Atypical Stüve-Wiedemann syndrome (STWS) masquerating as Cold-induced sweating syndrome (CISS): a patient homozygous for a LIFR mutation followed for 30 years

Introduction: Cold-induced sweating syndrome (CISS) is a rare autosomal recessive disorder caused by mutations in the CRLF1 or CLCF1 genes. It involves paradoxical sweating at cold ambient temperatures on the upper part of the body, along with craniofacial and skeletal features as progressive scoliosis. Mutations in LIFR (leukemia inhibitory factor receptor) responsible for the Stüve-Wiedemann syndrome (STWS), lead to a phenotype resembling CISS, with cold-induced sweating, scoliosis and cubitus valgus, but with a more severe clinical course. In fact, STWS is characterized by bowing of the long bones, respiratory distress, feeding difficulties, and hypertermic episodes responsible for early lethality. Materials and methods: We report clinical, molecular, skin biopsy, electrophysiological and temperature monitoring data of a 30-year-old Italian woman who has suffered from a cold-induced sweating and progressive scoliosis by the age of about 4 years. Results: Clinical data and the course showed a predominant CISS phenotype. Thermoregulatory sweat tests confirmed this paradoxical sweating response. There was clinical and electrophysiological evidence of a mild sensorimotor peripheral neuropathy. The morpho-functional study of cutaneous innervation showed a defective development of cutaneous sympathetic innervation with a lack of immunohistochemical shift from a noradrenergic to cholinergic phenotype. DNA sequencing showed homozygosity for a novel missense sequence variant, c2170> G in LIFR on 5p13-p12. Genome wide SNP arrays including parental samples revealed a complete maternal isodisomy for chromosome 5. Conclusions: Here, we report longitudinal observations on clinical consequences of LIFR dysfunction in a patient with a CISS-like phenotype.