Report of a case of Raine syndrome and literature review

Abstract

We report on a case of Raine syndrome with a mutation in FAM20C and typical phenotypic features consisting of midface hypoplasia, hypoplastic nose, choanal atresia, wide fontanelle, exophthalmos, generalized osteosclerosis and intracranial calcification. New features in our patient are cerebellar hypoplasia and pachygyria. We review the literature and conclude that the triad of hypoplastic nose, exophthalmos and generalized osteosclerosis and/or intracranial calcification is consistent in all molecularly confirmed cases.

A novel FAM20C mutation causes a rare form of neonatal lethal Raine syndrome

“…To date, 28 pathogenic variants in FAM20C have been reported in association with Raine syndrome of which 19/28 are missense variants (Acevedo et al, ; Boissel et al, ; Elalaoui et al, ; Fradin et al, ; Kochar et al, ; Mahmood N., 2014; Rafaelsen et al, ; Seidahmed et al, ; Sheth et al, ; Simpson et al, ; Simpson et al, ; Takeyari et al, ; Tamai et al, ; Whyte et al, ) (Table S1). These 19 reported pathogenic missense variants and polymorphisms identified in nominally healthy reference population were mapped onto the 3D structure of the FAM20C protein (Berman et al, ; Lek et al, ) (Figure ).…”

“…Forty‐six additional individuals with Raine syndrome have been reported to date, delineating its phenotypic spectrum which includes a consistent and well‐defined facial gestalt‐midface hypoplasia, proptosis, micrognathia, high and/or cleft palate, hypoplastic nose with depressed nasal bridge, low‐set ears, generalized osteosclerosis, fracture‐like rib lesions, and intracerebral calcifications. Affected individuals are typically short and have micro‐ and/or brachycephaly with wide open anterior and posterior fontanelles (Faundes et al, ; Seidahmed et al, ; Sheth, Bhavsar, Gandhi, Sheth, & Pancholi, ). Most newborns with the severe form die of respiratory failure due to pulmonary hypoplasia and small thorax within a few hours to weeks of life, although individuals with the milder form have been reported to live into adulthood, confirming the presence of a continuous phenotypic spectrum (Faundes et al, ; Seidahmed et al, ; Sheth et al, ).…”

“…To date, 28 different mutations in FAM20C have been reported in association with Raine syndrome, including missense variants ( n = 19), nonsense variants ( n = 1), splice site variants ( n = 5), and complex rearrangements ( n = 3) (Ababneh et al, ; Acevedo et al, ; Boissel et al, ; Elalaoui et al, ; Fradin et al, ; Kochar et al, ; Mahmood, Donne, Weber, & Dharmaraj, ; Rafaelsen et al, ; Seidahmed et al, ; Sheth et al, ; Simpson et al, ; Simpson et al, ; Takeyari et al, ; Tamai et al, ; Whyte et al, ). The genotype–phenotype correlation is unknown.…”

A Rare Cause of Hypophosphatemia: Raine Syndrome Changing Clinical Features with Age

“…FGF23 levels could be studied in a few cases and shown to be elevated [4,5,28,39], but elevated urinary phosphate excretion had been shown in almost all cases including the case herein [24,27,28,34,39]. However, serum phosphate levels were found to be normal in some of the patients [4,20,[32][33][34][35]. Additionally, the development of hypophosphatemia in cases with normal phosphate levels is also detected in later ages, in puberty and in adulthood [34].…”

Specific ablation of mouse Fam20C in cells expressing type I collagen leads to skeletal defects and hypophosphatemia

“…In vitro studies have shown that FAM20C catalyzes the attachment of phosphates to serine residues in the Ser-X-Glu (S-X-E) motifs of secretory proteins, which include dentin matrix protein 1 (DMP1) and osteopontin (OPN), two members of the “Small-Integrin-Binding LIgand, N-linked Glycoproteins” (SIBLING) family 2–6 . Inactivating mutations in the human FAM20C gene cause Raine syndrome, an autosomal recessive disorder that demonstrates a variety of manifestations 7–11 . Some Raine syndrome patients die shortly after birth 7, 12 , while others may live into middle childhood or even middle adulthood 8–10 .…”