Background
The
WNT10A (Wingless-type MMTV integration site family, member 10A) gene is a member of the WNT gene family that has been implicated in oncogenesis and in several developmental processes including tooth formation [
1,
2]. Bi-allelic
WNT10A mutations cause a spectrum of symptoms from ectodermal appendages. Patients may present with nail dystrophy, palmoplantar hyperkeratosis, hyperhidrosis as well as hypohidrosis, sparse or brittle hair, eye-lid cysts and keratoconus in different combinations and severity in a continuum of phenotypes [
3‐
6]. In some cases the constellation of features may be defined as a specific clinical entity among the ectodermal dysplasias (EDs), e.g., odonto-onycho-dermal dysplasia (OODD; OMIM 257980) or Schöpf-Schultz-Passarge syndrome (SSPS; OMIM 224750) [
3‐
5,
7]. The most consistent and specific symptom in cases with either bi-allelic or mono-allelic
WNT10A mutations reported to date is tooth agenesis of the permanent dentition [
3,
4,
6,
8‐
14]. Studies of patients with non-syndromic oligodontia (agenesis of 6–28 teeth) referred for centralized treatments revealed a carrier frequency of up to 56% for
WNT10A mutations [
8]. However, a population-based study of Swedish individuals with isolated oligodontia revealed that the frequency of at least one
WNT10A mutation in non-related probands was 28% [
11]. When adding mutations in the genes
MSX1, PAX9, AXIN2, EDA, EDAR, and
EDARADD in the same material the frequency of genetically verified isolated oligodontia reached 38.3%.
Taken together, independent reports from us and others indicate that
WNT10A mutations are the most frequent specific cause of isolated hypodontia (agenesis of at least one tooth), and oligodontia (agenesis of six or more teeth, third molars excluded) of the permanent dentition known to date. The different frequencies in
WNT10A associated tooth anomalies in these studies may be related to ethnicity, phenotypic differences and selection criteria of study participants. Noteworthy, mutations in the WNT co-receptor
LRP6 gene were recently identified in rare cases of isolated oligodontia bringing further evidence for the importance of WNT10A in tooth development [
15].
Bi-allelic
WNT10A mutations are usually associated with a larger number of missing teeth when compared to mono-allelic mutations [
3,
4,
6,
8‐
11,
14]. Noteworthy, the penetrance among heterozygotes is incomplete and a considerable proportion of carriers do not express any tooth anomalies at all [
12]. In addition to tooth agenesis,
WNT10A variants may cause abnormal shape of both roots and crowns of permanent teeth [
16,
17]. Deformities include taurodontism of molars, misshaped crowns and peg-shaped incisors [
10,
14,
16,
17]. Taurodontism is a condition in human molars in which the body of the tooth is enlarged vertically at the expense of the roots, causing the pulp chamber to extend apically below the cementoenamel junction [
18,
19]. Thus, isolated hypo- or oligodontia, and tapered frontal permanent teeth give reasons to suspect underlying
WNT10A mutations. Also, a less disturbed primary dentition with conical frontal teeth was reported by Bohring et al., 2009 [
4].
We hypothesized that the combined assessment of primary and permanent dentition as well as search for mild or unnoticed ectodermal symptoms may identify carriers of WNT10A mutations. In this study we present seven individuals with severe tooth anomalies in whom symptoms from other ectodermal appendages were identified. We made a detailed characterization of both the primary and permanent dentition together with symptoms from other ectodermal derivatives. Our aim was to evaluate if abnormalities in both primary and permanent dentitions, together with other ectodermal symptoms, may serve as predictors for WNT10A deficiency of diagnostic importance early in life.
