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Year : 2018  |  Volume : 7  |  Issue : 4  |  Page : 273-278

A case report of Crisponi/cold-induced sweating syndrome 1 in a Saudi family

1 King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences; Department of Pediatrics, King Abdulaziz Medical City-WR, National Guard Health Affairs, Jeddah, Kingdom of Saudi Arabia
2 Section of Molecular Medicine, Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City-WR, Jeddah, Kingdom of Saudi Arabia

Date of Web Publication15-Oct-2018

Correspondence Address:
Dr. Jubara Alallah
Department of Pediatric, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, National Guard Health Affair, P.O. Box: 9515, Jeddah 2123
Kingdom of Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcn.JCN_46_18

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Crisponi/cold-induced sweating syndrome 1 (CCIS1) is a rare autosomal recessive condition characterized by intermittent hyperthermia, camptodactyly, dysmorphic features, and paroxysmal muscular contraction in the face with crying or after minimal stimuli. Typical abnormal facial features include broad nose, anteverted nares, and long philtrum. Most of the affected individuals die in the first year of life. Here, we report two affected siblings from a consanguineous Saudi family who presented with phenotypic features of the early-onset CCIS1. The diagnosis was confirmed by identifying a novel homozygous pathogenic variant in the CRLF1 gene.

Keywords: Camptodactyly, Crisponi/cold-induced sweating syndrome 1, cold-induced sweating syndrome, Crisponi syndrome, cytokine receptor-like factor 1, hyperthermia, muscle contraction

How to cite this article:
Alallah J, Shawli A, Hakami F. A case report of Crisponi/cold-induced sweating syndrome 1 in a Saudi family. J Clin Neonatol 2018;7:273-8

How to cite this URL:
Alallah J, Shawli A, Hakami F. A case report of Crisponi/cold-induced sweating syndrome 1 in a Saudi family. J Clin Neonatol [serial online] 2018 [cited 2022 Jun 28];7:273-8. Available from: https://www.jcnonweb.com/text.asp?2018/7/4/273/243334

  Introduction Top

Sohar et al. described the adult presentation of Crisponi/cold-induced sweating syndrome 1 (CISS1) in 1978 and then in 1996, Giangiorgio Crisponi described[1] the infantile presentation of the same disease.[2] CISS1 (MIM#272430) is a rare autosomal recessive disorder; however, it might be more common in some areas such as in Sardinia, Italy, where it has an estimated incidence of 1 case per 20,700 newborns.[3] CISS1 is characterized at birth by congenital contractions of facial muscles during crying or in response to tactile stimuli similar to tetanic contraction, bilateral camptodactyly, and dysmorphic facial features including prominent cheek bone, anteverted nostrils with broad nose, small mouth, and micrognathia.[4] Major feeding and respiratory difficulties with episodes of hyperthermia occur during the course of the disease and usually lead to death within the first months of life.[4],[5],[6] Late-onset CISS1 is usually less severe and manifests as paradoxical sweating at cold ambient temperatures, scoliosis, and dysmorphic features (Herholz).[7]

Other less commonly reported features such as urinary system anomaly and multiple small hyperintense lesions in the subcortical white matter have been reported.[8],[9]

Cytokine receptor-like factor 1 (CRLF1) gene on chromosome 19 is the only gene known to cause CISS1;[10] this gene consists of 9 exons encoding a 1824 bp mRNA transcribed into 422 amino acid proteins. The CRLF1 protein dimerizes with cardiotrophin-like cytokine factor 1 (CLCF1) to form a secreted ligand (CLC/CLF) that acts on cells expressing ciliary neurotrophic factor receptors and promotes survival and protection of neuronal cells.[11] A recent study suggests that the difference in severity between the early- and late-onset diseases might be attributed to the impact of the mutations and the kinetics of CRLF1 protein secretion.[7] Nevertheless, a correlation between the phenotype and the type/localization of CRLF1 pathogenic variants could not be established.[3] Pathogenic variants in the CLCF1-encoding gene have been identified as the cause of a disease indistinguishable from CISS1 called CISS2.[12],[13] The number of reported CISS1 cases has been steadily growing over the last two decades. To date, at least 66 individuals from 56 different families from different geographic regions have been reported to have CISS1 with confirming DNA testing [Table 1]. Before the year 2003, when mutations in the CRLF1 gene were proven to be the cause of CISS1,[10] multiple reports described individuals with clinical features of CISS, yet not confirmed by genetic testing. Therefore, these reports were omitted from our statistical analysis. Most of the reported CRLF1 pathogenic variants were either private or very rare in the general population. Some of these variants were commonly identified in specific geographic regions, suggesting a founder effect. For example, both the c.226T>G (p. Trp76Gly) and c.676dupA (p. Thr226fs) variants were identified only in Italian CISS1 patients, while in Turkey, the c.708-709delCCinsT (p. Pro238fs) was the frequently identified pathogenic variant [Table 1]. Here, we report two siblings with typical clinical features of CISS1 born to a healthy consanguineous Saudi couple. The diagnosis has been confirmed by identifying a novel homozygous mutation in the CRLF1 gene in one of the siblings.
Table 1: Summary of all reported Crisponi/cold-induced sweating syndrome 1 cases confirmed by molecular testing

