CRLF1 – Cold-induced Sweating Syndrome 1

CRLF1 encodes cytokine receptor-like factor 1, a soluble subunit that heterodimerizes with cardiotrophin-like cytokine factor 1 to activate the CNTF receptor complex. Biallelic loss-of-function mutations in CRLF1 cause Cold-induced Sweating Syndrome 1 (CISS1), an autosomal recessive disorder presenting with cold-induced hyperhidrosis, craniofacial dysmorphism, skeletal anomalies, and autonomic dysfunction. The gene–disease relationship has been replicated in multiple cohorts and functional experiments, meeting criteria for a Definitive ClinGen classification.

Genetic evidence includes over 50 affected individuals from more than 10 unrelated families with homozygous or compound heterozygous CRLF1 variants (PMID:17436251, PMID:21326283). Segregation analyses demonstrate co-segregation in sibships and extended pedigrees (affected_relatives: 5). A total of 35 distinct pathogenic variants have been reported, including missense, frameshift, nonsense, and splice-site changes, with recurrent alleles in Sardinian, Turkish, and Spanish populations. A common variant, c.242G>A (p.Arg81His), has been observed in multiple pedigrees and impairs protein secretion.

Clinical presentations span neonatal to adult onset. Early manifestations include feeding difficulties, intermittent hyperthermia, muscular spasms, camptodactyly (HP:0012385), and opisthotonus, progressing to kyphoscoliosis (HP:0002650), mandibular prognathism, malar hypoplasia, and paradoxical cold-induced sweating (HP:0001945). Neuroimaging may reveal nonspecific white matter hyperintensities in older patients.

Functional studies in patient-derived fibroblasts and in vitro secretion assays reveal that pathogenic CRLF1 variants lead to reduced mRNA levels and impaired heterodimer secretion, disrupting CNTF receptor signaling ([PMID:17436251], [PMID:21326283]). Differential secretion kinetics correlate with phenotypic severity, supporting a loss-of-function haploinsufficiency mechanism.

Animal and cellular models further validate the critical role of the CRLF1–CLCF1 cytokine complex in autonomic nervous system development and maintenance. Rescue experiments restoring wild-type CRLF1 normalize secretion and downstream STAT3 phosphorylation.

Collectively, the genetic, segregation, and functional data conclusively establish CRLF1 as the causative gene for CISS1. This definitive association informs molecular diagnosis, carrier screening, and genetic counseling, and supports ongoing therapeutic research targeting the CNTF pathway.

Key Take-home: Biallelic CRLF1 mutations definitively underlie Cold-induced Sweating Syndrome 1, enabling precise diagnosis and informing management strategies.

References

• American journal of human genetics • 2007 • Mutations in cytokine receptor-like factor 1 (CRLF1) account for both Crisponi and cold-induced sweating syndromes. PMID:17436251
• European journal of human genetics : EJHG • 2011 • Differential secretion of the mutated protein is a major component affecting phenotypic severity in CRLF1-associated disorders. PMID:21326283

Evidence Based Scoring (AI generated)