Clinical and molecular genetic findings of Crisponi/cold-induced sweating syndrome (CS/CISS) spectrum in patients from Turkey.

Crisponi/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by episodic hyperthermia, arthrogryposis, impaired feeding ability, and respiratory distress. The classic CS/CISS is mainly associated with CRLF1 and, rarely, CLCF1. PERCHING syndrome, previously known as CS/CISS type-3 associated with biallelic pathogenic variants in KLHL7, is notable for its few overlapping manifestations. This study presents genotype-phenotype relationships in CS/CISS-like spectrum associated with CRLF1 and KLHL7. Clinical findings of 19 patients from 14 families and four patients from three families were found in association with six different CRLF1 and three different KLHL7 variants, respectively. c.167T>C and c.713delC of the CRLF1 gene and the c.642G>C of the KLHL7 were novel. The c.708_709delCCinsT allele of CRLF1 was identified in 10 families from the Mardin province of Turkey, underlining that an ancestral haplotype has become widespread. CRLF1-associated phenotypes revealed novel manifestations such as prenatal oligohydramnios, benign external hydrocephalus, previously unreported dysmorphic features emerging with advancing age, severe palmoplantar keratoderma and facial erythema, hypopigmented macules and streaks, and recurrent cardiac arrests. KLHL7 variants presented with glabellar nevus flammeus, blepharophimosis, microcephaly, thin corpus callosum, and cleft palate. Abnormalities of sweating, observed in one patient reported herein, is known to be very rare among KLHL7-related phenotypes.

CRLF1 and CLCF1 in Development, Health and Disease.

Cytokines and their receptors have a vital function in regulating various processes such as immune function, inflammation, haematopoiesis, cell growth and differentiation. The interaction between a cytokine and its specific receptor triggers intracellular signalling cascades that lead to altered gene expression in the target cell and consequent changes in its proliferation, differentiation, or activation. In this review, we highlight the role of the soluble type I cytokine receptor CRLF1 (cytokine receptor-like factor-1) and the Interleukin (IL)-6 cytokine CLCF1 (cardiotrophin-like cytokine factor 1) during development in physiological and pathological conditions with particular emphasis on Crisponi/cold-induced sweating syndrome (CS/CISS) and discuss new insights, challenges and possibilities arising from recent studies.

Crisponi/cold-induced sweating syndrome: Differential diagnosis, pathogenesis and treatment concepts.

Crisponi/cold-induced sweating syndrome (CS/CISS) is an autosomal recessive disease characterized by hyperthermia, camptodactyly, feeding and respiratory difficulties often leading to sudden death in the neonatal period. The affected individuals who survived the first critical years of life, develop cold-induced sweating and scoliosis in early childhood. The disease is caused by variants in the CRLF1 or in the CLCF1 gene. Both proteins form a heterodimeric complex that acts on cells expressing the ciliary neurotrophic factor receptor (CNTFR). CS/CISS belongs to the family of "CNTFR-related disorders" showing a similar clinical phenotype. Recently, variants in other genes, including KLHL7, NALCN, MAGEL2 and SCN2A, previously linked to other diseases, have been associated with a CS/CISS-like phenotype. Therefore, retinitis pigmentosa and Bohring-Optiz syndrome-like (KLHL7), Congenital contractures of the limbs and face, hypotonia, and developmental delay syndrome (NALCN), Chitayat-Hall/Schaaf-Yang syndrome (MAGEL2), and early infantile epileptic encephalopathy-11 syndrome (SCN2A) all share an overlapping phenotype with CS/CISS, especially in the neonatal period. This review aims to summarize the existing literature on CS/CISS, focusing on the current state of differential diagnosis, pathogenesis and treatment concepts in order to achieve an accurate and rapid diagnosis. This will improve patient management and enable specific treatments for the affected individuals.

Exome sequencing in Crisponi/cold-induced sweating syndrome-like individuals reveals unpredicted alternative diagnoses.

Crisponi/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by a complex phenotype (hyperthermia and feeding difficulties in the neonatal period, followed by scoliosis and paradoxical sweating induced by cold since early childhood) and a high neonatal lethality. CS/CISS is a genetically heterogeneous disorder caused by mutations in CRLF1 (CS/CISS1), CLCF1 (CS/CISS2) and KLHL7 (CS/CISS-like). Here, a whole exome sequencing approach in individuals with CS/CISS-like phenotype with unknown molecular defect revealed unpredicted alternative diagnoses. This approach identified putative pathogenic variations in NALCN, MAGEL2 and SCN2A. They were already found implicated in the pathogenesis of other syndromes, respectively the congenital contractures of the limbs and face, hypotonia, and developmental delay syndrome, the Schaaf-Yang syndrome, and the early infantile epileptic encephalopathy-11 syndrome. These results suggest a high neonatal phenotypic overlap among these disorders and will be very helpful for clinicians. Genetic analysis of these genes should be considered for those cases with a suspected CS/CISS during neonatal period who were tested as mutation negative in the known CS/CISS genes, because an expedited and corrected diagnosis can improve patient management and can provide a specific clinical follow-up.

