Nonsyndromic Tooth Agenesis Overview

Goal 1.

Describe the clinical characteristics of nonsyndromic tooth agenesis (NSTA).

Goal 2.

Review the genetic causes of NSTA.

Goal 3.

Provide an evaluation strategy to identify the genetic cause of NSTA in a proband (when possible).

Goal 4.

Review management of NSTA following diagnosis: evaluations, treatment, and surveillance.

Goal 5.

Inform genetic counseling of family members of an individual with NSTA.

Physical Examination

A thorough physical exam should be completed to assess the presence of any extraoral features that may indicate a syndromic presentation.

A detailed oral exam and review of current and previous intra- and extraoral radiographs should then follow to identify exactly how many and which permanent teeth are absent and identify the presence of other dental anomalies in individuals with tooth agenesis.

Microdontia (which includes peg laterals), malocclusion, and retention of primary teeth are common findings in affected individuals.

Family History

A three-generation family history should be taken (when possible), with attention to relatives with manifestations of tooth agenesis and other dental anomalies, such as enamel defects or differences in tooth shape. Direct examination by a dental professional with specific expertise in tooth agenesis may need to be completed on all pertinent relatives due to the difficulty in diagnosing tooth agenesis vs other causes of tooth loss in adults. Review and documentation of medical and dental records and results of molecular genetic testing is recommended, when available.

Genomic/Genetic Testing

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing does not.

Serial single-gene testing can be considered if clinical findings and/or family history indicate that pathogenic variants in a particular gene are most likely (see Table 1) [van den Boogaard et al 2012, Williams & Letra 2018, Yu et al 2019].

• In individuals with posterior tooth agenesis, molecular genetic testing of MSX1 and/or PAX9 may be considered first.
• In individuals with hypodontia and oligodontia affecting both anterior and posterior dentition alike, molecular genetic testing of AXIN2, IRF6, and/or WNT10A may be considered first.
• In individuals with microdontia (peg laterals) or abnormally shaped teeth in addition to missing teeth, molecular genetic testing of WNT10A and/or EDA may be considered first.

A multigene panel that includes some or all of the genes listed in Tables 1 and 2 is most likely to identify the genetic cause of the tooth agenesis while limiting identification of variants of uncertain significance and pathogenic variants in genes that currently do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of some of the genes associated with tooth agenesis, some panels may not include all the genes mentioned in this overview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Comprehensive genomic testing, which does not require the clinician to determine which gene(s) are likely involved, may be considered. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with NSTA, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Prevention of Secondary Complications

It is recommended that individuals with (or suspected of having) nonsyndromic tooth agenesis be followed by a dentist at least every six months to ensure maintenance of remaining dentition. Oral health disease prevention for remaining dentition often includes dietary counseling, fluoride sealants, and mouth guards (see Table 4).

Surveillance

Evaluation of Relatives at Risk

It is appropriate to clarify the clinical and/or genetic status (when possible) of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of dental treatment. Evaluations can include:

• Complete clinical intra- and extraoral examinations and radiographs (see Table 3);
• Molecular genetic testing if the pathogenic variant(s) in the family are known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Mode of Inheritance

Nonsyndromic tooth agenesis (NSTA) caused by pathogenic variants in AXIN2, EDAR, FGFR1, GREM2, IRF6, LRP6, MSX1, PAX9, or WNT10B is inherited in an autosomal dominant manner.

NSTA caused by pathogenic variants in EDA is inherited in an X-linked manner.

NSTA caused by pathogenic variants in WNT10A is inherited in an autosomal dominant or autosomal recessive manner; however, both decreased penetrance and variable expressivity (even within individuals from the same family) has been reported for some variants [Yang et al 2015]. Complex inheritance has also been proposed (see Complex/Multifactorial Inheritance).

Note: This section provides genetic risk assessment information for individuals and families with a molecular diagnosis of NSTA (see Table 1). If an individual has tooth agenesis as part of known syndromic disorder (see Table 2), counseling for that disorder is indicated; for more information, see Klein et al [2013], Williams & Letra [2018], and Yu et al [2019].

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Many individuals with a molecular diagnosis of autosomal dominant NSTA have an affected parent [Williams & Letra 2018, Yu et al 2019].
• Some individuals diagnosed with autosomal dominant NSTA have the disorder as the result of a de novo pathogenic variant. The proportion of individuals with NSTA caused by a de novo pathogenic variant is unknown.
• If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Though theoretically possible, no instances of germline mosaicism have been reported. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with NSTA may appear to be negative because of failure to recognize the disorder in affected family members, reduced penetrance, and variable expressivity. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Clinical manifestations may vary in heterozygous sibs; both reduced penetrance and intrafamilial variability are observed in autosomal dominant NSTA.
• If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with autosomal dominant NSTA has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant, the parent's family members may be at risk.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of a child with biallelic WNT10A pathogenic variants are presumed to be heterozygous for a WNT10A pathogenic variant, unless proven otherwise through molecular genetic testing of both parents.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a WNT10A pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes for a WNT10A pathogenic variant may appear to be asymptomatic or have hypodontia.

