Relationship between Malnutrition and Anemia among In-Patient Children at Rahmah Teaching Hospital, IrbidNorthern Jorda

1. Abstract Amyloidosis are rare diseases related to the pathological aggregation and accumulation of misfolded proteins in the extracellular space generating insoluble deposits. This may occur in almost any tissue and organ, leading to severe structural damages and functional impairments. Oral manifestations are frequent in systemic amyloidosis and represent 9% of the localized forms. The most common are: macroglossia, cutaneous or oral mucosa lesions (petechiae, xerostomia) and periodontal involvement. Teeth involvement (pain, mobility or loss) is only described as secondary to periodontal alterations. Abnormalities of teeth eruption have not yet been reported in amyloidosis. In this case report we highlighted uncommon oral manifestations - multiple mandibular impacted teeth and cystic peri-coronary bone lesions - in a 58-year-old patient, with an established diagnosis of severe hereditary ATTR amyloidosis, and illustrated the difficulties of etiologic diagnosis and therapeutic management of such oral and dental lesions in this context

2. Introduction Amyloidosis, also known as amylosis, is a large group of diseases that result from the pathological aggregation and accumulation of misfolded proteins in the extracellular space of different organs and tissues, generating insoluble deposits called amyloid. Amyloidosis is a rare disease, the number of people affected is difficult to evaluate and little epidemiological data are available. Incidence was estimated at 5 to 13 per million of population per year, according to data from British, American and Swedish studies. The prevalence estimated by the UK study would be about 20 per million of population [1,2]. Many different types of amyloidosis have been described and their nomenclature is based on the nature of the protein that forms the amyloid fibrils. These polypeptide aggregates are most often precursor forms of the mature soluble protein. Currently 36 proteins known to be able to form amyloid fibrils have been identified in human and their number is increasing as new discoveries are reported in this field [3,4]. The amyloid deposits are mainly composed of specific fibrillary proteins, but other components are also present, especially serum amyloid P component (SAP) and proteoglycans (heparan sulfate proteoglycan, HSPG) which are ubiquitous molecules. Amyloid fibrils measure approximately 10 nm diameter and can be histologically identified by Congo Red staining, with a specific green and yellow birefringence when combined with polarized light microscopy, regardless of the type of fibrillary protein. [1,5] The major forms, among a wide variety, are AL amyloidosis (deposition of monoclonal immunoglobulin light chain; systemic or localized form); AA amyloidosis (reactive, inflammatory form, with deposition of Apo Serum amyloid A; systemic form); hereditary forms including Aβ2M amyloidosis (deposition of β2 microglobulin; systemic form) and hereditary ATTR (deposition of transthyretin, with numerous genetic variants; systemic form). Hereditary forms are genetic pathologies with autosomal dominant inheritance. [6] The deposition of the amyloid can affect almost all tissues and organs. The progression is insidious and may lead to severe structural damage and functional impairments. The clinical manifestations are very diverse and rather nonspecific to a type of amyloidosis. These conditions contribute to the difficulty of diagnosis and delay the therapeutic interventions. The main organs affected are the heart, kidney, digestive tract, liver, skin, peripheral nerve and eye, as well as the central nervous system, with disastrous consequences. Depending on the site and extent of the amyloid deposit, systemic or localized amyloidosis have been described. Systemic amyloidosis may be primary or secondary to other diseases (rheumatic disease, malignant tumors, infectious diseases, inherited diseases or idiopathic conditions). About 45% of systemic forms are secondary or reactive AA amyloidosis.5 Localized forms of amyloidosis are limited to specific organs or sites and have an excellent prognosis while systemic amyloidosis may be life threatening.[7] Oral cavity can be affected by amyloidosis as a manifestation of a systemic or localized form. The most common of the oral manifestations are: cutaneous or oral mucosa lesions (petechiae, papulae, xerostomia); palate lesions; gingival lesions; macroglossia (not described in hereditary forms); periodontal involvement.[7,8,9] Teeth involvement - pain, mobility or loss - is only described as secondary to periodontal tissues alterations.9 Abnormalities of teeth eruption associated with amyloidosis have not yet been reported. An unerupted tooth is a mature tooth that has not erupted after the physiological date (24 months beyond the expected age) and whose peri-coronary sac has no communication with the oral cavity.[10] It is completely covered by the oral mucosa with or without bone tissue. The prevalence of unerupted tooth according to the studies ranges from 16.5 % in a study conducted in 3874 patients to 28.5 % in a study on 7486 patients. [11,12] Among the main etiologies of unerupted teeth we can list several local factors, including gingival fibromas, gingival hyperplasia, alveolar dental ankylosis.[13] Systemic causes may also explain dental impaction: deficiency of vitamin A, of vitamin D, systemic infections as tuberculosis or syphilis, hormonal disorders as hypoparathyroidism, metabolic diseases or idiopathic etiology when any causal factor is found.[14-19] Impacted teeth may also occur due to genetic factors (hereditary or not) or being part of genetic syndromes phenotype (see Table I)[20-32]. The presence of dental inclusions is therefore a signal that must lead the clinicians to perform further investigation, including genetic test, for early diagnosis, prevention and treatment. For the first time we described the clinical case of a patient with genetically diagnosed amyloidosis, who shows many impacted teeth without any known etiology

