Management of Two Cases with Supernumerary Teeth

Abstract

Supernumerary teeth are commonly observed as an isolated developmental anomaly. While familial tendency of supernumerary teeth has been documented, its genetic causality has not yet been determined. This communication presents two cases with supernumerary teeth and the process leading to the diagnosis and determination of their underlying conditions. Cases were evaluated and family histories reviewed. Genetic counseling was recommended for the probands and followed by genetic testing of selected family members.

Results

The proband of family 1, who has multiple supernumerary teeth, was determined to have a RUNX2 missense mutation (c.379C>T, p.Pro127Ser) and diagnosed with cleidocranial dysplasia. The proband of family 2 who has a premolar region supernumerary tooth and was reported to have no bone defects also presented with a RUNX2 missense mutation (c.1381G>C, p.Gly461Arg).

Conclusion

When patients present with multiple supernumerary teeth, a recommendation and guidance to genetic counseling and testing may facilitate accurate diagnosis and management.

Introduction

Anomalies of the dentition often alter the number, size, or shape of teeth. Hyperdontia, or supernumerary teeth, occurs when there is at least one extra tooth present in the jaw.^1–2 Hyperdontia occurs less frequently than hypodontia (missing teeth) in the permanent dentition; the anterior maxilla is most often involved.^3–4 Supernumerary teeth can pose adverse effects on adjacent teeth, including delayed or failure of eruption, malpositioning of permanent teeth, over-retention of primary teeth, resorption of roots, ectopic eruption, and dentigerous cysts.⁵ Accurate diagnosis and carefully planned removal of supernumerary teeth is crucial to the management of developing patients.

The reported incidence of supernumerary teeth varies from 0.4 to 3.0% with a male to female ratio of 1.5:1.0.^6–8 In 33% of cases, a supernumerary tooth in the primary dentition is followed by a supernumerary tooth complement in the permanent dentition.⁹ In a retrospective case series of 767 individuals aged 4 to 51 years, 74.7% were of Hispanic descent, and 20.5% had first-degree relatives with supernumerary teeth.¹⁰ Most cases of supernumerary teeth are thought to be idiopathic in origin, with 80% having a single tooth and 15–20% having two teeth.¹¹ Only 0.06% cases of idiopathic supernumerary teeth have 5 or more extra teeth present. Supernumerary teeth have been theorized to have a genetic component.^12–13 Many cases with supernumerary teeth are reported to have additional anomalies, so when multiple supernumerary teeth are present, they are more likely to be related to an underlying syndrome. The condition of supernumerary teeth (OMIM 187100) is present in more than 50 syndromes, suggesting the complexity of the genetic etiology. The most common syndromes associated with supernumerary teeth include cleidocranial dysplasia (RUNX2) and familial adenomatous polyposis (APC).¹¹ RUNX2 encodes a transcription factor involved in the formation of teeth, bones, and cartilage, and mutations in this gene are associated with multiple supernumerary teeth and cleidocranial dysplasia.¹¹ Additional syndromes and their causative genes associated with supernumerary teeth include but are not limited to Rubinstein-Taybi syndrome 1 and 2 (CREBBP, EP300), craniosynostosis and dental anomalies (IL11RA), microphthalmia and esophageal atresia syndrome (SOX2), and Nance-Horan syndrome (NHS). Theories for causes of single supernumerary tooth include local hyperactivity of the dental lamina, dichotomy of the tooth bud, and other molecular mechanisms during early tooth development.¹⁴

Case description

Two cases presented for routine dental care were reported as simplex cases of supernumerary teeth upon initial examination. The proband from family 1 had not received comprehensive medical or dental work prior to her dental visit, while the proband of family 2, who had no remarkable medical or dental history, was seeking orthodontic care to improve occlusion. Upon clinical and radiographic exam, the parents were informed of the finding of supernumerary teeth. The clinicians reviewed the patients’ signs and symptoms by referencing the Online Mendelian Inheritance of Man (OMIM), requested a consult from the Dental Research Lab, and worked with the patients’ physicians to determine a definitive diagnosis. The study protocol and subject consent used by the Dental Research Lab were reviewed and approved by the Institutional Review Board of the University of Michigan School of Medicine.