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  Case Report Top

The first sibling was a baby girl weighing 3035 g born at 40 weeks of gestation to a 39-year-old woman; she had five normal children with her first-degree cousin husband. Both parents were of Arab ethnic background from Saudi Arabia. Due to gestational diabetes, the mother was on diet. The first newborn's (patient 1) Apgar scores were 9 and 9 at 1 and 5 min, respectively. Birth weight was 3.5 kg (appropriate for gestational age). Right after birth, she was unable to suck and had trismus during crying with abundant salivation. Abnormal facial features included a broad nose with anteverted nostrils, micrognathia, and bilateral camptodactyly [Figure 1]a and [Figure 2]. She was noticed to have an exaggerated response to noise, tactile stimuli. Crying was accompanied by spasmodic contractions of the face, jaw, and neck muscles [Figure 3]a, in addition to noted opisthotonus. She was immediately transferred to the neonatal intensive care unit (NICU) for further evaluation. Feeding difficulty necessitated nasogastric (NG) intubation. The patient developed hyperthermia episodes unrelated to infectious agents with a temperature reaching up to 40°C. Laboratory investigations including blood cultures, complete blood counts, and electrolytes were all normal. The results of brain magnetic resonance imaging, echocardiography, and chromosome analysis were also normal. She was discharged on NG feeding at 38 days of life. CISS1 was the primary clinical diagnosis; however, no genetic testing was available at that time to confirm the diagnosis. Her trismus and spasmodic muscle contractures improved over time. She was also seen frequently in the emergency room due to hyperthermia. She was on regular follow-up in the clinic till 5 years of age and was doing well according to her mother attending school. The second newborn (patient 2) for the same family born at 38 weeks of gestation by spontaneous vaginal delivery, with Apgar scores of 9 and 9 at 1 and 5 min, respectively, birth weight of 3.5 kg, no NICU admission, stayed in normal nursery and discharged at 36 h, presented to the neonatology clinic at 28 days of life with poor feeding and poor weight gain, and noted to have an exaggerated response to noise, tactile stimuli. Crying was accompanied by spasmodic contractions of the face, jaw, and neck muscles while crying [Figure 1]b and [Figure 3]b. His weight was 3.7 kg which was below the 5th centile, while height and head circumferences were within normal for age; he had truncal hypotonia and bilateral undescended testicles. Other physical examinations were within normal limits. Workup was done and he was referred to genetics. He had several admissions to the pediatric ward with hyperthermia, gastroenteritis, and recurrent bronchopneumonia; at the age of 1 year, he was diagnosed to have hyperactive airway disease on salbutamol PRN and fluticasone.
Figure 1: (a) Facial features of patient 1 during sleep (a round face, chubby cheeks, and a broad nose with anteverted nostrils) (b) Camptodactyly and facial features of patient 2 during sleep

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Figure 2: Patient 1: Bilateral camptodactyly

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Figure 3: (a) Typical facial expressions of patient 1 during cry showing perioral muscular contractions (b) Typical facial expressions of patient 2 during cry showing perioral muscular contractions

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Molecular analysis

DNA samples from the second sibling and his parents were extracted from peripheral blood lymphocytes using MagNA Pure Compact Instrument (Roche, Indianapolis, IN, USA). Sequencing analysis of the CRLF1 gene was carried out on ABI Prism 3130XL Genetic Analyzer (Life Technologies, Carlsbad, CA, USA), and the result was compared with the reference sequence (NM_004750.4). Identified variants were classified as per the standards and guidelines recommended by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.[14] Any identified variant was described according to the Human Variation Society nomenclature system.[15] The analysis identified a novel homozygous pathogenic variant (c.322C>T) in exon 2 of CRLF1. This DNA variant is predicted to cause a loss of protein function (LOF) by introducing a premature stop codon at position 108 (p. Gln108X). Both parents were heterozygous carriers for this variant.

  Discussion Top

CISS1 was the primary diagnosis of the first sibling (patient 1) described in this report; however, no genetic testing was performed to confirm the diagnosis. The result of the molecular analysis confirmed the diagnosis in the second sibling (patient 2), showing a homozygous c.322C>T variant in the CRLF1 gene,[3] while his parents were heterozygous for the same variant. Obviously, there was no reason to do a molecular analysis for the first sibling due to the observed high phenotypic similarity with the second sibling. The c.322C>T variant (p. Gln108X) was classified as pathogenic because it is predicted to result not only in producing a truncated protein but also a protein that misses 1716 amino acids of its 1824 total amino acids. This variant was absent from many well-known databases such as the Human Gene Mutation Database; the Leiden Open Variation Database; the National Center for Biotechnology Information, including dbSNP and ClinVar; in addition to general population studies such as the Exome Aggregation Consortium. The identified variant here is different from the commonly observed c.983dupG variant in CISS1 patients from Saudi Arabia, which has been previously identified in six different families [Table 1].

In general, LOF variants vary considerably in their effects on human phenotype. However, in case of CISS1, there was no clear correlation between the phenotype severity and clustering of pathogenic variants in any exon of the CRFL1 gene.[3] Based on the four distinct features of CISS1 (hyperthermia and feeding difficulties in the neonatal period, scoliosis, and cold-induced sweating in the evaluative period), Piras et al. proposed classifying CISS1 patients into mild, intermediate, and severe phenotypes [Table 2].[3] It might be too early to classify the phenotype of the two siblings we are reporting here as they might still develop more features in the future; however, their phenotype is definitely not mild.
Table 2: Proposed classification of Crisponi/cold-induced sweating syndrome 1 phenotypes

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  Conclusion Top

We report two additional CISS1 cases from Saudi Arabia. Their clinical features agree with the described features of CISS1 in previous reports. The CRLF1 pathogenic variant identified in this family has not been previously reported in any affected individual. The new advances in molecular testing enhanced the accuracy of clinical diagnosis, which might be one of the main reasons behind the growing number of CISS1 reports.[27]

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2]

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