Introduction

Oculo-dento-digital dysplasia (ODDD, OMIM# 164200) is a rare congenital genetic disorder characterized by craniofacial, ocular, dental, and digital abnormalities [1]. It was initially recognized by Lohman in 1920 [2]. It is primarily an autosomal dominant disorder but, in a few cases, recessive forms of the disease have been identified [3]. ODDD is caused by a missense mutation in gap junction alpha 1 (GJA1) gene on chromosome 6q22.31 [3]. This gene encodes for connexin 43 (Cx43), a transmembrane protein [3]. In 2003, ODDD became known as the first human disease to be linked to germline Cx43 gene (GJA1) mutations [4]. Cx43 is one of the 20 members of the human connexin protein family [3]. It has been diagnosed in fewer than 300 people worldwide with an incidence of around 1 in 10 million [2]. ODDD has high penetrance and its phenotypic expression is variable [5, 6], ODDD has typical features (Table 1) of syndactyly [3], digital camptodactyly [7], ophthalmic [8], nasal [3], and dental abnormalities [9].

Table 1 Clinical features of the ODDD syndrome.
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Other than these mentioned features, ODDD also shows neurological [10,11,12], and cardiological involvement [13]. Some features of ODDD are evident at birth, while others may appear with increasing age. Despite undergoing medical treatment for eyesight, and multiple surgeries for syndactyly and camptodactyly in hands in childhood, the case presented here was first diagnosed in our dental practice. This shows that rare syndromes like ODDD can remain either undiagnosed or misdiagnosed. Therefore, this review aims to summarize the available dental literature on ODDD as it will enable better management of associated diseases to improve the quality of life of the patient.

Case report

A 16-year-old male patient visited the dental clinic in February 2020 with complaints of pain in the lower right posterior tooth and sensitivity to cold in all posterior teeth. On physical examination, the patient had syndactyly of fourth-fifth fingers of the right hand and third-fourth fingers of the left hand with camptodactyly and webbing (Fig. 1). Multiple surgeries were carried out from birth to 12 years of age, but digital abnormalities were still present. Another corrective surgery was done in 2021 which resulted in a successful resolution of syndactyly of left-hand digits (Fig. 2). On extra-oral examination patient’s nose was thin, elongated with hypoplastic alae nasi, anteverted nares and ocular findings included prominent epicanthic folds and hypertelorism (Fig. 3).

Fig. 1: Hand photograph and radiograph illustrating webbed fingers.
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a–c Syndactyly of fourth-fifth fingers of right hand and third-fourth fingers of left hand with camptodactyly.

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Fig. 2: Post-operative hand radiograph.
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Post-operative x-ray showing separation of third and fourth fingers of left hand.

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Fig. 3: Extra-oral frontal photograph.
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Arrows showing prominent epicanthal folds (blue), Hypertelorism (yellow), Hypoplastic and anteverted nares (red).

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Upon intra-oral examination, findings were generalized staining, hypoplastic, hypomineralized enamel with pitting (most obvious on posterior teeth), multiple carious teeth: # 16, 17, 26, 27, 36, 37, 45, 46, 47, deep fissures in tooth # 25, 34, 35 (Fig. 4). Tooth # 46 was non-vital on electric pulp testing (EPT) and cold test and tender to percussion.

Fig. 4: Intra-oral clinical photographs.
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a Right lateral view. b Frontal view. c Left lateral view. d Maxillary occlusal view. e Mandibular occlusal view showing generalized staining, hypoplastic enamel (most obvious on posterior teeth) and deep fissure and multiple carious teeth. Tooth #46 root canal treated and 47 was filled.

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On panoramic (A) and right (B) and left (C) bitewing radiographs, all upper and lower second and third molars had taurodontism and pulp stones (red arrows) along with curved roots (Fig. 5).

Fig. 5: Dental radiography: Orthopantomogram and bitewing radiographs.
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Orthopantomogram (a) showing taurodontism in all upper, lower second and third molars with curved roots in lower first molars. Right (b) and left (c) bitewings showing pulp stones (red arrows) in all first molars and lower right, left second molars.

