Enamel renal syndrome (ERS) (OMIM 204690) is a rare autosomal recessive disorder characterized by hypoplastic amelogenesis imperfecta (AI), failed tooth eruption, intrapulpal calcifications, gingival enlargement, and nephrocalcinosis [1]. In 1972, MacGibbon [2] described a condition presenting with renal dysfunction and enamel hypoplasia in several members of the same family. Although there has been an increasing number of publications about ERS in recent years, the rarity of the condition and the variability of the phenotype has led to ERS not being fully characterized.

Several phenotypes have been identified under various terms, including AI syndrome, AI with interradicular dentine dysplasia, AI with odontogenic fibroma-like hamartomas around nonerupted teeth, AI with gingival fibromatosis [3], MacGibbon syndrome, and Lubinsky-MacGibbon syndrome [4]. The lack of strict diagnostic criteria has led to patient’s renal status being overlooked within those phenotypes, along with underestimation of the actual disease prevalence [3]. This rare genetic entity accounts for less than 1 in 100,000 individuals of the global population, with only 70 cases in 50 different families being documented at present [5].

Recently, high throughput genetic technologies such as whole exome sequencing, next generation sequencing, and bioinformatics analysis implicated mutations in FAM20A (FAMily with sequence similarity 20A) as the defective gene in ‘‘Amelogenesis Imperfecta and Gingival Fibromatosis Syndrome’’ (AIGFS; OMIM 614253). A comprehensive review of AIGFS’s clinical aspect delineated a similar distinctive oral phenotype to ERS [6]. It is believed that both syndromes reflect different phenotypes of the same disease with frequent renal dysfunction association in ERS [3]. More than 40 homozygous or combined heterozygous FAM20A mutations have been identified in families (Human Gene Mutation Database). The protein encoded by the FAM20A gene is secreted by ameloblasts, odontoblasts, gingival, and dental pulp cells, reflecting an important role during enamel development and gingival homeostasis [1,7].

Generally, patients with ERS seek dental management, as the initial chief complaint relates to the lack of enamel and failure of permanent tooth eruption at a young age [6]. A review by de la Dure-Molla and colleagues [3] suggested a distinctive pathognomonic oral profile for patients with ERS (Textbox 1).

In addition to the “common profile” of ERS, several atypical features have been reported in the literature. Pêgo et al [8] reported an association of hypertrichosis and hearing loss in two patients with ERS. Hearing loss is a common feature of Raine syndrome (OMIM 259775), a syndrome caused by FAM20C mutation. This may explain the presence of such a feature in ERS [8]. A few characteristics that are considered atypical manifestations in individuals with ERS have been documented in a study conducted by Dourado et al [1]. These were malocclusion, periodontal disease, supraincisive diastema, and intellectual disability. One study documented a case in which all the permanent teeth had erupted, which is considered highly atypical of ERS [5].

It is clear from the growing list of atypical features of ERS that there is still much that is not known and poorly understood about ERS. This scoping review aims to account for the range and current state of knowledge on ERS. These findings will be synthesized into a comprehensive summary, focusing on the pathophysiology, genotype-phenotype correlations, and patient management from a dental perspective. The authors also aim to elucidate research gaps to inform future research and provide a useful summary for clinicians treating patients with ERS.

We will undertake this scoping review following the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews) guidelines [9]. This study is registered with the Open Science Framework (OSF) [10].

There was no patient participation in this study. This protocol was completed in July 2020 and registered in OSF [10] in August 2020. The electronic search for literature was undertaken in July 2020 and updated in April 2021. The first search yielded 122 titles. This study is intended for open access publication for wide dissemination of the findings.

This scoping review aims to determine the current state of knowledge on ERS and synthesize these findings into a comprehensive summary, focusing on the pathophysiology, genotype-phenotype correlations, and patient management from a dental perspective. We also aim to identify research gaps to inform future research and provide a useful summary for clinicians treating patients with ERS.

ERS is a rare disorder and not much awareness exists around the condition, even within the dental fraternity [11]. Conversely, AI is a relatively common disorder of enamel formation encountered by dentists and often occurs as an isolated trait or part of a syndrome [1]. Because dentists are often the first point of call for these patients, it is important that the dentist is able to identify patients with ERS and differentiate it from AI so that they receive appropriate referrals for renal evaluations and genetic counselling [5]. It is also important to provide the patient with oral rehabilitation to increase the patient’s quality of life, which can be severely impaired by this condition [5]. Primary failure of eruption is difficult to manage, and there is no current literature about assisted eruption with orthodontic traction in patients with ERS [11]. It does appear that the normal eruptive process of teeth is altered leading to impaction and ankylosis [11]. Progressive embedding of the teeth has also been reported [4]. Therefore, orthodontic treatment may be unpredictable. Current management involves surgical interventions and the placement of a fixed or removable dental prosthesis [12,13]. There is a need for guidelines on the dental management of patients with ERS and the development of referral protocols.

Identifying patients with ERS may not be as straightforward as it was previously believed to be. According to de la Dure-Molla et al [3], the oral features of ERS described in Table 1 are considered pathognomonic. However, more recent studies have found significant variability in phenotypes including identifying a patient with a pathogenic variant of the FAM20A gene and a full complement of erupted permanent teeth [5]. Therefore, a review is needed to consolidate this growing body of evidence and present it in a manner that is practical for the dental clinician. We believe that a scoping review is the most appropriate method to conduct a comprehensive exploration of the current evidence, which may be sparse due to the rarity of the condition. It will also enable us to identify gaps in the research.