Cold‐induced sweating syndrome with neonatal features of Crisponi syndrome: Longitudinal observation of a patient homozygous for a CRLF1 mutation

Abstract

Cold-induced sweating syndrome (CISS) is a rare autosomal recessive disorder caused by mutations in CRLF1 (cytokine receptor-like factor 1), characterized by profuse sweating in cold environmental temperature and craniofacial and skeletal features. Mutations in CRLF1 also cause Crisponi syndrome (CS), characterized by neonatal-onset paroxysmal muscular contractions as well as craniofacial and skeletal manifestations and abnormal functions of the autonomic nerve system. To date, it is an unresolved problem whether the two conditions are distinct clinical entities or a single clinical entity with variable expressions or with different presentations depending on the patients' age at diagnosis. We report on a 30-year-old Japanese woman with CISS and homozygous out-of-frame 23-base deletion of CRLF1. In infancy, she did not show paroxysmal muscular contractions, but showed feeding difficulty, hyperthermia, and facial characteristics including thick and arched eyebrows, a short nose with anteverted nostrils, full cheeks, an inverted upper lip, and a small mouth, resembling those observed in CS. Profuse sweating was noticed at 3 years of age. Cold-induced sweating was recognized in her elementary school days. In adolescence to adulthood, she showed a Marfanoid habitus with progressive kyphoscoliosis and craniofacial characteristics including dolichocephaly, a slender face with poor expression, a distinctive nose with hypoplastic nares, malar hypoplasia, prognathism, and a small mouth. This is the first report of detailed longitudinal observation of a patient with CRLF1 abnormalities, compatible with the notion that CISS and CS may be a single clinical entity.

Differential secretion of the mutated protein is a major component affecting phenotypic severity in CRLF1-associated disorders

“…This is in line with a most recent study reporting a CISS1 patient with neonatal features of Crisponi syndrome, supporting the notion that CISS1 and CS may be a single clinical entity. 25 The overlapping phenotypes (Table 1 and Supplementary Table 1) make it difficult at present to classify new patients. To elucidate a potential genotype/phenotype correlation, we carried out a detailed analysis in relation to the mutations found in the CRLF1 gene.…”

Cold-Induced Sweating Syndrome Type 1, with a <b><i>CRLF1 </i></b>Level<b> </b>Mutation, Previously Associated with Crisponi Syndrome

“…Since the description of the first 2 cases by Sohar in 1978, an additional 10 cases have supplemented the literature to date [1,2,6,8,9,10,11] plus the one reported here. In addition to profuse sweating at low temperatures, present in all patients with CISS1, our case had craniofacial dysmorphic features and camptodactyly.…”

“…In recent years there have been a series of articles that raise the question about whether CISS1 and CS are two allelic diseases or if they actually are the same entity, with different manifestations, depending on age at diagnosis [5,6,7,8]. Recent studies suggest that the phenotypic severity of the syndrome is related to the proportion of mutated CRLF1 protein [7].…”

“…In addition to these contractures they had hyperthermia crises that were sometimes fatal, facial morphological alterations and camptodactyly. In recent years there have been studies that determine that CISS1 and CS are a single entity with different clinical manifestations, depending on the age at diagnosis [6,7,8]. …”

A new Turkish infant with clinical features of CS/CISS1 syndrome and homozygous CRLF1 mutation

“…CISS1 and CISS 2 are clinically indistinguishable. It is now well demonstrated that surviving patients with an infantile-onset CS will develop CISS, demonstrating variation in clinical presentation of the disease at different ages [Hahn et al, 2010;Herholz et al, 2011;Yamazaki et al, 2010]. …”