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Management and follow-up

Orthograde endodontic treatment was initiated in tooth # 46, after copious sodium hypochlorite irrigation and intracanal medicament, temporary restoration was placed. After 1 week, endodontic treatment of tooth # 46 was completed followed by permanent restoration. Restoration of all carious teeth # 16, 17, 26, 27, 36, 37, 45, 46, 47 was done with amalgam filling material (Fig. 6). Deep fissures in tooth #25, 34, 35 were sealed with light cure resin composite (Fig. 6). Dietary modification and oral hygiene instruction were reinforced. Impressions were obtained for diagnostic casts to monitor tooth wear on follow-up visits (Fig. 7). A 3-monthly follow-up was scheduled to evaluate the further enamel loss of the unrestored dentition and check the restored teeth status. The patient was asymptomatic and tooth sensitivity had diminished. No further deterioration of enamel was apparent.

Fig. 6: Post-operative occlusal photographs.
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a, b Showing maxillary and mandibular teeth after completion of dental treatment.

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Fig. 7: Diagnostic cast.
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a–e Diagnostic cast to monitor tooth wear on follow-up visits.

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Review questions

We decide to systematically look into these cases as no such review has been published till now. For this review the authors (KDVH & FUMR) compiled the available dental literature on ODDD patients based on the following questions:

  1. 1.

    What are the diagnostic measures, i.e., clinical features or gene analysis?

  2. 2.

    What are the dental manifestations commonly seen in patients with ODDD?

  3. 3.

    What are the management options for dental abnormalities?

Materials and methods

Search strategy

The authors (KDVH & FUMR) conducted a pilot search based on various combinations of key search terms. The final search strategy was formulated based on this pilot search. A comprehensive online literature search was performed (in June 2021) in three major health sciences databases, PubMed NLM, EBSCO Dentistry & Oral Sciences Source, EBSCO CINAHL Plus, and a hand search was also done in collaboration with a medical information specialist (Librarian, Aga Khan University Hospital, Pakistan).

Search terms

(“Oculodentodigital Dysplasia” [Supplementary Concept] OR Oculodentodigital dysplasia OR Oculo-dento-digital dysplasia OR Oculodentodigital syndrome OR Oculo-dento-digital syndrome OR Oculo-dento-osseous syndrome OR Oculo-dento-osseous syndrome OR Oculo-dento-osseous dysplasia OR Oculo-dento-osseous dysplasia OR ODDD OR ODOD).

Screening process

Endnote 20 reference manager was used for article citations. After removing duplicate references, all the remaining articles were screened by two authors (KDVH & FUMR) according to the predetermined inclusion criteria. Later, data was extracted by KDVH on a calibrated predetermined proforma independently, which was rechecked by FUMR.

Inclusion criteria

  • Dental case reports

  • Dentistry-related original articles

Exclusion criteria

  • Animal studies/In vitro studies

  • Molecular studies (gene analysis)

  • Medical case reports/Original articles

  • Abstracts only

  • Letter to Editors

  • Conference proceedings

Data extraction

For data extraction customized proforma was designed by the authors to extract the required data from included studies:

  1. 1.

    Study details (title, type of study, authors, journal of publication, year of publication).

  2. 2.

    Study characteristics (specialty field, no. of cases included).

  3. 3.

    Age, gender, Oral manifestations, treatment provided, follow-up time.

  4. 4.

    Diagnostic measure (genetic analysis).

Results

A total of 309 studies were identified after a detailed literature search. After removing duplicates, the number of studies was reduced to 223. After screening these studies by the authors (KDVH & FUMR) following the predetermined inclusion and exclusion criteria, 17 articles were included in this study for final analysis (full text of 6 articles could not be retrieved due to their non-availability in the database). The full screening process is shown in the PRISMA flowchart shown in Fig. 8.

Fig. 8: PRISMA flow chart.
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PRISMA Flow Chart for literature search.

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Characteristics of included studies

The selected articles included dental case reports (n = 15), one case report with a review, and one original article. A total of 22 patients (8 = females, 14 = males) are reported with ODDD with dental malformations. Ten out of 17 studies confirmed gene analysis of reported patients. A summary of selected studies is given in Table 2. Below are brief results of the selected studies based on the diagnostic measure, dental manifestations, and their management options.

Table 2 Brief review of the selected articles.
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Diagnostic measures

As previously mentioned, ODDD is a genetic disorder caused by a missense mutation in the GJA1 gene that encodes for a transmembrane protein (Cx43). Eight studies reported diagnosis based on clinical features [7, 14,15,16,17,18,19,20], while nine studies confirmed missense mutation in GJA1 at chromosome 6q22-q23 by genetic analysis [8, 21,22,23,24,25,26,27,28].

