Variability of systemic and oro-dental phenotype in two families with non-lethal Raine syndrome with FAM20C mutations

Abstract

BackgroundRaine syndrome (RS) is a rare autosomal recessive bone dysplasia typified by osteosclerosis and dysmorphic facies due to FAM20C mutations. Initially reported as lethal in infancy, survival is possible into adulthood. We describe the molecular analysis and clinical phenotypes of five individuals from two consanguineous Brazilian families with attenuated Raine Syndrome with previously unreported features.MethodsThe medical and dental clinical records were reviewed. Extracted deciduous and permanent teeth as well as oral soft tissues were analysed. Whole exome sequencing was undertaken and FAM20C cDNA sequenced in family 1.ResultsFamily 1 included 3 siblings with hypoplastic Amelogenesis Imperfecta (AI) (inherited abnormal dental enamel formation). Mild facial dysmorphism was noted in the absence of other obvious skeletal or growth abnormalities. A mild hypophosphataemia and soft tissue ectopic mineralization were present. A homozygous FAM20C donor splice site mutation (c.784 + 5 g > c) was identified which led to abnormal cDNA sequence. Family 2 included 2 siblings with hypoplastic AI and tooth dentine abnormalities as part of a more obvious syndrome with facial dysmorphism. There was hypophosphataemia, soft tissue ectopic mineralization, but no osteosclerosis. A homozygous missense mutation in FAM20C (c.1487C > T; p.P496L) was identified.ConclusionsThe clinical phenotype of non-lethal Raine Syndrome is more variable, including between affected siblings, than previously described and an adverse impact on bone growth and health may not be a prominent feature. By contrast, a profound failure of dental enamel formation leading to a distinctive hypoplastic AI in all teeth should alert clinicians to the possibility of FAM20C mutations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-015-0154-5) contains supplementary material, which is available to authorized users.

Amelogenesis imperfecta in familial hypomagnesaemia and hypercalciuria with nephrocalcinosis caused byCLDN19gene mutations

“…Recently, ERS was linked to mutations in the FAM20A gene, which encodes a protein that stimulates kinase activity of FAM20C 43–46. Other molecular studies reported AI in patients affected by different diseases with kidney impairment such as Bartter syndrome due to potassium channel KCNJ1 mutation (#241200),47 Raine syndrome due to FAM20C mutations,48 polycystic kidney disease caused by a MSX2 mutation49 and more recently, FHHNC in patients carrying CLDN16 mutations 23. Additional studies without molecular data reported an AI phenotype in inherited kidney diseases such as renal osteodystrophy,50 distal renal tubular acidosis50 and FHHNC 51…”

Intrinsically disordered proteins and biomineralization

“…Raine's syndrome, a rare condition with an incidence of 1/1,000,000, is due to a mutation in FAM20C the Golgi protein kinase that phosphorylates most secreted phosphoproteins including SIBLING proteins [160,161]. The osteosclerosis characteristic of this skeletal dysplasia provides clinical support for the importance of controlled phosphorylation of IDPs for proper mineralization [162,163]. …”

Retinoic Acid Excess Impairs Amelogenesis Inducing Enamel Defects

“…Reductions in the SCPP cluster appeared specific to enamel expression. Other enamel-regulating targets included the kallikrein-related peptidase 4, essential for removing enamel proteins and bio-mineralization (OMIM: 603767), the peroxisome proliferator-activated receptor (PPAR) alpha, required to achieve normal enamel mineralization (OMIM: 170998) (Sehic et al, 2009), and FAM20C, whose mutation produces severe enamel defects in human and mouse (Wang et al, 2012; Acevedo et al, 2015). …”