Fetal costello syndrome with neuromuscular spindles excess and p.Gly12Val HRAS mutation

Abstract Costello syndrome (CS) is a rare multiple congenital disorder caused by activating germline mutations in HRAS gene and is characterized by coarse facial features, severe feeding difficulties, failure to thrive, mild to severe intellectual disability, severe postnatal growth retardation, cardiac abnormalities or cancer predisposition. Phenotypic spectrum associated with HRAS mutations is broad, ranging from attenuated CS phenotype to neonatal and lethal forms with limited genotype-phenotype correlations. Congenital myopathy with neuromuscular spindle excess has been rarely described in the literature. We report a new severe fetal case of CS with distal arthrogryposis due to neuromuscular spindle excess, confirmed by the detection of the p.Gly12Val mutation in HRAS gene. This case emphasizes the fact that HRAS is the only gene responsible for neuromuscular spindle excess, underlines a correlation between p.Gly12Val mutation and severe CS phenotype and points out the importance of a muscle biopsy performed according to the suitable procedure in neuromuscular disorders for any fetal arthrogryposis.