Abstract
Background
A heritable neurocutaneous condition known as Tuberous Sclerosis Complex (TSC), is characterized by multisystem involvement with multiple hamartomatous tumors, seizures, intellectual disability, and facial angiofibroma affects the human body.
Aim
We aim to study the literature and highlight all the oral and dental manifestations encountered in TSC patients.
Materials and methods
Published articles having a population of tuberous sclerosis patients with oral manifestations, regardless of age or gender, and articles written in English were included. An electronic search was conducted in the PubMed, Google Scholar, Lilac, EBSCO, and SciELO databases from 1964 to 2023. Google Scholar articles were searched and selected manually. To calculate the risk of bias, the Joanna Briggs Institute critical appraisal criteria for quality evaluation was used.
Results
A total of 37 articles were selected out of 1203 in which only case reports (CR) and cross-sectional studies (CS) [descriptive (CS-D) & analytical (CS-A)] met the eligibility criteria. The present systematic review is qualitative. The risk of bias for case reports, 35.7% (n = 10) received a low grade while 57.14% (n = 16) received a moderate grade. For cross-sectional studies, 33.3% (n = 3) received a moderate grade, while 11.1% (n = 1) received a low score. The primary oral outcomes were dental enamel pitting (60% in CR, 79% in CS-D, and 96% in CS-A). gingival growth/hyperplasia/enlargement, (63% in CR, 37.6% in CS-D, and 14% in CS-A), and intra-oral fibroma (18% in CR, 39% in CS-D, and 14% in CS-A). Other secondary oral manifestations were intra-oral hypopigmented macule (n = 3, CR), enamel hypoplasia of teeth (10% in CR, 11.7% in CS-A), dental anomalies like enamel pearl (9.9% in CS-D), odontogenic tumors like desmoplastic fibromas (n = 1, CR), odontogenic myxoma in the jaws (n = 2, CR), hemangioma of the tongue (n = 1, CR) compound odontoma (n = 1, CR), angiomyolipoma (n = 1, CR), and impacted teeth (10%, CR).
Conclusion
Dental enamel pitting, gingival hyperplasia, and intra-oral fibroma are the most common oral manifestations in TSC patients. Other features included intra-oral hypopigmented macules, enamel hypoplasia of teeth, gingival angiofibroma, and dental anomalies such as enamel pearls.
1
Introduction
A heritable neurocutaneous condition or phakomatosis known as Tuberous Sclerosis Complex (TSC), also known as Bourneville Disease, is characterized by multisystem involvement and the emergence of multiple hamartomatous tumors. Seizures, intellectual disability, and facial angiofibroma make up the traditional clinical triad (also known as the Vogt triad), but less than 50% of patients have all three of these conditions [ ]. It is a relatively uncommon autosomal dominant condition brought on by mutations in the TSC1 or TSC2 tumor suppressor genes. TSC1 mutations affect 20% of those with TSC, while TSC2 mutations affect 70% of those with TSC. Approximately 10% of patients with this illness may not have a lethal TSC gene mutation diagnosed by conventional testing, but next-generation genomics may reveal mosaic and intronic mutations in TSC1 or TSC2 [ ].
Its prevalence ranges from about 1/20,000 to 1/100,000 [ ]. Its incidence is predicted to be between 1 in 6000 and 1 in 10,000 live births [ ]. This tuberous sclerosis complex is thought to have impacted over 2 million persons in the world in 2016, with 50,000 of those cases occurring in the United States alone. One of the most exact prevalence estimates ever found for a Caucasian population was 1 in 25,000, which is regarded as one of the highest rates in the world. While in Europe, the occurrence is predicted to be 8.8/100,000 in the general population [ ].
It is well known that this neurocutaneous disease usually progresses faster and has a more severe outcome, yet dental surgeons are generally unaware of the oral aspects of TSC. Therefore, this study aimed to analyze the literature, selecting studies that were focused on oral lesions found in TSC patients to highlight all the oral and dental manifestations encountered in TSC.
2
Materials and methods
2.1
Study design
This is a qualitative systematic review (Registration number CRD42023437857 in PROSPERO), where the research question was initially framed and then defined according to the PECO model.
The research question was as follows: 1. What are the oral manifestations seen in patients suffering from Tuberous Sclerosis Complex? 2. What are the oral signs seen in patients suffering from Tuberous Sclerosis Complex? According to PECO model Participation (P) – The study population was patients diagnosed with TSC who have oral and dental signs and symptoms of all ages. Exposure (E) – Patients suffering from TSC. Comparison (C) – Not relevant Outcomes (O) – All Oral & dental findings in TSC patients.
