Pathognomonic oral profile of Enamel Renal Syndrome (ERS) caused by recessive FAM20A mutations

Abstract

Amelogenesis imperfecta (AI) is a genetically and clinically heterogeneous group of inherited dental enamel defects. Commonly described as an isolated trait, it may be observed concomitantly with other orodental and/or systemic features such as nephrocalcinosis in Enamel Renal Syndrome (ERS, MIM#204690), or gingival hyperplasia in Amelogenesis Imperfecta and Gingival Fibromatosis Syndrome (AIGFS, MIM#614253). Patients affected by ERS/AIGFS present a distinctive orodental phenotype consisting of generalized hypoplastic AI affecting both the primary and permanent dentition, delayed tooth eruption, pulp stones, hyperplastic dental follicles, and gingival hyperplasia with variable severity and calcified nodules. Renal exam reveals a nephrocalcinosis which is asymptomatic in children affected by ERS. FAM20A recessive mutations are responsible for both syndromes. We suggest that AIGFS and ERS are in fact descriptions of the same syndrome, but that the kidney phenotype has not always been investigated fully in AIGFS. The aim of this review is to highlight the distinctive and specific orodental features of patients with recessive mutations in FAM20A. We propose ERS to be the preferred term for all the phenotypes arising from recessive FAM20A mutations. A differential diagnosis has to be made with other forms of AI, isolated or syndromic, where only a subset of the clinical signs may be shared. When ERS is suspected, the patient should be assessed by a dentist, nephrologist and clinical geneticist. Confirmed cases require long-term follow-up. Management of the orodental aspects can be extremely challenging and requires the input of multi-disciplinary specialized dental team, especially when there are multiple unerupted teeth.

Oral manifestations in chronic uremia patients

“…ERS seems to be associated with recessive mutations in FAM20A, which is a gene that is normally expressed by osteoblasts, ameloblasts (during the secretion stage), and odontoblasts and plays an essential role in tooth development. 25 …”

A distinctive oral phenotype points to FAM20A mutations not identified by Sanger sequencing

“…It is predicted to be a kinase with targets specific to mineralization, calcium transport, and proteoglycan synthesis (de la Dure‐Molla et al. 2014), but this remains to be confirmed experimentally. As such, FAM20A may have additional unknown functions.…”

“…Both disorders involve hypoplastic AI in the primary and secondary dentitions, together with variable degrees of gingival hyperplasia, pulpal calcifications, and delayed tooth eruption (de la Dure‐Molla et al. 2014). In addition, nephrocalcinosis may subsequently develop with a variable age of onset that is incompletely defined.…”

“…It has therefore been suggested that recessive FAM20A mutations are responsible for a single disease which should now be termed ERS (de la Dure‐Molla et al. 2014). …”

“…The oral phenotypes observed in individuals with either recessive mutations in FAM20A or FAM20C share features and may appear isolated in milder or earlier stages of disease (de la Dure‐Molla et al. 2014; Acevedo et al. 2015).…”