Tooth Agenesis, Selective, 1

A number sign (#) is used with this entry because of evidence that selective tooth agenesis-1 (STHAG1) is caused by heterozygous mutation in the MSX1 gene (142983) on chromosome 4p16.

Description

Tooth agenesis in some form is a common human anomaly that affects approximately 20% of the population. Although tooth agenesis is associated with numerous syndromes, several case reports describe nonsyndromic forms that are either sporadic or familial in nature, as reviewed by Gorlin et al. (1990). The incidence of familial tooth agenesis varies with each class of teeth. Most commonly affected are third molars (wisdom teeth), followed by either upper lateral incisors or lower second premolars; agenesis involving first and second molars is very rare. Also see 114600 and 302400.

Selective tooth agenesis without associated systemic disorders has sometimes been divided into 2 types: oligodontia, defined as agenesis of 6 or more permanent teeth, and hypodontia, defined as agenesis of less than 6 teeth. The number in both cases does not include absence of third molars (wisdom teeth). Faulty use of the terms, however, have confounded their use. The term 'partial anodontia' is obsolete (Salinas, 1978).

Genetic Heterogeneity of Selective Tooth Agenesis

Other forms of selective tooth agenesis include STHAG2 (602639), mapped to chromosome 16q12; STHAG3 (604625), caused by mutation in the PAX9 gene (167416) on chromosome 14q12; STHAG4 (150400), caused by mutation in the WNT10A gene (606268) on chromosome 2q35; STHAG5 (610926), mapped to chromosome 10q11; STHAG7 (616724), caused by mutation in the LRP6 gene (603507) on chromosome 12p13; STHAG8 (617073), caused by mutation in the WNT10B gene (601906) on chromosome 12q13; STHAG9 (617275), caused by mutation in the GREM2 gene (608832) on chromosome 1q43; and STHAGX1 (313500), caused by mutation in the EDA gene (300451) on chromosome Xq13.

A type of selective tooth agenesis that was formerly designated STHAG6 has been incorporated into the dental anomalies and short stature syndrome (DASS; 601216).

Of 34 unrelated patients with nonsyndromic tooth agenesis, van den Boogaard et al. (2012) found that 56% (19 patients) had mutations in the WNT10A gene (STHAG4), whereas only 3% and 9% had mutations in the MSX1 (STHAG1) and PAX9 (STHAG3) genes, respectively. The authors concluded that WNT10A is a major gene in the etiology of isolated hypodontia.

Genotype-Phenotype Correlations

Yu et al. (2016) observed that the most frequently missing permanent teeth in WNT10B-associated oligodontia were the lateral incisors (83.3%), whereas premolars were missing only 51.4% of the time, which they noted was a pattern 'clearly different' from the oligodontia patterns resulting from WNT10A mutations. They also stated that the selective pattern in WNT10B mutants was different from that associated with mutations in other genes, such as MSX1, in which second premolars are missing, and PAX9, in which there is agenesis of molars.

Inheritance

Erwin and Cockern (1949) described absent second bicuspids and third molars in 9 members of 3 generations.

Mapping

In a family with autosomal dominant agenesis of second premolars and third molars, Vastardis et al. (1996) found linkage of the trait to chromosome 4p.

Molecular Genetics

In a family with autosomal dominant agenesis of second premolars and third molars, Vastardis et al. (1996) identified a missense mutation in the homeodomain of the MSX1 gene (142983.0001).

Van den Boogaard et al. (2000) identified a nonsense mutation in exon 1 of the MSX1 gene (142983.0002) in a 3-generation Dutch pedigree with tooth agenesis and combinations of cleft palate only (119540) and cleft lip and cleft palate (see 119530). Eleven of 12 affected members lacked some permanent teeth, and most were missing both mandibular and maxillary second premolars, similar to the family reported by Vastardis et al. (1996). The third molar was also frequently absent.

Lidral and Reising (2002) screened 92 individuals with tooth agenesis from 82 nuclear families for mutations in the MSX1 gene and identified a novel missense mutation (142983.0008) in 2 sibs from a large family segregating autosomal dominant oligodontia. The pattern of oligodontia was similar to that in previously reported patients with mutations in the MSX1 gene, suggesting that mutations in MSX1 are responsible for a specific pattern of inherited tooth agenesis.

De Muynck et al. (2004) analyzed the MSX1 gene in 55 individuals from 40 families with hypodontia with or without cleft lip and/or palate, and identified heterozygosity for a truncating mutation (142983.0006) in 3 affected members of 1 family with severe hypodontia. De Muynck et al. (2004) concluded that MSX1 mutations are not a frequent cause of familial hypodontia or cleft lip and/or palate.

In a family with autosomal dominant oligodontia, Kim et al. (2006) identified an MSX1 frameshift mutation (142983.0009) in all affected individuals. Multiple teeth were missing, including all second premolars and mandibular central incisors.

Genotype/Phenotype Correlations

Kim et al. (2006) analyzed the pattern of tooth agenesis in several kindreds with defined MSX1 and PAX9 mutations. They found that the probability of missing a particular type of tooth is always bilaterally symmetrical, but differences exist between the maxilla and mandible. MSX1-associated tooth agenesis typically includes missing maxillary and mandibular second premolars and maxillary first premolars. The most distinguishing feature of MSX1-associated tooth agenesis is the frequent (75%) absence of maxillary first premolars, whereas the most distinguishing feature of PAX9-associated tooth agenesis is the frequent (over 80%) absence of maxillary and mandibular second molars.

History

Gruneberg (1936) described a family in which a mother and 4 of 5 children lacked some or all wisdom teeth. Gorlin (1977) stated that in one-third or more of most populations one or more wisdom teeth are missing.