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Recessively inherited lower incisor hypodontia

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Editor—Hypodontia, congenitally missing teeth, is common in modern man. The teeth most often missing in populations of European origin are the upper lateral incisors and second premolars. The condition is known to have a strong genetic component. At present two mutated genes in humans,MSX1 1 andPAX9,2 are known to cause missing permanent teeth. Mutations in MSX1can also cause orofacial clefting.3 Several experimental and clinical studies indicate that other genetic components are also involved.4-8 Hypodontia is also often seen in syndromes, particularly in those which present with other ectodermal anomalies,9 and in non-syndromic patients with cleft lip/alveolus with or without cleft palate.

The population prevalence of the common incisor-premolar hypodontia (IPH, MIM 106600) is 8-10% in healthy European children. Some or all third molar teeth are missing in one-fifth of the population,10 and missing third molars are seen in varying combinations in IPH patients and/or family members.11Family studies also indicate that peg shaped upper lateral incisors, impacted canines, rotated bicuspids, and short root anomaly (SRA) are caused by the same genetic components that cause missing incisors and premolars.12-15 The condition is inherited as an autosomal dominant trait16 with reduced penetrance and is mostly restricted to the permanent dentition. When a large number of teeth (>6) are congenitally missing, the term used is oligodontia (MIM 6044625). The prevalence of oligodontia in European populations is estimated at 0.08%,17 but this figure also includes syndromic patients.

We describe 37 Finnish patients from 34 families with several lower incisors and upper lateral permanent incisors congenitally missing. In half of the patients, the corresponding deciduous teeth had either been missing or peg shaped. An atopic condition had been diagnosed in two thirds of the patients. Occurrence of the trait within the families followed an autosomal recessive mode of inheritance. We have called the condition Recessive Incisor Hypodontia (RIH) and suggest that it belongs to the Finnish Disease Heritage, the enrichment of some 40 rare disorders.

Methods

Ten patients with missing lower and upper lateral incisors were first seen at the Hypodontia Unit of the Department of Pedodontics and Orthodontics, University of Helsinki over the past five years. Their parents did not display similar hypodontia, but sometimes had one congenitally missing permanent tooth. In two families, the condition was seen in sibs. In order to discover the prevalence of this condition in Finland, a questionnaire was sent to all active orthodontists and municipal health centres in the country (362 letters). We received radiographs of 220 patients and 65 patients selected from these were further studied after giving their consent.

Inclusion criteria were three or four congenitally missing lower incisors, at least two congenitally missing or peg shaped lower permanent incisors together with missing upper lateral incisors, preceded by agenesis of at least one lower deciduous incisor, and a pedigree consistent with an autosomal recessive mode of inheritance. Exclusion of obvious dominant oligodontia, anhidrotic ectodermal dysplasia (EDA, also carriers), and incontinentia pigmenti (IP) was attempted by careful clinical examination, anamnestic information, and pedigree analysis. The final sample consisted of 37 patients from 34 families. Three pairs of sibs were included (fig 1).

Figure 1

The 34 families with RIH. The patients are the middle column, parents with minor dental anomalies are on the left, and the healthy and affected sibs with minor dental anomalies are on the right. In three families, two affected children were seen. The four single child families were excluded as uninformative in calculations of the proportion of affected sibs.

The patients, parents, some grandparents, and sibs were examined radiographically and interviewed, and facial and oral photographs were taken. Alginate impressions were made of all cooperative patients. Dental age was calculated from radiographs by the age medians for tooth formation18 and standard deviations (SD) for dental ages.19

Parents and sibs showing dental anomalies such as hypodontia of one or two teeth, peg shaped teeth, retained cuspids or taurodontic teeth are shown in fig 1. The ancestors were traced back to 1850 from local church registries using the names, dates, and birth places of parents. Microfilm copies in The National Archives of Finland were used for earlier periods. To analyse the mode of inheritance, the ratio of affected to healthy sibs was corrected for the absence of healthy sibships born to two heterozygous parents.20 For DNA analysis, samples of venous blood were taken from patients, grandparents, parents, and sibs. The study was approved by the Ethics Committee of the Institute of Dentistry, University of Helsinki.