Dental manifestations

Enamel hypoplasia, hypomineralization, microdontia, pulp stones, curved roots, taurodontism, discolored teeth, tooth loss with or without caries, and peri-apical abscess are common findings in ODDD patients [7, 8, 15,16,17,18,19, 21,22,23, 25,26,27,28]. Other rare findings, i.e., cleft lip and palate [20, 24] short mandibular ramus and body, absent frontal sinus [7], distally inclined condyles [22], and hypoplastic maxilla [14, 17, 22] may also be present.

Management and follow-up

Management described below was reported by selected articles and was primarily based on the minimum invasive options:

Primary teeth

Extraction of grossly carious teeth, deep fissure sealants, early restoration of dental caries, prevention of tooth wear with stainless steel crowns (SSCs) in posterior teeth with or without pulpectomy was carried out in studies [8, 21, 23].

Permanent teeth

Extraction of unrestorable teeth, restoration of caries, pulpotomy in immature asymptomatic teeth, root canal treatment (apexification in immature teeth) in symptomatic teeth followed by full coverage restorations were done in studies [22]. A regular, usually 3-monthly dental evaluation of restored teeth and unrestored dentition is recommended to monitor and early management of any abnormality [8, 22].

Discussion

Oculo-dento-digital dysplasia is an uncommon condition that is rarely recognized by dentists,

For this reason, we decided to write this report along with a literature search so that the readers can become more familiar with this condition to better serve their patients.

In our review, we found that ODDD is an autosomal dominant genetic disorder, which is characterized by abnormal ocular, dental, and digital findings. It is caused by a mutation in GJA1 gene encoding Cx43 [9, 29]. In our case, the patient presented with multiple dental caries, enamel hypoplasia, pulp stones, and taurodontism and syndactyly, which are typically digital and dental manifestations of this syndrome. Genetic analysis of 178 genes (List given in genetic analysis report) responsible for limb and digital malformations was done for this patient. An uncertain significance of heterozygous variant for DLX6 (Distal-less homeobox) [99_119del (p.Gln38_Gln44del)] which is responsible for autosomal dominant split-hand/foot malformation type 1 [30] and GJA1 [c.196 T > C (p.Tyr66His)] gene involved in autosomal dominant and recessive oculodentodigital dysplasia was identified (9). DLX6 gene abnormality rarely shows dental involvement usually crowding [31]. However, the facial (extra-oral) features were mild but consistent with ODDD (autosomal dominant), showing a thin nose with hypoplastic alae nasi, short palpebral fissures. The present case suggests, ODDD should be considered even when ocular symptoms are un-remarkable and this correlates with the previous literature that there is approximately 70% chance of ocular manifestations in ODDD patients [9].

The other conditions that have similar features to ODDD are amelogenesis imperfecta (AI), oral-facial-digital syndrome, Hallerman-Streiff syndrome (HSS) [32], and Saethre-Chotzen syndrome. ODDD can be differentiated from AI, as the later condition shows little systematic involvement [33]. Oral-facial-digital dysplasia involves the renal system and has features like lobulated tongue without ocular manifestations which differentiates it from ODDD [34]. HSS may share similar clinical ocular and dental features with ODDD but the presence of the skin conditions, dwarfism differentiate it from ODDD [35]. Saethre-chotzen syndrome has features of the characteristic craniosynostosis, ptosis, and absence of any dental manifestations that differentiate it from ODDD [36]. Further details are given in Table 3.

Table 3 Differential diagnosis of ODDD.
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In the present case, the primary goal was to treat the dental disease (i.e., pulpitis and tooth wear) and seal the other teeth for the preservation of arch integrity for patients well being (nutritional, esthetic, and psychological). Teeth were structurally compromised, thus prone to caries and fractures from trauma. Though the symptomatic management in ODDD patients is the same as non-syndromic patients in a few situations, special considerations are required for long-term prognosis, i.e., preservation of teeth by sealing the deep pits and fissures to prevent caries [22]. Conservative treatment plan was of utmost importance as extraction could have led to compromised development of alveolar bone. In ODDD patients, the remodeling process may not be as efficient as in unaffected population due to lack of coordinating events in the alveolar bone due to alteration in Cx43 (29). This can affect the ossteo-integration in case of implant placement or remodeling process in orthodontic movement, thus preservation of alveolar bone is of great importance [22].

Conclusions

In our patient after genetic analysis, clinical and radiological findings were consistent with ODDD. The primary goals of dental treatment in patients with ODDD should be intended to correct the current oral condition and prevent further tooth loss for maintaining masticatory efficiency, phonetics, and esthetics. In these cases, dentists, pediatric dentists, orthodontists, prosthodontists should work with coordination and multidisciplinary approaches should be provided to improve quality of life.