The phenotypic characteristics of patients with athelia and tooth agenesis

Introduction

Agenesis of the teeth, including the third molars, is one of the most common diseases, affecting 200 million people around the world (1,2). Based on the number of missing teeth, it includes hypodontia (<6 teeth missing), oligodontia (≥6 teeth missing), or anodontia (all teeth missing) (3). Tooth agenesis can occur as an isolated anomaly or in association with a syndrome or a cluster of other anomalies, such as cleft palate or nail dysplasia (4). The most common syndromic tooth agenesis is ectodermal dysplasia (EDs), which is characterized by the dysplasia of ectodermal structures (5-7). Patients present with defects relating to hair, nails, teeth, and sweat glands.

Congenital aplastic deformities of the nipple include inverted nipple, absent nipple (athelia), and can also involve the absence of breasts (amastia). The combination of nipple deformity and tooth agenesis rarely appears except in acro-dermato-ungual-lacrimal-tooth syndrome (ADULT syndrome) (8). The phenotypic features of ADULT syndrome include ectrodactyly, syndactyly, fingernail and toenail dysplasia, hypoplastic breasts and nipples, lacrimal duct atresia, and hypodontia.

In this study, we reviewed the literature in databases and summarized the features of previously reported patients who had both tooth agenesis and nipple deformity. Furthermore, we analyzed the underlying connection between athelia and tooth agenesis through predicted protein interaction.

Methods

Nomenclature

Gene symbols used in this article follow the protocol created by the Human Genome Organization (HUGO) Gene Nomenclature Committee (9).

Literature review

The databases of PubMed and Institute for Scientific Information (ISI) Web of Knowledge, were searched for relevant publications. The references listed in the retrieved full articles were also included in our literature review. The keywords, (“athelia” or “tooth agenesis”), (“athelia” or “tooth missing”), (“athelia” or “hypodontia”), and (“athelia” or “oligodontia”), were used as search terms. The full texts were reviewed by 2 researchers. Only English and Chinese publications were selected. Searches for nipple deformity-related syndromes were conducted in Online Mendelian Inheritance in Man (OMIM) and PubMed. The phenotypic features and causative genes of patients were summarized.

Study eligibility and data collection

The exclusion criteria were as follows: (I) patient phenotype was not reported; (II) the publication did not include original data; and (III) authors or institutes overlapped in the published literature. The reported patient phenotypes were extracted.

Bioinformatic analysis of nipple deformity-related genes

The systematic and integrative analysis was conducted through the Database for Annotation, Visualization, and Integrated Discovery (DAVID) Bioinformatics Resources (https://david-d.ncifcrf.gov) according to the instruction of the database (10,11). The predicted protein interaction was analyzed using the (Search Tool for the Retrieval of Interacting Genes/Proteins) STRING database (Version 10.0) (http://www.string-db.org) under stated instructions (12).

Results

Nipple deformity-related syndromes

We had observed athelia in 2 hypodontia patients in 2017 in the dental clinic. To further analyze whether there was a correlation between hypodontia and nipple deformity, we summarized the previously reported cases involving patients with hypodontia and nipple deformity (13-20) (Table 1). There were 12 studies that had reported patients with athelia and tooth agenesis. After literature review, 8 studies were included in this analysis. In addition, the 2 patients with severe hypodontia, hypohidrosis, and eczema whom we had encountered in clinic were also included (Figure 1). Then, we listed the nipple deformity-related syndromes identified in the literature review (Table 2). Nipple deformity was reported to be associated with 23 syndromes. Patients with these syndromes had abnormalities of the head and neck; cardiovascular, genitourinary, and skeletal systems; and the skin, nails, and hair. Hypodontia was documented in 10 syndromes which involve 16 genes including TP63, KCTD1, and IKBKG.

Figure 1 Flow diagram of the systematic review process.