Results

All 37 patients were under 22. Their clinical characteristics are presented in table 1 with typical panoramic radiographs in fig 2. Nine of the patients had no permanent lower incisors, two of them had also lacked the corresponding deciduous teeth. In seven, the upper permanent lateral incisors were also missing and in five the deciduous upper lateral incisors as well. In one, the upper central incisors were peg shaped with an anomalous structure (fig 2B). In four patients, three missing lower permanent incisors were evident. Of these 13 severely affected patients, 10 were boys. The remaining 24 had a varying combination of missing or peg shaped lower and upper permanent and deciduous incisors. A deciduous tooth/teeth was missing in 19/36 (53%). In addition to incisors, other permanent teeth were also missing (fig 3). Mean dental age based on tooth formation was slightly delayed (SDS 0.8). Taurodontism was noted in the molar teeth of 16/26 patients (62%).

Table 1

Dental and health characteristics of 37 patients with recessive lower incisor hypodontia (RIH)

Figure 2

Radiographs of four patients with RIH. In addition to missing lower and upper lateral incisors, missing permanent bicuspids are visible in all the patients and also missing cuspids and second molars in the most severely affected boy of the series (D). In patient B, the upper central incisors are conical with dens in dente. Later, his upper canines failed to erupt. Taurodontic upper first molars can be seen in all four.

Figure 3

Distribution and number of missing deciduous and permanent teeth in 33 patients with RIH.

Photographs of the younger patients are shown in fig 4. Hair, nails, eyelashes, eyebrows, and perspiration were normal. Heights and weights were also normal for age. A large proportion of the patients reported allergies (62%), such as atopic skin (52%) and asthma (43%), diagnosed by a doctor.

Figure 4

Photographs of four unrelated patients. A similarity in facial features (broad nasal bridge, deep mentolabial sulcus, reduced anterior facial height) can be seen. Hair, eyelashes, and eyebrows appeared normal.

The male/female ratio of the patients was 19/18 (1.05). The proportion of affected sibs was calculated from 30 sibships with 76 children. The apparent proportion of affected sibs was 0.43. After mathematical correction for the absence of healthy sibships born of two heterozygous parents, using the a priori correction of truncate complete ascertainment, the proportion was 0.22. Pedigrees of 31 families were traced back at least to the fifth generation, and, when possible, to the late 17th century (10 generations). In two families, the parents of the proband had a common ancestor six and seven generations back (fig5), but no other family linkages between the families were found. A map of Finland, where the birth places of the great grandparents of the patients are marked, is shown in fig 6. In the case of 23/31 index cases, the maternal and paternal ancestors originated from the same rural area.

Figure 5

Pedigrees of the two probands whose parents were found to have a common ancestor originating from Kalvola in the middle of the 1700s (on the left) and Kauhava in 1800 (on the right).

Figure 6

Birth places of patients' great grandparents, the pattern of the regional distribution of the ancestors coinciding with early settlement in Finland, and the population migration from north east to west and north. In 23 out of 31 cases the maternal and paternal grandparents originated from the same area.

Minor dental anomalies in the form of a missing upper lateral incisor or a missing third molar/molars was seen in 41% of the parents and in 27% of the healthy sibs (fig 1). Both parents and sibs reported allergies (46% and 40% respectively) and skin problems (46% and 35% respectively). Ten of the 29 examined mothers (34%), eleven of the 22 fathers (50%), six of the 22 healthy sisters (27%), and six of the 20 healthy brothers (30%) are shown in the pedigrees on the basis of their minor dental anomaly (fig 1).

Discussion

Our attempt at a nationwide ascertainment resulted in a response to more than half of our questionnaires, but because the oldest patient was only 22, it is likely that we only found a proportion of the total number of RIH patients in Finland. By using strict criteria in an effort not to overdiagnose, some of the cases reported to us and some of the mildly affected sibs were perhaps misclassified.