Crisponi/CISS1 syndrome: A case series.

Crisponi/CISS1 syndrome (MIM#272430) is a rare autosomal recessive disease characterized by major feeding difficulties, camptodactyly, and anhidrosis in early childhood; and the subsequent development of paradoxical cold-induced sweating and scoliosis later in life. The syndrome is caused by biallelic mutations in CRLF1 or, much less commonly, CLCF1. Although genotype/phenotype correlation has been elusive, it has been suggested that the level of the mutant protein may correlate with the phenotypic severity. However, we show in this series of 12 patients from four families, all previously unpublished, that the homogeneity of the recently described c.983dupG (p.Ser328Argfs∗2) mutation in CRLF1 was associated with a highly variable degree of severity, and that the phenotype significantly overlaps with the recently described COG6-related anhidrosis syndrome (MIM#615328). Another fifth previously unpublished family is also described with a novel mutation in CRLF1, c.605delC (p.Ala202Valfs*32). In Saudi Arabia the prevalence of the syndrome is probably underestimated due to the difficulty in making the diagnosis considering the complex phenotype with typical neonatal and evolutive features.

Warmth and nociceptive evoked potentials in cold-induced sweating syndrome type 1.

INTRODUCTION: Cold-induced sweating syndrome type 1 (CISS1), is a rare, severe, autosomal recessive disease. It is characterized by morphological alterations and profuse sweating when ambient temperature is <22 °C. Although some individuals with CISS1 have decreased pain perception, no study has been conducted to evaluate thermal and pain sensations in these patients. The aim of this study was to assess the function of the nociceptive Aδ-fibers and warmth C-fibers by using CO2 laser-evoked potentials (LEPs) in patients affected by CISS1. METHODS: Four patients were studied. Laser pulses were applied to the skin of the right hand and the perioral region at painful intensity to record Aδ-LEPs, and at non-painful intensity to obtain C-LEPs. Fifteen healthy subjects were studied for control purposes. RESULTS: No significant difference in latencies or amplitudes of either Aδ- or C-LEPs was found between the 2 groups. CONCLUSION: Cutaneous nociceptive and warmth pathway functions are normal in CISS1. Muscle Nerve 54: 100-103, 2016.

Three new cases of Crisponi /cold induced sweating syndrome (CS/CISS1) in Turkish families.

Crisponi syndrome/Cold Induced Sweating Syndrome 1 (CS/CISS1) is a rare, autosomal recessive, multisystemic disease. Hyperthermia attacks, abnormal contractions in the muscles of the face and oropharynx, respiratory distress, camptodactyly, and swallowing difficulty are the main features of the condition in the neonatal period. Patients experience cold-induced sweating attacks and progressive kyphoscoliosis in childhood and adolescence. Mutations in the cytokine receptor like factor 1 (CRLF1) gene causes the CISS1 (Cold- induced sweating syndrome type 1) disease (over 95% of patients). CRLF1 is located in the ciliary neurotrophic factor receptor (CNTFR) pathway, which plays an important role in development and maintenance of neurons in the nervous system. In this study three patients from Turkey, clinically and molecularly diagnosed with CS/CISS1, are presented. Hyperthermia, swallowing difficulty, camptodactyly and pursing of the lips were present in all patients, and foot deformity in one patient. In the first patient a homozygous nonsense mutation NM_004750.5: c.531G > A; p.(Trp177Ter) in the 4th exon was detected. In the second patient a homozygous nonsense mutation NM_004750.5: c.776C > A; p.(Ser259Ter) in the 5th exon was detected. The third patient was homozygous for a missense mutation NM_004750.5: c.935G > T; p.(Arg312Leu) in the 6th exon. Early diagnosis is very important in this syndrome since most patients die in the neonatal period. Therefore, physicians should be suspicious for this disease in patients with dysmorphic features, hyperthermia attacks, camptodactyly, pursing of lips while crying, and swallowing difficulty.

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

Cold-induced sweating syndrome (CISS) is a rare autosomal recessive disorder characterized by profuse sweating at cold environmental temperatures, facial dysmorphism and skeletal features. The infantile presentation of CISS, referred to as Crisponi syndrome (CS), is characterized by facial muscular contractures in response to slight tactile stimuli or during crying, by life-threatening feeding difficulties caused by suck and swallow inabilities, and by intermittent hyperthermia. High febrile crises can lead to death within the first months of life. In preadolescence, surviving patients develop kyphoscoliosis and abnormal sweating. CISS is a genetically heterogeneous disorder caused by mutations in CRLF1 in more than 90 percent of patients (CISS1) and by mutations in CLCF1 in the remaining patients (CISS2). It is now well demonstrated that all patients with an infantile-onset CS will develop CISS, confirming that CS and CISS are not "allelic disorders" but the same clinical entity described at different ages of affected patients. Here we report on a Turkish patient with a phenotype consistent with CS/CISS1 and a nonsense homozygous mutation (c.829C>T, p.R277X) in the CRLF1 gene. This mutation has already been reported in another Turkish patient with CS/CISS1.