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SUMMARY Background/Aim: Noonan syndrome (NS) is an autosomal dominant disorder, caused by mutations on genes located on the long arm of chromosome 12. The condition has no sex or race predilection and its incidence is 1 per 1,000 – 2,500 live births. Individuals affected with Noonan syndrome have distinctive facial features, hypertelorism, short stature, congenital heart disease; mainly pulmonary stenosis and hypertrophic cardiomyopathy, chest deformities, variable learning disabilities and mental retardation. Orofacial findings in Noonan syndrome may be high-arched palate, micrognathia, dental malocclusion and articulation difficulties. Case report: The present article reports on a male case of 12 years old, referred for treatment in the orthodontic office. Despite the difficulties of hyperactivity, the light mental delay and the gag reflex, the treatment was completed satisfactorily with fixed orthodontic appliances in 15 months. Both the patient and his parents were happy with the results. The patient is presently undergoing the retention period of this orthodontic treatment. Conclusions: Despite the difficulties of treating a child with a genetic syndrome for his/her malocclusion, the reported case presented in this article proves that it is always worth trying for the benefit of the patient. Key words: Noonan Syndrome, Genes Mutation, Orthodontics, Pediatric Dentistry Evangelia Chatzistavrou, Georgios Andreadis Private Practice, Thessaloniki, Greece CASE REPORT (CR) Balk J Dent Med, 2020;118-126 BALKAN JOURNAL OF DENTAL MEDICINE ISSN 2335-0245 Noonan Syndrome in 12 -Year-Old Male: Case Report and Orthodontic Management of the Occlusion Introduction Noonan syndrome (NS) was first described in 1963 by Jacqueline Noonan (a paediatric cardiologist of the University of Kentucky) who reported nine patients with pulmonary valve stenosis, small stature, hypertelorism, low-set ears, mild intellectual disability, undescended testes and skeletal deformities 1 . NS is an autosomal dominant multi-system disorder, with variable expressivity. Its incidence is one in 1,000 to 2,500 live births for severe phenotype whereas in mild cases, the incidence may be as common as one in 100 live births 2 . Both males and females are affected by the syndrome. Diagnosis of NS is based primarily on the identification of characteristic clinical features 3 . Molecular genetic testing can provide confirmation in 70% of cases. Patients with Noonan syndrome display similar clinical characteristics to patients with Turner syndrome. However, only females are affected by Turner syndrome (karyotype 45X identified). In addition, in Turner syndrome, left-side heart defects and renal anomalies are more common, developmental delay occurs less often, and primary hypogonadism causes amenorrhea and sterility 4 . Due to the resemblance of NS to Turner syndrome,

Noonan syndrome has been termed as “male Turner syndrome”, “pseudo-Ullrich Turner syndrome”, “female pseudo-Turner syndrome” and “webbed neck syndrome”. Noonan syndrome is one of a group of related conditions, with similar signs and symptoms, collectively known as RASopathies. These conditions are caused by changes in the same cell signaling pathway and besides NS, they include cardio-facio-cutaneous syndrome, Watson syndrome, Costello syndrome, neurofibromatosis 1, LEOPARD syndrome 5 . In Noonan syndrome, no consistent chromosomal abnormality has been found 6,7 . In a genome-wide linkage 10.2478/bjdm-2020-0020 sternum) and cubitus valgus deformity of upper extremity (increased carrying angle at elbow joint). In adulthood, there is high anterior hairline, the head is triangle-shaped, the skin is transparent and wrinkled and the nasolabial folds are prominent. Depending on the severity of expression of the syndrome, individuals with NS may face eye problems, including strabismus, refractive errors, amblyopia, or nystagmus 16 . As far as the sense of hearing is concerned, approximately 10% of affected people have auditory deficits in the low frequency range while 25% have deficits in the high frequency range 18 . The intelligence of most affected individuals with Noonan syndrome is within the normal range, with Intelligence Quotient (IQ) varying between 70 and 120 19,20 . About one third of affected children, have mild mental retardation and poor coordination 7,21,22 . As shown in the study of language phenotype of Pierpont et al. 23 , language impairments are more frequent in individuals with NS than in the general population and are associated with high risk of reading and spelling difficulties. The oral manifestations of Noonan syndrome include high-arched palate, micrognathia, malocclusion, central giant cell lesions of jaw and cherubism 3,24,25 . Not all of the oral features of NS are evident in every case. In the dental literature, there is a small number of reported cases with NS 25-32 . Of those, only two are treated with myofunctional therapy 29,30 and two with fixed orthodontic therapy 31,32 . The purpose of the present article was to report a male case of Noonan syndrome, treated for his malocclusion with fixed appliances orthodontic treatment. Case report A Caucasian boy of 12 years of age with Noonan Syndrome born from healthy parents, with no family history, was referred for orthodontic treatment from the pediatric dentist. A detailed medical history was obtained from the parents of the patient. Medical history The patient had been diagnosed with NS at the age of 2 months old from a clinical geneticist in a state Children’s Hospital based on the clinical appearance and confirmed by a molecular genetic testing sent to a specialized genetic labo

ratory center. At 2 months old, the patient presented pulmonary stenosis and underwent a surgery for a catheterization procedure for this stenosis. At 5 months old, an open-heart surgery was performed to open the stenosis of the pulmonary valve. Six months later, a successful replacement of this valve took place by a pediatric heart surgeon. Since birth, the child was facing feeding problems due to frequent vomiting but analysis of a large Dutch kindred group affected with autosomal dominant Noonan syndrome, Jamieson et al. localized the gene responsible on the long arm of chromosome 12, between D12S84 and D12S366 8 . Other studies demonstrated the heterogeneity of the condition by relating giant cell lesions and cherubism with Noonan syndrome 9-13 . Molecular genetic testing identified mutations in the gene PTPN11 (Protein Tyrosin Phosphatase Non- receptor type 11) in 50% of affected individuals with Noonan syndrome 14 . PTPN11 encodes the protein SHP2, which has essential roles in signal transduction pathways that control several developmental processes, including cardiac semilunar valvulogenesis. For the remaining percentage of affected individuals with NS, SOS1 in 13%, RAF1 and RIT1 each in 5%, and KRAS in fewer than 5% have been identified as candidate genes. Other genes with pathogenic variants reported to cause NS in fewer than 1% of cases include NRAS, BRAF, and MAP2K1. Noonan syndrome is a genetic disorder with multiple congenital abnormalities. NS is the second most common syndromic cause of congenital heart disease, following trisomy 21 15 . The most common cardiovascular phenotypes occurring in NS are pulmonary stenosis (at a percentage of 50-60%), followed by hypertrophic cardiomyopathy (20%) and secundum atrial septal defect (6-10%) 16 . Although birthweight and body length are usually normal, short stature is a common manifestation of Noonan syndrome. Since the pubertal growth spurt is often attenuated or delayed, the prevalence of short stature in NS is greatest during the time period of normal puberty. At onset of puberty, mean age is delayed in patients with NS compared with the general population. A percentage of 35% of boys enter puberty after the age of 13,5 years and 44% of girls enter puberty after the age of 13 years 17 . Even though bone ageing is delayed, growth of many patients catches up in patient’s late teens 16 . With respect to the facial features, most affected individuals with NS have some distinctive characteristics that evolve with age 3,16 . In a newborn baby, a tall forehead, wide-spaced eyes (hypertelorism), downslanting palpebral fissures, epicanthal folds, oval-shaped low- set posteriorly rotated ears, short and broad nose with depressed root and full tip, deeply grooved philtrum, full lips with high, wide peaks to the vermillion border of the upper lip, small chin, excess nuc