3. Case Report Mr. X, a 58-year-old patient from Guadeloupe, was referred to our specialized consultation in the Oral and Dental Rare Disease Competence Center, in the setting of an University Hospital (Paris area, France). The consulting purpose was an oral cavity check-up post-liver and cardiac graft, carried out in France in November 2018. This double transplantation results from a severe cardio-hepatic failure, due to his hereditary genetic ATTR amyloidosis (Val 122 fake antisense homozygous mutation of the TTR gene), confirmed on a fat-tissue biopsy performed in 2017. The panoramic X-Ray of the maxillae carried out as part of this assessment (Figure 1) revealed multiple mandibular impacted teeth associated with clinically asymptomatic cystic peri-coronary bone lesions. The results of the panoramic examination have been comforted by a Cone Beam Computed Tomography (CBCT Although asymptomatic, as part of the immunosuppressive treatment of this patient, these impacted teeth and associated lesions have been considered as potentially infectious risk foci and surgical management under general anesthesia was therefore recommended and realized. Excision of the cysts, avulsion of the unerupted teeth when their topography permitted and the benefit/risk ratio was favorable (teeth: 44 - lower right first bicuspid, and 34 - lower left first bicuspid), as well as coronectomies with ablation of the peri-coronary cysts (teeth: 35- lower left second bicuspid, 36 - lower left first molar, 45 - lower right second bicuspid and 46 - lower right first molar) have been performed. In this surprising and atypical clinical picture and regarding the patient’s medical history, a more in-depth investigation was conducted in parallel with the surgical care. The assessment of patient’s family history by a specific questionnaire revealed that patient’s brother and one of his six sisters present some unerupted teeth, suggesting a familial component (hereditary or environmental) in this clinical feature. However, no obvious, already described causes explaining these dental inclusions have been identified. Patient’s brother and sister, aged 31 and 34 respectively and who do not live in metropolitan France, did not benefit of investigations, therefore the status of a possible amyloidosis diagnosis remains uncertain. Finally, a more specific genetic screening was performed to search for a known genetic anomaly associated with multiple unerupted teeth using the salivary test Oragene.DNA® designed for maxillofacial genetic disorders. Unfortunately, this test did not allow the association of any known genetic anomaly of the oral sphere with this clinical picture of impacted teeth.

