Tooth Agenesis, Selective, 4

A number sign (#) is used with this entry because of evidence that selective tooth agenesis-4 with or without ectodermal dysplasia (STHAG4) is caused by homozygous, heterozygous, or compound heterozygous mutation in the WNT10A gene (606268) on chromosome 2q35.

For a general phenotypic description and a discussion of genetic heterogeneity of selective tooth agenesis, see STHAG1 (106600).

Clinical Features

Joehr (1934) reported absence of the upper lateral incisors or peg-shaped lateral incisors in one-third of a Swiss group. The latter feature was a partial expression of the gene. All affected members of the isolate were descendants of one man, born in the 18th century.

Woolf (1971) found that in 71 of 103 families of probands with missing maxillary lateral incisors, one or more first-, second-, or third-degree relatives had a missing or peg-shaped maxillary incisor. He concluded that at least part of the genetic component is autosomal dominant with reduced penetrance and variable expressivity. Families showed a high degree of intrafamilial concordance for type of minor anomaly, especially if the proband had bilaterally absent lateral incisors. Adolph H. Schultz (1891-1976), distinguished anthropologist (Biegert, 1976), gave an early report of an affected family he observed personally on the occasion of a large gathering. A peculiarity was that only females were affected and only females transmitted the trait. Sometimes vestigial lateral incisors in parents were followed by complete absence in children and then reappearance of vestigial incisors in the third generation.

Witkop (1987) reported 2 kindreds in which 3 individuals (2 in one family and 1 in the second) had agenesis of the succedaneous (permanent, or secondary) teeth. Both parents in each family had pegged or missing maxillary lateral incisors. In the offspring with the missing succedaneous teeth, permanent molar teeth were present. Witkop (1987) suggested that agenesis of the succedaneous teeth results from the homozygous state of the gene determining the trait for small/pegged/missing maxillary lateral incisors. Witkop (1987) stated that the prevalence of the small-pegged-missing incisor trait in the United States is approximately 1 in 67 (1.5%) and estimated that, on this basis, the prevalence of agenesis of succedaneous teeth should be about 1 in 18,000. Anodontia of permanent teeth unassociated with a syndrome is inherited as an autosomal recessive (206780).

Nieminen et al. (1995) reported 5 Finnish families with incisor and premolar hypodontia. The diagnosis in the probands was based on congenital absence of 1 to 4 teeth or the presence of 1 or more peg-shaped incisors. All members of the family were studied clinically and panoramic tomograms were taken. Hypodontia of deciduous dentition was assessed anamnestically. Nieminen et al. (1995) referred to this disorder as incisor and premolar hypodontia because of the teeth that are most often affected, and placed the prevalence of this type of hypodontia at 5 to 10% among European and Asian populations.

Hoo (2000) reported a family with 2 sibs with anodontia of permanent teeth. Both parents had normal dentition, but the paternal grandmother, her twin sister, and a paternal aunt all had only 2 maxillary incisors, and the maternal grandmother had only 2 mandibular incisors. The author concluded that this family provides further evidence for the hypothesis of Witkop (1987) that agenesis of permanent teeth is a homozygous state of the gene responsible for pegged or missing maxillary lateral incisors.

In a population-based cohort of 94 Swedish families including 102 individuals with nonsyndromic tooth agenesis (mean of 8.2 missing teeth), Arzoo et al. (2014) identified 26 probands (27.7%) with mutation in the WNT10A gene, 17 of whom had monoallelic mutations and 11 biallelic mutations. Individuals with biallelic mutations had a higher number of missing teeth (mean, 11.1) than those with monoallelic mutations (mean, 6.8). Upper and lower premolars were the most common type of missing teeth (59.7% of all missing teeth). Probands with biallelic mutations had a higher frequency of absent maxillary and mandibular molars (p = 3.63 x 10(-6)) and mandibular central incisors (p = 6.91 x 10(-3)). There were no differences in type or number of missing teeth between males and females.

Inheritance

Autosomal dominant inheritance of selective tooth agenesis with incomplete penetrance was proposed by Grahnen (1956) and several workers thereafter, including Burzynski and Escobar (1983) who calculated the penetrance to be 86% from data from Grahnen (1956). However, the possibility of polygenic inheritance was suggested by Suarez and Spence (1974) and Peck et al. (1993).

In a population-based cohort study including 102 Swedish individuals with selective tooth agenesis, Arzoo et al. (2014) identified 17 probands with monogenic and 11 with biallelic mutations in the WNT10A gene. Patients with biallelic mutations had a higher proportion of relatives with oligodontia (5/11 or 45%) compared to patients with monoallelic mutations (1/17 or 6%).