2.2
Search strategy
A literature search was conducted based on PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) guidelines in 5 databases–Lilac, EBSCO, SciELO, PubMed, and Google Scholar in June 2023 [ ]. The search was carried out using keywords and BOOLEAN operators AND and OR which are presented in Table 1 .
| DATABASES | KEYWORDS | NO OF ARTICLES |
|---|---|---|
| PubMed | (“tuberous sclerosis”[Title/Abstract] AND “oral manifestations”[Title/Abstract]) OR “mouth diseases”[Title/Abstract] | 1070 |
| Lilac | Tuberous sclerosis oral manifestations | 3 |
| SciELO | Tuberous sclerosis oral diseases | 2 |
| EBSCO | TI tuberous sclerosis AND TI oral manifestations OR TI dental manifestation OR TI enamel pits | 61 |
| Google Scholar | Oral manifestations, tuberous sclerosis, enamel pit, gingival growth | 67 (SELECTED MANUALLY) |
Google Scholar articles were searched and selected manually and no grey literature was searched. A software reference manager (Mendeley) was used to collect references and to remove duplicate articles.
2.3
Inclusion criteria
- •
Published articles that had the population of tuberous sclerosis patients with oral manifestations independent of age & gender (free full-text articles only)
- •
Articles that were written in English.
2.4
Exclusion criteria
- •
Narrative reviews on TSC
- •
Grey literature
- •
Articles on the TSC population not including oral manifestations.
- •
Articles on the TSC population having any other systemic diseases.
2.5
Selection process
Two authors completed the article selection in two steps. In step 1, two authors (AP and SM) independently reviewed all of the references’ titles and abstracts manually. The final conclusion was made in a discussion with the third author (NK) (no Cohen K test was conducted). In step 2, only those full-text articles were selected for this systematic review where the three authors reached a consensus based on inclusion criteria.
2.6
Data collection process
The first (AP) and second (SM) authors extracted the data from the chosen references. An extraction form was developed. Three different extraction forms were made based on their study designs. The third author (NK) then checked the assembled data to ensure its quality, precision, and authenticity. If there was any disagreement, it was settled through discussion and consensus among all the authors.
2.7
Risk of bias assessment
The risk of bias assessment was done using a quality evaluation checklist for case reports, RCT, observational studies, and cross-sectional studies modified by the Joanna Briggs Institute’s Critical Appraisal checklist [ , ]. A study was designated as having a high risk of bias when the “yes” score was up to 49%, a moderate risk (50% and 69%), and a low risk (>70%) for each article [ , ].
3
Results
3.1
Study selection & characteristics
A total of 1203 articles were retrieved from the year 1964–2023 from the databases after the search was conducted in which only case reports and cross-sectional studies (descriptive & analytical) had met the eligibility of the research question. A total of 37 articles were selected for the study after being reviewed for eligibility and included in the qualitative review. ( Fig. 1 ).
A description of the characteristics of the included case reports and cross-sectional studies in this systematic review is provided in Tables 2–4 [ ].
| S·NO | STUDY ID | STUDY DESIGN | SAMPLE SIZE (n) | AGE/SEX, MEAN | DIAGNOSIS | CLINICAL SIGNS & SYMPTOMS | ORAL MANIFESTATIONS | DIAGNOSTIC METHOD OF ORAL MANIFESTATIONS | CONCLUSION | RISK BIAS |
|---|---|---|---|---|---|---|---|---|---|---|
| 1. | Davis RK et al. [ ] (1964), Bethesda, MD | Case series | n = 2 | 24Y/M, 41Y/M | Tuberous sclerosis |
|
|
Extra-oral, intraoral physical, histopathological examination. | No conclusion | Moderate |
| 2. | Mackler SB et al. [ ] (1972), North Carolina | Case report | n = 1 | 21Y/F | Tuberous sclerosis |
|
|
Extra-oral, intraoral physical, radiographical, and histopathological examination | A rare syndrome known as tuberous sclerosis is described in this case study. In addition to Dilantin-induced hyperplasia, oral inspection also identified fibroma-like lesions on the connected gingiva. | Low |
| 3. | Papanayotou P et al. [ ] (1975), Greece | Case report | n = 1 | 40Y/F | Tuberous sclerosis |
|
|
Intraoral physical examination, histopathological examination | The majority of the anterior gingiva of the upper jaw was the site of the intraoral lesions, which were numerous, whitish nodules of various sizes. A case of gingival papillomatous hyperplasia was identified histologically. | Moderate |
| 4. | Stirrups DR et al. [ ](1980), Kentucky. | Case report | n = 1 | 08Y/M | Tuberous sclerosis |
