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.

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.

The bric-a-brac, tramtrack and broad complex (BTB) superfamily of conserved proteins are involved in ubiquitin-proteasome system that contains the Kelch-like (KLHL) gene family. Kelch-like family member 7 (KLHL7), one of the KLHL gene family, consists of one BTB/POZ domain, one BACK domain and five or six Kelch motifs. Numerous variants in KLHL7 gene domains have been reported with Crisponi syndrome/cold-induced sweating syndrome type 1 (CS/CISS1)-like features and retinitis pigmentosa 42, and have recently been identified as causing Bohring-Opitz syndrome (BOS)-like features. We report two siblings with BOS-like phenotype with healthy parents and living in Qazvin province (Central Iran). We performed whole-exome sequencing (WES) on the older patient and Sanger sequencing was carried out for validation of potential causative variants in the close family. A novel homozygous frameshift mutation, p.(Phe83Leufs*3), was identified in the BTB domain of KLHL7 that caused a premature translation-termination codon (PTC) in the two siblings with severe developmental delay, microcephaly, facial dysmorphism, peripheral retinal and optic disc atrophy and cardiac septal defects. Our findings are in agreement with the clinical spectrum of KLHL7 mutations, which are associated with BOS-like features that reports for first time in our population.

Mutations in the Kelch-like protein 7 (KLHL7) represent a recently described and, to date, poorly characterized etiology of inherited retinal dystrophy. Dominant mutations in KLHL7 are a cause of isolated, non-syndromic retinitis pigmentosa (RP). In contrast, recessive loss-of-function mutations are known to cause Crisponi or Bohring-Opitz like cold induced sweating syndrome-3 (BOS-3). In this study, the phenotype and progression of five unrelated patients with KLHL7 mediated autosomal dominant RP (adRP) are characterized. Clinical evaluation of these patients involved a complete ophthalmic exam, full-field electroretinography (ffERG), and imaging, including fundus photography, spectral domain optical coherence tomography (SD-OCT), short wavelength fundus autofluorescence (SW-AF), and near-infrared fundus autofluorescence (NIR-AF). Molecular diagnoses were performed using whole-exome sequencing or gene panel testing. Disease progression was monitored in three patients with available data for a mean follow up time of 4.5 ± 2.9 years. Protein modeling was performed for all variants found in this study in addition to those documented in the literature for recessive loss-of-function alleles causing Crisponi or Bohring-Opitz like cold-induced sweating syndrome. Genetic testing in three patients identified two novel variants within the 3-box motif of the BACK domain: c.472 T > C:p.(Cys158Arg) and c.433A > T:p.(Asn145Tyr). Clinical imaging demonstrated hyperautofluorescent ring formation on both SW-AF and NIR-AF in three patients, with diffuse peripheral and peripapillary atrophy seen in all but one case. SD-OCT demonstrated a phenotypic spectrum, from parafoveal atrophy of the outer retina with foveal sparing to widespread retinal thinning and loss of photoreceptors. Incidence of cystoid macular edema was high with four of five patients affected. Protein modeling of dominant alleles versus recessive loss-of-function alleles showed dominant alleles localized to the BTB and BACK domains while recessive alleles were found in the Kelch domain. We report the phenotype in five patients with KLHL7 mediated adRP, two novel coding variants, and imaging biomarkers using SW-AF and NIR-AF. These findings may influence future gene-based therapies for adRP and pave the way for mechanistic studies that elucidate the pathogenesis of KLHL7-mediated RP.