The gene network underlying hypodontia and nipple deformity

After we identified the genes related to hypodontia and nipple deformity, we further analyzed the biological function of these genes. Most of them negatively regulated the “transcription”, “gene expression”, and “nucleobase, nucleoside, nucleotide, and nucleic acid metabolic process” (Table 3). Furthermore, we analyzed their interactions through the STRING database. Among these nipple deformity-related proteins, KDM1A directly interacted with NSD1 and ASXL1 (Figure 2). The interactions among them were more complicated if they were connected with other molecules (Figure 3). Then, we added hypodontia-related (EDA, HYD2, LTBP3, MSX1, PAX9, STHAG5, and WNT10A) and ectodermal dysplasia-related (EDA, EDAR, EDARADD, and TRAF6) genes to the analysis. More complicated interactions were observed (Figures 4,5). It is worth mentioning that there are still many pedigrees with agenesis of the teeth in which the causative gene has not been successfully identified. The whole exome sequencing provides a solution to this problem and has been used successfully in several case.

Figure 2 Network view of athelia-related proteins analyzed using the STRING database. The confidence level of the minimum required interaction score was set at medium. STRING, Search Tool for the Retrieval of Interacting Genes/Proteins.

Figure 3 Network view of athelia-related proteins analyzed using the STRING database. The confidence level of the minimum required interaction score was set at low. STRING, Search Tool for the Retrieval of Interacting Genes/Proteins.

Figure 4 Network view of athelia- and hypodontia-related proteins analyzed using the STRING database. The confidence level of the minimum required interaction score was set at low. STRING, Search Tool for the Retrieval of Interacting Genes/Proteins.

Figure 5 Network view of athelia- and EDs-related proteins analyzed using the STRING database. The confidence level of the minimum required interaction score was set at low. STRING, Search Tool for the Retrieval of Interacting Genes/Proteins; EDs, ectodermal dysplasia.

Discussion

Congenital aplastic abnormalities of the breast and nipple were first reported in 1802 (21). Such abnormalities can be divided into 3 categories: total absence of the breasts and nipple (amastia), absence of the nipple (athelia), and absence of the mammary gland (amazia). They are predominantly isolated deformities, although approximately 15% are associated with other anomalies (22), in which the ADULT syndrome and Finlay-Marks syndrome (23) are known for nipple and tooth abnormality.

Athelia was first reported in EDs patients in 1886 (13). It has been reported in more than 10 cases since then. It is noteworthy that most athelia and tooth agenesis patients have been males who had alopecia or aplasia cutis, whereas EDs patients usually only displayed sparse hair. The missing number of teeth was also larger than that of EDs patients. Although there reports of patients with both athelia in tooth agenesis patients have been scarce, we believe that the combination of these 2 symptoms may not be so rare as patients infrequently mention nipple dysplasia when they visit the dental clinic. In our experience, our patient was referred to the prosthodontic clinic for oligodontia treatment, with no complaints of other deformities. Athelia was observed upon physical examination, although this critical defect would have remained unnoticed if we had only focused on his dental defect.

The correlation between hypodontia and athelia seems to be reasonable. First, the development of tooth and nipple in embryo is synchronous. Both nipple and teeth originate from the ectoderm. The development of breasts and nipples begins during the sixth embryonic week, while tooth development begins in the fifth week. Additionally, as shown in Figures 2-5, the causative genes for athelia and hypodontia are also closely connected. Molecular genetics research is needed to fully elucidate the underlying relationship between athelia and tooth agenesis in the future.

Conclusions

In this study, we reviewed the phenotype of previously reported patients with hypodontia and nipple deformity. The phenotypic summary and gene network analysis suggested that tooth agenesis might be correlated with athelia.

Acknowledgments

Funding: This work was supported by Fujian Natural Science Youth Innovation Fund Project (2020D034), Xiamen Medical and Health Guidance Project (3502Z20214ZD1275) and the Scientific and Technological Plan Projects in Xiamen (Medical and Health Program) (3502Z20199086).

