Abstract
Enamel renal syndrome (ERS) is a rare recessive disorder caused by loss-of-function mutations in FAM20A (family with sequence similarity 20 member A, OMIM #611062). Enamel renal syndrome is characterized by amelogenesis imperfecta, delayed or failed tooth eruption, intrapulpal calcifications, gingival overgrowth and nephrocalcinosis. Although gingival overgrowth has consistently been associated with heterotopic calcifications the pathogenesis, structure and interactions of the mineral deposits with the surrounding connective tissue are largely unknown. We here report a novel FAM20A mutation in exon 1 (c.358C > T) introducing a premature stop codon (p.Gln120*) and resulting in a complete loss of FAM20A. In addition to the typical oral findings and nephrocalcinosis, ectopic calcified nodules were also seen in the cervical and thoracic vertebrae regions. Histopathologic analysis of the gingiva showed an enlarged papillary layer associated with aberrant angiogenesis and a lamina propria displaying significant changes in its extracellular matrix composition, including disruption of the collagen I fiber network. Ectopic calcifications were found throughout the connective gingival tissue. Immunomorphological and ultrastructural analyses indicated that the calcification process was associated with epithelial degeneration and transformation of the gingival fibroblasts to chondro/osteoblastic-like cells. Mutant gingival fibroblasts cultures were prone to calcify and abnormally expressed osteoblastic markers such as RUNX2 or PERIOSTIN. Our findings expand the previously reported phenotypes and highlight some aspects of ERS pathogenesis.
Highlights
Enamel renal syndrome (ERS, OMIM #204690) or amelogenesis imperfecta type IG (OMIM #614253) is an autosomal recessive disorder characterized by enamel hypoplasia, delayed or failed tooth eruption, intrapulpal calcifications, and gingival overgrowth
In this study we reported an ERS patient with extreme oligodontia, tooth agenesis, hypoplastic amelogenesis imperfecta, severe gingival overgrowth and ectopic calcifications including in the gingiva, the dental pulp, the kidney and the proximity of the cervical and thoracic vertebrae
We identified a new homozygous point mutation in exon 1 resulting in a premature stop codon and complete lack of FAM20A protein
Summary
Enamel renal syndrome (ERS, OMIM #204690) or amelogenesis imperfecta type IG (OMIM #614253) is an autosomal recessive disorder characterized by enamel hypoplasia, delayed or failed tooth eruption, intrapulpal calcifications, and gingival overgrowth. We and others previously showed that bi-allelic loss of function FAM20A mutations cause ERS (Martelli-Júnior et al, 2008; Jaureguiberry et al, 2012; Wang et al, 2013; de la DureMolla et al, 2014; Kantaputra et al, 2014). Mutations in FAM20C cause the frequently lethal Raine syndrome (RNS, #OMIM259775) characterized by bone dysplasia and cerebral calcifications (Whyte et al, 2017). The oral findings of the nonlethal RNS forms are reminiscent of ERS and include gingival overgrowth and enamel hypoplasia (Acevedo et al, 2015)
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