CLCF1 – Cold-induced Sweating Syndrome

Cold-induced sweating syndrome (CISS) is a rare autosomal recessive disorder characterized by neonatal feeding difficulties, episodic fevers with seizures, and later-life scoliosis and abnormal sweating. Biallelic loss-of-function variants in CLCF1 (HGNC:17412), encoding cardiotrophin-like cytokine factor 1, define the CISS2 subtype and confirm locus heterogeneity with CRLF1-associated CISS1.

Genetic evidence includes three unrelated probands: one compound heterozygous patient with c.321C>A (p.Tyr107Ter) and c.590G>T (p.Arg197Leu) (PMID:16782820); and two additional cases each harboring either c.676T>C (p.Ter226Arg) or c.46T>C (p.Cys16Arg) (PMID:20400119). All variants segregate with disease under an autosomal recessive model.

The variant spectrum comprises nonsense alleles (c.321C>A (p.Tyr107Ter), c.676T>C (p.Ter226Arg)) and missense changes (c.590G>T (p.Arg197Leu), c.46T>C (p.Cys16Arg)), all predicted to abolish CLCF1 function.

Functional assays demonstrate that p.Arg197Leu CLCF1 fails to bind CNTFRα and activate downstream signaling, and structural modeling reveals destabilization of the cytokine–receptor interface (PMID:16782820). This supports a loss-of-function mechanism consistent with autosomal recessive inheritance.

Clinical features across CISS2 probands include camptodactyly (HP:0012385), neonatal bulbar dysfunction, and progressive scoliosis (HP:0002650), with abnormal cold-induced sweating becoming the most disabling adult symptom (PMID:20400119). Recognition of these features enables targeted symptomatic management.

No conflicting evidence has been reported. Integration of genetic and experimental data solidifies CLCF1 as a disease gene for CISS2, facilitating accurate molecular diagnoses, carrier screening, and potential therapeutic interventions.

Key Take-home: Biallelic inactivating CLCF1 variants underlie autosomal recessive cold-induced sweating syndrome through disrupted CNTFRα signaling, providing a clear target for diagnosis and treatment.

References

• Journal of the neurological sciences • 2010 • Cold-induced sweating syndrome: CISS1 and CISS2: manifestations from infancy to adulthood. Four new cases. PMID:20400119
• Proceedings of the National Academy of Sciences of the United States of America • 2006 • Inactivation of cardiotrophin-like cytokine, a second ligand for ciliary neurotrophic factor receptor, leads to cold-induced sweating syndrome in a patient. PMID:16782820

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