Raine syndrome: Prenatal diagnosis based on recognizable fetal facial features and characteristic intracranial calcification

Abstract

Objective: The purpose of this study was to elucidate the facial morphology and the pattern of internal malformations in three fetuses with RS born to first cousins of Egyptian decent. Methods: The fetal ultrasonography findings were highly suggestive of RS leading to targeted Sanger sequencing of FAM20C and postnatal assessment. Results: The prenatal ultrasound findings of osteosclerotic skull, exorbitism, hypoplastic nose, midface hypoplasia, small mouth with down-curved corners, and a distinct and recognizable pattern of intracranial calcification were identified in three fetuses with RS. The calcifications were evident specifically around the corpus callosum and/or ventricular walls. Ectopic renal and hepatic calcifications, pulmonary hypoplasia, mild rhizomelic shortening of the upper limbs, intrauterine fractures, and cerebellar hypoplasia were also noted. Molecular analysis identified three novel homozygous variants, two frameshift: [c.456delC (p.Gly153Alafs*34)] in exon 1 and [c.905delT (Phe302Serfs*35)] in exon 4 and one nonsense mutation in exon 10, [c.1557C>G(p.Tyrs519*)]. The three variants were segregated with the phenotype. This is the first description of a phenotype associated with homozygous truncating variants of FAM20C. Conclusion: RS has characteristic prenatal ultrasound findings which can improve the prenatal identification of this condition and help in guiding the molecular diagnosis and counseling. 1 | INTRODUCTION Raine syndrome (RS) (OMIM # 259775) is characterized by the combination of generalized osteosclerosis with periosteal bone formation, characteristic dysmorphic facial features, and intracerebral calcification. 1-4 It was initially described as an early neonatal lethal disorder with early onset that usually results in death within the first few days of life. 5-7 In 2009, non-lethal RS cases were described and subsequently new cases were found in adolescents and adults with significant variability in the severity of this condition, thus expanding our knowledge of the prognosis and long-term manifestations of this condition. 8-20 Periosteal bone formation is a cornerstone feature of this disorder and differentiates it from osteopetrosis and other known lethal and nonlethal osteosclerotic bone dysplasias. 3,8 The periosteal bone formation typically extends along the diaphysis of long bones adjacent to areas of cellular soft tissue. 8 Ectopic mineralization has been reported at different sites including the brain and kidneys in both lethal and non-lethal cases. 9,14,21-23 Preferential sites of calcification were the basal ganglia, the corpus callosum, and the frontal lobes. 5,17,22 In lethal type, the cause of death in all patients was the respiratory failure, with survival time varying from 45 minutes to 8 weeks in

Prenatal sonographic phenotype of Raine syndrome: detection of novel FAM20C gene mutation at 20 weeks

“…Another striking feature is intracranial calcification, which can occur in the periventricular white matter, basal ganglia, corpus callosum and cerebellum 7 . Calcification has also been reported in the fetal liver and kidneys 2 .…”

“…Raine syndrome is an autosomal recessive condition, characterized by distinctive facial and skeletal features along with intracranial calcification 1 . It is a rare disorder with a prevalence of 1:1 000 000, which occurs due to a mutation in both alleles of the FAM20C gene located on chromosome 7 2 . It can be either lethal or non-lethal 3 .…”

Raine syndrome: Prenatally identified severe craniofacial phenotype with multisuture synostosis and brain abnormalities associated with variants in FAM20C

“…3,4 Typical calcifications were seen in the brainstem and cerebellum, as has been appreciated for other patients. 5,6 These calcium deposits, termed "calcospherites", have also been described in the perivascular spaces. [7][8][9][10][11] Some reports also comment on the lack of significant inflammation associated with the calcium deposits.…”

FAM20C Overview: Classic and Novel Targets, Pathogenic Variants and Raine Syndrome Phenotypes

“…Variants producing short transcripts potentially undergo non-sense-mediated decay, resulting in absent or truncated proteins (gene deletion and indels out of frame) with secondary KD absence. These FAM20C variants include two homozygous gene deletions [ 1 ] (45, XY psudic (7;7) (p22;p22) and a 487-kb homozygous deletion in 7p22 [ 137 ] in two cases, and one compound heterozygous case with variants predicted to produce very short proteins of 206 and 186 aa (c.456dupC/Gly153Argfs*56 and c.474delC/Ser159Profs*28) [ 139 ], one case with a homozygous variant c.456delC (p.Gly153Alafs*34) in exon 1 producing a protein of 190aa [ 137 ], one case with an homozygous frameshift variant in exon 4 (c.905delT, p.Phe302Serfs*35) producing a 337 aa protein [ 138 ] and one case with a homozygous nonsense variant in exon 10 (c.1557C>G, p.Tyr519*) producing a protein of 519 aa, with incomplete KD that keeps 165 aa and lacks 46 aa from the KD 5′end. The variant c.1680C>A p.Cys560* was identified in two unrelated cases [ 153 , 154 ], affecting only the last 5 aa from the KD 5′end.…”

“…In accordance with recessive inheritance, the history of consanguinity is described in ~50% (19/40 LRS and 18/30 NLRS). Although most cases are detected at birth, facial alterations that are Binder-like (such as a flat facial profile, hypoplasic nose and prominent eyes) or Crouzon-like have been described prenatally, in addition to cerebral alterations, such as large choroid plexuses and an echogenic appearance of the brain, indicative of intracerebral calcifications [ 7 , 8 , 9 , 10 , 11 , 138 , 153 ].…”