Cardiotrophin-like cytokine factor 1 (CLCF1) is an essential gene that shows exceptional sequence conservation among vertebrates. CLCF1 loss-of-function mutations cause Crisponi/cold-induced sweating syndrome-2, a disorder with severe and complex phenotypes, underscoring the non-redundant roles of CLCF1. Initially identified as a member of the interleukin-6 (IL-6) cytokine family with activity in neurons and immune cells, CLCF1 is now recognized for broader roles in thermoregulation, glomerular function, myelopoiesis, oncogenesis, and muscle fitness. Despite growing interest in the multifaceted biology of CLCF1, the mechanisms regulating its transcription, translation, secretion, receptor binding, and signaling remain incompletely understood. This review integrates data from multiple open databases and functional studies to outline the current state of knowledge regarding CLCF1 regulatory landscape, receptor interactions, and downstream signaling. It also highlights recent discoveries about the CLCF1 interactome and intracellular functions and underlines its emerging potential as a therapeutic target.

Background: Crisponi/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by severe neonatal manifestations including paroxysmal muscle contractions, tendency for hyperthermia, and feeding and swallowing difficulties with high neonatal mortality. Pathogenic variants in the Cytokine Receptor-Like Factor 1 (CRLF1) gene have been associated with CS/CISS. These variants result in a loss of function of the encoded protein, which disrupts the formation of a functional heterodimer with Cardiotrophin-Like Cytokine Factor 1 (CLCF1). This complex is essential for the development of autonomic and sensory nervous systems, as well as for bone remodeling. We report two patients affected by CS harboring pathogenic variants in the CRLF1 gene. Methods-case reports: The first patient was diagnosed postnatally, presenting with non-epileptic paroxysmal events characterized by opisthotonus and orofacial contractions. He survived beyond infancy, later developing scoliosis and persistent episodes of hyperthermia. In the second patient, a prenatal ultrasound at 20 weeks of gestation revealed bilateral camptodactyly, also referred to as the 'horn's sign', raising early suspicion of CS. The diagnosis was subsequently confirmed both clinically and genetically. After birth, the infant developed severe dysphagia, apnea, and paroxysmal events not associated with epileptiform activity on EEG. Sanger sequencing identified a homozygous c.708_709delinsT frameshift variant in the CRLF1 gene. The patient died at 30 days of age due to respiratory failure. Results and conclusions: With this manuscript, we aim to further delineate the phenotypic spectrum of this rare condition and propose the 'horn's sign' as a targeted prenatal marker for early diagnosis in populations with known founder mutations or familial risk factors.

Background: Perceptual analysis has highlighted that the voice characteristics of patients with rare congenital genetic syndromes differ from those of normophonic subjects. In this paper, we describe the voice phenotype, also called the phonotype, of patients with Crisponi/cold-induced sweating syndrome type 1 (CS/CISS1). Methods: We conducted an observational study at the Department of Life Sciences and Public Health, Rome. Thirteen patients were included in this study (five males; mean age: 16 years; SD: 10.63 years; median age: 12 years; age range: 6-44 years), and five were adults (38%). We prospectively recorded and analyzed acoustical features of three corner vowels [a], [i], and [u]. For perceptual analysis, the GIRBAS (grade, instability, roughness, breathiness, asthenia, and strain) scale was utilized. Acoustic analysis was performed through BioVoice software. Results: We found that CS/CISS1 patients share a common phonotype characterized by articulation disorders and hyper-rhinophonia. Conclusions: This study contributes to delineating the voice of CS/CISS1 syndrome. The phonotype can represent one of the earliest indicators for detecting rare congenital conditions, enabling specialists to reduce diagnosis time and better define a spectrum of rare and ultra-rare diseases.

Background/Objectives: Crisponi/cold-induced sweating syndrome 1 (CISS1/CISS, MIM#272430) is a genetic disorder due to biallelic variants in CRFL1 (MIM*604237). The related phenotype is mainly characterized by abnormal thermoregulation and sweating, facial muscle contractions in response to tactile and crying-inducing stimuli at an early age, skeletal anomalies (camptodactyly of the hands, scoliosis), and craniofacial dysmorphisms, comprising full cheeks, micrognathia, high and narrow palate, low-set ears, and a depressed nasal bridge. The condition is associated with high lethality during the neonatal period and can benefit from timely symptomatic therapy. Methods: We collected frontal images of all patients with CISS1/CISS published to date, which were analyzed with Face2Gene (F2G), a machine-learning technology for the facial diagnosis of syndromic phenotypes. In total, 75 portraits were subdivided into three cohorts, based on age (Cohort 1 and 2) and the presence of the typical facial trismus (Cohort 3). These portraits were uploaded to F2G to test their suitability for facial analysis and to verify the capacity of the AI tool to correctly recognize the syndrome based on the facial features only. The photos which passed this phase (62 images) were fed to three different AI algorithms-DeepGestalt, Facial D-Score, and GestaltMatcher. Results: The DeepGestalt algorithm results, including the correct diagnosis using a frontal portrait, suggested a similar facial phenotype in the first two cohorts. Cohort 3 seemed to be highly differentiable. The results were expressed in terms of the area under the curve (AUC) of the receiver operating characteristic (ROC) curve and p Value. The Facial D-Score values indicated the presence of a consistent degree of dysmorphic signs in the three cohorts, which was also confirmed by the GestaltMatcher algorithm. Interestingly, the latter allowed us to identify overlapping genetic disorders. Conclusions: This is the first AI-powered image analysis in defining the craniofacial contour of CISS1/CISS and in determining the feasibility of training the tool used in its clinical recognition. The obtained results showed that the use of F2G can reveal valid support in the diagnostic process of CISS1/CISS, especially in more severe phenotypes, manifesting with facial contractions and potentially lethal consequences.

Feeding difficulties are constantly present in patients with Crisponi/cold-induced sweating syndrome type 1 (CS/CISS1). The aim of our study was to describe their prevalence and evolution from birth to adult age. We performed an observational study at the Department of Life Sciences and Public Health, Rome. Fourteen patients were included in this study (six M; mean age: 18 years; SD: 10.62 years; median age: 15 years; age range: 6-44 years); six were adults (43%). Data on oral motor abilities from birth were collected. Meal duration, presence of swallowing reflex, dysphagia symptoms, difficulty chewing, and drooling management were assessed. At birth, all patients needed enteral feeding. Introduction of solid food was postponed beyond the age of 18 months in 43% of patients. During childhood and adolescence, mealtime was characterized by increased duration (43%) accompanied by fatigue during chewing (43%), food spillage from the nasal cavities (21%), sialorrhea (86%), and poor/reduced appetite (57%). A mature rotatory chewing skill was never achieved. This report expands the phenotype description of CS/CISS1 and also improves the overall management and prevention of complications in this ultra-rare disease.