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.

Bi-allelic Mutations in KLHL7 Cause a Crisponi/CISS1-like Phenotype Associated with Early-Onset Retinitis Pigmentosa.

Crisponi syndrome (CS)/cold-induced sweating syndrome type 1 (CISS1) is a very rare autosomal-recessive disorder characterized by a complex phenotype with high neonatal lethality, associated with the following main clinical features: hyperthermia and feeding difficulties in the neonatal period, scoliosis, and paradoxical sweating induced by cold since early childhood. CS/CISS1 can be caused by mutations in cytokine receptor-like factor 1 (CRLF1). However, the physiopathological role of CRLF1 is still poorly understood. A subset of CS/CISS1 cases remain yet genetically unexplained after CRLF1 sequencing. In five of them, exome sequencing and targeted Sanger sequencing identified four homozygous disease-causing mutations in kelch-like family member 7 (KLHL7), affecting the Kelch domains of the protein. KLHL7 encodes a BTB-Kelch-related protein involved in the ubiquitination of target proteins for proteasome-mediated degradation. Mono-allelic substitutions in other domains of KLHL7 have been reported in three families affected by a late-onset form of autosomal-dominant retinitis pigmentosa. Retinitis pigmentosa was also present in two surviving children reported here carrying bi-allelic KLHL7 mutations. KLHL7 mutations are thus associated with a more severe phenotype in recessive than in dominant cases. Although these data further support the pathogenic role of KLHL7 mutations in a CS/CISS1-like phenotype, they do not explain all their clinical manifestations and highlight the high phenotypic heterogeneity associated with mutations in KLHL7.

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.

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.

Expanding the mutational spectrum of CRLF1 in Crisponi/CISS1 syndrome.

Crisponi syndrome (CS) and cold-induced sweating syndrome type 1 (CISS1) share clinical characteristics, such as dysmorphic features, muscle contractions, scoliosis, and cold-induced sweating, with CS patients showing a severe clinical course in infancy involving hyperthermia associated with death in most cases in the first years of life. To date, 24 distinct CRLF1 mutations have been found either in homozygosity or in compound heterozygosity in CS/CISS1 patients, with the highest prevalence in Sardinia, Turkey, and Spain. By reporting 11 novel CRLF1 mutations, here we expand the mutational spectrum of CRLF1 in the CS/CISS1 syndrome to a total of 35 variants and present an overview of the different molecular and clinical features of all of them. To catalog all the 35 mutations, we created a CRLF1 mutations database, based on the Leiden Open (source) Variation Database (LOVD) system (https://grenada.lumc.nl/LOVD2/mendelian_genes/variants). Overall, the available functional and clinical data support the fact that both syndromes actually represent manifestations of the same autosomal-recessive disorder caused by mutations in the CRLF1 gene. Therefore, we propose to rename the two overlapping entities with the broader term of Crisponi/CISS1 syndrome.

3MC syndrome: molecular findings in previously reported and milder patients expand the natural history and phenotypic spectrum.

The 3MC syndromes types 1-3 (MIM#257920, 265050 and 248340, respectively) are rare autosomal recessive genetic disorders caused by pathogenic variants in genes encoding the lectin complement pathway. Patients with 3MC syndrome have a distinctive facial phenotype including hypertelorism, highly arched eyebrows and ptosis. A significant number of patients have bilateral cleft lip and palate and they often exhibit genitourinary and skeletal anomalies. A clinical clue to 3MC syndrome is the presence of a characteristic caudal appendage. Genetic variants in MASP1, COLEC11 and COLEC10 genes have been identified as the causation of this syndrome, yet relatively few patients have been described so far. We consolidate and expand current knowledge of phenotypic features and molecular diagnosis of 3MC syndrome by describing the clinical and molecular findings in five patients. This includes follow-up of two brothers whose clinical phenotypes were first reported by Crisponi et al in 1999. Our study contributes to the evolving clinical and molecular spectrum of 3MC syndrome.

Isolated 'sign of the horns': a simple, pathognomonic, prenatal sonographic marker of Crisponi syndrome.

The case of a patient presenting with Crisponi syndrome recently hospitalized at our institution is described. During pregnancy a diagnosis of this syndrome was hypothesized following sonographic observation of the fetus with the hands showing 'the sign of the horns'. Such a finding, if isolated, as in our case, may represent a simple, pathognomonic sonographic marker of Crisponi syndrome.

Genital anomalies in newborns.