The proband of family 1, a Hispanic girl, was 8y 9m when first presented to the Pediatric Dental clinic. The mother reported that the patient had developmental, speech, and cognitive delays. Physically, the proband and her mother were below average in height. The proband presented with a brachyfacial appearance with a concave profile and hypoplastic midface. She also had slight frontal bossing and hypertelorism. The proband’s hands were noted to be small and to have short fingers in relation to her palm. She was referred from a general dentist for extraction of primary molar tooth #K. The maxillary occlusal radiograph showed the presence of two mesiodens. It was recommended that teeth #D, #E, #F, and #G be extracted to allow for potential eruption of the mesiodens. The recommended extractions were completed; however, there was no evidence of eruption of the mesiodens or the permanent incisors after 13 months. At the recall appointment, a panoramic radiograph was taken that revealed multiple supernumerary teeth in both jaws (Figure 1A, Table 1). The patient’s mother was further consulted. She denied any family history of syndromes but stated that she had extra premolar and molar teeth removed at 12 and 20 years old. She also indicated that her sister had an extra canine in her upper jaw. At this time, referrals were made for the patient to have a cone beam computed tomography (CBCT) taken by the Radiology Department and a comprehensive evaluation by the Oral and Maxillofacial Surgery Department. The CBCT covering the maxilla, the mandible, and the maxillary sinuses was obtained with the 3D Accuitomo 170 (JMorita). The image was taken in 1mm cross-sections and reconstructed. Sixteen supernumerary teeth were identified. One of the supernumerary teeth was fused with tooth #27 (Figures 1B–H). The patient was noted to have Class III malocclusion with maxillary deficiency. Other notable findings included visible spheno-occipital synchondroses and aplasia of the sphenoid sinus. The radiologist recommended medical evaluation to rule out cleidocranial dysplasia.

Figure 1.

Family 1 proband radiograph, CBCT images, pedigree, and chromatograms. (A) Panoramic radiograph of proband at age 11. There is a general delay of primary tooth exfoliation and permanent tooth eruption. The tooth roots, pulp chamber, and root canals are within normal limits. * denotes mesiodens. CBCT revealed supernumerary teeth in the (B) Maxillary incisor region, (C) Mandibular premolar region, (D) Right premolar regions, (E) Left premolar regions, (F) Maxillary right canine region, (G) Maxillary left canine region, and (H) Anterior mandible region showing a fused supernumerary tooth on the left (white arrow). (I) The family pedigree was constructed based on an interview of subject II:4. Both the mother and the affected child participated in the study. Maternal grandmother was reported to have tooth problems, but no specifics were confirmed. Subjects II:1 and II:2 were reported to have normal dentition. Subject II:4 was reported to have extra premolars extracted at age 12 and extra molars extracted at age 20. Subject II:7 was reported to have one extra maxillary canine. The proband has 16 supernumerary teeth at various developmental stages. Chromatogram of (J) affected mother and (K) affected proband showing the sequence variant of RUNX2, NM_001024630.3: c.379C>T; NP_001019801.3:p.(Pro127Ser).

Table 1.

Location of Supernumerary Teeth

Maxilla	1	2		4	s 5 s	s 6	7		9	10	11 s	12	13		15	16
Case 1			3	A	B	C		8 s	s		s H s	I	J	14
			30	T s	s S	R s	26	25	24	23	s M	21		19
Mandible	32	31		29	28	s 27					22	s s	20 s		18	17
Maxilla	1															16
Case 2		2	3	4	5	6	7	8	9	10	11	12	13	14	15
		31	30	s 29	28	27	26	25	24	23	22	21	20	19	18
Mandible	32															17

Location of probands’ teeth. “s” denotes the supernumerary teeth. Numbers in the “Maxilla” and “Mandible” rows represent unerupted teeth. Numbers in the “Case 1” and “Case 2” rows represent erupted teeth.

A phone interview of the family was conducted. The mother’s questions about the potential disorder, genetic study, and consent forms were answered. A family pedigree was constructed according to the mother’s report (Figure 1I). At this time, the proband was 11y 2m. Her weight and height were 42.5kg (70^th percentile) and 135cm (10^th percentile). CBCT was effective in identifying the number and three-dimensional locations of supernumerary teeth. Removal of supernumerary teeth was to be carried out in phases. Orthodontic consultation was initiated for the evaluation of mid-face deficiency and management of delayed eruption and malocclusion. Following the recommendation, the mother brought the child to a pediatrician who ordered genetic counseling and confirmed the diagnosis of cleidocranial dysplasia. Unfortunately, the patient did not follow-up after completion of initial treatment at the Pediatric Dental Clinic.

The proband of family 2 was a 16-year-old Asian boy of average height and weight (50^th percentile). During the initial workup, he was determined to have normal cephalic with Class I malocclusion and minor crowding. A supernumerary tooth (29s) was detected on his panoramic radiograph (Figure 2A). The patient was referred to an oral surgeon for extraction of 29s and to the Dental Research Lab for consultation. The family was interviewed by phone and consented to participate in the genetic study. The father reported that no other family members have supernumerary teeth. Careful examination of the panoramic and lateral cephalometric radiographs revealed straight lateral profile, no frontal bossing, no cranial suture widening, and no Wormian bones (Figure 2B). The father was unaware of any growth or developmental anomalies of the boy. Orthodontic treatment was subsequently initiated.