hal skin and swollen edematous dorsum of hands and feet are noted. In infancy, a tall and prominent forehead, hypertelorism, thickly hooded prominent eyes, wide-based depressed nose with bulbous, upturned tip and cupid bow appearance of upper lip are present. In childhood and adolescence, the head is inverted triangle-shaped, the facial features are coarse, the hair is curly/wooly, the forehead is wide, the chin is small, the neck skin is webbing, there is pectus sternal deformity (prominent superior sternum and depressed inferior Balk J Dent Med, Vol 24, 2020 Noonan Syndrome 119 120 Evangelia Chatzistavrou, Georgios Andreadis Balk J Dent Med, Vol 24, 2020 The facial photographs of the patient demonstrated hypoplasia in the maxilla, lip incompetence for closure when at rest and a protruding lower lip (Figures 2a-c). The patient presented the typical facial characteristics of NS, such as wide forehead, hypertelorism, low-set of ears, prominent nasolabial folds, transparent and wrinkled skin, webbed neck, sunken chest (pectus excavatum) and arachnodactyly (Figures 3a-b, 4). The intraoral examination demonstrated a Class I molar relationship but Class III cuspid relationship, with anterior cross-bite from #12-22/#33-43, cross- bite #24/#34, buccal cross-bite #16/#46, ectopic palatal eruption of #15, high-arched palate (typical oral finding in NS), lingually inclined #46, Overjet -2mm, Overbite 15% and midline deviation of the lower midline to the left by 3mm (Figures 5a-e). The radiographic examination showed a normal permanent dentition with the sperms of 3 rd molars present, a horizontal type of growth, retroclined and retruded upper incisors and proclined and protruded lower incisors (Figures 6a-c). The space analysis performed on the dental casts, which were taken with many difficulties due to gagging reflex, revealed 4mm lack of space in the maxillary arch and 3 mm excess of space in the mandibular arch. the patience of the mother was exceptional and effective all the time. Ever since the age of 6 years old, every 6 months, growth hormone has been administered to the patient by the endocrinology team of the same health care unit where he was initially diagnosed with NS and has been followed till present. The patient has been wearing prescription glasses to correct his short-sightedness. Dental history Five years prior to his referral to the orthodontic office, at the age of 7 years old, the patient initiated regular dental visits for check-ups and oral prophylaxis to the pediatric dentist. At the mixed dentition period, the patient needed preventive and restorative treatment for several primary teeth. Preventive fissure sealants were performed to all permanent first molars, as well as premolars once erupted in the oral cavity. The patient’s cooperation with the pediatric dentist was satisfactory and the parents we

re always assisting with the oral hygiene at home and the elimination of cariogenic foods from the daily nutrition. According to the data provided by the pediatric dentist, ever since the first visit at his office, the patient had a prognathic profile due to a small upper arch and an anterior cross-bite. Despite the good intention of the pediatric dentist to apply a removable expansion appliance to the upper ach for the alleviation of the crowding, the severe gagging reflex of the patient did not permit the wear of this appliance. It was at that time that the decision was made to refer the patient to the orthodontic office for treatment for his malocclusion. Case follow-up The patient presented to the orthodontic office at the age of 12 years old. His skeletal age was 4 years behind, as documented by the hand-wrist radiograph and the Greulich & Pyle standards of age (Figure 1). His physical examination revealed a relatively short stature (height: 129,8cm and weight: 25kg), following the growth chart of below the 3 rd percentile of the average children. Figure 1. Hand-wrist radiograph for the measurement of skeletal age of the patient Figure 2 (a-c). Facial photographs of the patient a b c Balk J Dent Med, Vol 24, 2020 Noonan Syndrome 121 Figure 5 (a-e). Intra-oral photographs of the patient Figure 3 (a-b). Body photographs of the patient with apparent