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

Abstract

Background: Raine 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.

Methods: The 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.

Results: Family 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.

Conclusions: The 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.

Figure 1

Pedigree and genetic results from Family 1. (A) Pedigree of the family I suggesting an autosomal recessive mode of inheritance. (B) Electropherogram showing wild-type and mutant sequence of the p.W202Cfs*37 mutation identified in Family 1. (C) Analysis of the cDNA from affected family members revealed the mutation resulted in skipping of exon 2. (D) RT-PCR over the mutation shows the reduction in transcript size in the mutant allele and also the presence of some wild-type sized transcript.

Figure 2

Pedigree and genetic analysis of Family 2. (A) Pedigree of family II suggesting an autosomal recessive mode of inheritance. (B) Electropherograms showing the wild-type and mutant alleles for the p.P496L mutation identified in Family 2.

Figure 3

Radiographic and oro-dental features of Family 1. (A) Computerized tomography (CT) scan revealed intracranial calcifications in the parieto-occipital region in patient IV-6. (B) Clinical photograph of patient IV-4 showing alterations in the tooth shape, reduction of the enamel thickness and yellow and brown discoloration. Note the rough and pitted surface of enamel. Incisal notches were observed in the central incisors. (C) Dental radiographs illustrated absence of the normal, differential radiodensity between enamel and dentine, whilst periapical radiolucency’s and associated alveolar bone loss were consistent with loss of dental pulp vitality and associated periodontal involvement. (D) The histopathological analysis of the alveolar gingival tissue showed ectopic calcifications. (E) Macroscopic and (F) ground sections of an extracted left first molar revealed severe hypoplastic enamel with surface pitting. (G) Interglobular dentine of the circumpulpar dentine was observed, alongside normal dentine in some areas.

Figure 4

Radiographic and oro-dental features of Family 2. CT scanning identified (A) intracranial calcifications and (B) probably vascular calcifications in patient VI-1. Radiographs show (C) undermineralised long bones, (D) carpal bones and phalanges (E) and a mild radius bowing in patient VI-2. (F) Dental radiograph showing an absence of density differences between enamel and dentin, incomplete root formation and enlarged pulp chambers. Apical radiolucencies associated with permanent teeth are also present. (G & H) Affected family members presented permanent erupted teeth with yellow discoloration, hypomineralised and hypoplastic enamel. Severe delays in permanent tooth eruption were observed in both siblings.

Figure 5

Histopathological analyses of gingiva and teeth of Family 2. (A) Histological analysis of patient gingiva revealed the presence of inflammatory infiltrate, epithelial acanthosis and gingival fibromatosis. (B) In pericoronal tissues, areas of ectopic calcifications were observed. (C) Analysis of first right molar of the patient VI-2 showed occlusal dental decay and incomplete root formation. (D) Sagittal median section of the teeth show large pulp chamber. (E) Ground sections reveal interglobular dentine except in the mantle dentine. (F) Severely affected circumpulpar dentine in increasing magnification. (G) Dentinal changes also observed in slides stained with HE after the same tooth demineralization.