Examination of genitalia should be an essential part of newborn assessment. Early detection of congenital disorders is essential to begin appropriate medical or surgical therapy and to prevent complications that could profoundly affect a child's life. The present review aims to describe the main genital anomalies in infants and provide images in order to help the physician in current clinical practice.

Anomalies of the oral cavity in newborns.

Examination of the oral cavity should be an essential part of the newborn assessment. Early detection of congenital disorders is essential to begin appropriate medical or surgical therapy and to prevent complications that could profoundly affect a child's life. The present review aims to describe the main anomalies of the oral cavity in infants and provide images in order to help the physician in current clinical practice.

New mutations in DYNC2H1 and WDR60 genes revealed by whole-exome sequencing in two unrelated Sardinian families with Jeune asphyxiating thoracic dystrophy.

Jeune asphyxiating thoracic dystrophy (JATD; Jeune syndrome, MIM 208500) is a rare autosomal recessive chondrodysplasia, phenotypically overlapping with short-rib polydactyly syndromes (SRPS). JATD typical hallmarks include skeletal abnormalities such as narrow chest, shortened ribs, limbs shortened bones, extra fingers and toes (polydactyly), as well as extraskeletal manifestations (renal, liver and retinal disease). To date, disease-causing mutations have been found in several genes, highlighting a marked genetic heterogeneity that prevents a molecular diagnosis of the disease in most families. Here, we report the results of whole-exome sequencing (WES) carried out in four JATD cases, belonging to three unrelated families of Sardinian origin. The exome analysis allowed to identify mutations not previously reported in the DYNC2H1 (MIM 603297) and WDR60 (MIM 615462) genes, both codifying for ciliary intraflagellar transport components whose mutations are known to cause Jeune syndrome.

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

Crisponi syndrome (CS) and cold-induced sweating syndrome type 1 (CISS1) are disorders caused by mutations in CRLF1. The two syndromes share clinical characteristics, such as dysmorphic features, muscle contractions, scoliosis and cold-induced sweating, with CS patients showing a severe clinical course in infancy involving hyperthermia, associated with death in most cases in the first years of life. To evaluate a potential genotype/phenotype correlation and whether CS and CISS1 represent two allelic diseases or manifestations at different ages of the same disorder, we carried out a detailed clinical analysis of 19 patients carrying mutations in CRLF1. We studied the functional significance of the mutations found in CRLF1, providing evidence that phenotypic severity of the two disorders mainly depends on altered kinetics of secretion of the mutated CRLF1 protein. On the basis of these findings, we believe that the two syndromes, CS and CISS1, represent manifestations of the same disorder, with different degrees of severity. We suggest renaming the two genetic entities CS and CISS1 with the broader term of Sohar-Crisponi syndrome.

Crisponi syndrome is caused by mutations in the CRLF1 gene and is allelic to cold-induced sweating syndrome type 1.

Crisponi syndrome is a severe autosomal recessive condition that is phenotypically characterized by abnormal, paroxysmal muscular contractions resembling neonatal tetanus, large face, broad nose, anteverted nares, camptodactyly, hyperthermia, and sudden death in most cases. We performed homozygosity mapping in five Sardinian and three Turkish families with Crisponi syndrome, using high-density single-nucleotide polymorphism arrays, and identified a critical region on chromosome 19p12-13.1. The most prominent candidate gene was CRLF1, recently found to be involved in the pathogenesis of cold-induced sweating syndrome type 1 (CISS1). CISS1 belongs to a group of conditions with overlapping phenotypes, also including cold-induced sweating syndrome type 2 and Stuve-Wiedemann syndrome. All these syndromes are caused by mutations of genes of the ciliary neurotrophic factor (CNTF)-receptor pathway. Here, we describe the identification of four different CRLF1 mutations in eight different Crisponi-affected families, including a missense mutation, a single-nucleotide insertion, and a nonsense and an insertion/deletion (indel) mutation, all segregating with the disease trait in the families. Comparison of the mutation spectra of Crisponi syndrome and CISS1 suggests that neither the type nor the location of the CRLF1 mutations points to a phenotype/genotype correlation that would account for the most severe phenotype in Crisponi syndrome. Other, still-unknown molecular factors may be responsible for the variable phenotypic expression of the CRLF1 mutations. We suggest that the syndromes can comprise a family of "CNTF-receptor-related disorders," of which Crisponi syndrome would be the newest member and allelic to CISS1.