Differential secretion of the mutated protein is a major component affecting phenotypic severity in CRLF1-associated disorders

Abstract

Crisponi syndrome (CS) and cold-induced sweating syndrome type 1 (CISS1) are disorders caused by mutations in CRLF1. The two syndromes share clinical characteristics, such as dysmorphic features, muscle contractions, scoliosis and cold-induced sweating, with CS patients showing a severe clinical course in infancy involving hyperthermia, associated with death in most cases in the first years of life. To evaluate a potential genotype/phenotype correlation and whether CS and CISS1 represent two allelic diseases or manifestations at different ages of the same disorder, we carried out a detailed clinical analysis of 19 patients carrying mutations in CRLF1. We studied the functional significance of the mutations found in CRLF1, providing evidence that phenotypic severity of the two disorders mainly depends on altered kinetics of secretion of the mutated CRLF1 protein. On the basis of these findings, we believe that the two syndromes, CS and CISS1, represent manifestations of the same disorder, with different degrees of severity. We suggest renaming the two genetic entities CS and CISS1 with the broader term of Sohar-Crisponi syndrome.

Cold-Induced Sweating Syndrome Type 1, with a <b><i>CRLF1 </i></b>Level<b> </b>Mutation, Previously Associated with Crisponi Syndrome

“…The clinical characteristics of the 12 patients published and the current one are listed in table 1. None of the previous cases had the mutation found in ours, but it had been described in another case diagnosed with CS [7]. …”

“…In recent years there have been a series of articles that raise the question about whether CISS1 and CS are two allelic diseases or if they actually are the same entity, with different manifestations, depending on age at diagnosis [5,6,7,8]. Recent studies suggest that the phenotypic severity of the syndrome is related to the proportion of mutated CRLF1 protein [7].…”

“…Recent studies suggest that the phenotypic severity of the syndrome is related to the proportion of mutated CRLF1 protein [7]. Therefore, CS and CISS1 represent manifestations of the same disorder with varying severity, suggesting the identification of both diseases under a broader heading, such as Sohar-Crisponi syndrome [7].…”

“…Recent studies suggest that the phenotypic severity of the syndrome is related to the proportion of mutated CRLF1 protein [7]. Therefore, CS and CISS1 represent manifestations of the same disorder with varying severity, suggesting the identification of both diseases under a broader heading, such as Sohar-Crisponi syndrome [7]. We believe that in our patient the presence of signs such as facial trismus and muscle spasms during childhood, along with the detection of the described mutation not associated to date with any CISS1 case, but which has been described as the cause of CS, serve to confirm the idea of the latest studies, and, therefore, CISS1 and CS should be considered manifestations of the same disorder.…”

“…In addition to these contractures they had hyperthermia crises that were sometimes fatal, facial morphological alterations and camptodactyly. In recent years there have been studies that determine that CISS1 and CS are a single entity with different clinical manifestations, depending on the age at diagnosis [6,7,8]. …”