Craniofacial characteristics in cri-du-chat syndrome

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Please check the accuracy of the affiliation(s) of each author and make changes as appropriate. a Lecturer, Master’s Program in Orthodontics and Dentofacial Orthopedics, School of Dentistry, University of Seville, Seville, Spain b Clinical Assistant in Oral Surgery, University of Seville, Seville, Spain c Professor of Oral Surgery, Department of Stomatology, University of Seville, Seville, Spain d Professor of Special Care Patients, Department of Stomatology, University of Seville, Seville, Spain e Professor of Orthodontics, Chairman of Orthodontics, Department of Stomatology, University of Seville, Seville, Spain f Professor of Oral Surgery, Chairman of Oral Surgery, Department of Stomatology, University of Seville, Seville, Spain AUTHOR QUERIES AUTHOR PLEASE ANSWER ALL QUERIES 1 Craniofacial characteristics in cri-du-chat syndrome Rosa-María Yáñez-Vico, BDS, MSc, a Ángela Rodríguez-Caballero, BDS, b Alejandro Iglesias-Linares, DDS, MSc, a Noelia Guerra-López, BDS, b Daniel Torres-Lagares, DDS, MSc, c Guillermo Machuca-Portillo, MD, d Enrique Solano-Reina, MD, MSc, e and José-Luis Gutiérrez-Pérez, MD, f Seville, Spain UNIVERSITY OF SEVLLE Objective. The purpose of this study was to analyze craniofacial characteristics from lateral head profile radiographs of patients with cri-du-chat (CdC) syndrome. Study design. The craniofacial morphology of 10 CdC patients was evaluated using standard cephalometric methods, measuring 39 craniofacial variables on cephalometric x-ray images. Results. The principal characteristics were skeletal class II malocclusion, caused by mandibular retrognathism, dental biprotrusion, and a small upper airway. Additionally, 70% of patients had a steep palatal plane angle; the cranial base angle was flattened, also in 70% of patients. Conclusions. Results indicated that the deletion of 5p had an impact on the cranial base, maxilla, mandible, and upper airway, causing distinctive features to become apparent through irregular growth. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;xx:xxx) The cri-du-chat (CdC) syndrome, first described by Lejeune et al., 1 is characterized by partial deletion of the short arm of chromosome 5. The size of the deletion ranges from the entire short arm to region 5p15 and 3 (5 to 40 Mb) only. 2,3 Its frequency is estimated to be between 1:15,000 4 and 1:50,000 5 of live-born infants, but the prevalence found by Niebuhr 4 in 6000 individuals with mental retardation was approximately 1:350. Furthermore, Schinzel’s data 6 suggest that it is the most common autosomal deletion syndrome in humans. The syndrome is characterized by a high-pitched monochromatic cry like the mewing of a distressed kitten, probably because of anomalies of the larynx and epiglottis as well as neurological, structural, and functional alterations. 4 Additional clinical features are severe psychomotor and mental retardation, growth delay, and hypotonia. 2,4 Although the characteristic cry is usually considered diagnostic for the syndrome, 2 the catlike cry has been found without the typical dysmorphic and severe developmental features of the syndrome in individuals with the limited 5p15.3 deletion. 2,7 Craniofacial abnormalities include microcephaly, slight hypertelorism, epicanthal folds, downslanting palpebral fissures, strabismus, malformed ears, and hypodontia. 8,9 Even though the clinical features are well known as the result of descriptions by several authors, 2,7,10 little is known about craniofacial development. There are some studies based on anthropometric data, such as skull size, inner canthal distance, and retrognathia. 4,11,12 More recently, Kjaer and Niebuhr 13 investigated the cranial base of patients with CdC syndrome using profile radiographs and found that the condition involved a malformation of the cranial base. They pointed out that this particular cranial base region develops around the notochord, at the location where the rhombencephalic-derived brainstem, pons, and cerebellum develop dorsally and where the neurons migrate ventrally to the larynx. They suggested that a cranial developmental field, originating at the notochord location, is involved in the manifestations of CdC syndrome. Cephalometrics involves the use of lateral head radiographs to measure the skull and facial bones with respect to specific reference points. It is useful for evaluating and quantifying growth and development features, such as the relationship between the jaws, and between the jaws and the cranial bones. The purpose of This work was supported by a grant to the Department of Stomatology (CTS-523), awarded by the Research Institute of the University of Seville (Spain). a Lecturer, Master’s Program in Orthodontics and Dentofacial Orthopedics, School of Dentistry, University of Seville, Seville, Spain. b Clinical Assistant in Oral Surgery, University of Seville, Seville, Spain. c Professor of Oral Surgery, Department of Stomatology, University of Seville, Seville, Spain. d Professor of Special Care Patients, Department of Stomatology, University of Seville, Seville, Spain. e Professor of Orthodontics, Chairman of Orthodontics, Department of Stomatology, University of Seville, Seville, Spain. f Professor of Oral Surgery, Chairman of Oral Surgery, Department of Stomatology, University of Seville, Seville, Spain. Received for publication May 24, 2010; returned for revision Jul 21, 2010; accepted for publication Aug 20, 2010. 