, J.H. Kim, T.W. Kim, et al., Otologic manifestations of Hunter syndrome and their relationship with speech development, Audiol. Neuro. Otol. 13 (3) (2008) 206–212. [28] Ç. Gökdoğan, Ş. Altinyay, O. Gökdoğan, et al., Audiologic evaluations of children with mucopolysaccharidosis, Braz J Otorhinolaryngol 82 (3) (2016) 281–284. [29] A.E. Oestreich, The stylohyoid ligament in Hurler syndrome and related conditions: comparison with normal children, Radiology 154 (3) (1985) 665–666. [30] A.R. Pal, E.J. Langereis, M.A. Saif, et al., Sleep disordered breathing in mucopolysaccharidosis I: a multivariate analysis of patient, therapeutic and metabolic correlators modifying long term clinical outcome, Orphanet J. Rare Dis. 10 (2015) 42.
5. Stylohyoid ligament calcification Prominent calcification of the stylohyoid ligament has been reported in 8 out of 9 children with Hurler syndrome [29] and was defined as a thickness greater than 2 mm on conventional radiographs. This finding is frequently seen on imaging studies of patients with mucopolysaccharidoses (Fig. 8). Its relative prevalence and clinical relevance have not been evaluated. 6. Effect of treatment on ENT complications of MPS The effect of treatment with enzyme replacement therapy (ERT) or bone marrow transplantation on airway involvement by MPS is still unknown. Bone marrow transplantation appears to improve airway obstruction [30]. Enzyme replacement therapy is usually less successful as its efficiency is hindered by inhibitory antibodies to ERT [30]. 7. Conclusion The ENT manifestations of MPS are very common and contribute greatly to the increased morbidity, mortality and risk of anesthetic complications in these patients. Macroglossia, restricted mouth opening, tracheobronchomalacia, adenotonsillar hypertrophy along with other factors such as a short, rigid and unstable cervical spine, cardiac disease and increased susceptibility to respiratory infections result in a high perioperative mortality and morbidity [6]. Imaging is most beneficial for evaluation of the airway, in particular in patients with obstructive symptoms and prior to intubation. 3-D reconstructions of the trachea, which is routinely captured on CT imaging of the spine, can be of great value for planning intubation. Declaration of competing interest The author declares no conflict of interest. Acknowledgements No funding was received for this study. References [1] E.U. Neufeld, J. Muenzer, The mucopolysaccharidoses, in: C.R. Scriver (Ed.), The Metabolic and Molecular Bases of Inherited Disease, McGraw-Hill, New York, 2001, pp. 3421–3452. [2] L. Vedolin, I.V. Schwartz, M. Komlos, et al., Brain MRI in mucopolysaccharidosis: effect of aging and correlation with biochemical findings, Neurology 69 (9) (2007) 917–924. [3] S. Palmucci, G. Attinà, M.L. Lanza, et al., Imaging findings of mucopolysaccharidoses: a pictorial review, Insights Imaging 4 (4) (2013) 443–459. [4] P.M. Bianchi, R. Gaini, S. Vitale, ENT and mucopolysaccharidoses, Ital. J. Pediatr. 44 (Suppl 2) (2018) 127. [5] B. Gönüldaş, T. Yılmaz, H.S. Sivri, et al., Mucopolysaccharidosis: otolaryngologic findings, obstructive sleep apnea and accumulation of glucosaminoglycans in lymphatic tissue of the upper airway, Int. J. Pediatr. Otorhinolaryngol. 78 (6) (2014) 944–949.
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