Discussion
We investigated seven individuals with severe oligodontia for their primary dentition, presence of ectodermal symptoms and WNT10A mutations. The selection of patients was based on severe oligodontia of permanent dentition and suspected but yet unspecified ED. Following assessment of primary dentition and presence of other ectodermal symptoms, the patients were analyzed for WNT10A gene variants. Bi-allelic mutations were confirmed in all seven individuals. In total, three different WNT10A alleles were detected that predict the previously described variants C107X, E222X and F228I. Clinical investigations at age 6–14 years revealed that the most distinctive initial sign in all examined individuals was the presence of numerous primary teeth in areas without succedaneous teeth. In total, seven primary incisors were missing from agenesis in three out of seven individuals, 5% of all primary teeth, compared to 76% of permanent teeth (mean 21.3). Notably, all three females but none of the males had primary tooth agenesis. This observed gender difference for absent primary teeth is significant (p = 0.02) but needs to be confirmed in larger and randomized cohorts. The most stable teeth were the maxillary central incisors, which were missing in only one individual. Severe dental abnormalities were found in individual Ia, who was missing three primary teeth and all permanent teeth, as well as individual II, missing two primary teeth and 26 permanent teeth, all but the maxillary central incisors.
Notably, all well-preserved primary incisors examined were peg teeth. Similarly, the permanent maxillary central incisors were severely tapered in 75% that were present. Taurodontism of primary or permanent molars was found in all of the examined individuals using biometric analysis from panoramic radiographs. This method is superior and more sensitive than cursory examination, especially in cases of milder forms of taurodontism [
23]. The most evident signs were found in the single individual in whom permanent molars were assessed. In mandibular molars from either the primary or permanent dentitions present in each individual 84.6% were taurodontic. However, taurodontism is frequently found in individuals with hypodontia [
21], with or without ED.
Besides tooth agenesis and misshaped teeth, all patients presented with an overlapping spectrum of mostly mild or previously unnoticed ectodermal symptoms including hyperhidrosis of palms and soles, aberrant hair texture, dry skin and nail dystrophy. None of the patients presented with the typical phenotype of
EDA- or
EDAR-induced hypohidrotic ED [
24,
25] and the ectodermal signs and symptoms were incongruous with any defined ED-entity. The spectrum of ectodermal symptoms among our seven patients is consistent with that previously reported in patients with bi-allelic
WNT10A mutations [
3‐
6,
8,
10], and even in some patients with mono-allelic mutations [
4,
6,
8,
11,
12]. Notably, with the exception of tooth agenesis, the signs and symptoms from ectodermal appendages in a majority of individuals in our cohort were subtle and in several cases even not experienced as abnormal by the study persons or their parents. Furthermore, we confirmed that carriers for bi-allelic
WNT10A mutations have more primary teeth in positions where permanent teeth are missing [
4]. Thus, in children with severe tooth agenesis it is important to consider mild or neglected symptoms from other ectodermal appendages. The molecular basis for the broad range of clinical expression due to WNT10A deficiency, from completely asymptomatic carriers to severely disabling ED entities, is yet unclear [
10]. Interestingly, a thin upper lip was observed in all but one individual in our study. We observed a similar feature in photographs in three out of five patients from the study by Bohring et al., 2009 [
4] Supplemental data]. This sign is distinct from the typical facial phenotype of
EDA- and
EDAR-induced ED and further studies are now needed to confirm this observation in carriers of
WNT10A mutations.
Besides the critical role in the development of ectodermal lineages, increased expression of
WNT10A has previously been implicated in a variety of cancers by up-regulation of the β-catenin pathway [
1,
26]. In contrast, the structural
WNT10A mutations known to be associated with abnormal development of ectodermal tissues are predicted to disrupt or reduce WNT mediated signaling [
27]. Taken together, this is consistent with the fact that patients with structural
WNT10A mutations are not reported to have increased risk for cancer.
Our study shows that bi-allelic
WNT10A mutations are associated with a full or nearly full set of primary teeth with typical peg-shaped crowns of the mandibular incisors, persisting primary teeth in areas with missing permanent successors, and extensive tooth agenesis (oligodontia) in the permanent dentition, often with severely tapered maxillary central incisors. This is consistent with and adds to the dental features described by Bohring et al., 2009 [
4], Supplemental data]. Furthermore, in combination with mild abnormalities in other ectodermal appendages, this typical dental pattern strongly suggests a
WNT10A-associated ED that differs from what is seen in
EDA- and
EDAR-induced hypohidrotic ED.
Acknowledgements
We thank the patients and their families for participating in this research. We are also indebted to Marie Danell and Eine Ståhl, specialists in dentomaxillofacial radiology, The Institute for Postgraduate Dental Education, Jönköping, Sweden, for valuable assistance in assessment of taurodontism.