Mapping

Nieminen et al. (1995) performed linkage analysis using intragenic microsatellite markers in 20 affected individuals from 5 Finnish families with incisor and premolar hypodontia. Pairwise lod scores excluded both the MSX1 (142983) and MSX2 (123101) genes as causative loci for hypodontia in these families.

Molecular Genetics

In patients with a recessive form of ectodermal dysplasia (OODD; 257980) caused by mutation in the WNT10A gene (606268), Bohring et al. (2009) observed a pattern of tooth anomalies comparable to that seen in patients with anodontia of permanent dentition (206780) and selective tooth agenesis-4, and suggested that testing for mutations in WNT10A might be worthwhile in the latter patients.

In an American family with variable hypodontia involving the lateral incisors and premolar teeth, Kantaputra and Sripathomsawat (2011) analyzed the candidate gene WNT10A and identified heterozygosity for a missense mutation (F228I; 606268.0003) in the father, who had congenitally absent maxillary first premolars and 3 third molars, and his oldest son, who had absent maxillary permanent lateral incisors and mandibular second premolars. A second son, who had absence of the maxillary permanent lateral incisors, mandibular second premolars, and a mandibular permanent lateral incisor, was heterozygous for a different missense mutation (D217N; 606268.0007) that he inherited from his mother, who had normal dentition. A third son, who was compound heterozygous for the mutations, had only microdontia of the left mandibular second molar. None of the family members had other manifestations of ectodermal dysplasia.

Van den Boogaard et al. (2012) identified WNT10A mutations in 19 (56%) of 34 unrelated patients with nonsyndromic tooth agenesis (see, e.g., 606268.0002-606268.0004), 8 of whom were homozygous, 4 compound heterozygous, and 7 heterozygous for the mutations. MSX1 (142983), PAX9 (167416), and AXIN2 (604025) mutations were present in 3%, 9%, and 3% of the patients, respectively. The authors concluded that WNT10A is a major gene in the etiology of isolated hypodontia.

Van den Boogaard et al. (2012) also identified homozygosity, heterozygosity, or compound heterozygosity for the same C107X (606268.0002) and F228I (606268.0003) WNT10A mutations in 11 patients with tooth agenesis who displayed mild features of ectodermal dysplasia, including sparse hair, sparse eyebrows, short eyelashes, and abnormalities of the toenails. The authors stated that characteristic features of OODD, including facial telangiectases, evident palmoplantar keratoderma, and smooth tongue were not observed in the latter patients, but noted that hypoplastic lingual papillae can be difficult to identify and that specific imaging methods were not applied in their study. Overall, no specific pattern of tooth agenesis was observed for WNT10A mutation carriers, and van den Boogaard et al. (2012) stated that the percentages of tooth agenesis per tooth type were similar to those from a larger population of nonsyndromic oligodontia patients (Creton et al., 2007).

In a cohort of 34 probands referred with features of ectodermal dysplasia, who were negative for mutation in the EDA gene (300451), Plaisancie et al. (2013) sequenced the WNT10A and EDAR (604095) genes and identified heterozygosity, homozygosity, or compound heterozygosity for mutations in WNT10A in 16 (44%) of the probands. The C107X and F228I mutations represented 43% and 18% of the detected WNTA10A variants, respectively. Mutations in EDAR were identified in 5 (14%) of the probands (see ECTD10A, 129490, and ECTD10B, 224900), and no mutations were detected in the remaining 15 probands. The authors observed associated ectodermal features in 15 of the 16 patients with WNT10A mutations, consisting primarily of hair anomalies, with sparse, thin, or thick hair; nail involvement, with thin nails or reduced nail growth; and sweating anomalies, with either hypo- or hyperhidrosis. Noting that features of ectodermal dysplasia were present in only 11 of the 30 patients studied by van den Boogaard et al. (2012), Plaisancie et al. (2013) suggested that this reflected different methods of recruitment.

In 6 of 9 unrelated Thai patients with agenesis or isolated hypodontia of the maxillary permanent canines, Kantaputra et al. (2014) identified 3 different heterozygous mutations in the WNT10A gene (see, e.g., 606268.0009). One of the affected individuals also had pegged maxillary permanent lateral incisors with dens invaginatus. Two mothers of the patients carried the mutation and had pegged maxillary permanent lateral incisors.

Animal Model

Schultz (1934) found selective tooth agenesis in 1 gorilla and 1 gibbon.