Alternative titles; symbols
SNOMEDCT: 109477002; ORPHA: 1031; DO: 0110066;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q24.2 | Amelogenesis imperfecta, type IG (enamel-renal syndrome) | 204690 | Autosomal recessive | 3 | FAM20A | 611062 |
A number sign (#) is used with this entry because amelogenesis imperfecta type IG (AI1G), also known as enamel-renal syndrome (ERS), is caused by homozygous or compound heterozygous mutation in the FAM20A gene (611062) on chromosome 17q24.
Amelogenesis imperfecta type IG, also known as enamel-renal syndrome, is characterized by hypoplastic enamel on primary and secondary dentition, pulp stones, delayed or failed eruption of secondary dentition, gingival overgrowth, and nephrocalcinosis. Blood chemistry analyses are typically normal, and nephrocalcinosis, which is found on renal ultrasound, may not appear until later in life (summary by Wang et al., 2013).
MacGibbon (1972) reported a brother and sister with absent enamel, nephrocalcinosis, and apparently normal calcium metabolism. Lubinsky et al. (1985) also described an affected brother and sister, aged 11 and 9 years, respectively. The parents were not related. Lifelong nocturnal enuresis, progressive punctate nephrocalcinosis and decreased calcium and phosphate excretion 'at rest' and after an acute load were features in addition to absent enamel. Increased serum osteocalcin and decreased urinary delta-carboxyglutamic acid suggested to Lubinsky et al. (1985) abnormality of vitamin K-dependent calcium binding proteins, although the authors recognized that the above findings could represent secondary changes.
Witkop and Sauk (1976) and Witkop (1988) described an autosomal recessive form of enamel agenesis in which the tooth surface is rough, granular, and light yellow-brown. There is no contact between adjacent teeth and no radiographic evidence of enamel. Many teeth are unerupted and partially resorbed in the alveolus. The coronal dentin is covered with granular or agate-like cementum, and anterior open bite occurs frequently. Witkop (1988) suggested that this form of AI, which he designated type IG (AI1G), may be the same as that described by Lubinsky et al. (1985) and may include renal features.
Hall et al. (1995) described a brother and sister with amelogenesis imperfecta and nephrocalcinosis. The sister also had bilateral pelvic calcifications adjacent to the internal iliac vessels. Renal biopsy revealed focal clusters of sclerosed glomeruli and interstitial infiltration with lymphocytes and plasma cells. Extensive investigations of calcium metabolism and excretion were normal.
Normand de la Tranchade et al. (2003) described a 15-year-old girl with severe delay of eruption affecting the premolars, permanent canines, and molars. Intraoral examination revealed the presence of all primary teeth, except the maxillary and mandibular incisors and a mandibulary premolar, where permanent teeth had partially erupted. All the teeth were discolored light yellow, and the primary teeth were severely abraded. The permanent incisors had erupted by only 2 mm and were small and widely spaced. There was slight gingival enlargement. Orthopantomogram revealed a number of nonerupted permanent teeth, with well-developed roots and occasional intracoronal resorption. There were no supernumerary teeth and no agenesis. Intraoral radiographs showed the rarity of enamel on both primary and permanent dentition, and scan analysis showed numerous voluminous follicular cysts. Examination by light microscopy of a primary molar and incisor confirmed the absence of enamel. Small bilateral calcification foci in renal areas were seen on plain abdominal films, and medullary nephrocalcinosis was confirmed by renal ultrasound; subsequent investigation revealed slightly impaired renal function. The patient was of normal intelligence and had no other dysmorphic features, and no other family members were affected.
Martelli-Junior et al. (2008) described 4 patients in a 3-generation, consanguineous family with a syndrome of gingival fibromatosis and dental anomalies. The patients, 3 females (13-year-old twins and a 19 year old) and a male (18 years old), had yellow teeth with thin enamel of normal hardness, gingival fibromatosis, unerupted teeth, and coronal and radicular pulpal calcifications. Histologic analysis of the gingival overgrowth showed a well-structured epithelium with elongated and thin papillae inserted in fibrous connective tissue. The connective tissue showed an increased amount of collagen fiber bundles running in all directions. None of the patients had a history of renal impairment and all had normal renal ultrasound scans and normal calcium levels in the serum. Mental retardation was segregating independently in this family (O'Sullivan et al., 2011).
