Enamel Renal Syndrome: A Systematic Review

Introduction

The enamel renal syndrome (ERS) is considered a rare disease according to the Office of Rare Diseases (ORD) of the National Institutes of Health (NIH), affecting less than 200,000 people in the United States population.[1] It is an autosomal recessive disorder characterized by amelogenesis imperfecta of the hypoplastic type and nephrocalcinosis (OMIM #204690), presenting with presence of thin or absence of enamel, delayed dental eruption, intrapulpal calcifications, bilateral nephrocalcinosis, and normal plasma calcium level.[1].

Amelogenesis imperfecta (AI) is a hereditary group of disorders that affects the quality and quantity of enamel on deciduous and/or permanent teeth, and may affect all or only a few teeth.[23] The clinical characteristics of AI vary depending on the type: in the hypoplastic, which is present in the syndrome, the teeth have a white to dark brown chalk color, occlusal surfaces, and incisal edges are generally worn, and occasionally complete loss of enamel is observed; In the hypocalcified, the enamel exhibits a consistency of cheese and can be easily removed with a sharp explorer and in the hypomaturated is characterized by the enamel with normal thickness and white opaque areas on the incisal surfaces.[4].

Nephrocalcinosis is a condition characterized by calcium deposition in renal tissue and may be predominantly cortical or, more commonly, medullary. It is found in conditions, such as primary hyperparathyroidism, distal renal tubular acidosis, spongy spinal cord kidney, hypervitaminosis D, oxalosis, and some forms of Bartter's syndrome.[356] Nephrocalcinosis may remain unnoticed until patients have recurrent urinary tract infections, pyelonephritis, or the passage of a stone, leading to renal failure.[7].

The ERS diagnosis is clinical, based on orodental alterations and renal findings that represent the degree of impairment of the kidneys.[8] However, as renal changes occur late, the presence of the characteristic oral phenotype, even in the absence of other manifestations, is sufficient to clinically diagnose this syndrome.[9].

Thus, the objective of the systematic review is to present and discuss the characteristics of the ERS, which is relevant due to the scarcity of studies and knowledge about the syndrome.

Methodology

The present review was carried out in accordance with the Cochrane Collaboration Group protocol for systematic reviews. Our review was performed in March 2018, when we searched on PubMed database the following terms: 'Enamel Renal Syndrome' [title/abstract] OR 'Enamel Renal Gengival Syndrome' [title/abstract] OR 'Amelogenesis imperfecta and nephrocalcinosis syndrome' [title/abstract] OR 'Enamel hypoplasia and renal dysfunction' [title/abstract], including a literature search strategy, selection of papers through the inclusion and exclusion of criteria, data extraction, and quality assessment. Meta-analysis was not possible since selected studies did not observe the same variables, methods, participants, and outcomes, which prevented comparisons.

As seen in figure 1, in the search, 108 studies were identified and after removing the repeated results, 69 articles remained. Of these, 39 were excluded, after 2 authors analyzed their abstracts, as criteria not to approach the ERS and non-English language; thus remaining 30 studies. From each of these articles, the following data were extracted for analysis: type of study, first author, publication year, country of publication, age, sex, family history, consanguinity, presence of amelogenesis imperfect, nephrocalcinosis and gingival fibromatosis, laboratory tests results, and mutation in the FAM20A gene.

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Figure 1

Flowchart of process of systematic literature search, using Cochrane and flowchart of process of systematic literature search

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Results

The results found with the research are summarized in Table 1. Of a total of 69 articles found after research, only 30 (43.47%) were in agreement with the methodology,[178910111213141516171819202122232425262728293031323334] of these 27 (39,13%) were case reports,[1781011121314151617182021232425262728293031323334] 1 (1.44%) was case series[22] and 2 were review of scientific literature.[919] The most recent publication date was in May 2018[34] and the older was in February 1972.[11].

Among the case reports, we can observe that the average age was 38.3 years old. The youngest age reported was in the first year of life[25] and the highest age was at 64 years old.[21] In ten (14.4%) patients,[781114172733] there was a difference between the ages of diagnosis of AI and nephrocalcinosis. In 6 (8.64%) patients,[781433] AI was first identified at 1,[8] 6,[33] 8[714] and 12 years[733] and in 4 patients[111727] nephrocalcinosis was first diagnosed at 8,[27] 11,[11] and 15 years.[1117] When it comes to gender, there were 33 (47.82%) women[16791011121316171921222325272931] and 36 (52.17%) men.[679101112141517212224252628293031323334].

The presence of consanguinity was reported in 18 (26.08%) cases[16141516171922232426293132] and in 30 (43.47%), there were positive family history for ERS.[69101112151720212223242932] Among the 69 evaluated patients, all had Al.[1679101112131415161719202122232425262728293031323334] 62 (89.85%) presented with nephrocalcinosis,[167910111213141516192021222425262728293031323334] 46 (66.66%) had gingival fibromatosis[171213141719313233] and in 4 (5.79%) patients there was no appearance of this affection.[23262728].

