Mutations in CRLF1 (cytokine receptor-like factor 1) account for both Crisponi syndrome (CS; MIM#601378) and cold-induced sweating syndrome type 1 (CISS1; MIM#272430).
Crisponi syndrome was initially described in 1996 in 17 patients from 12 different families in southern Sardinia.1
Further patients have been reported later.2, 3, 4, 5, 6, 7, 8
The syndrome usually manifests at birth, when patients present with hyperthermia and abnormal paroxysmal contractions of the facial and oropharyngeal muscles, as well as feeding and respiratory difficulties often requiring the use of nasogastric feeding. Physical dysmorphisms such as a large face, broad nose and camptodactyly have been described in most of the patients.3, 4, 5, 7, 8
Hyperthermia is frequently associated with death within the first months of life. Feeding difficulties and hyperthermia often resolve after infancy in the rare surviving patients, who then develop scoliosis and sometimes psychomotor retardation. In pre-adolescent patients, evidence of cold-induced sweating was reported.3
Cold-induced sweating syndrome type 1 (CISS1) was first reported in two Israeli sisters in 1978.9
It involves paradoxical sweating at cold ambient temperatures on the upper part of the body, along with progressive scoliosis. In both sisters, dysmorphic features including a high arched palate, nasal voice and joint contractures have been observed. Two Norwegian brothers and a Canadian woman with a similar phenotype have been described more recently.10, 11
CS and CISS1 belong to a group of genetic disorders with similar phenotypes associated with mutations of genes in the ciliary neurotrophic factor receptor (CNTFR) pathway, which is known to be important for the development and maintenance of the nervous system and muscles.12
This group includes cold-induced sweating syndrome type 2 (CISS2; MIM#610313), caused by mutations in CLCF1
and Stüve–Wiedemann syndrome (SWS; MIM#601559), caused by mutations in LIFR.14
Mutations in CLCF1
lead to a phenotype similar to mutations in CLRF1,
with cold-induced sweating, scoliosis and cubitus valgus.10, 13
Clinical features of SWS also include camptodactyly, feeding difficulties, scoliosis and temperature instability, also present in the other syndromes, but the characteristic bowing of the long bones is not present in CS, CISS1 and CISS2.14, 15, 16, 17, 18, 19
Clinical similarities between Crisponi syndrome and cold-induced sweating syndrome type 1, along with the involvement of the same gene (CRLF1
), led to the question whether these two syndromes represent two allelic diseases or, in fact, manifestations of the same disorder, reported at different ages of affected patients.1, 2
In an effort to delineate the specific clinical features attributed to CS and CISS1, we investigated the clinical history, physical characteristics and experimental data of 19 patients with mutations in CRLF1
, 14 of them classified as CS (9 reported and 5 unreported cases) and 5 as CISS1 (all reported),9, 10, 11
by means of a standardized questionnaire.
Because a genotype/phenotype correlation has not been found in previous studies,2, 3
we attempted to carry out a detailed analysis of the clinical phenotype and compare it with the genetic and functional data from the investigation of the CRLF1
gene and protein for all the probands analyzed.
We found that phenotypic severity of CRLF1-associated disorders depends on altered kinetics in the secretion of the mutated CRLF1 protein, suggesting that CS and CISS1 are manifestations of the same disease.