|
|
Intraoral physical examination | The general condition is likely a consequence of the gingival alterations, | Low |
| 5. | Caballero LR et al. [ ] (1987), Madrid, Spain | Case report | n = 1 | 18Y/M | Tuberous sclerosis |
|
|
The histopathological investigation, Radiographical investigation, Extra-oral, and intraoral physical examination. | Despite the fact that these pits are smaller and less common in deciduous teeth than in permanent teeth, this characteristic nonetheless makes them a valuable early indicator of tuberous sclerosis and may even aid in making the diagnosis in cases when there are only a few symptoms. | Moderate |
| 6. | Tillman HH et al. [ ] (1991), Boston | Case report | n = 2 | 62Y/F, 54Y/M | Tuberous sclerosis |
|
|
Intraoral physical Examination |
Understanding the oral symptoms of tuberous sclerosis is crucial since they can occasionally aid in the diagnosis of this condition. | High |
| 7. | Thomas D et al. [ ] (1992), Kansas City. | Case report | n = 1 | 28Y/M | Tuberous sclerosis |
|
|
Intraoral physical, radiographical, and histopathological examination | It should be highlighted that because this is a single case report, it is impossible to determine whether the cause of the unexpected outcome is tuberous sclerosis or the relative contributions of phenytoin | Low |
| 8. | Harrison MG et al. [ ] (1997), London | Case report | n = 1 | 17Y/F | Tuberous sclerosis |
|
|
Intraoral physical, histopathological & radiological examination | There haven’t been any prior reports of odontogenic myxoma in this condition; it could be an atypical phenotypic manifestation of a mutation thought to cause tuberous sclerosis or it could be an unrelated coincidental finding. | Moderate |
| 9. | Cutando A. et al. [ ] (2000), Spain | Case report | n = 6 | 9Y/M, 14Y/M, 12Y/M, 12Y/F, 11Y/F, 16Y/M, Mean – 12Y. |
Tuberous sclerosis |
|
|
Extraoral and intraoral physical examination | No significant conclusion mentioned | Low |
| 10. | López-López J et al. [ ] (2004), Barcelona, Spain | Case report | n = 1 | 55Y/F | Tuberous sclerosis |
|
|
Extra-oral, intraoral physical, radiographical, and histopathological examination. | As a result, it is believed that the few oral angiomyolipoma instances associated with TS that have been described are all related to a single tumor. As a result, it is thought this case demonstrated a pattern of multiple labial and jugal fibromata, linked to the underlying disease (TS), in a somewhat uncommon site, with atypical fat, vascular, and muscle contents. | Moderate |
| 11. | Korol UB et al. [ ] (2008), New York | Case report | n = 1 | 26Y/M | Tuberous sclerosis |
|
|
Extra-oral, intraoral physical, histopathological, and radiographical examination | Histologically, the gingival enlargement complies with the typical angiofibroma of tuberous sclerosis. | Moderate |
| 12. | Wong A et al. [ ] (2008), California. | Case report | n = 1 | 33Y/F | Tuberous sclerosis |
|
|
Intraoral physical, radiographical Examination |
Future research could help in the early detection of TSC by doctors and dentists, which would lead to lower morbidity and better quality of life for this patient population. | Low |
| 13. | Harutunian K et al. [ ] (2011), Barcelona, Spain | Case report | n = 1 | 35Y/F | Tuberous sclerosis |
|
|
Intraoral physical, histopathological & radiological examination | The prevention and early detection of any sort of oral lesion require meticulous oral and dental care as well as regular dental checkups. The proper care of these individuals must take into account the frequent renal, pulmonary, and cardiac abnormalities reported in TSC. | Moderate |
| 14. | Tandon S et al. [ ] (2012), India | Case report | n = 1 | 8Y/F | Tuberous sclerosis |
|
|
Extra-oral, radiographical, histopathological, and intraoral physical examination | It is reported on a patient who has a jaw fibrous lesion and has been diagnosed with tuberous sclerosis. Because of this, rather than being unexplained findings, it is believed that this intraosseous fibrous proliferation is a symptom of tuberous sclerosis. | Moderate |
| 15. | Araujo LD et al. [ ] (2013), Brazil. | Case report | n = 1 | 66Y/M | Tuberous sclerosis |
|
|
Extra-oral, histopathological, and intraoral physical examination | This case study highlights the significance of oral clinical indicators, such as tooth enamel pits and angiofibroma, in establishing an early diagnosis of TSC, as well as the relevance of screening exams, treatment, and genetic counseling. | Moderate |
| 16. | Curi MM et al. [ ] (2014), Brazil. | Case report | n = 1 | 25Y/F | Tuberous sclerosis |
|
|
Intraoral physical, histopathological Examination |