4. Discussion In this case report we highlighted some particular oral manifestations - presence of multiple mandibular impacted teeth, associated with clinically asymptomatic cystic peri-coronary bone lesions - in a 58-year-old patient, with an established diagnosis of hereditary ATTR (hATTR) amyloidosis. To our knowledge there is no other similar description among specialized studies. With the complex example of this patient we have illustrated the difficulties of diagnosis and therapeutic management of such oral and dental lesions. 4.1. Clinical Aspects As we mentioned above, various oral manifestations may occur in systemic amyloidosis. The forms located in the oral cavity represent only 9% of all amyloidosis.[33] Clinically 25% of patients with systemic amyloidosis have macroglossia with an enlarged, poorly mobile tongue affecting elocution, feeding (mastication, swallowing) and breath. Oral mucous membranes often show bruises, papules and ulcers and when the salivary glands are affected, xerostomia is almost systematic.[7,34,35] In contrast, the presence of unerupted teeth seems to be uncommon. Dental eruption is a complex phenomenon involving multiple molecular and cellular mechanisms, whose understanding is still incomplete. To this day, the theory of multifactorial eruption has been accepted by many authors.[36,37] In some cases teeth remain unerupted and submucosal. The discovery of an unerupted tooth is fortuitous since it is asymptomatic. [38]However, when the risk of infection is present, the decision to perform surgery can be taken. This was the case in our patient with an already diagnosed severe ATTR amyloidosis, undergoing immunosuppressive therapy and presenting numerous unerupted teeth in association with cystic lesions, found out during an oral cavity assessment after heart and liver transplantation. Patients with suspected amyloidosis are often directed to us (by different departments of our hospital or by other physicians) for labial biopsy of minor salivary glands in order to clarify diagnosis. Furthermore, patients with an established diagnosis of amyloidosis, like Mr X, are referred for In this case report we highlighted some particular oral manifestations - presence of multiple mandibular impacted teeth, associated with clinically asymptomatic cystic peri-coronary bone lesions - in a 58-year-old patient, with an established diagnosis of hereditary ATTR (hATTR) amyloidosis. To our knowledge there is no other similar description among specialized studies. With the complex example of this patient we have illustrated the difficulties of diagnosis and therapeutic management of such oral and dental lesions. 4.1. Clinical Aspects As we mentioned above, various oral manifestations may occur in systemic amyloidosis. The forms located in the oral cavity represent only 9% of all amyloidosis.[33] Clinically 25% of patients with systemic amyloidosis have macroglossia with an enlarged, poorly mobile tongue affecting elocution, feeding (mastication, swallowing) and breath. Oral mucous membranes often show bruises, papules and ulcers and when the salivary glands are affected, xerostomia is almost systematic.[7,34,35] In contrast, the presence of unerupted teeth seems to be uncommon. Dental eruption is a complex phenomenon involving multiple molecular and cellular mechanisms, whose understanding is still incomplete. To this day, the theory of multifactorial eruption has been accepted by many authors.[36,37] In some cases teeth remain unerupted and submucosal. The discovery of an unerupted tooth is fortuitous since it is asymptomatic. [38]However, when the risk of infection is present, the decision to perform surgery can be taken. This was the case in our patient with an already diagnosed severe ATTR amyloidosis, undergoing immunosuppressive therapy and presenting numerous unerupted teeth in association with cystic lesions, found out during an oral cavity assessment after heart and liver transplantation. Patients with suspected amyloidosis are often directed to us (by different departments of our hospital or by other physicians) for labial biopsy of minor salivary glands in order to clarify diagnosis. Furthermore, patients with an established diagnosis of amyloidosis, like Mr X, are referred for

5. Conclusion Amyloidosis is a group of rare diseases due to amyloid accumulation that can occur in almost any tissue and organ. Localized forms have usually good prognostic, while the evolution of the more frequent systemic forms may be life threatening. Oral manifestations of amyloidosis are found in systemic as well as in localized forms of the disease. With this case report we have shown the importance of the early diagnosis in the optimal therapeutically management of both systemic amyloidosis and oral lesions. Oral cavity check-up is suitable to be completed before initiating any heavy treatment of the systemic disease. Clinical suspicion of amyloidosis must be the subject of adequate investigations, allowing the identification of the amyloid fibrils and the typing of the involved protein. Among these diagnostic approaches, genetic tests are appropriate, easy to use tools and able to accurately confirm or label an amyloidosis diagnosis. In a long-term perspective, a larger utilization of these genetic tools is advisable. Moreover, the results of these tests will feed the genetic databases, allowing to find new correlations between the different clinical, biological and genetic parameters. Genetic counseling and screening are also helpful to identify a possible risk of hereditary transmission of amyloidosis. Finally, with the only example of our patient we did not have enough elements to find an association of the unerupted teeth with amyloidosis. Therefore, the presence of impacted teeth in this context, although uncommon, should be further explored to better understand whether this manifestation is associated with amyloidosis.

References 1. Wechalekar AD, Gillmore JD, Hawkins PN. Systemic amyloidosis. Lancet 2016; 387(10038): 2641-2654. doi: 10.1016/S0140- 6736(15)01274-X.

2. Nienhuis HL, Bijzet J, Hazenberg BP. The Prevalence and Management of Systemic Amyloidosis in Western Countries. Kidney Dis (Basel) 2016; 2(1): 10-9. doi: 10.1159/000444206.

3. Benson MD, Buxbaum JN, Eisenberg DS et al. Amyloid nomenclature 2018: recommendations by the International Society of Amyloidosis (ISA) nomenclature committee. Amyloid 2018; 25(4): 215-219. doi: 10.1080/13506129.2018.1549825.

4. Mollee P, Renaut P, Gottlieb D, Goodman H. How to diagnose amyloidosis. Intern Med J 2014; 44(1): 7-17. doi: 10.1111/imj.12288.

5. Röcken C, Shakespeare A. Pathology, diagnosis and pathogenesis of AA amyloidosis. Virchows Arch 2002; 440(2): 111-122. doi: 10.1007/s00428-001-0582-9. Review.

6. Rowczenio DM, Noor I, Gillmore JD et al. Online registry for mutations in hereditary amyloidosis including nomenclature recommendations. Hum Mutat 2014; 35(9): E2403-12. doi: 10.1002/ humu.22619.