chest deformities and webbed neck Figure 4. Arachnodactyly of the patient’s hands Figure 6 (a-c). Orthopantomogram, postero-anterior cephalogram and lateral cephalogram of the patient before the orthodontic treatment a b c c a a b b d e 122 Evangelia Chatzistavrou, Georgios Andreadis Balk J Dent Med, Vol 24, 2020 followed by completion of bonding at the next visit after 1 month (Figures 9a-b). Instructions for proper oral hygiene were given and monitored by the pediatric dentist that was following the case from the beginning. Bonding of the mandibular dental arch took place afterwards (Figures 10a- c). Eight months in fixed appliances, all teeth were levelled and aligned and at that time, Class III ¼’’ medium (4 ½ oz.) and later heavy (6 ½ oz.) elastics were prescribed. After 3 months of proper use of elastics, a good Class I cuspid relationship was established (Figures 11a-b). Unfortunately, despite the multiple applications of cement as posterior bite blocks, no opening of the bite was accomplished to enable uprighting of the inclined #46 and in addition, it was impossible to bond the #47. As a final effort to correct the right-sided buccal cross-bite, X-cross elastics were prescribed from the upper posterior teeth to lingual sheaths and buttons bonded on the lower posterior teeth (Figures 12a-c). Little was accomplished with this modality and as a result, 15 months in treatment, it was decided to debond the case. Fixed appliances were removed and the teeth we

re cleaned properly (Figures 13a-e). Removable retention appliances (Essixes type C+) were delivered to the patient with instructions for full time wear, except for eating and brushing the teeth (Figure 14). Retention follow-up will take place to preserve the result of the patient’s dentition, as well as his face (Figures 15a-c). It should be worth mentioning that the patient had a very active behaviour, was demonstrating satisfactory level of cooperation, had a light mental retardation but presented an extremely high emotional status at the beginning of every procedure followed in the office (starting to cry out of fear for the unknown). Special care was taken by the orthodontist to follow the “Tell- Show-Do” method of approach, in order to achieve the cooperation of the patient. As the principal treatment approach, expansion in the maxillary arch was selected. Considering the initial failed effort to use a removable expansion appliance, a skeletal expansion protocol with a Hyrax appliance was chosen (Figures 7a-c). Since nothing could predict the successful application of fixed orthodontic appliances, labial hooks were fabricated and incorporated in the Hyrax appliance, for possible need of use of face mask to correct the negative overjet. Upon cementation of the Hyrax, instructions were given to the parents for 2 turns per day. Expansion occurred for only 14 days. Right at that time, breakage of the appliance took place and the patient no longer wished to have a new one made. The treatment plan changed to fixed appliances and use of resin-reinforced glass ionomer posterior bite blocks to open the bite. Due to the difficulties of bonding in a hyperactive child, partial initial bonding of the maxillary dental arch took place (Figures 8a-b), Figure 7 (a-c). Hyrax appliance cemented in the upper arch Figure 8 (a-b). Initial partial bonding of the maxillary dental arch due to poor patient cooperation c a a b b Balk J Dent Med, Vol 24, 2020 Noonan Syndrome 123 Figure 9 (a-b). Completion of bonding of the maxillary dental arch Figure 10 (a-c). Bonding of the mandibular dental arch Figure 11(a-b). Final alignment of both dental arches with fixed appliances Figure 12 (a-c). Patient wearing X-cross elastics in an effort to correct the R-sided buccal crossbite a a a a b b b b c c 124 Evangelia Chatzistavrou, Georgios Andreadis Balk J Dent Med, Vol 24, 2020 Figure 13 (a-e). Final photographs of the occlusion of the patient at the end of the orthodontic treatment Figure 14. Removable appliances for retention (type C+ Essixes) for maxillary and mandibular dental arches Figure 15 (a-c). Facial photographs at the end of orthodontic treatment c d a b c e a b Balk J Dent Med, Vol 24, 2020 Noonan Syndrome 125 Conclusions In patients with Noonan syndrome, dental and orthodontic treatment is advised and may be accomplished. Even

