Indian Pediatrics Case Reports

: 2023  |  Volume : 3  |  Issue : 1  |  Page : 18--22

Troublesome teeth, search for stones – Enamel-renal syndrome

Soumya Reddy1, Niranjana Arumugam2, Aparna Iyengar1,  
1 Department of Paediatric Nephrology, St. John's Medical College Hospital, Bengaluru, Karnataka, India
2 Clove Dental, Bengaluru, Karnataka, India

Correspondence Address:
Dr. Aparna Iyengar
Department of Paediatric Nephrology, St. John's Medical College Hospital, Bengaluru, Karnataka


Background: Enamel-renal syndrome (ERS), is a rare autosomal recessive disorder involving family with sequence similarity 20 member A (FAM20A) gene. This unique syndrome is characterized by severe enamel hypoplasia, intrapulpal calcification, nephrocalcinosis, or nephrolithiasis. This case report highlights the early presentation and incidental detection of chronic kidney disease (CKD) in a young child with enamel defects. Clinical Description: A 10-year-old girl, with no significant past or family history, presented with delayed tooth eruption and abnormal shaped teeth. She was detected to have generalized gingival hyperplasia and multiple unerupted teeth. Suspecting amelogenesis imperfecta, she was screened for coexisting systemic conditions. On evaluation, abdominal ultrasound demonstrated bilateral nonobstructive nephrolithiasis. Further renal workup done showed an abnormal creatinine (stage 2 CKD) and mild metabolic acidosis. Reduced urinary citrate excretion with no evidence of hypercalciuria was noted on extensive urine assessment. Genetic testing revealed a novel pathogenic variant in FAM20A, confirming the diagnosis of ERS. Management: The child was initiated on citrate supplements, salt restriction, and adequate hydration. She was advised of dental interventions, including pulp therapy and full-coverage restoration of decayed teeth. The family was counseled about the need for close monitoring of growth, renal function, and progression of nephrolithiasis. Conclusion: Prompt screening for renal associations in oro-dental and systemic disease must be undertaken to ensure early detection of kidney disease and timely institution of appropriate treatment. In children diagnosed to have kidney involvement, the importance of regular follow-up with clinical, biochemical, and imaging modalities, even during adulthood, must be emphasized.

How to cite this article:
Reddy S, Arumugam N, Iyengar A. Troublesome teeth, search for stones – Enamel-renal syndrome.Indian Pediatr Case Rep 2023;3:18-22

How to cite this URL:
Reddy S, Arumugam N, Iyengar A. Troublesome teeth, search for stones – Enamel-renal syndrome. Indian Pediatr Case Rep [serial online] 2023 [cited 2023 Jun 6 ];3:18-22
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Full Text

Amelogenesis imperfecta (AI) encompasses a group of developmental conditions affecting the structure and clinical appearance of enamel. Children with AI usually present to the dentist with irregular misshapen teeth and/or discoloration. Commonly seen as an isolated trait, AI may also be observed with systemic disorders. One of these is AI type 1G, also known as enamel-renal syndrome (ERS) (OMIM #204,690). This is a rare (reported in <1 in 200,000), autosomal recessive disorder caused by a pathogenic variant of the family with sequence similarity 20 member A (FAM20A) gene. The characteristic manifestations are AI, gingival fibromatosis, ectopic calcification, and nephrocalcinosis or nephrolithiasis.[1]

While the oral phenotype of enamel defects, gingival hyperplasia, and delayed tooth eruption present in early childhood, renal features are usually clinically silent and appear beyond the second decade. Thus, in children, kidney disorders are usually incidental findings that are detected during the evaluation of other manifestations. Late diagnosis of renal problems delays timely management, with potential progression to chronic kidney disease (CKD) and its associated morbidity and mortality.[2],[3] There are many gaps in the literature pertaining to the holistic approach to a child with ERS, especially related to renal evaluation, management, and long-term monitoring. Collaborative teamwork involving dentists, pediatricians, pediatric nephrologists, and geneticists is required to provide appropriate multi-disciplinary care.

This case report describes the clinical, oro-dental, and genetic phenotype of a young child with early presentation of ERS, and highlights the importance of keen observation, comprehensive evaluation, and interdisciplinary management. By sensitizing pediatricians, we hope that they start screening their patients who also happen to have enamel defects in their teeth for AI, and, if positive, for associated renal disease.