Figure 2.

Family 2 pedigree and proband radiographs. (A) Panoramic radiograph revealed a single supernumerary tooth, distal to the mandibular second premolar #29, in crown formation stage (Nolla’s stage 5 crown almost completed). All the third molars are present but not yet erupted. (B) Lateral cephalometric film demonstrated normal jaw size and anterior-posterior position. No sign of widening cranial sutures or Wormian bones. (C) Pedigree shows a simplex case with no other affected individual in the immediate family. Both parents and the proband participated in the study. Chromatogram of (D) father, (E) mother, and (F) proband showing the sequence variant of RUNX2, NM_001024630.3:c.1381G>C; NP_001019801.3:p.(Gly461Arg).

Research-based genetic analysis was conducted at the Dental Research Lab using subject saliva samples from which genomic DNA was extracted and subjected to whole exome sequencing and validation. The proband of family 1 was determined to have a single allele RUNX2 c.379C>T change that resulted in a substitution of Pro¹²⁷ with Ser (p.Pro127Ser), a damaging mutation. This single nucleotide change has a SIFT score of 0.002, Polyphen 2 score of 0.966 indicative of a damaging mutation. Pro¹²⁷ is highly conserved and is never a Serine among the known sequences from other species (Figure 1J–K). This change is also present in the proband’s mother, although the mother was never diagnosed with a medical condition.

The proband of family 2 has a single allele RUNX2 c.1381G>C change that resulted in a substitution of Gly⁴⁶¹ with Arg (p.Gly461Arg), a potentially damaging variant (Figure 2C–F). This single nucleotide change has a SIFT score of 0, Polyphen 2 score of 1 indicative of a damaging variant.

Discussion

The affected girl from family 1 at age 11y 2m had a short stature, a body weight of 42.5 kg (70^th percentile), a height of 135 cm (10^th percentile), and multiple supernumerary teeth with severe maxillary hypoplasia. RUNX2 Pro¹²⁷ is located within the Runt domain (residues 101 to 229 of the protein), which confers DNA binding ability and mediates the interaction with the core-binding factor beta to increase the DNA binding affinity. Altered DNA binding ability will likely result in changes in gene transcription and cell function.

The affected boy from family 2 was of normal stature and has one supernumerary tooth in his right mandible. His lateral cephalometric film revealed normal jaw size and anterior-posterior position without apparent deficiencies of surrounding skull bones. RUNX2 Gly⁴⁶¹ is located in a highly conserved region of the protein that interacts with histone acetyltransferase KAT6B.¹⁵ While RUNX2 Gly⁴⁶¹ is highly conserved, which typically infers functional significance, the downstream effect of RUNX2 Gly⁴⁶¹ and KAT6B interactions cannot be predicted based on available databases. The father who also has this variant is of average height and reported to have no supernumerary teeth. This observation suggested variable expressivity of RUNX2 (p.Gly461Arg) mutation.

While cases of various ethnic backgrounds with premolar region supernumerary teeth have been reported,^16–19 the only report of a potential genetic etiology for premolar region supernumerary teeth considered single allele change of PDGFRB (c. 2053C>T, p.R685C) to be responsible in a three-generation Korean family with dominant inheritance of mandibular premolar supernumerary teeth.²⁰ The proband of family 2 does not have any PDGFRB mutation that is predicted to be damaging. The parents were recommended to follow up with the boy’s physician. A thorough medical examination and clinical genetic testing should be conducted in order to afford the patient a definitive diagnosis.

In case 1, the research-based genetic testing supported the medical diagnosis and rendered the child eligible to receive State support for the management of her medical and dental needs. It is understandable that following a definitive medical diagnosis, the family may feel overwhelmed. Strong support from the health care providers and arrangement to bring in social workers to guide the family in leveraging resources, such as additional medical and dental insurance coverage and travel support, may make a huge difference to the affected child. While the definitive diagnosis of case 2 relies on the physician’s order of a clinical genetic test, the family was made aware of the importance to have the proband undergo a thorough medical evaluation to define additional clinical phenotypes outside of the dentition.

Both pediatric dentists and orthodontists are care providers in positions to discover growth and developmental anomalies associated with their patients’ dentitions. When encountering patients with genetic conditions, OMIM is an accurate and frequently updated online resource. Dental Research Lab at the University of Michigan School of Dentistry accepts referrals of dental genetic cases from health care providers and works with affected families to provide information and conduct research-based genetic analyses. While many dental anomalies are isolated, there are syndromic conditions in which dental anomalies are the early manifestations that can potentially lead to the correct diagnosis of the underlying disorders. As the awareness of genetic testing and precision medicine are heightened, the expectation on health care providers’ knowledge and ability to guide affected patients to proper diagnosis and treatment may soon become a standard of care.