Natural history of non-lethal Raine syndrome during childhood

Abstract

Background: Raine syndrome (RS) is a rare autosomal recessive disorder caused by biallelic loss-of-function mutations of FAM20C. The most common clinical features are microcephaly, exophthalmos, hypoplastic nose and severe midface hypoplasia, leading to choanal atresia. The radiological findings include generalized osteosclerosis and brain calcifications. RS is usually lethal during the neonatal period due to severe respiratory distress. However, there exists a non-lethal RS form, the phenotype of which is extremely heterogeneous. There is paucity of data about clinical course and life expectancy of these patients. Results: This is the first description of follow-up features of non-lethal RS patients. Moreover, we present three unpublished cases. There are five Asian and two Arab patients. All were born to consanguineous parents. The most common neonatal comorbidity was respiratory distress secondary to choanal atresia. A variable degree of neurodevelopmental delay was seen in the majority of our cases and seizures and hearing or vision involvement were also frequent. Neurological and orthopedic issues were the most frequent complications seen at follow-up in our group. Persistent hypophosphatemic rickets was the most striking endocrinological manifestation, which was scarcely responsive to therapy with phosphate salts and alfacalcidol. Life expectancy of our patients goes beyond childhood, with the oldest of those described being 18 years old at present. Conclusions: Manifestations of RS in those surviving the neonatal period are being increasingly recognized. Our study supports previous findings and provides clinical and biochemical observations and data from longer follow up. Finally, we propose multidisciplinary follow up for patients with non-lethal RS.

Lack of FAM20A, Ectopic Gingival Mineralization and Chondro/Osteogenic Modifications in Enamel Renal Syndrome

“…It has also been proposed that extracellular FAM20C sustains mineralization sustains mineralization of osteoblast cells (MC3T3) in vitro (Ohyama et al, 2016). This is partly in agreement with the bone osteosclerosis displayed by patients suffering RNS, which is a syndrome caused by the lack or reduced Fam20C activity (Sheth et al, 2018;Mameli et al, 2020). Indeed, bone osteosclerosis could be related to the lack or reduced activity of extracellular FAM20C in the developing osteoid.…”

Hypophosphataemic Rickets Secondary to Raine Syndrome: A Review of the Literature and Case Reports of Three Paediatric Patients’ Dental Management

“…Metabolic bone disorders, such as hypophosphataemic rickets, pose a relatively new characteristic of Raine Syndrome (RS) [ 1 , 3 ]. Biallelic variations in the FAM20C gene provide the genetical basis of RS [ 1 , 2 ].…”

“…Raine syndrome (RS) (OMIM # 259775) is an especially rare autosomal recessive disorder with an estimated prevalence of <1 in 1,000,000 [ 1 , 2 ]. Endocrinological manifestations such as hypophosphataemic rickets are a newly described feature within the phenotypical plethora of RS [ 3 ].…”

“…RS is commonly referred to as lethal osteosclerotic bone dysplasia due to high mortality in the neonatal period [ 8 ]. More recently, a milder phenotype has been described that is compatible with life [ 1 – 3 ]. RS characteristically presents with exophthalmos, cerebral calcifications, choanal atresia, and osteosclerosis [ 2 , 8 ].…”

“…Exorbitism and midfacial hypoplasia often present as a Crouzon-like facial appearance. Heterogeneity is considerable amongst the nonlethal type, and a paucity of data results in the possibility of the complete phenotypic spectrum not being delineated [ 1 – 3 ]. Genetically, mutations in the FAM20C gene on chromosome 7, which encodes a Golgi Casein Kinase that phosphorylates fibroblast growth factor 23 (FGF23), account for RS, with a high frequency of consanguineous parents in affected patients [ 2 , 3 , 9 , 10 ].…”