 Clinical Description

A 10-year-old girl presented to the oro-dental surgeon with discolored and abnormally shaped teeth since 1 year of age. There was also a history of delayed teeth eruption and unerupted teeth, but no early tooth loss, tooth pain, or swelling of her jaw. Oro-dental examination [Figure 1] revealed significant generalized gingival hyperplasia with firm mucosa and multiple unerupted teeth (maxillary and mandibular right and left 1st permanent molars). The remaining teeth were misshaped with rough surfaces indicating generalized enamel defects. Dental caries was detected in both upper primary and secondary molars, and lower left molar teeth. The overall impression was generalized enamel defects and gingival hyperplasia.{Figure 1}

Radiographic examination [Figure 2] showed impacted first permanent molars with pulp stones. A diagnosis of AI with isolated gingival fibromatosis was made, and the possibility of ERS was considered. When an abdominal ultrasound identified bilateral nephrocalcinosis, a pediatric nephrology consultation was sought for further management.{Figure 2}

There was no history of polyuria, rapid breathing, bony deformities, tetany, episodes of muscle weakness, fractures, blood transfusions, the passage of urinary stones, urinary tract infections (UTI) or being administrated high doses of Vitamin D. There was no significant history. The child had the normal acquisition of development milestones, studied in class 4, and was average in studies. She was first born to nonconsanguineous parentage. There was no family history of dental defects, renal calculi, kidney problems, or early-onset kidney failure.

Examination revealed stable vitals with a heart rate of 90 beats/min and blood pressure of 104/70 mmHg (normotensive). According to the Indian Academy of Paediatrics (IAP) growth charts, her weight was 21 kg (−3.3 Z score), height 130.5 cm (−1.7 Z score), and body mass index (BMI) 12.3 kg/m2 (−3.3, severe thinness). There was no evidence of dehydration, acidotic breathing, rickets, anemia, or dysmorphic features. The fundus was normal and systemic examination unremarkable.

Management and outcome

A repeat renal ultrasound [Figure 3] showed normal-sized kidneys (7.2–7.5 cm, +0.05 Z score for age) with normal echotexture, and bilateral multiple scattered nonobstructive calculi (8–9 mm) in the upper, mid, and lower pole calyces. There was no evidence of nephrocalcinosis, pyelonephritis, or cysts. Laboratory investigations were done to determine renal function. She was noted to have abnormal serum creatinine (0.8 mg/dL), normal blood urea nitrogen (23 mg/dL), estimated glomerular filtration rate (eGFR) 65 ml/min/1.73 m2 (CKD Stage 2), and mild metabolic acidosis plasma bicarbonate (20.6 mEq/L) with a normal anion gap. Normal serum electrolytes (Na+ 136 mEq/L, K+ 4.2 mEq/L, and Cl− 101 mEq/L) ruled out renal tubular acidosis (RTA) and Bartter syndrome. Urinalysis was not suggestive of UTI. Metabolic workup for the etiology of urolithiasis revealed normal levels of serum calcium (10.2 mg/dL), magnesium (2.0 mg/dL), phosphorus (5.2 mg/dL), alkaline phosphatase (248 U/L), and uric acid (3.1 mg/dL). There was no evidence of hypercalciuria (24-h urine calcium 0.5 mg/kg/day; normal <4 mg/kg/day). However, she was noted to have hypocitraturia (24-h urine citrate 30.8 mg/day; normal >250 mg/day) and mild hyperoxaluria (24-h urine oxalate 53 mg/1.73 m2/day; normal <50 mg/1.73 m2/day), with no hyperuricosuria (24-h urine uric acid 146 mg/1.73 m2/day; normal <815 mg/1.73 m2/day). Routine tests undertaken for CKD stage 2 showed normal hemoglobin (11 g/dL), low 25-hydroxy-vitamin D (16.6 ng/mL), and normal parathormone (27 pg/mL) levels.{Figure 3}

In view of the presence of AI, urolithiasis, and CKD stage 2, genetic testing was undertaken to ascertain the presence of syndromic associations of AI such as ERS and WDR72 mutations (less likely due to the absence of RTA). Clinical-exome sequencing revealed a homozygous autosomal recessive pathogenic variant (as per the American College of Medical Genetics classification) in FAM20A gene, exon 8, c. 1216_1219del (p.Ile406GlyfsTer48) confirming ERS. Other family members were screened for clinical features and found to have normal teeth, normal renal functions, and no evidence of nephrolithiasis or nephrocalcinosis. The family was referred for genetic counseling and testing (sequencing) of the parents.

The child was initiated on potassium citrate (2 mEq/kg/day) and 25-hydroxy-vitamin D supplements (60,000 IU every 2 weeks for 6 weeks). Adequate hydration and salt restriction were advised. The family was counseled regarding the need for regular (every 3–6 months) monitoring of renal function tests and electrolytes. Dental intervention (teeth restoration and root canal therapy) was undertaken.

During the most recent follow-up, 9 months after diagnosis, mild improvement in growth parameters (1 kg gain in weight, 1.5 cm increment in height in 6 months, and increase in BMI to 12.1 kg/m2) were observed. Her renal functions were stable though eGFR is still indicative of CKD stage 2, with normal acid-base balance and 25-hydroxy vitamin D levels (45 ng/mL). Repeat urine analysis 3 months after initiation of treatment revealed normal oxalate excretion (9.4 mg/1.73 m2/day) and improvement in hypocitraturia. The renal ultrasound is status quo with no increase in nephrolithiasis or new nephrocalcinosis.