1079-2104/$ - see front matter © 2010 Published by Mosby, Inc. doi:10.1016/j.tripleo.2010.08.021 e1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 this study was to analyze craniofacial characteristics on lateral head profile x-rays in patients with CdC syndrome. MATERIAL AND METHODS Sixteen patients from the Spanish Cri-du-chat Association and diagnosed with CdC syndrome by their respective reference hospitals belonging to the Public Health Service were selected from among patients who had undergone some procedure in the Department of Oral and Maxillofacial Surgery at the Faculty of Dentistry, University of Seville (Spain). Six of these individuals were excluded because the images showed poor quality and motion artifacts; excluded subjects were those with severe mental retardation who were unable to remain still during the x-ray exposure. As a result, 10 patients—2 males and 8 females with a mean age of 23.9 ⫾6.7 years—were selected for the analysis. The present study was carried out with the full knowledge and written consent of each subject and in accordance with the ethical principles governing medical research and human subjects, as laid down in the Helsinki Declaration (2002 version, http://www.wma.net/e/policy/ b3.htm). The data have been treated with absolute confidentiality. Methods of gathering and storing data are subject to the Spanish Organic Law governing personal data protection. The Experimental Ethics Committee at the University of Seville independently approved the procedure. All subjects were photographed and examined intra- and extraorally for general medical and dental findings. The protocol included generating lateral cephalometric digital x-ray images, at 70 kV, 12 mA, with an exposure time of 0.80 seconds (Odontorama PC, Trophy, Cedex, France). Specific software (Nemotec, Madrid, Spain) was used for the digital images from which craniofacial and dental measurements were taken. Anatomical landmark coordinates were defined and summarized as shown in Table I. Craniofacial bones and relationships were measured after being classified into 4 groups: airway analysis, skeletal problems, dental problems, and esthetic problems. This classification provides useful information for determining which, if any, developmental field is affected in CdC syndrome. In each group, angular and linear measurements were assessed and quantified for this purpose, as shown in Table II. Measurements obtained from subjects with the CdC syndrome were compared with standard measurements provided by the specific software we used, and standard deviations calculated on the basis of standardized age, sex, and race norms. Cephalometric analysis methods by Steiner, 14,15 Ricketts, 16 Jaraback and Fizzel, 17 and McNamara 18 were used to obtain standard measurements. The measurements referred to previously correspond to the most representative and widely used methods according to orthodontic and craniofacial researchers. The correspondence between cephalometric analyses and measurements used are also shown in Table II. Intraobserver error was calculated for the sample, which was twice tested. It was calculated in the following way: SE ⫽公(⌺d2/2n), where d is the difference between the double measurements and n is the number of paired double measurements. It was evaluated using the Student ttest for paired samples, with absence of significance regarded as indicative of concordance between mean values. The data obtained were analyzed using SPSS 17.0 software for Windows (LEAD Technologies, USA). RESULTS The accuracy of intraobservational error was 0.41 mm for linear measurements and 0.63° for angle measurements. There were no statistically significant differences between original and repeat measurements (P⬎.05). Airway analysis emphasized the reduced volume in the upper respiratory tract (Table III). The great majority of the facial pattern measurements included shared mesofacial characteristics. However, there are parameters that demonstrate an obvious vertical component in the growth of study subjects, such as a decreased upper gonial angle and an increased lower gonial angle. By contrast, we also found an increased anterior facial height (the distance between the nasion and menton landmarks). In contrast, standard measurements were found for lower facial height (ans-xi-pm) and anteroinferior facial height (Na-me) (Table III). An inclined palatal plane was found to be a standard feature of the analyzed subjects. Statistical frequencies for this variable show that only 30% of subjects had standard measurements and 70% had a marked slope. These data represent one of the most characteristic features of CdC syndrome (Table IV). Measurements of the anterior and posterior cranial base showed that both were reduced compared with established age, sex, and racial norms. However, in 70% of cases, the cranial base angle (s-na-ba) was large (Table V) when compared with age-related standards for normal individuals. 