7. Fahrner KS, Black CC, Gosselin BJ. Localized amyloidosis of the tongue: a review. Am J Otolaryngol. 2004; 25(3): 186-9. doi: 10.1016/j.amjoto.2004.01.007.

8. Khoury S, Dusek JJ, Anderson GB, Vigneswaran N. Systemic amyloidosis manifesting as localized, severe periodontitis. J Am Dent Assoc 2004; 135(5): 617-23. doi: 10.14219/jada.archive.2004.0250.

9. Cengiz MI, Wang HL, Yıldız L. Oral involvement in a case of AA amyloidosis: a case report. J Med Case Rep 2010; 4: 200. doi: 10.1186/1752-1947-4-200.

10. Almonaitiene R, Balciuniene I, Tutkuviene J. Factors influencing permanent teeth eruption. Part one-general factors. Stomatologija 2010; 12(3): 67-72.

11. Stephen F. Dachi D, Francis V, Howell D. A survey of 3,874 routine full-mouth radiographs: II. A study of impacted teeth. Oral Surgery, Oral Medicine, Oral Pathology. 1961; 14(10): 1165-1169. doi:

10.1016/0030-4220(61)90204-3.

12. Chu FC, Li TK, Lui VK, Newsome PR, Chow RL, Cheung LK. Prevalence of impacted teeth and associated pathologies-a radiographic study of the Hong Kong Chinese population. Hong Kong Med J 2003; 9(3): 158-63.

13. Andersson L, Blomlöf L, Lindskog S, Feiglin B, Hammarström L. Tooth ankylosis. Clinical, radiographic and histological assessments. Int J Oral Surg 1984; 13(5): 423-31. doi: 10.1016/S0300- 9785(84)80069-1

14. Granström G, Kullaa-Mikkonen A, Zellin G. Malformations of the maxillofacial region induced by retinoids in an experimental system. Int J Oral Maxillofac Surg 1990; 19(3): 167-71. doi: 10.1016/s0901 -5027(05)80138-9

15. Piette E, Reychler H. Traité de pathologie buccale et maxillo-faciale. Edition DE BOECK Université, 1991; 2804114570 9782804114572.

16. Hall K. R. Pediatric orofacial medicine and pathology. Edition CHAPMAN & HALL MEDICAL 1994; ISBN: 0412348608.

17. Chandna S, Bathla M. Oral manifestations of thyroid disorders and its management. Indian J Endocrinol Metab. 2011; 15(Suppl 2): S113-6. doi: 10.4103/2230-8210.83343.

18. Kamarthi N, Venkatraman S, Patil PB. Dental findings in the diagnosis of idiopathic hypoparathyroidism. Ann Saudi Med 2013; Jul-Aug; 33(4): 411-3. doi: 10.5144/0256-4947.2013.411.

19. Rhoads SG, Hendricks HM, Frazier-Bowers SA. Establishing the diagnostic criteria for eruption disorders based on genetic and clinical data. Am J Orthod Dentofacial Orthop 2013; 144(2): 194- 202. doi: 10.1016/j.ajodo.2013.03.015.

20. Shapira J, Chaushu S, Becker A. Prevalence of tooth transposition, third molar agenesis, and maxillary canine impaction in individuals with Down syndrome. Angle Orthod 2000; 70(4): 290-6. doi: 10.1043/0003-3219(2000)070<0290:POTTTM>2.0.CO;2

21. Kamer AR, Fortea JO, Videla S et al. Periodontal disease’s contribution to Alzheimer’s disease progression in Down syndrome. Alzheimers Dement (Amst) 2016; 2:49-57. doi: 10.1016/j.dadm.2016.01.001.

22. Järvinen HJ, Peltokallio P, Landtman M, Wolf J. Gardner’s stigmas in patients with familial adenomatosis coli. Br J Surg 1982; 69(12): 718-21. doi: 10.1002/bjs.1800691211

23. Kubo K, Miyatani H, Takenoshita Y et al. Widespread radiopacity of jaw bones in familial adenomatosis coli. J Craniomaxillofac Surg 1989; 17(8): 350-3. doi: 10.1016/s1010-5182(89)80104-0.

24. Davies DR, Armstrong JG, Thakker N et al. Severe Gardner syndrome in families with mutations restricted to a specific region of the APC gene. Am J Hum Genet 1995; 57(5): 1151-8

25. Wolf J, Järvinen HJ, Hietanen J. Gardner’s dento-maxillary stigmas in patients with familial adenomatosis coli. Br J Oral Maxillofac Surg 1986; 24(6):410-6. doi: 10.1016/0266-4356(86)90054-9.