The first case report of ERS was published in 1972, and <100 cases have been reported since then. The diagnosis of ERS is based on oro-dental alterations with or without renal findings. A recent review of 69 children reported AI in 100%, gingival fibromatosis in 67%, and nephrocalcinosis in 89%.[4] Oral cavity involvement presents in early childhood with AI, gingival hyperplasia, heterotopic calcifications, and delayed tooth eruption.[1] In the present case, apart from AI, the child had gingival fibromatosis, multiple unerupted teeth, pulpal calcifications, and delayed exfoliation of deciduous teeth, similar to previous reports.[5] In such cases, a comprehensive dental treatment plan is required, including pulp therapy, full-coverage restoration of decayed teeth, extraction of root stumps, gingivectomy, exposure of impacted teeth with orthodontic extrusion, and esthetic correction of anterior permanent teeth with crowns and veneers.

Enamel defects have been reported in 58% of patients with CKD and hypophosphatemic rickets.[6],[7] The renal disorders associated with AI include renal agenesis, Bartter syndrome, distal RTA, pyelonephritis, polycystic kidney diseases, nephrocalcinosis, and nephrolithiasis.[8] The closest differential diagnosis considered was due to the WDR72 mutation, which encompasses AI, distal RTA of variable severity, occasionally proximal tubular dysfunction, and nephrocalcinosis. The genetic defect causes impaired function or trafficking of V-type ATPase, leading to hypokalemia, metabolic acidosis, hypercalciuria, and hypocitraturia.[9] Our case had urolithiasis. Distal RTA or nephrocalcinosis was absent.

In the past decade, the breakthrough discovery of the FAM20A gene located on 17q24.2 has shed light on the pathophysiology of ERS. FAM20 genes encode for protein kinases, FAM20A, B, and C, which phosphorylate secreted proteins and proteoglycans. FAM20A activates FAM20C, which plays an important role in the biomineralization of enamel, gingiva, and kidney.[1] The most common pathogenic variant described is protein truncation. Genotype–phenotype correlation has been described with missense changes having a milder phenotype than protein truncation.[10] In this case, the frameshift change caused premature truncation of FAM20A, probably leading to the earlier appearance of renal manifestations. The mutation p.Ile406GlyfsTer48 identified in this case is a novel pathogenic variant that has not been reported earlier.

The pathophysiological basis of nephrocalcinosis in ERS is still elusive. It has been proposed that the absence of functional FAM20A leads to heterotopic calcifications in the gingiva, dental follicles, and renal parenchyma. One hypothesis suggests the role of dysregulated calcium homeostasis as the cause of nephrolithiaisis or nephrocalcinosis. Abnormal production and/or urinary excretion of stone modulators like citrate can also lead to nephrolithiasis. Recent literature highlights the upregulation of the transforming growth factor-β signaling cascade in gingival fibroblasts in ERS. It was demonstrated that ectopic mineralization (as seen by dental radiograph) was preceded by significant upregulation of factors like periostin (POSTN), transcription factor RUNX2 and alkaline phosphate transcripts.[11]

Patients usually present with renal manifestations beyond the second decade with recurrent UTI, renal colic, electrolyte disturbances, and acidosis.[1] One-fourth of ERS patients have no laboratory abnormality. In the rest, abnormalities such as hypocalciuria (11.6%), hypocitraturia (5.7%), reduced phosphate excretion (5.8%), and elevation of serum creatinine (7.3%) have been documented.[5] In the present case, abnormal creatinine, hypocitraturia, and transient hyperoxaluria were noted. We were unable to explain the reason for transient hyperoxaluria, but it normalized later with treatment, probably secondary to urinary alkalinization. A previous report of ERS with nephrolithiasis and normal glomerular filtration rate has been described earlier.[12] [Table 1] describes the Indian case reports on ERS. Progressive nephrocalcinosis or nephrolithiasis has been associated with significant morbidity and increased risk of progression to CKD.[2] The exact etiology of high serum creatinine levels in this child is still not clear but may be attributed to chronic tubulointerstitial nephritis in evolution. Regular monitoring of serum creatinine, metabolic acidosis, and annual imaging by ultrasound or computed tomography will determine the eventual clinical course. Early detection of nephrolithiasis and CKD (stage 2) in this child enabled us to initiate appropriate treatment. Apart from monitoring renal function, we will also need to review associated clinical issues such as growth failure, anemia, and mineral bone disorder.{Table 1}


Renal associations in ERS often get missed due to a lack of overt symptoms. These entities are identified only if suspected and actively looked for by detailed clinical evaluation, laboratory evaluation, and imaging. In this case, if prompt screening for renal involvement had not been undertaken by the dental surgeon, the presence of nephrolithiasis and renal dysfunction would have been overlooked. Health-care professionals dealing with children having orodental issues or noting them as incidental findings in their pediatric patients presenting with totally unrelated health issues, must be aware of AI so that they can be screened, evaluated accordingly, and referred for further management. Thus, interdisciplinary collaboration is crucial for the appropriate management of children with ERS.


Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.



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