Expanding the Mutational Spectrum ofCRLF1in Crisponi/CISS1 Syndrome

Abstract

Crisponi syndrome (CS) and cold-induced sweating syndrome type 1 (CISS1) 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 date, 24 distinct CRLF1 mutations have been found either in homozygosity or in compound heterozygosity in CS/CISS1 patients, with the highest prevalence in Sardinia, Turkey, and Spain. By reporting 11 novel CRLF1 mutations, here we expand the mutational spectrum of CRLF1 in the CS/CISS1 syndrome to a total of 35 variants and present an overview of the different molecular and clinical features of all of them. To catalog all the 35 mutations, we created a CRLF1 mutations database, based on the Leiden Open (source) Variation Database (LOVD) system (https://grenada.lumc.nl/LOVD2/mendelian_genes/variants). Overall, the available functional and clinical data support the fact that both syndromes actually represent manifestations of the same autosomal-recessive disorder caused by mutations in the CRLF1 gene. Therefore, we propose to rename the two overlapping entities with the broader term of Crisponi/CISS1 syndrome.

Cardiotrophin-like cytokine factor 1 (CLCF1) and neuropoietin (NP) signalling and their roles in development, adulthood, cancer and degenerative disorders

“…The range of CRLF1 mutations in Crisponi/CISS1 syndromes is wide [30,31], as is the severity of the conditions associated with them, ranging from severe neonatal lethal conditions that include respiratory dysfunction [32], through to more mild syndromes observed clinically only late in adulthood [31]. Likely there are many that remain un-noticed due to subclinical symptoms.…”

Crisponi/cold‐induced sweating syndrome: Differential diagnosis, pathogenesis and treatment concepts

“…In contrast to the cold‐induced sweating, CS/CISS1 individuals show minimal sweating at hot environmental temperatures, which results in overheating . Piras et al classified CS/CISS1 in three groups with different severity based on the presence of four distinct disease symptoms, namely hyperthermia and feeding difficulties in infancy, scoliosis and cold‐induced sweating in childhood/adolescence: (1) mild phenotype: cold‐induced sweating and scoliosis in adolescence but no periods of hyperthermia or feeding difficulties in infancy; (2) intermediate phenotype: episodes of hyperthermia or feeding difficulties within the first year of life and scoliosis and cold‐induced sweating later; and (3) severe phenotype: episodes of hyperthermia and feeding difficulties in infancy, scoliosis and cold‐induced sweating in childhood/adolescence.…”

“…Most CS/CISS1 individuals originate from Europe, especially from the Mediterranean region [Italy mainland (4) and Sardinia (12 + 15 not tested for variants in CRLF1 ), Turkey (23), Spain (8), Lybia (3) and France (2)]. Others are from the Saudi Arabia (13), India, Pakistan, Japan, Australia, North or Central America . Although most of the disease‐associated CRLF1 variants are private and found only in single families, some variants occur frequently in distinct CS/CISS1 individuals from a specific geographical region (eg, c.226T>G and c.676_677dupA in Sardinia, c.708_709delinsT in Turkey, c.983dupG in Saudi Arabia and c.713dupC in Spain, Turkey, Roma population).…”

“…Although most of the disease‐associated CRLF1 variants are private and found only in single families, some variants occur frequently in distinct CS/CISS1 individuals from a specific geographical region (eg, c.226T>G and c.676_677dupA in Sardinia, c.708_709delinsT in Turkey, c.983dupG in Saudi Arabia and c.713dupC in Spain, Turkey, Roma population). Piras et al assumed that the occurrence of identical variants might originate from a founder effect and not from a mutational hotspot . In Sardinia, where CS/CISS1 is more common than in the rest of world, Piras et alcalculated the allele frequency of the two most common alleles (c.226 T > G and c.676_677dupA) and predicted an allele frequency of 1% and 0.4%, respectively, and calculated a joint carrier frequency of 1.4% with an expected incidence of about one case per 20 700 newborns.…”

Exome sequencing in Crisponi/cold‐induced sweating syndrome–like individuals reveals unpredicted alternative diagnoses

“…So far, more than 95% of cases are caused by mutations in CRLF1 (CISS1), while the remaining by mutations in CLCF1 (CISS2) . Alterations in CRLF1 and CLCF1 can be found in more than 60% of individuals with clinical diagnosis of CS/CISS . Therefore, a subset of CS/CISS cases (about 40%) remains yet genetically unexplained.…”