though, by the time the patient with NS presents to the dental office, his/her medical condition is already diagnosed, the pediatric dentist should recognize the syndrome and try to offer his/her services to the patient if needed. The case presented in this article reinforces the statement that, in syndromic cases, a treatment plan difficult to accomplish due to compromises in cooperation, is always worth trying. References 1. Noonan JA, Ehmke DA. Associated noncardiac malformations in children with congenital heart disease. J Pediatr, 1963;31:150-153. 2. Mendez HM, Opitz JM. Noonan syndrome: a review. Am J Med Genet, 1985;21:493-506. 3. Bhambhani V, Muenke M. Noonan Syndrome. Am Fam Physician, 2014;89:37-43. 4. Morgan T. Turner syndrome: diagnosis and management. Am Fam Physician, 2007;76:405-410. 5. Tidyman WE, Rauen KA. The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev, 2009;19:230-236. 6. Sharland M, Morgan M, Smith G. Genetic counseling in Noonan syndrome. Am J Med Genet, 1993;45:437-440. 7. Allanson JE. Noonan syndrome. J Med Genet, 1987;24:9- 13. 8. Jamieson CR, van der Burgt I, Brady AF, Vn Reen M, Elsawi MM, Hol F et al . Mapping a gene for Noonan syndrome to the long arm of chromosome 12. Nat Genet, 1994;8:357-360. 9. Addante RR, Breen GH. Cherubism in a patient with Noonan’s syndrome. J Oral Maxillofac Surg, 1996;54:210- 213. 10. Betts NJ, Stewart JCB, Fonseca RJ, Scott RF. Multiple central giant cell lesions with a Noonan-like phenotype. Oral Surg Oral Med Oral Pathol, 1993;76:601-607. 11. Cancino CM, Gaiao L, Sant’Ana Filho M, Oliveira FA. Giant cell lesions with a Noonan-like phenotype: a case report. J Contemp Dent Pract, 2007;8:67-73. 12. de Lange JD, van den Akker HP, van den Berg H. Central giant cell granuloma of the jaw: a review of the literature with emphasis on therapy options. Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 2007;104:603-615. 13. Lee SM, Cooper JC. Noonan syndrome with giant cell lesions. Int J Paediatr Dent, 2005;15:140-145. 14. Allanson JE, Roberts AE. Noonan syndrome. Gene-Tests: Reviews. National Center for Biotechnology Information. http://www.ncbi.nlm.nih.gov/books/NBK1124 . Accessed Aug 03, 2019. Discussion Noonan syndrome is a common genetic disorder, associated mainly with congenital heart disease and skeletal malformations. The severity of the orofacial features may vary greatly in patients with NS. In the present article, the case reported had the typical facial dimorphism and malformations featuring NS, including congenital heart disease due to pulmonary valve stenosis, short stature, abnormal chest shape, webbed neck, hypertelorism and mild mental retardation. Regarding the dental findings, the patient presented had malaligned teeth, crowded upper arch, high-arched palate, severely proclined lower teeth, cross- bite

, negative overjet and midline deviation. All the above mentioned problems requested orthodontic treatment for the benefit of the patient. In the dental literature, there aren’t so many reports on treated cases for their malocclusion. A small number of reported cases are treated with removable appliances (mostly myofunctional) 29,30 and few with fixed appliances mechanotherapy 31,32 . In general, there is lacking reported evidence on the treatment with fixed orthodontic appliances, probably due to the complexity of cases where mental retardation is involved. In the case presented, the combination of hyperactivity on behalf of the patient and the highly emotional status at the introduction of bonding brackets, limited any complicated biomechanics that could be applied for the benefit of the patient. The “Tell-Show-Do” technique for reinforcement of cooperation proved to be very effective during the whole orthodontic treatment. In addition, rewarding the patient with a gift, for instance a toy, at every visit at the orthodontic office encouraged him to keep calm and comply with the instructions while bonding at the office. The parallel assistance of the parents at home was valuable, not only for preservation of good oral hygiene but, additionally, for preventing as much as possible breakages of the appliances by eliminating all the hard food from the patient’s