Jaureguiberry et al. (2012) studied 25 patients from 16 families with nephrocalcinosis, amelogenesis imperfecta, gingival hyperplasia, and impaired tooth eruption. Four of the families had previously been reported by Hall et al. (1995), Dellow et al. (1998), Paula et al. (2005), and Martelli-Junior et al. (2011).
Wang et al. (2014) described 2 families, one of Irish and Norwegian descent and one of Mexican descent, with an autosomal recessive disorder characterized by severe enamel hypoplasia, delayed and failed tooth eruption, misshapen teeth, intrapulpal calcifications, and localized gingival hyperplasia. The 12-year-old girl from family 1 tested negative for nephrocalcinosis, and members of family 2 declined kidney ultrasound analysis. Wang et al. (2014) noted that not much is known about the age of onset of nephrocalcinosis in this disorder.
In a family segregating amelogenesis imperfecta and gingival fibromatosis, originally described by Martelli-Junior et al. (2008), O'Sullivan et al. (2011) identified a single region of homozygosity greater than 1 Mb: a 6-Mb interval flanked by SNPs rs2361486 and rs8066872 on chromosome 17q.
Jaureguiberry et al. (2012) performed whole-genome parametric multipoint linkage studies on 4 families with enamel-renal syndrome and found linkage to chromosome 17q24 with a lod score of 3.1.
By whole-exome sequencing, O'Sullivan et al. (2011) identified a homozygous nonsense mutation in exon 2 of the FAM20A gene (R136X; 611062.0001) segregating with the syndrome in the family reported by Martelli-Junior et al. (2008). The mutation was not present in the dbSNP database, the 1000 Genomes Project database, or the CEPH Diversity Panel. O'Sullivan et al. (2011) demonstrated that mouse Fam20a is expressed in ameloblasts and gingivae.
In affected members of 4 of 9 families with an amelogenesis imperfecta phenotype resembling that in the family reported by Martelli-Junior et al. (2008), Cho et al. (2012) identified homozygous or compound heterozygous mutations in the FAM20A gene (611062.0002-611062.0006). None of the affected mutation-positive individuals had any extra-oral syndromic features, and all had generalized hypoplastic enamel with yellowish hue, varying degrees of gingival hyperplasia, and delayed or failed eruption of permanent teeth with dilaceration of the root. Late-developing teeth were particularly susceptible to impaction and root dilaceration.
Using a combination of exome capture and next-generation and Sanger sequencing, Jaureguiberry et al. (2012) identified homozygous or compound heterozygous mutations in the FAM20A gene in 25 patients from 16 families segregating enamel-renal syndrome (see, e.g., 611062.0002 and 611062.0009). The mutations segregated with the disorder in all of the families.
Cho, S. H., Seymen, F., Lee, K.-E., Lee, S.-K., Kweon, Y.-S., Kim, K. J., Jung, S.-E., Song, S. J., Yildirim, M., Bayram, M., Tuna, E. F., Gencay, K., Kim, J.-W. Novel FAM20A mutations in hypoplastic amelogenesis imperfecta. Hum. Mutat. 33: 91-94, 2012. [PubMed: 21990045] [Full Text: https://doi.org/10.1002/humu.21621]
Dellow, E. L., Harley, K. E., Unwin, R. J., Wrong, O., Winter, G. B., Parkins, B. J. Amelogenesis imperfecta, nephrocalcinosis, and hypocalciuria syndrome in two siblings from a large family with consanguineous parents. Nephrol. Dial. Transplant. 13: 3193-3196, 1998. [PubMed: 9870488] [Full Text: https://doi.org/10.1093/ndt/13.12.3193]
Hall, R. K., Phakey, P., Palamara, J., McCredie, D. A. Amelogenesis imperfecta and nephrocalcinosis syndrome: case studies of clinical features and ultrastructure of tooth enamel in two siblings. Oral Surg. Oral Med. Oral Path. Oral Radiol. Endod. 79: 583-592, 1995. [PubMed: 7600222] [Full Text: https://doi.org/10.1016/s1079-2104(05)80100-3]