26. Ha SW, Jung YJ, Bae HS, Ryoo HM, Cho IS, Baek SH.

Characterization of dental phenotype in patients with cleidocranial dysplasia using longitudinal data. Angle Orthod 2018; 88(4): 416- 424. doi: 10.2319/092617-647.1.

27. Grothe R, Anderson-Cermin C, Beiraghi S. Autosomal recessive Robinow syndrome: a case report. J Dent Child (Chic) 2008; 75(1): 48-54.

28. Kantaputra PN, Gorlin RJ, Ukarapol N, Unachak K, Sudasna J. Robinow (fetal face) syndrome: report of a boy with dominant type and an infant with recessive type. Am J Med Genet 1999; 84(1): 1-7. doi: 10.1002/(sici)1096-8628(19990507)84:1<1::aidajmg1>3.0.co;2-c.

29. Brooks JK, Ahmad R. Oral anomalies associated with the oculocerebrorenal syndrome of Lowe: case report with multiple unerupted teeth and pericoronal radiolucencies. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009; 107(3): e32-5. doi: 10.1016/j. tripleo.2008.11.023.

30. Ruellas AC, Pithon MM, Oliveira DD, Oliveira AM. Lowe syndrome: literature review and case report. J Orthod 2008; 35(3): 156-60. doi: 10.1179/146531207225022599.

Annals of Clinical and Medical Case Reports http://acmcasereports.com/ Page 06 Case Report Volume 10 Issue 17

31. Harrison M, Odell EW, Sheehy EC. Dental findings in Lowe syndrome. Pediatr Dent 1999; 21(7):425-8.

32. da Silva Pierro VS, Marins MR, Borges de Oliveira RC, Cortezzi W, Janini ME, Maia LC. Clinical and oral findings in an Afro-Brazilian family with Gorlin-Goltz syndrome: case series and literature review. Spec Care Dentist 2015; 35(1): 43-50. doi: 10.1111/scd.12079.

33. Deng J, Chen Q, Ji P, Zeng X, Jin X. Oral amyloidosis: A strategy to differentiate systemic amyloidosis involving the oral cavity and localized amyloidosis. Oral Dis 2019; 25(3): 670-675. doi :10.1111/ odi.12870.

34. Stoopler ET, Sollecito TP, Chen SY. Amyloid deposition in the oral cavity: a retrospective study and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003; 95(6): 674-80. doi: 10.1067/moe.2003.136

35. Juusela P, Tanskanen M, Nieminen A et al. Xerostomia in hereditary gelsolin amyloidosis. Amyloid 2013; 20(1): 39-44. doi: 10.3109/13506129.2013.764284.

36. Raghoebar GM, Boering G, Vissink A, Stegenga B. Eruption disturbances of permanent molars: a review. J Oral Pathol Med 1991; 20(4): 159-66. doi: 10.1111/j.1600-0714. 1991.tb00913.x.

37. Grover PS, Lorton L. The incidence of unerupted permanent teeth and related clinical cases. Oral Surg Oral Med Oral Pathol 1985; 59(4): 420-5. doi: 10.1016/0030-4220(85)90070-2.

38. Kaczor-Urbanowicz K, Zadurska M, Czochrowska E. Impacted Teeth: An Interdisciplinary Perspective. Adv Clin Exp Med 2016; 25(3): 575-85. doi: 10.17219/acem/37451.

39. Sacsaquispe SJ, Antúnez-de Mayolo EA, Vicetti R, Delgado WA. Detection of AA-type amyloid protein in labial salivary glands. Med Oral Patol Oral Cir Bucal 2011; 16(2): e149-52. doi:10.4317/ medoral.16.e149.

40. Gaultier F, Sitbon IY, Gogly B. Labial biopsy of minor salivary glands: Indications in clinical diagnostics. Biomed J Sci &Tech Res 2019; 15(4)-2019. doi: 10.26717/BJSTR.2019.15.002738

41. Ladanza MG, Jackson MP, Hewitt EW, Ranson NA, Radford SE. A new era for understanding amyloid structures and disease. Nat Rev Mol Cell Biol 2018; 19(12): 755-773. doi: 10.1038/s41580-018- 0060-8.

42. Buxbaum JN, Ruberg FL. Transthyretin V122I (pV142I)* cardiac amyloidosis: an age-dependent autosomal dominant cardiomyopathy too common to be overlooked as a cause of significant heart disease in elderly African Americans. Genet Med 2017; 19(7): 733-742. doi: 10.1038/gim.2016.200

Rudy Benmoha.Unerupted Teeth, A New Symptom Of Amyloidosis?. Annals of Clinical and Medical Case Reports 2023