Oral symptoms may be used to recognize or pinpoint the genetic condition that is present. In order to establish a diagnosis and deliver appropriate care, practitioners must be aware of the wide range of clinical presentations of TS. | Moderate |
| 17. | Ammari MM et al. [ ] (2015), Rio de Janeiro, Brazil. | Case report | n = 3 | 34Y/F, 11Y/M, 9Y/M | Tuberous sclerosis |
|
|
Extraoral and intraoral physical examination | When treating a patient with TSC, the oral healthcare provider must always request a thorough medical report on the patient’s condition. They must also adhere to evidence-based clinical practice recommendations and collaborate with the patient’s entire medical care team. | Low |
| 18. | Sodhi SP et al. [ ] (2016), Punjab, India | Case report | n = 1 | 18Y/F | Tuberous sclerosis |
|
|
Intraoral physical, radiographical examination | To avoid aggravating factors and ensure the early diagnosis of any potential lesions, patients with TSC must practice precise oral and dental hygiene and visit the dentist frequently. | Moderate |
| 19. | Purwar P et al. [ ] (2016), India | Case report | n = 1 | 40Y/F | Tuberous sclerosis |
|
|
Intraoral physical examination | The diagnosis of TSC may benefit from an early and correct detection of oral abnormalities. To get rid of potential irritants, TSC patients must adopt steps for meticulous oral and dental hygiene with regular dental appointments. A thorough medical report on the patient’s condition must be requested by the oral healthcare provider. |
Low |
| 20. | Bhoyar N et al. [ ] (2016), New Delhi, India | Case report | n = 1 | 08Y/F | Tuberous sclerosis |
|
|
Extra-oral, intraoral physical, radiographical, and histopathological examination | Because TSC tends to affect multiple body organs, including the oral cavity, early detection of the condition with meticulous clinical and radiological findings is important for preventing major complications. | High |
| 21. | Varma K. et al. [ ] (2017), Ujjain, India. | Case report | n = 2 | 40Y/F, 18Y/F | Tuberous sclerosis |
|
|
Intraoral physical Examination |
No significant conclusion was made | Moderate |
| 22. | Nakanishi T et al. [ ] (2017), Japan | Case report | n = 1 | 43Y/F | Tuberous sclerosis |
• |
|
Extra-oral, intraoral physical, radiographical, and histopathological examination | It was documented as a rare instance of a patient who had both TS and odontogenic myxoma (OM). Uncertainty surrounds the relevance of tumors like OM in TS patients. It is anticipated that the connection between these two diseases will soon be made clear. | Moderate |
| 23. | Reddy LS et al. [ ] (2018), India. | Case report | n = 1 | 32Y/M | Tuberous sclerosis |
|
|
Extraoral and intraoral physical examination | An early diagnosis of this condition and the subsequent initiation of suitable screening tests, treatments, and genetic counseling may be aided by accurate identification of clinical oral characteristics such as tooth enamel pits and angiofibroma. | Moderate |
| 24. | Nath S et al. [ ] (2018), Ranchi, India | Case report | n = 1 | 13Y/M | Tuberous sclerosis |
|
|
Intraoral physical examination, histopathological examination | This case report emphasizes the value of a periodontal exam in determining a TSC diagnosis. | Low |
| 25. | Isayev A. et al. [ ] (2019), USA | Case report | n = 1 | 17Y/M | Tuberous sclerosis |
|
|
Intraoral physical, examination. | Dentists must be aware of the oral symptoms of TSC in order to give an early diagnosis, genetic counseling, better therapy in coordination with the medical team, and improve quality of life for patients. | Moderate |
| 26. | Goyal L et al. [ ] (2020), India | Case report | n = 1 | 23Y/F | Tuberous sclerosis |
|
|
Extra-oral and intraoral physical examination | Identification of oral features like dental enamel pits and angiofibroma aid in achieving early diagnosis and initiating early appropriate screening examinations, treatment, and genetic counseling | Low |
| 27. | Ankar R et al. [ ] (2021), India. | Case report | n = 1 | 35Y/M | Tuberous sclerosis |
|
|
The radiographical investigation, Extra-oral, and intraoral physical examination. | No significant-conclusion mentioned | Low |
| 28. | Noor N et al. [ ] (2022), Dhaka, Bangladesh | Case report | n = 1 | 17Y/M | Tuberous sclerosis |
|
|
Intraoral physical examination | Despite the rarity of TS, it is essential to get a diagnosis right away to avoid long-term organ damage. Since there is no treatment for the condition, the patients should be managed using a multidisciplinary strategy and symptomatic care. Additionally, support groups should be created. | Moderate |
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