Enamel Renal Syndrome (ERS) is a rare disorder characterized by a combination of dental and renal abnormalities, including stones and hypophosphatemia. ERS is genetically heterogeneous. We report on four pediatric cases of homozygous LoF FAM20A mutations (2 families). Biological (including oral calcium load) and imaging (dental and renal) data were reviewed. Results are presented as median(range). All patients were referred for renal screening by the specialized dental team at a median age of 14.5 [11–19] years. None of them presented symptoms of microscopic/macroscopic hematuria, nor renal colic despite the presence of multiple bilateral nephrolithiasis in all and nephrocalcinosis in one family. Biological parameters were vastly similar, with preserved renal function (eGFR 109(93–111) mL/min/1.73 m²), hypophosphatemia (median − 1.9(-3.4;-1.7) SDS for age), elevated FGF-23 (98(84–117) RU/mL, normal range 21–91 RU/mL) with hypocalciuria and low TmP/GFR. Oral calcium load tests confirmed the absence of resorptive and absorptive hypercalciuria, with adequate PTH inhibition during the test; of note, “baseline” PTH levels tended to be at the upper normal limit (83(65–131) ng/L, local upper normal limit 65ng/L) that was not adequate in view of hypophosphatemia, with 25D levels at 44(19–92) nmol/L. All patients were subsequently followed in pediatric nephrology and received hyperhydration and prudent vitamin D supplementation. These cases highlight the need for interdisciplinary collaboration between pediatric nephrologists, dental specialists and geneticists, to ensure that patients receive timely renal evaluation. The identification of elevated FGF-23 levels in FAM20A-related ERS with severe nephrolithiasis and hypophosphatemia raises the question of the interest of burosumab as targeted therapy. The online version contains supplementary material available at 10.1186/s13023-026-04232-6.

Amelogenesis imperfecta (AI) is a group of hereditary conditions that affect enamel formation and may signal underlying systemic diseases. Although rare, renal involvement is increasingly being reported, particularly in the context of enamel-renal syndrome (ERS). This study describes and analyzes five pediatric cases of amelogenesis imperfecta associated with renal anomalies, aiming to raise awareness of this rare but significant syndromic association. We retrospectively examined the medical records of five children diagnosed with AI and renal pathology. A review of the clinical, biochemical, radiological, and dental findings was conducted. Outcomes and management strategies were analyzed. All patients exhibited enamel defects that were compatible with AI, ranging from hypoplasia to delayed eruption. The renal presentations were as follows: nephrocalcinosis, Bartter syndrome, chronic kidney disease, distal renal tubular acidosis, and ectopic calcifications. Two siblings presented with chronic kidney disease and tubular defects of unknown origin, raising suspicion of a hereditary tubulopathy. Despite the absence of molecular confirmation, the clinical profiles were suggestive of syndromic forms, such as Enamel Renal Syndrome (ERS) and WDR72-related conditions. AI should prompt a systemic evaluation, particularly renal screening. Pediatric dentists play a pivotal role in early detection. Multidisciplinary management, including nephrology and genetics, is essential for timely diagnosis and prevention of renal complications.

FAM20C is part of the FAM20 family and is crucial for phosphorylating secreted proteins. It plays roles in various biological processes, including cellular calcium regulation and cardiovascular function. Pathogenic variants of FAM20C cause Raine syndrome, resulting in osteosclerotic dysplasia or hypophosphatemic rickets. Its paralog, FAM20A, is a secreted pseudokinase needed for optimal FAM20C activity. Mutations in FAM20A cause Enamel-Renal Syndrome. Common features in both syndromes include Amelogenesis Imperfecta, gingival fibromatosis and ectopic mineralization. We summarize current knowledge about the activity, interactions and regulation of FAM20C and FAM20A, with a focus on the possible role of bioactive lipids like sphingosine in activating FAM20C. We highlight the involvement of FAM20A and FAM20C in gingival fibromatosis, a fibrocalcifying disorder directly linked to the dysfunction of these proteins and the underlying molecular mechanisms. Additionally, we provide an overview of how FAM20C and FAM20A influence calcium homeostasis and mineralization. Since FAM20C-mediated phosphorylation is crucial in oral health, we detail how specific substrates such as osteopontin, periostin, or fetuin contribute to normal and ectopic mineralization and periodontal health. Although many questions about the roles of FAM20A and FAM20C in both oral and systemic diseases remain unresolved, targeting their activities could offer promising therapeutic options.

Enamel Renal Syndrome (ERS) (OMIM 204690) is a rare genetic condition characterised by a distinct oral profile and sometimes nephrocalcinosis. This autosomal recessive condition, caused by pathogenic variants in the FAM20A gene, is linked to ectopic mineralisation in tissues such as dental pulp, follicles, gingiva, and kidneys. Although the oral phenotype has been well-characterised, less common features have been described, highlighting possible gaps in the literature on the phenotypic variability of the condition. This scoping review follows PRISMA-ScR guidelines and aimed to synthesise existing literature on ERS, focusing on clinical and radiographic features, oral histology, systemic manifestations, and molecular findings. A comprehensive search was conducted in multiple databases, with inclusion criteria broad enough to capture relevant studies under various nomenclatures. The screening process involved independent review and data extraction with a custom tool. The initial search yielded 430 references, supplemented by additional publications identified through Google Scholar and citation searching. After removing duplicates and resolving inter-rater discrepancies, 62 studies were included, encompassing a diverse global sample. Publications spanned from the first report in 1972 to recent studies in 2024. The included studies highlight the characteristic oral profile of ERS and less consistently reported renal manifestations. While the pathognomonic oral profile remains consistent, long-term studies are required to fully understand renal and systemic impacts. Current management strategies are patient-specific, with a need for standardised reporting and long-term follow-up to develop evidence-based guidelines. Until more comprehensive data is available, vigilant monitoring of kidney function in ERS patients remains essential. This review confirms that ERS presents with a distinct oral and dental profile. However, inconsistencies in the reporting of craniofacial, renal, and other systemic features were noted. To improve patient care, further research is essential to better understand the systemic implications and long-term outcomes of ERS. This will support the development of evidence-based guidelines and foster a more holistic approach to managing the condition.