nutrition. Taking into consideration the specific nature of the medical condition of the patient and the degree of cooperation, the treatment results were very satisfying. The occlusion accomplished at the end of treatment was Class I both in molars and cuspids with the anterior cross-bite completely corrected. All teeth were nicely aligned. Proper overjet and overbite were established and the midlines coincided. However, the buccal cross-bite on the right side remained untreated. Despite the efforts, the lower first molar on the right side was left lingually inclined and in cross-bite with the upper first molar. For everyone in the family, and especially for the young patient that felt relieved after removal of the braces, the result at the end of treatment was more than pleasing and worth treating. Neither the parents nor the patient wished any further treatment for the correction of the buccal cross-bite left. As such, retention was the only procedure that could follow. 126 Evangelia Chatzistavrou, Georgios Andreadis Balk J Dent Med, Vol 24, 2020 26. Okada M, Sasaki N, Kaihara Y, Okada R, Amano H, Miura K et al. Oral findings in Noonan syndrome: report of a case. J Oral Sci, 2003;45:117-121. 27. Ortega AdeOL, Guaré RdeO, Kawaji NS, Ciamponi AL. Orofacial aspects in Noonan syndrome: 2 case report. J Dent Child (Chic), 2008;75:85-90. 28. Emral ME, Akcam MO. Noonan syndrome: a case report. J Oral Sci, 2009;51:301-306. 29. Ierardo G, Luzzi V, Panet

ta F, Sfasciotti GL, Polimeni A. Noonan Syndrome: A case report. Eur J Paed Dent, 2010;11:97-100. 30. Mocanu RM, Zetu IN, Vulpoiu C, Bălan A. Orofacial findings in Noonan syndrome: a case report. Orthod, 2013;3:162-165. 31. Uloopi KS, Madhuri V, Gopal AS, Vinay C, Chandrasekhar R. Multiple unerupted permanent teeth associated with Noonan syndrome. Ann Med Health Sci Res, 2015;5:317- 320. 32. Cardiel Rios SA. Correction of a severe Class II malocclusion in a patient with Noonan syndrome. Am J Orthod Dentofacial Orthop, 2016;150:511-520. Con�ict of Interests: Nothing to declare. Financial disclosure Statement: Nothing to declare. Human Rights Statement: All the procedures on humans were conducted in accordance with Helsinki Declaration of 1975, as revised 2000. Consent was obtained from the patient/s and approved for current study by national ethical committee. Animal Rights Statement: None required. Received on September 23, 2019. Revised on November 20, 2019. Accepted on December 2, 2019. Correspondence: Evangelia Chatzistavrou Private Practice, Thessaloniki Thessaloniki, Greece e-mail: liaortho@hotmail.com 15. Marino B, Digilio MC, Toscano A, Giannotti A, Dallapiccola B. Congenital heart diseases in children with Noonan syndrome: an expanded cardiac spectrum with high prevalence of atrioventricular canal. J Pediatr, 1999;135:703-706. 16. Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lancet, 2013;381:333-342. 17. Romano AA, Dana K, Bakker B, Davis DA, Hunold JJ, Jacobs J et al. Growth response, near-adult height, and patterns of growth and puberty in patients with noonan syndrome treated with growth hormone. J Clin Endocrinol Metab, 2009;94:2338-2344. 18. Qiu WW, Yin SS, Stucker FJ. Audiologic manifestations of Noonan syndrome. Otolaryngol Head Neck Surg, 1998;118:319-323. 19. Allanson JE. Noonan syndrome. Am J Med Genet C Semin Med Genet, 2007;145:274-279. 20. Cesarini L, Alfieri P, Pantaleoni F, Vasta I, Cerutti M, Petrangeli V et al. Cognitive profile of disorders associated with dysregulation of the RAS/MAPK signaling cascade. Am J Med Genet, 2009;149:140-146. 21. Noonan JA. Noonan syndrome revisited. J Pediatr, 1999;135:667-668. 22. Sharland M, Burch M, McKenna WM, Paton MA. A clinical study of Noonan syndrome. Arch Dis Child, 1992;67:178- 183. 23. Pierpont EI, Weismer SE, Roberts AE, Tworog-Dube E, Pierpont ME, Mendelson NJ et al. The language phenotype of children and adolescents with Noonan syndrome. J Speech Lang Hear Res, 2010;53:917-932. 24. Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME et al. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 2010;126:746-759. 25. Mallineni SK, Yung Yiu CK, King NM. Oral manifestations of Noonan syndrome: review of the literature and a report of four cases. Rom J Morphol Embryol, 2014;55:1503-1509