There are many published reports of conditions with missing lower incisors. In Japan the prevalence of tooth agenesis is of the same order as in Europeans, but the lower lateral incisor is the most commonly missing tooth.21 Witkop syndrome is an autosomal dominant condition with missing lower incisors and dysmorphic nails.22 In a patient from Minnesota,23dentition and a face very similar to that of our patients can be seen. First cousins of Egyptian origin, born of consanguineous marriages, with absent or conical lower deciduous incisors and thin hair and finger nails, with cleft palate in one and a branchial cyst in the other, were described by Fried,24 who suggested autosomal recessive inheritance. A similar patient from Turkey, a child of first cousins, has also been described.25 The Norwegian sibs reported26 could also well have the autosomal recessive condition described here. A brother and sister from Lebanon with only a few permanent teeth and thin nails were recently reported27 with the suggestion that they may have the condition described by Fried.24 The pattern of missing teeth, including deciduous teeth, can also be similar in incontinentia pigmenti28 and in Kabuki syndrome.29

Congenitally missing deciduous teeth, as seen in 53% of the present patients, is not common in IPH. The prevalence figures are commonly close to 0.5%30-32 and, interestingly, are higher (0.9%) in Finland.33 All these figures may also include children with syndromic hypodontia or oligodontia. The genetics of hypodontia in the deciduous dentition has not been systematically studied, but has been assumed to be a symptom of IPH, as the corresponding permanent tooth is also usually missing. Detailed descriptions of the distribution of missing teeth in hypodontia patients are rare, However, in two Scandinavian studies, the pattern of missing lower and upper lateral incisors typical of RIH is evident.16 34 This also suggests that the condition also exists in other populations but has perhaps been overlooked because of overlapping symptoms with IPH. Retarded dental development and short rooted (taurodontic) molar tooth form are characteristic of hypodontia and oligodontia and were clearly seen in the condition described here.

The number of cases of atopic diseases, commonly seen in our patients and also reported by the family members, exceeds the reported population prevalences35 and is an interesting finding in the present context. Of the similar published conditions, only the Norwegian report mentions asthma as a symptom of the patient. Recently, a distinct anhidrotic ectodermal syndrome with missing teeth and immunological abnormalities, EDA-ID, has been described. The condition seems to be caused by impaired NF-kB signalling.36

In recessively inherited conditions heterozygous manifestations may occur. Here, minor dental anomalies were noted in less than half of the parents (41%), regarded as carriers of one mutated gene. Theoretically, two thirds of the healthy sibs are also heterozygous. In the sibs, minor dental anomalies were seen in 27%. As dental anomalies are quite common in the population, it is difficult to know whether these minor aberrations reflect the normal variation or represent heterozygous manifestations.

Several rare genetic conditions, mostly autosomal recessive, have been found in the Finnish population and this “Finnish Disease Heritage” has been explained by national and regional isolation of small population groups. Recent findings confirming that mostly one major mutation is seen in 70 to 100% of affected subjects37 has shown this assumption to be correct. The results of our genealogical studies indicate that RIH is a new disease of the Finnish Disease Heritage, although it obviously is also seen in other populations.

In conclusion, we have diagnosed in Finland (population 5.2 million) 37 patients with a specific type of hypodontia with an autosomal recessive mode of inheritance, characterised by missing deciduous and permanent incisors, and an increased inclination to eczema and asthma. We have named the condition Recessive Incisor Hypodontia (RIH). The patients resemble reported patients from consanguineous marriages from various parts of the world. Attempts to clarify the molecular pathology of this condition are at present being carried out and the results will be of interest in developmental studies and in the study of molecular mechanics of atopic diseases.

Acknowledgments

We warmly thank our patients and the numerous families for making this study possible. We thank dentists throughout Finland, in particular Professor Satu Alaluusua for informing us about patients with missing lower incisors. We thank Professors Reijo Norio and Leena Palotie-Peltonen for valuable advice and support. The study was supported by the Foundation of Paediatric Research, the Ulla Hjelt Fund, and the Academy of Finland.

References

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