19-21 Sagittal skeletal features are all consistent with skeletal class II malocclusion caused by mandibular retrognathism (Table III). With regard to dental cephalometric data, we found dental biprotrusion, protruding lower incisors, and outward-protruding upper incisors (Table III). The main esthetic problem observable from the cephalometric tracing was the presence of a short upper lip with a right nasolabial angle. The lower lip normally protruded (Table III). OOOOE e2 Yáñez-Vico et al. Month 2010 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 AQ: 1 T1 T2 AQ: 2 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 AQ: 3 T3 T4 T5 DISCUSSION Cri-du-chat syndrome was first described in 1963 by Lejeune et al., 1 who comprehensively explained the common clinical manifestations. Since then, the literature has referred to patients with CdC as expressing craniofacial features that include hypertelorism, antimongoloid obliquity of the palpebral fissures, and a moon face. Radiological features, such as microencephaly and faulty long bone development have also been described. Many authors have reported on the clinical and radiological findings associated with this syndrome 8,10,13,22-25 ; none, however have measured craniofacial features involving the maxillary and mandibular bones. In CdC syndrome, the monotonous, high-pitched cry like a cat is probably the most characteristic and striking clinical feature. 26 This has also been found in certain kinds of disorders or neurological diseases. 4 Morphologic laryngeal alterations, such as a small floppy, curved epiglottis, 27 laryngeal hypoplasia, a narrow, diamond-shaped or quadrangular larynx, or an abnormal air space in the posterior area during phonation, 28 have all been said to result in this characteristic cry. Airway analysis found a narrow upper airway volume, confirmed by computed tomography studies. 22 Nevertheless, subsequent studies established that such anatomical alterations were not necessarily present in every patient and the existence of some other organic or functional factor was not being considered. 4 Thus, the statistical frequency of a markedly inclined palatal plane, found in 70% of the subjects, suggests that it is a characteristic feature and probably involved in the Table I. Anatomical landmarks used Point Definition Sella (S) Point representing the center of the pituitary fossa Nasion (Na) Most anterior point of the frontonasal suture on the midplane Basion (Ba) Most postero-inferior point of the clivus Articulare (Ar) The intersection between the external contour of the cranial base and the dorsal contour of the condylar head or neck. Tangent-gonion (tgo) The point of intersection between the base and the ramus tangents through gnation and articulare Menton (Me) The lowest point of the jaw at the level of the midsagittal plane of the symphysis Condylion (Co) The uppermost point of the mandibular condyle A point (A) The most posterior point on the anterior contour of the upper alveolar process Gnation (Gn) The most inferior point on the mandibular symphysis Pogonion (Pg) The most anterior point on the mandibular symphisis Apex superius (As) The apex of the root of the most prominent maxillary central incisor Incisor surperius (Is) The midpoint of the incisal edge of the most prominent maxillary central incisor Incisor inferius (Ii) The midpoint of the incisal edge of the most prominent mandibular central incisor Apex inferius (Ai) The apex of the root of the most prominent mandibular central incisor Psps point (psp) The most posterior point on the soft palate Ppws point (ppws) Closest point on the posterior to pharyngeal wall to psp point Pbt point (pbt) Intersection of the posterior border of the tongue and the inferior border of the mandible Ppwi point (ppwi) Closest point on the posterior to pharyngeal wall to pbt point Pm point (pm) The point where the curvature of the anterior border of the symphysis changes from concave to convex Xi point (Xi) A point located at the center of the ramus Pterigomaxillare (Pt) The intersection point of the inferior border of the foramen rotundum and the posterior wall of the pterigomaxillary fissure Gonion (Go) The lowest, most posterior point on the gonial angle of the mandible Porion (Po) The most superior point on the radiolucency of the external and internal audigory meati. It is located posterior to the mandibular condyle and posterior clivus. Orbitale (Or) The most inferior point on the lower border of the bony orbit CF point (CF) The intersection point of the FH plane (Frankfort horizontal plane: a line connecting the Po and Or points) and the PTV plane (Pterygoid vertical plane: a line perpendicular to the FH plane thorugh the PT point). Anterior nasal spine (ANS) The apex of the anterior nasal spine Posterior nasal spine (PNS) The most posterior point on the bonu hard palate in the midsagittal plane Stomion superius (Sts) The lowest midline point of the upper lip B point (B) The deepest point on the contour of the mandible Soft tisue pogonion (Pg´) The most prominent point on the soft tissue contour of the chin in the midsagittal plane Labrale superius (Ls) The point denoting the vermillion border of the upper lip in the midsagittal plane Labrale inferius (Li) The point denoting the vermillion border of the lower lip in the midsagittal plane Subnasale (Sn) The point in the midsagittal plane where the base of the columella of the nose meets the upper lip Columela nasal medium (Nm) Geometric center on columela to de subnasal point to the tip of the nose Center of cranium (Ce) The intersection point of the Ba-Na plane and the facial axis plane Condyle (Dc) The point in the center of the condyle neck along Ba-N plane OOOOE Volume xx, Number x Yáñez-Vico et al. e3 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163