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-5159). The authors declare that this work was supported by Fujian Natural Science Youth Innovation Fund Project (2020D034), Xiamen Medical and Health Guidance Project (3502Z20214ZD1275) and the Scientific and Technological Plan Projects in Xiamen (Medical and Health Program) (3502Z20199086). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Yin W, Bian Z. The Gene Network Underlying Hypodontia. J Dent Res 2015;94:878-85. [Crossref] [PubMed]
2. Vieira AR, Modesto A, Meira R, et al. Interferon regulatory factor 6 (IRF6) and fibroblast growth factor receptor 1 (FGFR1) contribute to human tooth agenesis. Am J Med Genet A 2007;143A:538-45. [Crossref] [PubMed]
3. Yin W, Ye X, Bian Z. Phenotypic findings in Chinese families with X-linked hypohydrotic ectodermal dysplasia. Arch Oral Biol 2012;57:1418-22. [Crossref] [PubMed]
4. Romano RA, Solomon LW, Sinha S. Tp63 in oral development, neoplasia, and autoimmunity. J Dent Res 2012;91:125-32. [Crossref] [PubMed]
5. Clauss F, Manière MC, Obry F, et al. Dento-craniofacial phenotypes and underlying molecular mechanisms in hypohidrotic ectodermal dysplasia (HED): a review. J Dent Res 2008;87:1089-99. [Crossref] [PubMed]
6. Yin W, Ye X, Bian Z. The second deletion mutation in exon 8 of EDA gene in an XLHED pedigree. Dermatology 2013;226:105-10. [Crossref] [PubMed]
7. Yin W, Ye X, Fan H, et al. Methylation state of the EDA gene promoter in Chinese X-linked hypohidrotic ectodermal dysplasia carriers. PLoS One 2013;8:e62203 [Crossref] [PubMed]
8. Propping P, Zerres K. ADULT-syndrome: an autosomal-dominant disorder with pigment anomalies, ectrodactyly, nail dysplasia, and hypodontia. Am J Med Genet 1993;45:642-8. [Crossref] [PubMed]
9. Povey S, Lovering R, Bruford E, et al. The HUGO Gene Nomenclature Committee (HGNC). Hum Genet 2001;109:678-80. [Crossref] [PubMed]
10. Huang da W. Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 2009;37:1-13. [Crossref] [PubMed]
11. Huang da W. Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 2009;4:44-57. [Crossref] [PubMed]
12. Szklarczyk D, Franceschini A, Wyder S, et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res 2015;43:D447-52. [Crossref] [PubMed]
13. Hutchinson J. Congenital Absence of Hair and Mammary Glands with Atrophic Condition of the Skin and its Appendages, in a Boy whose Mother had been almost wholly Bald from Alopecia Areata from the age of Six. Med Chir Trans 1886;69:473-7. [Crossref] [PubMed]
14. Tendlau B. Uber angeborene underworbene Atrophia cutis igiopathica. Virchows Arch Path Anat 1902;167:465-90. [Crossref]
15. Kaalund-Jörgensen O, Christensen J. Congenital ectodermal dysplasia of anhidrotic type. Acta Derm Venereol 1941;22:1-23.
16. Upshaw BY, Montgomery H. Hereditary anhidrotic ectodermal dysplasia, a clinical and pathologic study. Arch Derm Syphilol 1949;60:1170-83, illust. [Crossref] [PubMed]
17. Osbourn RA. Congenital ectodermal defect with amastia. J Am Med Assoc 1952;148:644-5. [Crossref] [PubMed]
18. Burck U, Held KR. Athelia in a female infant - heterozygous for anhidrotic ectodermal dysplasia. Clin Genet 1981;19:117-21. [Crossref] [PubMed]
19. Tuffli GA, Laxova R. Brief clinical report: new, autosomal dominant form of ectodermal dysplasia. Am J Med Genet 1983;14:381-4. [Crossref] [PubMed]
20. Iamin MT, Kumar VP. Complete absence of breasts in a 24-year-old woman associated with ectodermal dysplasia. Plast Reconstr Surg 2003;111:959-61. [Crossref] [PubMed]
21. Hubert C. Etude Sur l’Amastie (Doctor Thesis). Paris: A. Michalon, 1907.
22. Trier WC. Complete breast absence. Case report and review of the literature. Plast Reconstr Surg 1965;36:431-9. [Crossref] [PubMed]
23. Naik P, Kini P, Chopra D, et al. Finlay-Marks syndrome: report of two siblings and review of literature. Am J Med Genet A 2012;158A:1696-701. [Crossref] [PubMed]

(English Language Editor: J. Jones)