Jaureguiberry, G., De la Dure-Molla, M., Parry, D., Quentric, M., Himmerkus, N., Koike, T., Poulter, J., Klootwijk, E., Robinette, S. L., Howie, A. J., Patel, V., Figueres, M.-L., and 59 others. Nephrocalcinosis (enamel renal syndrome) caused by autosomal recessive FAM20A mutations. Nephron Physiol. 122: 1-6, 2012. [PubMed: 23434854] [Full Text: https://doi.org/10.1159/000349989]
Lubinsky, M., Angle, C., Marsh, P. W., Witkop, C. J., Jr. Syndrome of amelogenesis imperfecta, nephrocalcinosis, impaired renal concentration, and possible abnormality of calcium metabolism. Am. J. Med. Genet. 20: 233-243, 1985. [PubMed: 3872071] [Full Text: https://doi.org/10.1002/ajmg.1320200205]
MacGibbon, D. Generalized enamel hypoplasia and renal dysfunction. Aust. Dent. J. 17: 61-63, 1972. [PubMed: 4504766] [Full Text: https://doi.org/10.1111/j.1834-7819.1972.tb02747.x]
Martelli-Junior, H., Bonan, P. R. F., dos Santos, L. A. N., Santos, S. M. C., Cavalcanti, M. C., Coletta, R. D. Case reports of a new syndrome associating gingival fibromatosis and dental abnormalities in a consanguineous family. J. Periodont. 79: 1287-1296, 2008. [PubMed: 18597613] [Full Text: https://doi.org/10.1902/jop.2008.070520]
Martelli-Junior, H., dos Santos Neto, P. E., de Aquino, S. N., de Oliveira Santos, C. C., Borges, S. P., Oliveira, E. A., Lopes, M. A., Coletta, R. D. Amelogenesis imperfecta and nephrocalcinosis syndrome: a case report and review of the literature. Nephron Physiol. 118: p62-p65, 2011. [PubMed: 21212699] [Full Text: https://doi.org/10.1159/000322828]
Normand de la Tranchade, I., Bonarek, H., Marteau, J.-M., Boileau, M.-J., Nancy, J. Amelogenesis imperfecta and nephrocalcinosis: a new case of this rare syndrome. J. Clin. Pediat. Dent. 27: 171-176, 2003. [PubMed: 12597691] [Full Text: https://doi.org/10.17796/jcpd.27.2.3188100w6t4516j8]
O'Sullivan, J., Bitu, C. C., Daly, S. B., Urquhart, J. E., Barron, M. J., Bhaskar, S. S., Martelli-Junior, H., dos Santos Neto, P. E., Mansilla, M. A., Murray, J. C., Coletta, R. D., Black, G. C. M., Dixon, M. J. Whole-exome sequencing identifies FAM20A mutations as a cause of amelogenesis imperfecta and gingival hyperplasia syndrome. Am. J. Hum. Genet. 88: 616-620, 2011. [PubMed: 21549343] [Full Text: https://doi.org/10.1016/j.ajhg.2011.04.005]
Paula, L. M., Melo, N. S., Silva Guerra, E. N., Mestrinho, D. H., Acevedo, A. C. Case report of a rare syndrome associating amelogenesis imperfecta and nephrocalcinosis in a consanguineous family. Arch. Oral Biol. 50: 237-242, 2005. [PubMed: 15721155] [Full Text: https://doi.org/10.1016/j.archoralbio.2004.11.023]
Wang, S. K., Reid, B. M., Dugan, S. L., Roggenbuck, J. A., Read, L., Aref, P., Taheri, A. P. H., Yeganeh, M. Z., Simmer, J. P., Hu, J. C.-C. FAM20A mutations associated with enamel renal syndrome. J. Dent. Res. 93: 42-48, 2014. [PubMed: 24196488] [Full Text: https://doi.org/10.1177/0022034513512653]
Wang, S.-K., Aref, P., Hu, Y., Milkovich, R. N., Simmer, J. P., El-Khateeb, M., Daggag, H., Baqain, Z. H., Hu, J. C.-C. FAM20A mutations can cause enamel-renal syndrome (ERS). PLoS Genet. 9: e1003302, 2013. Note: Electronic Article. [PubMed: 23468644] [Full Text: https://doi.org/10.1371/journal.pgen.1003302]
Witkop, C. J., Jr., Sauk, J. J., Jr. Heritable defects of enamel. In: Stewart, R. E.; Prescott, G. H. (eds.): Oral Facial Genetics. St. Louis: C. V. Mosby (pub.) 1976.
Witkop, C. J., Jr. Amelogenesis imperfecta, dentinogenesis imperfecta and dentin dysplasia revisited: problems in classification. J. Oral. Path. 17: 547-553, 1988. [PubMed: 3150442] [Full Text: https://doi.org/10.1111/j.1600-0714.1988.tb01332.x]