Sibs of a proband

• If both parents are known to be heterozygous for a WNT10A pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic WNT10A pathogenic variants, a 50% chance of inheriting one pathogenic variant, and a 25% chance of inheriting neither of the familial WNT10A pathogenic variants.
• While clinical manifestations of tooth agenesis vary among affected family members, sibs who inherit biallelic WNT10A pathogenic variants will often have oligodontia.
• Sibs who inherit one WNT10A pathogenic variant (heterozygotes) may be asymptomatic or have hypodontia.

Offspring of a proband. The offspring of an individual with biallelic WNT10A pathogenic variants are obligate heterozygotes for a pathogenic variant in WNT10A and may appear to be asymptomatic or have hypodontia.

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for a WNT10A pathogenic variant.

Carrier (heterozygote) detection. Heterozygote testing for at-risk relatives requires prior identification of the WNT10A pathogenic variants in the family.

X-Linked Inheritance – Risk to Family Members

Parents of a male proband

• The father of an affected male will not have EDA-related NSTA nor will he be hemizygous for the EDA pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the EDA pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a de novo EDA pathogenic variant (in which case the mother is not a carrier), or the mother may have somatic/germline mosaicism. The frequency of de novo EDA pathogenic variants is unknown.
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

• If the mother of the proband has an EDA pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
  • Males who inherit the pathogenic variant will be affected;
  • Females who inherit the pathogenic variant will be heterozygotes and may have a range of clinical manifestations.
• If the proband represents a simplex case and if the EDA pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism.

Offspring of a male proband. Affected males transmit the EDA pathogenic variant to all of their daughters and none of their sons.

Other family members. The maternal aunts and maternal cousins of a male proband may be at risk of having an EDA pathogenic variant.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose, information that could help determine genetic risk status of the extended family.

Heterozygote detection. Identification of female heterozygotes requires prior identification of the EDA pathogenic variant in an affected family member.

Complex/Multifactorial Inheritance

Oligogenic inheritance due to multilocus variation has recently been proposed for nonsyndromic tooth agenesis. For example, pathogenic variants in WNT10A have been found to cosegregate with pathogenic variants in GREM2, LAMA3, and/or BCOR in individuals with nonsyndromic tooth agenesis [Kantaputra et al 2015, Dinckan et al 2018b, Du et al 2018].

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

Prenatal Testing and Preimplantation Genetic Testing

Once the nonsyndromic tooth agenesis-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Author Notes

Ariadne Letra is a dentist with additional formal training in Human Molecular Genetics and a Professor in the Department of Diagnostic and Biomedical Sciences and Center for Craniofacial Research at UTHealth School of Dentistry at Houston. Dr Letra has adjunct faculty appointments at the Pediatric Research Center, UTHealth McGovern Medical School, and at the University of Texas MD Anderson Cancer Center Graduate School of Biomedical Sciences. Dr Letra's research focuses on the cellular and molecular basis of complex oral traits and anomalies, particularly craniofacial and dental anomalies. Her work has identified numerous genes and gene variants associated with these conditions. Additional work in her lab focuses on identifying common molecular players linking oral and general health conditions. Dr Letra has published 98 peer-reviewed original articles, two invited book chapters, four invited review articles, and more than 180 abstracts related to craniofacial anomalies and oral diseases/conditions. Her research has been continuously supported by grants from the National Institutes of Health and additional funding agencies.

Brett Chiquet is a board-certified pediatric dentist and Associate Professor in the Department of Pediatric Dentistry at UTHealth School of Dentistry. Dr Chiquet treats all children, including patients with special health care needs. Dr Chiquet helps teach dental residents how to comprehensively treat all pediatric patients, including anticipatory guidance, prevention, restorative dentistry, growth and development, special health care needs, hospital dentistry, behavior guidance, trauma, and oral pathology. The resident clinic provides comprehensive care for children ages 0-21, including management of developing oral tissues and occlusion. Patients with tooth agenesis are monitored for treatment at appropriate time points, balancing growth and development of the oral structures and the developing psyche of the patient. Dr Chiquet's clinical and research interest is cleft lip and palate, which often co-occur with tooth agenesis.

Emily Hansen-Kiss is a board-certified genetic counselor and Assistant Professor in the Department of Diagnostic and Biomedical Sciences at UTHealth School of Dentistry. Ms Hansen-Kiss has served as the genetic counselor in the Cleft and Craniofacial Clinics at Shriners Hospitals for Children – Houston, and UTHealth/Memorial Herman Hospital for the last two years, where she has gained extensive experience counseling patients and families about syndromic and nonsyndromic orofacial conditions. Ms Hansen-Kiss has also been involved in teaching genetics with an orofacial focus to the UTHealth School of Dentistry and the UTHealth Genetic Counseling graduate program students.

Acknowledgments

This study was supported by the UTHealth School of Dentistry Summer Student Research Program (SM and EH) and UTHealth School of Dentistry start up funds to AL and BC.

Revision History

• 22 July 2021 (ma) Review posted live
• 2 October 2020 (al) Original submission

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