CRLF1 – Cold-induced Sweating Syndrome

The autosomal recessive association between CRLF1 and Cold-induced Sweating Syndrome was first established through linkage and mutational analyses in families presenting with cold-induced hyperhidrosis, skeletal and craniofacial anomalies. Genome-wide screening in two Israeli sisters and two Norwegian brothers identified a 1.4-Mb homozygous region on chromosome 19p12 harboring deleterious CRLF1 variants that co-segregated with disease (PMID:12509788).

Genetic evidence supports a biallelic loss-of-function model. Truncating alleles (e.g., c.31_53del (p.Gln11ArgfsTer)) and missense changes (c.242G>A (p.Arg81His)) have been reported in at least 13 unrelated probands, with parental segregation confirming heterozygous carriage consistent with recessive inheritance ([PMID:20186812]; [PMID:23026229]; [PMID:24613578]).

Clinically, affected individuals exhibit profuse sweating in response to cold exposure, camptodactyly, kyphoscoliosis, marfanoid habitus, feeding difficulties, and episodic hyperthermia (HP:0001945, HP:0012385, HP:0002751, HP:0011968) ([PMID:12509788]; [PMID:20400119]).

Functional assays demonstrate mutation-mediated CRLF1 transcript decay and impaired secretion in patient fibroblasts, with more severe secretion defects correlating with infantile presentation ([PMID:17436251]; [PMID:21326283]).

In vitro studies further show disrupted CLF–CNTF receptor complex formation and downstream signaling, confirming a loss-of-function mechanism ([PMID:16782820]).

Collectively, these data provide strong evidence for CRLF1’s role in Cold-induced Sweating Syndrome, supporting molecular diagnostics, carrier screening, and management strategies. Key take-home: molecular testing for CRLF1 variants is essential for early diagnosis and tailored clinical care.

References

• American Journal of Human Genetics • 2003 • Cold-induced sweating syndrome is caused by mutations in the CRLF1 gene. PMID:12509788
• American Journal of Medical Genetics Part A • 2010 • Cold-induced sweating syndrome with neonatal features of Crisponi syndrome: longitudinal observation of a patient homozygous for a CRLF1 mutation. PMID:20186812
• Brain & Development • 2013 • Multiple small hyperintense lesions in the subcortical white matter on cranial MR images in two Turkish brothers with cold-induced sweating syndrome caused by a novel missense mutation in the CRLF1 gene. PMID:23026229
• European Journal of Medical Genetics • 2014 • A new Turkish infant with clinical features of CS/CISS1 syndrome and homozygous CRLF1 mutation. PMID:24613578
• Journal of the Neurological Sciences • 2010 • Cold-induced sweating syndrome: CISS1 and CISS2: manifestations from infancy to adulthood. Four new cases. PMID:20400119
• 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 • 2011 • Differential secretion of the mutated protein is a major component affecting phenotypic severity in CRLF1-associated disorders. PMID:21326283
• Proceedings of the National Academy of Sciences USA • 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

Evidence Based Scoring (AI generated)