In the laboratory evaluation of patients, several types of alterations were reported, as seen in Table 1. In 35 cases (50.72%), there was no description of laboratory tests.[71721233134] Thus, the laboratory parameters were evaluated in 34 cases (49.27%):[16710121314162026272832] in 18 (26.08%) no abnormalities were found[91112151922242529303233] and the main alterations identified were: hypocalciuria (11.59%),[16101327] elevated serum creatinine levels (7.24%),[6122027] reduced phosphate excretion (5.79%)[11013] and hypocitraturia (5.79%).[13262832].

Since the discovery of the relationship between the syndrome and the gene FAM20A,[21] 51 patients were analyzed in 17 of the 28 case report studies.[78172122232425262728293031323334] Among these 51 patients, 41 (80.39%) were screened by mutation in the gene and all 41 (100%) were positive.[717212325293132] A total of 10 (19.60%) of the 51 patients analyzed after the discovery were not investigated about mutation on these gene,[2224262728303334] that is, a total of 28 (40.57%) patients were not screened by mutation in the FAM20A gene.[19101112131415161819202224262728303334].

Discussion

MacGibbon was the first to conduct a study, in 1972, that associates age of the diagnosis of imperfect amelogenesis and nephrocalcinosis. The case of a young woman diagnosed with both pathologies was described when her 26-year-old brother died of nephrocalcinosis and teeth similar to her own. In the reported cases, renal function remained stable until the patient was 16 years old, but progressive renal insufficiency led to the death of the patient.[10].

Nearly 40 years after the publication of the MacGibbon case report,[11] Jaureguiberry et al.[22] identified autosomal recessive FAM20A mutations as the cause of ERS. The study consisted in the genetic analysis of 25 patients from 16 families affected by the syndrome. As a result, all patients had biallelic mutations in FAM20A, with 20 different mutations. This gene, under normal conditions, has an inhibitory effect on mineralization, allowing it to occur only in bones and teeth. But in patients with homozygous mutation in FAM20A, an increase in the promoter activity and decrease of the inhibitory activity on the growth of oxalate crystals has been reported, so as to allow mineralization of the gingiva, kidneys, lungs, and dental follicles.[8919222527].

Laboratory alterations are not always present and, when exist, are varied. Hypocalciuria was identified in 11.59% of the cases,[17121529] being common in patients with ERS, although hypercalciuria is an important cause of stones formation.[35] Hypocitraturia was found in 5.79% of the cases.[15283034] This alteration predisposes the formation of renal stones or nephrocalcinosis, because the citrate acts in the formation of soluble complexes with calcium, inhibiting the formation of renal stones.[30] The reduction of phosphate excretion was also identified in 5.79% of the cases,[11215] as a consequence of the mutation on FAM20A that changes calcium and phosphate homeostasis in the kidneys.[25].

The hereditary relationship of the syndrome can be observed because there was consanguinity in 18 cases,[16141516171922232426293132] indicating a percentage of 26. 08% and family history in 30,[61112131415171922232425263134] that is, 43.47%. Another relevant fact is the lack of relationship with gender, since it affects almost equally men and women. The relationship between the syndrome and the mutation in the FAM20A gene can be proven from the data, since all the patients with ERS analysed by the mutation were positive.

Some studies[378914161720212730313234] cited the nationality of the patients and, according to these data, there was no association of a certain geographic area with the occurrence of the syndrome. The countries of origin were: Iran,[3] Caribbean,[3] Jordania,[3] England,[7] Turkey,[8] France,[9] Macedonia,[14] Brazil,[1620303134] Japan,[17] India,[21] Israel,[27] and Thailand.[32].

With the advancement of studies on ERS, it has been suspected to have some associations with the syndrome. Kantaputra et al. reported in 2014[26] two patients who presented, simultaneously, ERS and Al and gingival fibromatosis syndrome (AIGFS). Knowing that FAM20A gene is involved in both, the genetic study of the patients was carried out, confirming the presence of the mutation in the cases. Besides that, as several studies have cited the triad of AI, nephrocalcinosis, and gingival fibromatosis, the authors suggested that ERS and AIGFS would be the same entity with different manifestations, giving rise to the new term “Enamel-Renal-Gingival Syndrome”.[92731].

In 2016, Pêgo et al., related two cases that presented typical features of ERS, such as hypoplastic AI, nephrocalcinosis, gingival overgrowth, and other dental abnormalities, besides the presence of FAM20A mutation. Both patients also presented hearing loss and hypertrichosis, without the presence of exposition to environmental factors and mutations frequently associated with nonsyndromic deafness in Brazil. Thus, the study suggested the association with ERS, FAM20A gene, hearing loss, and hypertrichosis as expansion of the phenotypic spectrum of the disease.[29].

With the data obtained from the discovery of the disease with Mac Gibbon until the last studies, it was possible to trace the profile of the patients with ERS and the main alterations found. There is equivalence between the genders and absence of predilection by any age group. The main laboratory findings were hypocalciuria, hypocitraturia, reduction of phosphate excretion, and elevation of serum creatinine levels. The presence of the hereditary character of the syndrome and the relationship with the FAM20A gene were also confirmed. But there is still a need for further studies to increase knowledge about the syndrome and its newly discovered phenotype expansions.

Conclusion

Among the data analyzed, it is possible to emphasize an equivalence of cases in men and women, excluding a possibility of any association with gender and the presence of ERS. The FAM20A gene was a finding of great relevance for the syndrome, since all patients with clinical characteristics have homozygous or heterozygous mutations in this gene.